Abstract Cancertiab Set

1. Phytother Res. 2024 Apr 11. doi: 10.1002/ptr.8196. Online ahead of print.
Phytoestrogens: Chemistry, potential health benefits, and their medicinal

importance.
Chavda VP(1), Chaudhari AZ(2), Balar PC(3), Gholap A(4), Vora LK(5).
Author information:
(1)Department of Pharmaceutics and Pharmaceutical Technology, L.M. College of
Pharmacy, Ahmedabad, India.
(2)Department of Pharmaceutical Chemistry, L. M. College of Pharmacy, Ahmedabad,
Gujarat, India.
(3)Pharmacy section, L.M. College of Pharmacy, Ahmedabad, India.
(4)Department of Pharmaceutics, St. John Institute of Pharmacy and Research,
Palghar, Maharashtra, India.
(5)School of Pharmacy, Queen's University Belfast, Belfast, UK.
Phytoestrogens, also known as xenoestrogens, are secondary metabolites derived

from plants that have similar structures and biological effects as human
estrogens. These compounds do not directly affect biological functions but can
act as agonists or antagonists depending on the level of endogenous estrogen in
the body. Phytoestrogens may have an epigenetic mechanism of action independent
of estrogen receptors. These compounds are found in more than 300 plant species
and are synthesized through the phenylpropanoid pathway, with specific enzymes
leading to various chemical structures. Phytoestrogens, primarily phenolic
compounds, include isoflavonoids, flavonoids, stilbenes, and lignans. Extensive
research in animals and humans has demonstrated the protective effects of
phytoestrogens on estrogen-dependent diseases. Clinical trials have also shown
their potential benefits in conditions such as osteoporosis, Parkinson's
disease, and certain types of cancer. This review provides a concise overview of
phytoestrogen classification, chemical diversity, and biosynthesis and discusses
the potential therapeutic effects of phytoestrogens, as well as their
preclinical and clinical development.
© 2024 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.
DOI: 10.1002/ptr.8196
PMID: 38602108
2. Heliyon. 2024 Mar 27;10(7):e28616. doi: 10.1016/j.heliyon.2024.e28616.

eCollection 2024 Apr 15.
Anti-cancer mechanisms of natural isoflavones against melanoma.
Liang C(1)(2), Wang P(2), Li M(2), Li R(2), Lai KP(2), Chen J(1)(2).
Author information:
(1)Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation,
Guilin Medical University, Guilin, China.
(2)Key Laboratory of Environmental Pollution and Integrative Omics, Guilin
Medical University, Education Department of Guangxi Zhuang Autonomous Region,
Guilin, China.
The incidence of skin-related neoplasms has generally increased in recent years.

Melanoma arises from malignant mutations in melanocytes in the basal layer of
the epidermis and is a fatal skin cancer that seriously threatens human health.
Isoflavones are polyphenolic compounds widely present in legumes and have drawn
scientists' attention, because they have good efficacy against a variety of
cancers, including melanoma, without significant toxic side effects and
resistance. In this review article, we summarize the research progress of
isoflavones in melanoma, including anti-melanoma roles and mechanisms of
isoflavones via inhibition of tyrosinase activity, melanogenesis, melanoma cell
growth, invasion of melanoma cells, and induction of apoptosis in melanoma
cells. This information is important for the prevention, clinical treatment, and
prognosis and survival of melanoma.
© 2024 The Authors.
DOI: 10.1016/j.heliyon.2024.e28616
PMCID: PMC10998210
PMID: 38586368
Conflict of interest statement: The authors declare that they have no known
competing financial interests or personal relationships that could have appeared
to influence the work reported in this paper.
3. Front Nutr. 2024 Mar 21;11:1338392. doi: 10.3389/fnut.2024.1338392. eCollection

2024.
Changes in the consumption of isoflavones, omega-6, and omega-3 fatty acids in

women with metastatic breast cancer adopting a whole-food, plant-based diet:
post-hoc analysis of nutrient intake data from an 8-week randomized controlled
trial.
Lee J(1), Campbell EK(1), Culakova E(2), Blanchard LM(3), Wixom N(4), Peppone
LJ(2), Campbell TM(3).
Author information:
(1)Department of Public Health Sciences, University of Rochester Medical Center,
Rochester, NY, United States.
(2)Department of Surgery, Cancer Control, University of Rochester Medical
Center, Rochester, NY, United States.
(3)Department of Family Medicine, University of Rochester Medical Center,
Rochester, NY, United States.
(4)Clinical Research Center, University of Rochester Medical Center, Rochester,
NY, United States.
BACKGROUND: Diets rich in minimally processed plant-based foods are recommended

to breast cancer patients, and some may have an interest in whole-food,
plant-based (WFPB) diets that avoid animal-based foods, added fats, and refined
sugars. Within WFPB diets, the intakes of isoflavones, omega-6 polyunsaturated
fatty acids (n-6 PUFAs), and omega-3 polyunsaturated FAs (n-3 PUFAs), which have
been discussed in reference to breast cancer outcomes, have not been well
characterized.
METHODS: Women with stage IV breast cancer on stable therapy were randomized 2:1
into (1) a WFPB intervention (N = 21) or (2) usual care (N = 11) for 8 weeks.
Three meals per day were provided. Outcomes presented here include dietary
intake of isoflavones, n-3 and n-6- PUFAs, which were assessed using three-day
food records at baseline and 8 weeks. Baseline and 8-week mean intake within
groups were compared using the Wilcoxon signed-rank test and between control and
intervention groups by a two-sample t-test.
RESULTS: The WFPB intervention participants increased their daily consumption of
total isoflavones from a mean of 0.8 mg/day to 14.5 mg/day (p < 0.0001) and
decreased the n-6:n-3 ratio of their diet from a mean of 9.3 to 3.7
(p < 0.0001). Within the WFPB group, linoleic acid (n-6 PUFA) consumption
decreased by a mean of 3.8 g (p = 0.0095), from 12.8 g/day to 9.0 g/day; total
n-3 PUFA consumption increased by a mean of 1.1 g (p = 0.0005), from 1.6 g/day
to 2.7 g/day.
CONCLUSION: Transitioning to a WFPB diet resulted in significantly increased
isoflavone intake and decreased n-6:n-3 ratio in women with breast cancer.
Copyright © 2024 Lee, Campbell, Culakova, Blanchard, Wixom, Peppone and

Campbell.
DOI: 10.3389/fnut.2024.1338392
PMCID: PMC10991800
PMID: 38577156
Conflict of interest statement: TC: royalties from general interest books about
plant-based nutrition (Benbella Books, Penguin Random House) and income from a
lifestyle medicine practice, TC, MD PLLC; EKC: conflicts of spouse (TC). The
remaining authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential
conflict of interest.
4. Molecules. 2024 Mar 20;29(6):1377. doi: 10.3390/molecules29061377.
Unveiling the Chemical Composition, Bioactive Profile and Antioxidant Capacity

of Dried Egyptian Jew's Mallow Stems as a Promising Anticancer Agent.
Ali MR(1), Ibrahim HH(2), Salah-Eldin AA(2).
Author information:
(1)Food Science Department, Faculty of Agriculture, Cairo University, Giza
12613, Egypt.
(2)Food Technology Research Institute, Agricultural Research Center, Giza 12619,
Egypt.
Phytochemicals from waste materials generated by agricultural and industrial

processes have become globally significant due to their accessibility and
potential effectiveness with few side effects. These compounds have essential
implications in both medicine and the economy. Therefore, a quantitative
analysis of the phytochemical profile, sugar types, and water-soluble vitamins
of dried Corchorus olitorius L."DJMS" extract (dried Jew's mallow stem) was
carried out with HPLC. In addition, the chemical composition, TPC, chlorophyll a
and b, beta-carotene, and antioxidant effect using DPPH were investigated.
Furthermore, the anticancer activity of the DJMS was evaluated by SRB assay
using Huh-7 and MDA-MB-231 cell lines. In the quantitative study, DJMS extract
showed a high antioxidant potential (67%) due to its content of bioactive
compounds such as TPC (276.37 mg 100 g-1) and chlorophyll a and b (20.31, 12.02
mg 100 g-1, respectively), as well as some vitamins and minerals such as
B-complex (B12; 146.8 mg 100 g-1 and vitamin C 6.49 mg 100 g-1) and selenium
(<0.2 μg kg-1). Moreover, the main sugar types found were sucrose and stachyose,
which recorded 9.23 and 6.25 mg 100 g-1, respectively. Identifying phenolic and
flavonoids showed that the major components were ellagic acid (4905.26 μg kg-1),
ferulic acid (3628.29 μg kg-1), chlorogenic acid (3757.08 μg kg-1),
luteolin-7-O-glucoside (4314.48 μg kg-1), naringin (4296.94 μg kg-1) and
apigenin-6-rhamnose-8 glucoside (3078.87 μg kg-1). The dried stem extract showed
significant MDA-MB-231 inhibition activity and reached 80% at a concentration of
1000 µg/mL of DJMS extract, related to the content of phytochemical components
such as isoflavones like genistein (34.96 μg kg-1), which had a tremendous
anticancer effect. Hence, the stem of Jew's mallow (which is edible and
characterized by its viability and low production cost) possesses the capacity
to serve as a pharmaceutical agent for combating cancer owing to its abundance
of bioactive components.
DOI: 10.3390/molecules29061377
PMCID: PMC10975874
PMID: 38543013 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
5. Fitoterapia. 2024 Mar 24;175:105920. doi: 10.1016/j.fitote.2024.105920. Online

ahead of print.
Biological effects and phytochemical study of the underground part of Iris

scariosa Willd. ex Link extract: A new source of bioactive constituents.
Omarova BA(1), Shults EE(2), Zhakipbekov KS(3), Abekova АО(4), Ishmuratova

MY(5), Petrova TN(6), Kartbayeva EB(7).
Author information:
(1)Asfendiyarov Kazakh National Medical University, Tole Bi St. 94, Almaty
050000, Republic of Kazakhstan.
(2)Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian
Academy of Sciences, Acad. Lavrentyev Ave. 9, 630090 Novosibirsk, Russia.
Electronic address: schultz@nioch.nsc.ru.
050000, Republic of Kazakhstan. Electronic address: zhakipbekov.k@kaznmu.kz.
(4)JSC «Scientific Center for Anti-Infectious Drugs», al-Farabi Ave. 75A, 050060
Almaty, Republic of Kazakhstan.
(5)NCJSC "Buketov Karaganda University", Universitetskaya Str., 28/3, 100028
Karaganda, Republic of Kazakhstan.
(6)Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian
Academy of Sciences, Acad. Lavrentyev Ave. 9, 630090 Novosibirsk, Russia.
050000, Republic of Kazakhstan; Higher School of Medicine, Al-Farabi Kazakh
National University, 71 al-Farabi Ave., Almaty 050040, Republic of Kazakhstan.
The expected toxicity and resistance of chemotherapeutic agents necessitate and

encourage for the use of natural chemotherapeutic sources of plant origin in the
clinical stage of cancer therapy. Plants of the genus Iris (Iridaceae) used by
local populations for the treatment of cancer, bacterial and viral infections.
In this study, an ethanol extract of rhizomes of I. scariosa was prepared and
tested for the cytotoxicity using the MTT assay. The extract exhibited the most
potent cytotoxicity against the breast cancer cell line MCF7
(IC50 = 9.28 ± 0.49 μg/ml, selectively index ˃5), and induced apoptosis in MCF7
lines. Notably, the extract significantly inhibited the colony formation of MCF7
and HepG2 cancer cells at a concentration range from 10.6 to 85.0 μg/ml,
including non-toxic concentrations for HepG2 cells. The ethanol extract was
analyzed by HPLC, revealed the identification of 5 secondary metabolites
(quercetin, rutin, myricetin, apigenin, artemisetin), the content of which was
shown to reach around 15% of the extract. The petroleum ether (PE) part of the
extract (yield 2.62%) was analyzed by GC-MS. The composition of tert-butyl
methyl ether (TBME) part of the extract (yield 23.72%) was studied. Total of 15
individual compounds: two benzophenones, eight isoflavones, four flavones and a
(2R)-flavanone were isolated. The pentamethoxyflavone artemisetin and flavanone
pinocembrin were isolated for the first from Iris sp. The readily available
isoflavones from the TBME part of extract (irilone, iriflogenin, irigenin and
tectorigenin) may serve as new leads for the discovery of anticancer drugs.
Copyright © 2024 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.fitote.2024.105920
PMID: 38531480
Conflict of interest statement: Declaration of competing interest The authors

declare that there are no conflicts of interest.
6. Br J Pharmacol. 2024 Mar 25. doi: 10.1111/bph.16353. Online ahead of print.
Soy-derived isoflavones as chemo-preventive agents targeting multiple signalling

pathways for cancer prevention and therapy.
Kaufman-Szymczyk A(1), Jalmuzna J(1), Lubecka-Gajewska K(1).
Author information:
(1)Department of Biomedical Chemistry, Faculty of Health Sciences, Medical
University of Łódź, Łódź, Poland.
The chemopreventive and chemotherapeutic properties of soy and soy-derived

compounds, especially isoflavones, have been extensively studied in recent
years. However, in contrast to their anticancer effects, such as cell growth
inhibition, cell cycle arrest and apoptosis induction, isoflavones have also
been found to promote the growth of cancer cells. Therefore, the aim of this
comprehensive review article is to present the current state of knowledge
regarding the molecular mechanisms by which soy-derived isoflavones target
multiple cellular signalling pathways in cancer cells. Our findings indicate
that soy-derived isoflavones act as, among other things, potent modulators of
HOX transcript antisense RNA (HOTAIR)/SWI/SNF-related matrix-associated
actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), vascular
endothelial growth factor (VEGF)/C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C
motif chemokine receptor type 4 (CXCR4), 17-β-oestradiol (E2)/oestrogen
receptor-α (ERα)/neuroglobin (NGB) and sonic hedgehog signalling pathways,
epigenetic modulatory agents (i.a. miR-155, miR-34a and miR-10a-5p) and cancer
stem cells and epithelial-to-mesenchymal transition inhibitors. The paper also
discusses the latest epidemiological studies and clinical trials and provides an
insight into recent extensive research on the chemo-preventive and therapeutic
potential of soy-derived isoflavones.
© 2024 British Pharmacological Society.
DOI: 10.1111/bph.16353
PMID: 38528688
7. Molecules. 2024 Feb 28;29(5):1044. doi: 10.3390/molecules29051044.
Chickpea Sprouts as a Potential Dietary Support in Different Prostate

Disorders-A Preliminary In Vitro Study.
Galanty A(1), Prochownik E(2), Grudzińska M(2)(3), Paśko P(2).
Author information:
(1)Department of Pharmacognosy, Jagiellonian University Medical College,
Medyczna 9, 30-688 Kraków, Poland.
(2)Department of Food Chemistry and Nutrition, Jagiellonian University Medical
College, Medyczna 9, 30-688 Kraków, Poland.
(3)Doctoral School of Medical and Health Sciences, Jagiellonian University
Medical College, 16 Łazarza Str., 31-530 Cracow, Poland.
BACKGROUND: Prostate cancer (PC) and benign prostatic hyperplasia (BPH) are
common health problems in the aging male population. Due to the unexplored and
unconfirmed impact of food containing isoflavones, like sprouts, on the
development of the management of BPH and prostate cancer, we decided to extend
the knowledge in this area.
RESULTS: We have demonstrated for the first time that chickpea sprouts may play
an important role in the chemoprevention of prostate disorders. However,
attention should be paid to the isoflavone content in the sprouts, as in our
study, chickpea sprouts with a moderate concentration of the compounds,
harvested in natural light conditions (CA10L) and blue LED light (CA7B), showed
the best scores in terms of their potential towards prostate disorders.
METHODS: Chickpea seeds were grown in LED chambers. The methanol extracts from
sprouts were quantitatively defined using the HPLC system. Experiments such as
the determination of PSA, 5-α-reductase, and dihydrotestosterone were performed
on PNT2 and LNCaP cells. For anti-inflammatory assays (determination of NO,
IL-6, and TNF-alpha release), murine RAW264.7 macrophages were used.
CONCLUSIONS: The role of legume products as a diet element should be deeply
evaluated for the development of future dietary recommendations for prostate
cancer and BPH prevention.
PMCID: PMC10934777
Conflict of interest statement: The authors declare no conflicts of interest.
8. Heliyon. 2024 Feb 20;10(5):e26562. doi: 10.1016/j.heliyon.2024.e26562.

eCollection 2024 Mar 15.
Protective effects of hepatic diseases by bioactive phytochemicals in Fusarium

oxysporum - A review.
Shalapy NM(1)(2), Liu M(1), Kang W(1)(3).
Author information:
(1)National R & D Center for Edible Fungus Processing Technology, Henan
University, Kaifeng, 475004, China.
(2)Microbial Chemistry Department, Biotechnology Research Institute, National
Research Center, Cairo, Egypt.
(3)Joint International Research Laboratory of Food & Medicine Resource Function,
Henan Province, Kaifeng, 475004, China.
Lately, liver diseases were categorized as one of the most prevalent health
problems globally as it causes a severe threat to mankind all over the world due
to the wide range of occurrence. There are multiple factors causing hepatic
disorders, such as alcohol, virus, poisons, adverse effects of drugs, poor diet,
inherited conditions and obesity. Liver diseases have various types including
alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune
hepatitis, liver cancer, hepatocellular carcinoma, liver fibrosis and hepatic
inflammation. Therefore, it is imperative to find effective and efficacious
agents in managing liver diseases. Fusarium oxysporum, an endophytic fungus and
containing many bioactive compounds, could be served as a forked medication for
enormous number and types of maladies. It was characterized by producing
biochemical compounds which had rare pharmacological properties as it may be
found in a limit number of other medicinal plants. The majority of the past
researches related to Fusarium oxysporum recited the fungal negative field
either on the pathogenic effects of the fungus on economical crops or on the
fungal chemical components to know how to resist it. The present review will
highlight on the bright side of Fusarium oxysporum and introduce the functional
activities of its chemical compounds for treating its target diseases. The key
point of illustrated studies in this article is displaying wide range of
detected bioactive compounds isolated from Fusarium oxysporum and in other
illustrated studies it was elucidated the therapeutical and pharmacological
potency of these biologically active compounds (isolated from medicinal plants
sources) against different types of liver diseases including non-alcoholic fatty
liver disease, alcoholic liver disease, cirrhosis and others. It was
demonstrated that F. oxysporum contains unique types of isoflavones, flavonoids,
phenols and another active chemical compounds, and these compounds showed
recently a fabulous clinical contribution in the therapy of liver injury
diseases, which opens new and unprecedented way for evaluating the maintaining
efficacy of Fusarium oxysporum bioactive compounds in dealing with hepatic
complications and its remedy impacting on liver diseases and injured hepatocytes
through recommending implement a practical study.
DOI: 10.1016/j.heliyon.2024.e26562
PMCID: PMC10918022
PMID: 38455549
Conflict of interest statement: The authors declare the following financial

interests/personal relationships which may be considered as potential competing
interests: Wenyi Kang reports financial support was provided by Research on
Precision Nutrition and Health Food, 10.13039/501100006407Department of Science
and Technology of Henan Province (CXJD2021006). Wenyi Kang reports a
relationship with Research on Precision Nutrition and Health Food,
10.13039/501100006407Department of Science and Technology of Henan Province
(CXJD2021006). that includes: funding grants. There is no room for wrong
interpretation by the reader as conflict of interest.
9. Mini Rev Med Chem. 2024 Feb 21. doi: 10.2174/0113895575283895240207065454.

Online ahead of print.
Dietary Plant Metabolites Induced Epigenetic Modification as a Novel Strategy

for the Management of Prostate Cancer.
Singh V(1), Shirbhate E(1), Kore R(1), Mishra A(1), Johariya V(1), Veerasamy
R(2), Tiwari AK(2), Rajak H(1).
Author information:
(1)Department of Pharmacy, Guru Ghasidas University, Bilaspur-495 009, (C.G.),
India.
(2)Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul
Aman, Malaysia.
Prostate cancer is a widespread malignancy among men, with a substantial global

impact on morbidity and mortality. Despite advances in conventional therapies,
the need for innovative and less toxic treatments remains a priority. Emerging
evidence suggests that dietary plant metabolites possess epigenetic-modifying
properties, making them attractive candidates for prostate cancer treatment. The
present work reviews the epigenetic effects of dietary plant metabolites in the
context of prostate cancer therapy. We first outline the key epigenetic
mechanisms involved in prostate cancer pathogenesis, including histone
modifications, DNA methylation, and miRNA or Long Noncoding RNA (lncRNA)
dysregulation. Next, we delve into the vast array of dietary plant metabolites
that have demonstrated promising anti-cancer effects through epigenetic
regulation. Resveratrol, minerals, isothiocyanates, curcumin, tea polyphenols,
soy isoflavones and phytoestrogens, garlic compounds, anthocyanins, lycopene,
and indoles are among the most extensively studied compounds. These
plant-derived bioactive compounds have been shown to influence DNA methylation
patterns, histone modifications, and microRNA expression, thereby altering the
gene expression allied with prostate cancer progression, cell proliferation, and
apoptosis. We also explore preclinical and clinical studies investigating the
efficacy of dietary plant metabolites as standalone treatments or in combination
with traditional treatments for people with prostate cancer. The present work
highlights the potential of dietary plant metabolites as epigenetic modulators
to treat prostate cancer. Continued research in this field may pave the way for
personalized and precision medicine approaches, moving us closer to the goal of
improved prostate cancer management.
Copyright© Bentham Science Publishers; For any queries, please email at

epub@benthamscience.net.
DOI: 10.2174/0113895575283895240207065454
PMID: 38385496
10. Carcinogenesis. 2024 Feb 20:bgae015. doi: 10.1093/carcin/bgae015. Online ahead

of print.
Dietary phytoestrogen intake and ovarian cancer risk: a prospective study in the
Prostate, Lung, Colorectal and Ovarian (PLCO) cohort.
Song Y(1)(2), Huang H(3), Jin M(3), Cheng B(3), Wang S(3), Yang X(3), Hu
X(1)(2).
Author information:
(1)Department of Obstetrics and Gynecology, the First Affiliated Hospital of
Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
(2)Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology,
the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000,
Zhejiang, China.
(3)Department of Epidemiology and Health Statistics, School of Public Health and
Management, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Estrogen plays crucial roles in ovarian tumorigenesis. Phytoestrogens (PEs) are

a type of daily dietary nutrients for humans and possess a mild estrogenic
characteristic. This study aimed to assess the correlation of the consumption of
dietary PEs with ovarian cancer risk using data in the Prostate, Lung,
Colorectal and Ovarian (PLCO) Cancer Screening Trial. Participants were enrolled
in PLCO from 1993 to 2001. Hazard ratios (HRs) and 95% confidence intervals
(CIs) were utilized to determine the association between the intake of PEs and
ovarian cancer occurrence, which were calculated by the Cox proportional hazards
regression analysis. Totally, 24,875 participants were identified upon
completion of the initial dietary questionnaire (DQX). Furthermore, the analysis
also included a total of 45,472 women who filled out the diet history
questionnaire (DHQ). Overall, after adjustment for confounders, the dietary
intake of total PEs was significantly associated with the risk of ovarian cancer
in the DHQ group (HRQ4vsQ1 = 0.69, 95% CI: 0.50-0.95; P for trend = 0.066).
Especially, individuals who consumed the highest quartile of isoflavones were
found to have a decreased risk of ovarian cancer in the DHQ group (HRQ4vsQ1 =
0.68, 95% CI: 0.50-0.94; P for trend = 0.032). However, no such significant
associations were observed for the DQX group. In summary, this study suggests
that increased dietary intake of total PEs especially isoflavones was linked
with a lower risk for developing ovarian cancer. More researches are necessary
to validate the findings and explore the potential mechanisms.
© The Author(s) 2024. Published by Oxford University Press.
DOI: 10.1093/carcin/bgae015
PMID: 38375679
11. Curr Med Chem. 2024 Feb 1. doi: 10.2174/0109298673278897231229121524. Online

ahead of print.
The Use of Isoflavones as Lung Cancer Chemoprevention Agents and their

Implications in Treatment through Radio Sensitization.
Athanasiou E(1), Papageorgiou S(2)(3), Dafni MF(4)(3), Kelesis I(5)(3),

Vasileiou M(6)(3), Tatsiou T(7)(3), Kouveloglou V(4)(3), Kanatas P(1)(3),
Stouras I(1)(3), Gatsis A(4)(3), Agiassoti VT(1)(3), Nasimpian P(1)(3),
Dafnoudis D(8)(3), Degaita K(1), Verras GI(9)(3), Alexiou A(10)(11)(12),
Papadakis M(13), Kamal MA(14)(15)(16)(17).
Author information:
(1)Department of Medicine, School of Health Sciences, National and Kapodistrian
University of Athens, Athens, Greece.
(2)Department of Molecular and Cell Biology, University of Leicester, Leicester,
United Kingdom.
(3)Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi,
Greece.
(4)Department of Medicine, School of Health Sciences, Aristotle University of
Thessaloniki, Thessaloniki, Greece.
(5)School of Medicine, Poznań University of Medical Sciences, Poznań, Poland.
(6)Department of Pharmacy, School of Health Sciences, National and Kapodistrian
University of Athens, Athens, Greece.
(7)Department of Biology, University of Crete, Heraklion, Crete, Greece.
(8)Applied Bioinformatics Master Department, Aristotle University of
Thessaloniki, Thessaloniki, Greece.
(9)Department of Surgery, General University Hospital of Patras, Patra, Greece.
(10)Department of Science and Engineering, Novel Global Community Educational
Foundation, Hebersham, NSW2770, Australia.
(11)University Centre for Research & Development, Chandigarh University,
Chandigarh- Ludhiana Highway, Mohali, Punjab, India.
(12)AFNP Med, Wien1030, Austria.
(13)Department of Surgery II, University Hospital Witten-Herdecke,
Heusnerstrasse 40, University of Witten- Herdecke, 42283, Wuppertal, Germany.
(14)King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia.
(15)Institutes for Systems Genetics, Frontiers Science Center for
Disease-related Molecular Network, West China Hospital, Sichuan University,
China.
(16)Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil
International University, Bangladesh.
(17)Enzymoics, 7 Peterlee place, Hebersham, NSW 2770; Novel Global Community
Educational Foundation, Australia.
Epidemiological trends in cancer research show that lung cancer can affect up to
1 in 15 men and 1 in 17 women. With incidence rates as high as these and
significant associated mortality and morbidity, it is no wonder that lung cancer
is one of the main areas of research focused on cancer. Advances in targeted
treatments and specialized irradiation protocols have allowed the treatment of
more advanced cases. However, as the patient numbers grow, so does the need for
cancer-preventive strategies. The present narrative review focuses on soy
isoflavones' role in the chemoprevention of lung cancer and their possible role
in therapeutic adjuncts. Laboratory studies on lung cancer cell lines have shown
that isoflavones can induce apoptosis, tamper with the expression of
proliferative molecular pathways, and even reduce tumor angiogenesis.
Additionally, population-level studies have emerged that correlate the
consumption of isoflavonoids with reduced risk for the development of lung
cancer. Interestingly enough, the literature also contains small-scale studies
with evidence of isoflavones being effective chemotherapeutic adjuncts that are
currently understudied. Our literature review underlines such findings and
provides a call for the enhancement of research regarding naturally occurring
dietary products with possible anticarcinogenic effects.

DOI: 10.2174/0109298673278897231229121524
PMID: 38369709
12. Phytochemistry. 2024 Apr;220:114005. doi: 10.1016/j.phytochem.2024.114005. Epub

2024 Feb 1.
Chemical and biological investigation of Indigofera ammoxylum (DC.) Polhill. red

and white phenotypes through feature-based molecular networking.
Gerometta E(1), Garayev E(2), Herbette G(3), Marvilliers A(4), Di Giorgio C(5),
Clerc P(6), Frederich M(7), Baghdikian B(8), Grondin I(9), Gauvin-Bialecki
A(10).
Author information:
(1)Laboratoire de Chimie et de Biotechnologie des Produits Naturels, Faculté des
Sciences et Technologies, Université de La Réunion, St Denis, La Réunion,
France. Electronic address: elise.gerometta@univ-reunion.fr.
(2)Aix Marseille Université, Avignon Université, CNRS, IRD, IMBE, Marseille,
France, Faculty of Pharmacy, Service of Pharmacognosy, Marseille, France.
Electronic address: elnur.garayev@univ-amu.fr.
(3)Aix-Marseille Université, CNRS, Centrale Marseille, FSCM, Spectropole, Campus
de St Jérôme - Service 511, Marseille, France. Electronic address:
gaetan.herbette@univ-amu.fr.
France. Electronic address: arnaud.marvilliers@univ-reunion.fr.
(5)Aix-Marseille Université, Avignon Université, CNRS, IRD, IMBE, Marseille,
France, Faculty of Pharmacy, Service of Environmental Mutagenesis, Marseille,
France. Electronic address: carole.di-giorgio@univ-amu.fr.
France. Electronic address: patricia.clerc@univ-reunion.fr.
(7)Université de Liège, Département de Pharmacie, Centre Interfacultaire de
Recherche sur le Médicament (CIRM), Laboratoire de Pharmacognosie, Campus Du
Sart-Tilman, Quartier Hôpital, Liège, Belgium. Electronic address:
m.frederich@uliege.be.
(8)Aix Marseille Université, Avignon Université, CNRS, IRD, IMBE, Marseille,
France, Faculty of Pharmacy, Service of Pharmacognosy, Marseille, France.
Electronic address: beatrice.baghdikian@univ-amu.fr.
France. Electronic address: isabelle.grondin@univ-reunion.fr.
(10)Laboratoire de Chimie et de Biotechnologie des Produits Naturels, Faculté
des Sciences et Technologies, Université de La Réunion, St Denis, La Réunion,
France. Electronic address: anne.bialecki@univ-reunion.fr.
Chemical investigation of ethyl acetate bark extracts of Indigofera ammoxylum

red and white phenotypes led to the bio-guided isolation of four previously
undescribed flavonoids, named (2S,3R)-3',7-dihydroxy-4',6-dimethoxyflavanol (1),
(2S,3R)-6-methoxy-7-hydroxyflavanol (2),
2',3',7-trihydroxy-4',6-dimethoxyisoflavone (7) and 2',5'
-dimethoxy-4',5,7-trihydroxyisoflavanone (8), along with 14 known compounds (3-6
and 9-18). The previously undescribed structures were characterized based on
NMR, HRESIMS, UV and IR data. Published spectroscopic data were used to deduce
the structure of the known compounds. Eleven of the 18 isolated metabolites were
evaluated for anti-inflammatory activity and cytotoxic activity against human
liver carcinoma cells and human colon and colorectal adenocarcinoma cells. All
tested compounds showed an anti-inflammatory activity (IC50 NO < 25 μg/mL), and
compounds 2 and 3 were more selective than the positive control dexamethasone.
Afromorsin (6) showed promising cytotoxic properties against both cancer cell
lines (IC50 18.9 and 11.4 μg/mL). Feature-based molecular networking approach
applied to bark and leaves extracts of the two phenotypes allowed to detect
bioactive analogues, belonging to the families of flavones, isoflavones,
flavanones, flavanols and flavonols, and to explore the chemodiversity of the
species. The red and white phenotypes have a similar composition, whereas bark
and leaves contain specific chemical entities. Finally, this approach
highlighted a cluster of potentially bioactive and undescribed metabolites.
Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.phytochem.2024.114005

declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.
13. Curr Drug Targets. 2024 Jan 12. doi: 10.2174/0113894501277556231221072938.

Online ahead of print.
An Updated Insight into Phytomolecules and Novel Approaches used in the

Management of Breast Cancer.
Nooreen Z(1), Tandon S(2), Wal A(1), Rai AK(1).
Author information:
(1)PSIT-Pranveer Singh Institute of Technology (Pharmacy), Bhautipratapur, Uttar
Pradseh 209305, India.
(2)Phytochemistry Division, CSIR-Central Institute of Medicinal and Aromatic
Plants, P.O.- CIMAP, Lucknow-226015, India.
Breast cancer is a widespread condition that kills more women from

cancer-related causes than any other type of cancer globally. Women who have
estrogen-dependent, initial metastatic breast cancer frequently receive
treatment with surgery, radiation therapy, and chemotherapy. They may also get
more specialized treatments like tamoxifen or aromatase inhibitors (anastrozole
or letrozole). The World Health Organisation reported in 2012 that by 2030,
breast cancer will be more common worldwide. There are several phytochemicals,
such as isoflavones, coumestans, lignans, and prenylflavonoides. Isoflavones
have been shown in studies to prevent the spread of breast cancer and to trigger
apoptosis. Targeting BCs in metastatic breast cancer may be made possible by
combining well-formulated phytochemicals in nanoparticles or other novel drug
delivery agents with currently accepted endocrine and/or conventional
chemotherapies. Cell signaling, regulation of cell cycles, oxidative stress
action, and inflammation could be positively impacted by phytoconstituents. They
have the ability to alter non-coding RNAs, to prevent the proliferation and
regeneration of cancer cells. The availability of novel approaches helps in
disease targeting, safety, effectiveness and efficacy. The current literature
helps to know the available drugs i.e. phytoconstituents or novel drug delivery
like nanoparticle, microsphere, micelles, liposomes and neosomes. The literature
has been taken from PubMed, Google Scholar, SciFinder, or other internet sites.

DOI: 10.2174/0113894501277556231221072938
PMID: 38231060
14. Iran J Basic Med Sci. 2024;27(1):57-65. doi: 10.22038/IJBMS.2023.70554.15353.
Moraea sisyrinchium inhibits proliferation, cell cycle, and migration of

cancerous cells, and decreases angiogenesis in chick chorioallantoic membrane.
Rashidi R(1)(2), Montazeri A(1), Soukhtanloo M(3), Ghasemian S(4), Amiri MS(5),
Hasanpour M(6), Einafshar E(1), Ghorbani A(1).
Author information:
(1)Department of Pharmacology, Faculty of Medicine, Mashhad University of
Medical Sciences, Mashhad, Iran.
(2)Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad
University of Medical Sciences, Mashhad, Iran.
(3)Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University
of Medical Sciences, Mashhad, Iran.
(4)Department of Pharmacognosy, School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran.
(5)Department of Biology, Payame Noor University, Tehran, Iran.
(6)Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad
OBJECTIVES: Experimental studies reported that some plants in the genus of

Moraea (Iridaceae family) show anticancer potential. This study aimed to
evaluate the effects of Moraea sisyrinchium on U87 glioblastoma multiforme and
HepG2 liver cancer cells.
MATERIALS AND METHODS: The cells were incubated for 24 hr with hydroalcoholic
extract of the stem, flower, and bulb of M. sisyrinchium. Then, the cell
proliferation (MTT) assay, cell cycle analysis (propidium iodide staining), cell
migration test (scratch), Western blotting (Bax and Bcl-2 expression), and
gelatin zymography (for matrix metalloproteinases, MMPs) were performed.
Oxidative stress was evaluated by determining the levels of reactive oxygen
species and lipid peroxidation. Angiogenesis was evaluated on chick embryo
chorioallantoic membrane.
RESULTS: The extracts of the flower, stem, and bulb significantly decreased the
proliferation of HepG2 and U87 cells. This effect was more for U87 than HepG2
and for the bulb and stem than the flower. In U87 cells, the bulb extract
increased oxidative stress, cell cycle arrest, and the Bax/Bcl-2 ratio. Also,
this extract suppressed the migration ability of HepG2 and U87 cells, which was
associated with the inhibition of MMP2 activity. In addition, it significantly
reduced the number and diameter of vessels in the chorioallantoic membrane.
Liquid chromatography-mass spectrometry revealed the presence of xanthones
(bellidifolin and mangiferin), flavonoids (quercetin and luteolin), isoflavones
(iridin and tectorigenin), and phytosterols (e.g., stigmasterol) in the bulb.
CONCLUSION: M. sisyrinchium bulb decreased the proliferation and survival of
cancer cells by inducing oxidative stress. It also reduced the migration ability
of the cells and inhibited angiogenesis.
DOI: 10.22038/IJBMS.2023.70554.15353
PMCID: PMC10722474
PMID: 38164487
Conflict of interest statement: The authors report no conflicts of interest.
15. J Enzyme Inhib Med Chem. 2024 Dec;39(1):2288806. doi:

10.1080/14756366.2023.2288806. Epub 2023 Dec 28.
Anti-cancer activity and cellular uptake of 7,3',4'- and

7,8,4'-trihydroxyisoflavone in HepG2 cells under hypoxic conditions.
Tzeng WS(1)(2), Teng WL(3), Huang PH(4), Yen FL(2)(4)(5)(6), Shiue YL(2).
Author information:
(1)Department of Radiology, Pingtung Christian Hospital, Pingtung, Taiwan.
(2)Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung,
Taiwan.
(3)Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung
Medical University, Kaohsiung, Taiwan.
(4)Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung
Medical University, Kaohsiung, Taiwan.
(5)Drug Development and Value Creation Research Center, Kaohsiung Medical
University, Kaohsiung, Taiwan.
(6)Department of Medical Research, Kaohsiung Medical University Hospital,
Kaohsiung, Taiwan.
Transarterial chemoembolisation (TACE) is used for unresectable hepatocellular

carcinoma (HCC) treatment, but TACE-induced hypoxia leads to poor prognosis. The
anti-cancer effects of soybean isoflavones daidzein derivatives
7,3',4'-trihydroxyisoflavone (734THIF) and 7,8,4'-trihydroxyisoflavone (784THIF)
were evaluated under hypoxic microenvironments. Molecular docking of these
isomers with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor
receptor 2 (VEGFR2) was assessed. About 40 μM of 734THIF and 784THIF have the
best effect on inhibiting the proliferation of HepG2 cells under hypoxic
conditions. At a concentration of 40 μM, 784THIF significantly inhibits COX-2
expression in pre-hypoxia conditions compared to 734THIF, with an inhibition
rate of 67.73%. Additionally, 40 μM 784THIF downregulates the expression of
hypoxic, inflammatory, and metastatic-related proteins, regulates oxidative
stress, and inhibits the expression of anti-apoptotic proteins. The uptake by
HepG2 confirmed higher 784THIF level and slower degradation characteristics
under post- or pre-hypoxic conditions. In conclusion, our results showed that
784THIF had better anti-cancer effects and cellular uptake than 734THIF.
DOI: 10.1080/14756366.2023.2288806
PMCID: PMC10763887
Conflict of interest statement: The authors report there are no competing

interests to declare.
16. Molecules. 2023 Dec 8;28(24):8012. doi: 10.3390/molecules28248012.
Antitumor and Phytochemical Properties of Ferula assa-foetida L. Oleo-Gum-Resin

against HT-29 Colorectal Cancer Cells In Vitro and in a Xenograft Mouse Model.
Elarabany N(1)(2), Hamad A(1)(3), Alzamel NM(1).
Author information:
(1)Department of Biology, College of Science and Humanities, Shaqra University,
Shaqra 11961, Saudi Arabia.
(2)Zoology Department, Faculty of Science, Damietta University, New Damietta
34517, Egypt.
(3)Biology Department, College of Applied and Industrial Science, Bahri
University, Khartoum 1660, Sudan.
Colorectal cancer (CRC) is one of the most frequently occurring tumors. Ferula
assa-foetida oleo-gum-resin (OGR) extract is a traditional cooking spice known
for its broad spectrum of biological activities such as antifungal,
antiparasitic, and anti-inflammatory activities. This study evaluated the
antitumor effect of OGR extract against HT-29 colorectal cancer cells. The OGR
chemical composition was analyzed using LC-ESI-MS/MS; MTT, clonogenic assays,
and a xenograft model were used to measure cytotoxicity, while apoptotic
proteins were detected using Western blotting. Phytochemical analysis revealed
that the extract was a rich source of isoflavones, xanthones, and other
derivatives. In a dose-dependent manner, the OGR extract significantly inhibited
colony formation ability and HT-29 cell growth (IC50 was 3.60 ± 0.02 and 10.5 ±
0.1 mg/mL, respectively). On the other hand, the OGR extract significantly
induced apoptosis and increased the expression of some pro-death proteins
involved in cellular apoptosis including PUMA, BIM, BIK, and BAK. Moreover, in a
subcutaneous HT-29 xenograft model, the tumor volume and burden decreased after
treatment with the OGR extract (550 ± 32 mm3 and 16.3 ± 3.6, respectively) This
study demonstrated that Ferula assa-foetida OGR ethanolic extract has potential
antitumor effects against HT-29 CRC cell lines by reducing cell viability and
the function of apoptosis. More studies are needed to reveal the underlying
mechanisms related to cytotoxicity and apoptosis induction.
PMCID: PMC10746072
17. F1000Res. 2023 Dec 11;12:107. doi: 10.12688/f1000research.126059.3. eCollection

2023.
Mechanisms Behind the Pharmacological Application of Biochanin-A: A review.
Anuranjana PV(1), Beegum F(1), K P D(1), George KT(1), Viswanatha GL(2), Nayak
PG(1), Kanwal A(3), Kishore A(1), Shenoy RR(1), Nandakumar K(1).
Author information:
(1)Department of Pharmacology, Manipal College of Pharmaceutical Sciences,
Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
(2)Independent Researcher, Bengaluru, Karnataka, India.
(3)Department of Pharmacology, All India Institute of Medical Sciences,
Bathinda, Punjab, India.
This review was aimed at summarizing the cellular and molecular mechanisms
behind the various pharmacological actions of biochanin-A. Many studies have
been reported claiming its application in cancers, metabolic disorders, airway
hyperresponsiveness, cardiac disorders, neurological disorders, etc. With regard
to hormone-dependent cancers like breast, prostate, and other malignancies like
pancreatic, colon, lung, osteosarcoma, glioma that has limited treatment
options, biochanin-A revealed agreeable results in arresting cancer development.
Biochanin-A has also shown therapeutic benefits when administered for
neurological disorders, diabetes, hyperlipidaemia, and other chronic
diseases/disorders. Isoflavones are considered phenomenal due to their high
efficiency in modifying the physiological functions of the human body.
Biochanin-A is one among the prominent isoflavones found in soy (glycine max),
red clover (Trifolium pratense), and alfalfa sprouts, etc., with proven potency
in modulating vital cellular mechanisms in various diseases. It has been popular
for ages among menopausal women in controlling symptoms. In view of the
multi-targeted functions of biochanin-A, it is essential to summarize it's
mechanism of action in various disorders. The safety and efficacy of biochanin-A
needs to be established in clinical trials involving human subjects. Biochanin-A
might be able to modify various systems of the human body like the
cardiovascular system, CNS, respiratory system, etc. It has shown a remarkable
effect on hormonal cancers and other cancers. Many types of research on
biochanin-A, particularly in breast, lung, colon, prostate, and pancreatic
cancers, have shown a positive impact. Through modulating oxidative stress,
SIRT-1 expression, PPAR gamma receptors, and other multiple mechanisms
biochanin-A produces anti-diabetic action. The diverse molecular mechanistic
pathways involved in the pharmacological ability of biochanin-A indicate that it
is a very promising molecule and can play a major impact in modifying several
physiological functions.
Copyright: © 2023 Anuranjana PV et al.
DOI: 10.12688/f1000research.126059.3
PMCID: PMC10725524
Conflict of interest statement: No competing interests were disclosed.
18. JNCI Cancer Spectr. 2024 Jan 4;8(1):pkad104. doi: 10.1093/jncics/pkad104.
Phytonutrients and outcomes following breast cancer: a systematic review and

meta-analysis of observational studies.
van Die MD(1), Bone KM(2)(3), Visvanathan K(4)(5), Kyrø C(6), Aune D(7)(8)(9),
Ee C(1), Paller CJ(4).
Author information:
(1)NICM Health Research Institute, Western Sydney University, Penrith, NSW,
Australia.
(2)Integria (MediHerb), Warwick, QLD, Australia.
(3)Northeast College of Health Sciences, Seneca Falls, NY, USA.
(4)Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins Medicine, Baltimore, MD, USA.
(5)Department of Epidemiology, Johns Hopkins University Bloomberg School of
Public Health, Baltimore, MD, USA.
(6)Department of Diet, Cancer and Health, Danish Cancer Institute, Danish Cancer
Society, Copenhagen, Denmark.
(7)Department of Epidemiology and Biostatistics, School of Public Health,
Imperial College London, London, UK.
(8)Department of Nutrition, Oslo New University College, Oslo, Norway.
(9)Department of Research, The Cancer Registry of Norway, Oslo, Norway.
BACKGROUND: Phytonutrient intakes may improve outcomes following breast cancer,

but the impact of postdiagnosis introduction vs established prediagnostic
exposure as well as optimum doses has not been established. Evidence from
observational studies for key exposures was evaluated, including dosage and
intake time frames.
METHODS: MEDLINE, EMBASE, CINAHL, Cochrane Library, ClinicalTrials.gov, and the
ISRCTN registry were searched for prospective and retrospective observational
studies investigating the impact of soybean, lignans, cruciferous
(cabbage-family) vegetables, green tea, or their phytonutrients on breast cancer
survival outcomes. A random-effects model was used to calculate summary hazard
ratios (HRs) and 95% confidence intervals (CIs). Nonlinear dose-response
analyses were conducted using restricted cubic splines.
RESULTS: Thirty-two articles were included. Soy isoflavones were associated with
a 26% reduced risk of recurrence (HR = 0.74, 95% CI = 0.60 to 0.92),
particularly among postmenopausal (HR = 0.72, 95% CI = 0.55 to 0.94) and
estrogen receptor-positive survivors (HR = 0.82, 95% CI = 0.70 to 0.97), with
the greatest risk reduction at 60 mg/day. In mortality outcomes, the reduction
was mostly at 20 to 40 mg/day. Soy protein and products were inversely
associated with cancer-specific mortality for estrogen receptor-positive disease
(HR = 0.75, 95% CI = 0.60 to 0.92). An inverse association was observed for
serum or plasma enterolactone, measured prediagnosis and early postdiagnosis,
with cancer-specific mortality (HR = 0.72, 95% CI = 0.58 to 0.90) and all-cause
mortality (HR = 0.69, 95% CI = 0.57 to 0.83). No effects were observed for
cruciferous vegetables. There was a 44% reduced risk of recurrence with
prediagnostic green tea for stage I and II breast cancer (HR = 0.56, 95%
CI = 0.38 to 0.83).
CONCLUSIONS: Soy, enterolactone, and green tea demonstrated significant risk
reductions in outcomes following breast cancer. Evidence is needed regarding the
impact of postdiagnostic introduction or substantial increase of these
exposures.
DOI: 10.1093/jncics/pkad104
PMCID: PMC10868383
Conflict of interest statement: Kerry Bone is a paid consultant for MediHerb,

which markets products containing green tea and broccoli extracts. He and Diana
van Die are former in-laws. Kala Visvanathan, Cecilie Kyrø, Dagfinn Aune, and
Channing Paller have no conflicts of interest to declare. K. Visvanathan reports
grants from Cepheid during the conduct of the study, unfunded collaboration with
Optra Health, and a patent for US 10,316,361 issued. C.K.’s work was funded by a
phytoestrogen grant: Danish Cancer Society grant “Knæk Cancer: R174-A11507. C.E.
declares that she is the Jacka Foundation principal research fellow, chair of
the Royal Australian College of General Practitioners (RACGP) Integrative
Medicine Specific Interest Network (voluntary role), program lead of an academic
integrative health-care center (no financial interest), and past GP Advisory
Board member for Blackmores Research Institute; she has received industry
funding from nutraceutical and acupuncture device companies to conduct clinical
trials and has received honoraria and had travel expenses covered for presenting
at complementary medicine events. As a medical research institute, NICM Health
Research Institute receives research grants and donations from foundations,
universities, government agencies, and industry. Sponsors and donors provide
untied and tied funding for work to advance the vision and mission of the
institute.
19. Int J Mol Sci. 2023 Nov 22;24(23):16596. doi: 10.3390/ijms242316596.
TRAIL-Sensitizing Effects of Flavonoids in Cancer.
Luiz-Ferreira A(1), Pacifico T(2), Cruz ÁC(1), Laudisi F(2), Monteleone G(2),
Stolfi C(2).
Author information:
(1)Inflammatory Bowel Disease Research Laboratory, Department of Biological
Sciences, Institute of Biotechnology, Federal University of Catalão (UFCAT),
Catalão 75704020, GO, Brazil.
(2)Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome,
Italy.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a

promising anticancer agent, as it selectively induces apoptosis in transformed
cells without altering the cellular machinery of healthy cells. Unfortunately,
the presence of TRAIL resistance mechanisms in a variety of cancer types
represents a major hurdle, thus limiting the use of TRAIL as a single agent.
Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated
in resistant tumors by combined treatment with antitumor agents, ranging from
synthetic molecules to natural products. Among the latter, flavonoids, the most
prevalent polyphenols in plants, have shown remarkable competence in improving
TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice
with minimal side effects. Here, we summarize the molecular mechanisms, such as
the upregulation of death receptor (DR)4 and DR5 and downregulation of key
anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP),
X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the
TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones,
flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss
limitations, mainly related to bioavailability issues, and future perspectives
regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based
therapies.
DOI: 10.3390/ijms242316596
PMCID: PMC10706592
Conflict of interest statement: G.M. has served as a consultant for First Wave
BioPharma and as a speaker for Takeda, Abbvie, Galapagos, and Pfizer, and filed
a patent related to the treatment of inflammatory bowel diseases with Smad7
antisense oligonucleotides. The other authors declare no conflict of interest.
20. Nutrients. 2023 Nov 21;15(23):4856. doi: 10.3390/nu15234856.
The Use of Soy Isoflavones in the Treatment of Prostate Cancer: A Focus on the
Cellular Effects.
Van der Eecken H(1), Joniau S(2), Berghen C(3), Rans K(3), De Meerleer G(3).
Author information:
(1)Department of Urology, University Hospital Brussels, 1090 Brussels, Belgium.
(2)Department of Urology, University Hospitals Leuven, 3000 Leuven, Belgium.
(3)Department of Radiation Oncology, University Hospitals Leuven, 3000 Leuven,
Belgium.
A possible link between diet and cancer has long been considered, with growing
interest in phytochemicals. Soy isoflavones have been associated with a reduced
risk of prostate cancer in Asian populations. Of the soy isoflavones, genistein
and daidzein, in particular, have been studied, but recently, equol as a
derivative has gained interest because it is more biologically potent. Different
mechanisms of action have already been studied for the different isoflavones in
multiple conditions, such as breast, gastrointestinal, and urogenital cancers.
Many of these mechanisms of action could also be demonstrated in the prostate,
both in vitro and in vivo. This review focuses on the known mechanisms of action
at the cellular level and compares them between genistein, daidzein, and equol.
These include androgen- and estrogen-mediated pathways, regulation of the cell
cycle and cell proliferation, apoptosis, angiogenesis, and metastasis. In
addition, antioxidant and anti-inflammatory effects and epigenetics are
addressed.
DOI: 10.3390/nu15234856
PMCID: PMC10708402
21. Anticancer Res. 2023 Dec;43(12):5387-5392. doi: 10.21873/anticanres.16742.
Genistein Induces Antiproliferative Activity and Apoptosis in Human Osteosarcoma

Saos-2 Cells.
Hagiwara H(1), Wako H(2), Nakata K(2), Aida R(2).
Author information:
(1)Department of Biomedical Engineering, Toin University of Yokohama, Yokohama,
Japan hagiwara@toin.ac.jp.
(2)Department of Biomedical Engineering, Toin University of Yokohama, Yokohama,
Japan.
BACKGROUND/AIM: Genistein (4', 5, 7-trihydroxyisoflavone) and daidzein (4',

7-dihydroxyisoflavone) are isoflavones derived from soybean and have anti-cancer
effects in various cells. However, the effects of genistein and daidzein on the
human osteosarcoma cell line Saos-2 has not been investigated before.
MATERIALS AND METHODS: Human osteosarcoma Saos-2 cells were treated with
genistein for 24 and 48 hours. Cytotoxicity and apoptosis were measured.
RESULTS: Genistein significantly inhibited proliferation of Saos-2 cells
stronger than daidzein in a dose-dependent manner (0 to 80 μM). Genistein also
significantly suppressed Saos-2 cell viability in a dose-dependent manner (0 to
100 μM). In contrast, daidzein did not affect Saos-2 cell viability. Real-time
PCR revealed that genistein caused G1-arrest by increasing the expression of p21
and p27 mRNAs in Saos-2 cells. In addition, genistein induced apoptosis through
the up-regulation of effector caspase-3/7 activity in Saos-2 cells. Genistein
also enhanced initiator caspase-9 and TNF-α mRNA expression in cells.
CONCLUSION: Genistein may inhibit proliferation through the up-regulation of p21
and p27 and viability by inducing apoptosis in Saos-2 cells.
Copyright © 2023 International Institute of Anticancer Research (Dr. George J.

Delinasios), All rights reserved.
DOI: 10.21873/anticanres.16742
22. Pharmaceuticals (Basel). 2023 Nov 10;16(11):1591. doi: 10.3390/ph16111591.
Potential Chemopreventive Effects of Dietary Combination of Phytochemicals

against Cancer Development.
Tanaka T(1), Aoki R(1), Terasaki M(2)(3).
Author information:
(1)Department of Diagnostic Pathology, Gifu Municipal Hospital, 7-1 Kashima-cho,
Gifu 500-8513, Japan.
(2)School of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
(3)Advanced Research Promotion Center, Health Sciences University of Hokkaido,
1757 Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan.
Cancer remains a major cause of cancer-related death worldwide. Over 70% of

epithelial malignancies are sporadic and are related to lifestyle.
Epidemiological studies suggest an inverse correlation between cancer incidence
and fruit and vegetable intake. Numerous preclinical studies using in vitro
(cell lines) and in vivo animal models of oncogenesis have reported the
chemopreventive effects of dietary phytochemical agents through alterations in
different biomarkers and signaling pathways. However, there is contrasting
evidence from preclinical studies and clinical trials. To date, the most studied
compounds include curcumin, resveratrol, isoflavones, green tea extract
(epigallocatechin gallate), black raspberry powder (anthocyanins and
ellagitannins), bilberry extract (anthocyanins), ginger extract (gingerol
derivatives), and pomegranate extract (ellagitannins and ellagic acid). Overall,
the clinical evidence of the preventive effects of dietary phytochemicals
against cancer development is still weak, and the amount of these phytochemicals
needed to exert chemopreventive effects largely exceeds the common dietary
doses. Therefore, we propose a combination treatment of natural compounds that
are used clinically for another purpose in order to obtain excess inhibitory
efficacy via low-dose administration and discuss the possible reasons behind the
gap between preclinical research and clinical trials.
DOI: 10.3390/ph16111591
PMCID: PMC10674766
PMID: 38004456
23. Biomed Pharmacother. 2023 Dec 31;169:115783. doi: 10.1016/j.biopha.2023.115783.

Epub 2023 Nov 7.
Phytosterols activating nuclear receptors are involving in steroid

hormone-dependent cancers: Myth or fact?
Bakrim S(1), El Omari N(2), Khan EJ(3), Khalid A(4), Abdalla AN(5), Chook JB(6),
Goh KW(7), Ming LC(8), Aboulaghras S(9), Bouyahya A(10).
Author information:
(1)Geo-Bio-Environment Engineering and Innovation Laboratory, Molecular
Engineering, Biotechnology and Innovation Team, Polydisciplinary Faculty of
Taroudant, Ibn Zohr University, Agadir 80000, Morocco.
(2)Laboratory of Histology, Embryology, and Cytogenetic, Faculty of Medicine and
Pharmacy, Mohammed V University in Rabat, Rabat 10100, Morocco.
(3)Frontier Medical &amp, Dental College, Pakistan.
(4)Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box:
114, Jazan 45142, Saudi Arabia; Medicinal and Aromatic Plants and Traditional
Medicine Research Institute, National Center for Research, P. O. Box 2404,
Khartoum, Sudan. Electronic address: akahmed@jazanu.edu.sa.
(5)Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura
University, Makkah 21955, Saudi Arabia.
(6)School of Medical and Life Sciences, Sunway University, Sunway City,
Malaysia. Electronic address: jackbeec@sunway.edu.my.
(7)Faculty of Data Science and Information Technology, INTI International
University, Nilai, Malaysia. Electronic address: khangwen.goh@newinti.edu.my.
(8)School of Medical and Life Sciences, Sunway University, Sunway City,
Malaysia. Electronic address: longchiauming@gmail.com.
(9)Laboratory of Human Pathologies Biology, Department of Biology, Faculty of
Sciences, Mohammed V University in Rabat, Rabat 10106, Morocco.
(10)Laboratory of Human Pathologies Biology, Department of Biology, Faculty of
Sciences, Mohammed V University in Rabat, Rabat 10106, Morocco. Electronic
address: a.bouyahya@um5r.ac.ma.
Nuclear receptors (NRs) represent intracellular proteins that function as a

signaling network of transcriptional factors to control genes in response to a
variety of environmental, dietary, and hormonal stimulations or serve as orphan
receptors lacking a recognized ligand. They also play an essential role in
normal development, metabolism, cell growth, cell division, physiology,
reproduction, and homeostasis and function as biological markers for tumor
subclassification and as targets for hormone therapy. NRs, including steroid
hormone receptors (SHRs), have been studied as tools to examine the fundamentals
of transcriptional regulation within the development of mammals and human
physiology, in addition to their links to disturbances. In this regard, it is
widely recognized that aberrant NR signaling is responsible for the pathological
growth of hormone-dependent tumors in response to SHRs dysregulation and
consequently represents a potential therapeutic candidate in a range of
diseases, as in the case of prostate cancer and breast cancer. On the other
hand, phytosterols are a group of plant-derived compounds that act directly as
ligands for NRs and have proven their efficacy in the management of diabetes,
heart diseases, and cancers. However, these plants are not suggested in cases of
hormone-dependent cancer since a certain group of plants contains molecules with
a chemical structure similar to that of estrogens, which are known as
phytoestrogens or estrogen-like compounds, such as lignans, coumestans, and
isoflavones. Therefore, it remains an open and controversial debate regarding
whether consuming a phytosterol-rich diet and adopting a vegetarian lifestyle
like the Mediterranean diet may increase the risk of developing steroid
hormone-dependent cancers by constitutively activating SHRs and thereby leading
to tumor transformation. Overall, the purpose of this review is to better
understand the relevant mechanistic pathways and explore epidemiological
investigations in order to establish that phytosterols may contribute to the
activation of NRs as cancer drivers in hormone-dependent cancers.
Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights
reserved.
DOI: 10.1016/j.biopha.2023.115783
Conflict of interest statement: Declaration of Competing Interest None declared.
24. Nutr Cancer. 2024;76(1):42-54. doi: 10.1080/01635581.2023.2279220. Epub 2023

Dec
27.
Dietary Isoflavone Intake and Breast Cancer Prognosis: A Prospective Analysis
and Meta-Analysis.
Song S(1)(2), Cheun JH(3), Moon HG(4), Noh DY(4), Jung SY(5), Lee ES(5), Kim
Z(6), Youn HJ(7), Cho J(8), Yoo YB(9), Jun S(10), Joung H(11), Lee JE(1)(12).
Author information:
(1)Department of Food and Nutrition, Seoul National University, Seoul, Republic
of Korea.
(2)Division of Population Health Research, Department of Precision Medicine,
Korea National Institute of Health, Cheongju, Republic of Korea.
(3)Department of Surgery, Seoul Metropolitan Government Seoul National
University, Boramae Medical Center, Seoul, Republic of Korea.
(4)Department of Surgery and Cancer Research Institute, Seoul National
University College of Medicine, Seoul, Republic of Korea.
(5)Research Institute and Hospital, National Cancer Center, Goyang, Republic of
Korea.
(6)Department of Surgery, Soonchunhyang University Bucheon Hospital,
Soonchunhyang University College of Medicine, Bucheon, Republic of Korea.
(7)Department of Surgery, Jeonbuk National University Medical School, Jeonju,
Republic of Korea.
(8)Department of Surgery, Keimyung University School of Medicine, Daegu,
Republic of Korea.
(9)Department of Surgery, Konkuk University Medical Center, Seoul, Republic of
Korea.
(10)Department of Food Science and Nutrition, Soonchunhyang University, Asan,
Republic of Korea.
(11)Department of Public Health, Graduate School of Public Health, Seoul
National University, Seoul, Republic of Republic of Korea.
(12)Research Institute of Human Ecology, Seoul National University, Seoul,
Republic of Korea.
We aimed to examine the association between dietary isoflavone intake and the
risk of breast cancer recurrence and summarize evidence on the role of dietary
isoflavone intake in breast cancer prognosis. This prospective study included
592 breast cancer survivors who completed a dietary assessment. Hazard ratios
(HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional
hazards models. Of the studies published until May 31, 2023, that were searched
in PUBMED and EMBASE databases, 14 studies were selected. Adjusted HRs were
combined using fixed- or random-effects models. During the median follow-up of
4.3 years, 47 recurrences were identified. The HR (95% CI) for recurrence
comparing the highest versus the lowest tertile of isoflavones intake was 1.29
(0.60-2.78). In a meta-analysis of previously published data and ours, dietary
isoflavone intake was associated with a better breast cancer prognosis. The
combined HRs (95% CIs) comparing the extreme categories were 0.81 (0.67-0.98)
for recurrence and 0.85 (0.76-0.96) for all-cause mortality. A nonlinear inverse
association was observed between isoflavone intake and the risk of recurrence
and all-cause mortality. Our study suggests that dietary isoflavone intake is
associated with a favorable prognosis in breast cancer survivors and warrants
further investigation.
DOI: 10.1080/01635581.2023.2279220
25. Biomed Pharmacother. 2023 Dec;168:115811. doi: 10.1016/j.biopha.2023.115811.

Epub 2023 Nov 2.
The potential role of formononetin in cancer treatment: An updated review.
Aliya S(1), Alhammadi M(1), Park U(1), Tiwari JN(2), Lee JH(3), Han YK(4), Huh
YS(5).
Author information:
(1)Department of Biological Sciences and Bioengineering, Inha University,
Incheon 22212, Republic of Korea.
(2)Department of Energy and Materials Engineering, Dongguk University-Seoul,
Seoul 100-715, Republic of Korea.
(3)3D Convergence Center, Inha University, Incheon 22212, Republic of Korea;
Department of Materials Science and Engineering, Inha University, Incheon 22212,
Republic of Korea.
(4)Department of Energy and Materials Engineering, Dongguk University-Seoul,
Seoul 100-715, Republic of Korea. Electronic address: ykenergy@dongguk.edu.
(5)Department of Biological Sciences and Bioengineering, Inha University,
Incheon 22212, Republic of Korea. Electronic address: yunsuk.huh@inha.ac.kr.
Currently, cancer is one of the main research topics, due to its high incidence
and drug resistance to existing anti-cancer drugs. Formononetin, a natural
product with phytoestrogenic properties and diverse biological functions, has
attracted the attention of researchers working on anticancer drugs. Formononetin
emerges as an intriguing bioactive substance compared to other isoflavones as it
exhibits potent chemotherapeutic activity with less toxicity. Formononetin
effectively plays a significant role in inhibiting cell proliferation, invasion,
and metastatic abilities of cancer cells by targeting major signaling pathways
at the junction of interconnected pathways. It also induces apoptosis and cell
cycle arrest by modulating mediator proteins. It causes upregulation of key
factors such as p-AKT, p38, p21, and p53 and downregulation of NF-κB.
Furthermore, formononetin regulates the neoplastic microenvironment by
inactivating the ERK1/2 pathway and lamin A/C signaling and has been reported to
inactivate JAK/STAT, PKB or AKT, and mitogen-activated protein kinase pathways
and to suppress cell migration, invasion, and angiogenesis in human cancer
cells. To assist researchers in further exploring formononetin as a potential
anticancer therapeutic candidate, this review focuses on both in vitro and in
vivo proof of concept studies, patents, and clinical trials pertinent to
formononetin's anticancer properties. Overall, this review discusses
formononetin from a comprehensive perspective to highlight its potential
benefits as an anticancer agent.
Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights
reserved.
DOI: 10.1016/j.biopha.2023.115811
Conflict of interest statement: Declaration of Competing Interest The authors

paper.
26. Chronic Dis Transl Med. 2023 Jul 19;9(4):277-287. doi: 10.1002/cdt3.87.
eCollection 2023 Dec.
Nut consumption and urogenital and genital, gastrointestinal and women-related

cancers: Assessment and review.
Mohamadi M(1), Dousdampanis P(2), Ahmadi Z(3), Pourmasumi S(4)(5), Naderi M(6),
Zainodini N(7), Nazari A(8).
Author information:
(1)Occupational Safety and Health Research Center, NICICO World safety
organization and Rafsanjan University of Medical Sciences Rafsanjan Iran.
(2)Department of Nephrology Saint Andrews State General Hospital Patras Greece.
(3)Pistachio Safety Research Center Rafsanjan University of Medical Sciences
Rafsanjan Iran.
(4)Social Determinants of Health Research Center Rafsanjan University of Medical
Sciences Rafsanjan Iran.
(5)Clinical Research Development Unit, Ali-Ibn Abi-Talib Hospital Rafsanjan
University of Medical Sciences Rafsanjan Iran.
(6)Vice Chancellor for Research and Technology Rafsanjan University of Medical
(7)Immunology of Infectious Diseases Research Center, Research Institute of
Basic Medical Sciences Rafsanjan University of Medical Sciences Rafsanjan Iran.
(8)Department of Surgery, School of Medicine Rafsanjan University of Medical
The prevalence of cancer, especially in industrial countries, is a major problem

for health and treatment systems. Cancer can affect the quality of life of all
family members and has many negative effects on the community. Despite many
advances in cancer treatment, this disease is still a major worldwide problem.
There is strong evidence that dietary habits are effective in protecting against
cancer and even helping in the disease treatment progress. Nuts with various
biologically-active compounds, such as vitamins, phytosterols, isoflavones,
flavonoids, and polyphenols have been reported to possess anticarcinogenic
properties. Accordingly, this review provides an insight into the association
between nut consumption and the prevention of some cancers. We considered the
cancers related to the urogenital and genital tract, gastrointestinal tract, as
well as women-related cancers. Both cell culture examinations and experimental
animal studies alongside observational epidemiological studies demonstrated that
regular consumption of a nut-enriched diet is able to reduce the risk of these
cancers.
© 2023 The Authors. Chronic Diseases and Translational Medicine published by

John Wiley & Sons Ltd on behalf of Chinese Medical Association.
DOI: 10.1002/cdt3.87
PMCID: PMC10617366
PMID: 37915385
27. J Ethnopharmacol. 2024 Jan 30;319(Pt 3):117225. doi: 10.1016/j.jep.2023.117225.

Epub 2023 Oct 4.
Down-regulation of human papillomavirus E6 oncogene and antiproliferative effect

of Schisandra chinensis and Pueraria lobata natural extracts on Hela cell line.
Cardona-Mendoza A(1), Fonseca-Benitez A(1), Buitrago DM(2), Coy-Barrera E(3),

Perdomo SJ(4).
Author information:
(1)Cellular and Molecular Immunology Group-INMUBO, School of Dentistry,
Universidad El Bosque, Bogotá, Colombia.
Universidad El Bosque, Bogotá, Colombia; Unidad de Investigación Básica
Oral-UIBO, Facultad de Odontología, Universidad El Bosque, Bogotá, Colombia.
(3)Bioorganic Chemistry Laboratory, Department of Chemistry, Universidad Militar
Nueva Granada, Cajicá, 250247, Colombia.
Universidad El Bosque, Bogotá, Colombia. Electronic address:
perdomosandraj@unbosque.edu.co.
ETHNOPHARMACOLOGICAL RELEVANCE: Cervical cancer is one of the most common

malignancies in women that continues to be a public health problem worldwide.
Human papillomavirus (HPV) infection is closely related as the causative agent
of almost all cases of cervical cancer. Currently, there is no effective
treatment for the persistence of HPV. Although vaccines have shown promising
results in recent years, they are still a costly strategy for developing
countries and have no therapeutic effect on existing infections, which is why
the need arises to search for new strategies that can be used in treatment,
suppressing oncogenic HPV and disease progression. Extracts of Schisandra
Chinensis and Pueraria lobata have been used in traditional medicine, and it has
been shown in recent years that some of their bioactive compounds have
pharmacological, antioxidant, antitumor, apoptotic, and proliferation effects in
HPV-positive cells. However, its mechanism of action has yet to be fully
explored.
AIM OF THE STUDY: The following study aimed to determine the chemical
composition, antioxidant activity, and potential antiproliferative and viral
oncogene effects of natural extracts of S. chinensis and P. lobata on HPV-18
positive cervical cancer cells.
MATERIALS AND METHODS: The HPV-18-positive HeLa cells were treated for 24 and
48 h with the ethanolic extracts of S chinensis and P. lobata. Subsequently,
cell viability was evaluated using the resazurin method, the effect on the cell
cycle of the extracts (1.0, 10, and 100 μg/mL) was measured by flow cytometry,
the gene of expression of the E6/E7, P53, BCL-2, and E2F-1 were determined by
RT-PCR and the protein expression of p53, Ki-67, x|and Bcl-2 by
immunohistochemistry. Additionally, the chemical characterization of the two
extracts was carried out using LC-MS, and the total phenolics content (TPC),
Total flavonoid content (TFC), and DPPH radical scavenging capacity were
determined. Data were analyzed using the Mann-Whitney and Kruskal Wallis U test
with GraphPad Prism 6 software.
RESULTS: The natural extracts of Schisandra chinensis and Pueraria lobata
induced down-regulation of E6 HPV oncogene (p<0.05) and a strong up-regulation
of P53 (p<0.05), E2F-1 (p<0.05), and Bcl-2 (p<0.05) gene expression.
Simultaneously, the natural extracts tend to increase the p53 protein levels and
arrest the cell cycle of HeLa in the G1/S phase (p<0.05). Investigated extracts
were characterized by the occurrence of bioactive lignans and isoflavones in S.
chinensis and P. lobata, respectively.
CONCLUSION: The extracts of S. chinensis and P. lobata within their chemical
characterization mainly present lignan and isoflavone-type compounds, which are
probably responsible for inhibiting the expression of the HPV E6 oncogene and
inducing an increase in the expression of p53, Bcl -2 and E2F-1 producing cell
cycle detection in S phase in HeLa cells. Therefore, these extracts are good
candidates to continue studying their antiviral and antiproliferative potential
in cells transformed by HPV.
Copyright © 2023. Published by Elsevier B.V.
DOI: 10.1016/j.jep.2023.117225

reported no potential conflicts of interest.
28. ACS Omega. 2023 Aug 27;8(36):32271-32293. doi: 10.1021/acsomega.3c03741.
eCollection 2023 Sep 12.
Daidzein from Dietary Supplement to a Drug Candidate: An Evaluation of

Potential.
Ubaid M(1), Salauddin(1), Shadani MA(1), Kawish SM(1), Albratty M(2), Makeen
HA(3), Alhazmi HA(2)(4)(5), Najmi A(2), Zoghebi K(2), Halawi MA(6)(7), Ali A(8),
Alam MS(2), Iqbal Z(9), Mirza MA(9).
Author information:
(1)School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi
110062, India.
(2)Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan
University, Jazan 45142, Saudi Arabia.
(3)Pharmacy Practice Research Unit, Department of Clinical Pharmacy, College of
Pharmacy, Jazan University, Jazan 45142, Saudi Arabia.
(4)Substance Abuse and Toxicology Research Center, Jazan University, Jazan
45142, Saudi Arabia.
(5)Medical Research Center, Jazan University, Jazan 45142, Saudi Arabia.
(6)Pharmacy Practice, College of Pharmacy, Jazan University, Jazan 45142, Saudi
Arabia.
(7)Department of Haematology, Division of Cancer & Genetics School of Medicine,
Cardiff University, Cardiff, Wales CF14 4XN, U.K.
(8)Department of Pharmacognosy, College of Pharmacy, Taif University, P.O. Box
11099, Taif, 21944, Saudi Arabia.
(9)Department of Pharmaceutics, School of Pharmaceutical Education and Research,
Jamia Hamdard, New Delhi 110062, India.
Daidzein (DDZ) is a well-known nutraceutical supplement belonging to the class

of isoflavones. It is isolated from various sources such as alfalfa, soybean,
and red clover. It demonstrates a broad array of pharmacological/beneficial
properties such as cardiovascular exercise, cholesterol reduction, and
anticancer, antifibrotic, and antidiabetic effects, which make it effective in
treating a wide range of diseases. Its structure and operation are the same as
those of human estrogens, which are important in preventing osteoporosis,
cancer, and postmenopausal diseases. It is thus a promising candidate for
development as a phytopharmaceutical. Addressing safety, efficacy, and
physicochemical properties are the primary prerequisites. DDZ is already
ingested every day in varying amounts, so there should not be a significant
safety risk; however, each indication requires a different dose to be
determined. Some clinical trials are already being conducted globally to confirm
its safety, efficacy, and therapeutic potential. Furthermore, as a result of its
therapeutic influence on health, in order to establish intellectual property,
patents are utilized. In light of the vast potential of eugenol, this review
presents a detailed data collection on DDZ to substantiate the claim to develop
it in the therapeutic category.
© 2023 The Authors. Published by American Chemical Society.
DOI: 10.1021/acsomega.3c03741
PMCID: PMC10538961
PMID: 37780202
Conflict of interest statement: The authors declare no competing financial

interest.
29. Nutrients. 2023 Sep 12;15(18):3949. doi: 10.3390/nu15183949.
Integrated Network Pharmacology, Molecular Docking, Molecular Simulation, and In

Vitro Validation Revealed the Bioactive Components in Soy-Fermented Food
Products and the Underlying Mechanistic Pathways in Lung Cancer.
Elkhalifa AEO(1), Banu H(1), Khan MI(2), Ashraf SA(1).
Author information:
(1)Department of Clinical Nutrition, College of Applied Medical Sciences,
University of Ha'il, Ha'il P.O. Box 2440, Saudi Arabia.
(2)Department of Clinical Nutrition, College of Applied Health Sciences in Ar
Rass, Qassim University, Ar Rass 51921, Saudi Arabia.
Globally, lung cancer remains one of the leading causes of cancer-related

mortality, warranting the exploration of novel and effective therapeutic
approaches. Soy-fermented food products have long been associated with potential
health benefits, including anticancer properties. There is still a lack of
understanding of the active components of these drugs as well as their
underlying mechanistic pathways responsible for their anti-lung cancer effects.
In this study, we have undertaken an integrated approach combining network
pharmacology and molecular docking to elucidate the mechanism of action of
soy-fermented food products against lung cancer through simulation and in vitro
validation. Using network pharmacology, we constructed a comprehensive network
of interactions between the identified isoflavones in soy-fermented food
products and lung cancer-associated targets. Molecular docking was performed to
predict the binding affinities of these compounds with key lung cancer-related
proteins. Additionally, molecular simulation was utilized to investigate the
stability of the compound-target complexes over time, providing insights into
their dynamic interactions. Our results identified daidzein as a potential
active component in soy-fermented food products with high binding affinities
towards critical lung cancer targets. Molecular dynamic simulations confirmed
the stability of the daidzein-MMP9 and daidzein-HSP90AA1 complexes, suggesting
their potential as effective inhibitors. Additionally, in vitro validation
experiments demonstrated that treatment with daidzein significantly inhibited
cancer cell proliferation and suppressed cancer cell migration and the invasion
of A549 lung cancer cells. Consequently, the estrogen signaling pathway was
recognized as the pathway modulated by daidzein against lung cancer. Overall,
the findings of the present study highlight the therapeutic potential of
soy-fermented food products in lung cancer treatment and provide valuable
insights for the development of targeted therapies using the identified
bioactive compounds. Further investigation and clinical studies are warranted to
validate these findings and translate them into clinical applications for
improved lung cancer management.
DOI: 10.3390/nu15183949
PMCID: PMC10537301
PMID: 37764733
Conflict of interest statement: The authors declare no conflict of interest. The

funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
30. Molecules. 2023 Sep 12;28(18):6577. doi: 10.3390/molecules28186577.
Advances in Extraction, Purification, and Analysis Techniques of the Main

Components of Kudzu Root: A Comprehensive Review.
Xuan T(1), Liu Y(1), Liu R(1), Liu S(1), Han J(1), Bai X(1), Wu J(1), Fan R(1).
Author information:
(1)Department of Sanitary Inspection, School of Public Health, Shenyang Medical
College, Shenyang 110034, China.
Kudzu root (Pueraria lobate (Willd.) Ohwi, KR) is an edible plant with rich
nutritional and medicinal values. Over the past few decades, an ample variety of
biological effects of Pueraria isoflavone have been evaluated. Evidence has
shown that Pueraria isoflavone can play an active role in antioxidant,
anti-inflammatory, anti-cancer, neuroprotection, and cardiovascular protection.
Over 50 isoflavones in kudzu root have been identified, including puerarin,
daidzein, daidzin, 3'-hydroxy puerarin, and genistein, each with unambiguous
structures. However, the application of these isoflavones in the development of
functional food and health food still depends on the extraction, purification
and identification technology of Pueraria isoflavone. In recent years, many
green and novel extraction, purification, and identification techniques have
been developed for the preparation of Pueraria isoflavone. This review provides
an updated overview of these techniques, specifically for isoflavones in KR
since 2018, and also discusses and compares the advantages and disadvantages of
these techniques in depth. The intention is to provide a research basis for the
green and efficient extraction, purification, and identification of Pueraria
isoflavone and offers investigators a valuable reference for future studies on
the KR.
PMCID: PMC10535729
31. J Microbiol Biotechnol. 2023 Dec 28;33(12):1552-1562. doi:

10.4014/jmb.2308.08016. Epub 2023 Aug 28.
Benefits of Soybean in the Era of Precision Medicine: A Review of Clinical

Evidence.
Kang JH(1), Dong Z(2)(3), Shin SH(1)(4).
Author information:
(1)Department of Food and Nutrition, Gyeongsang National University, Jinju
52828, Republic of Korea.
(2)Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou
University, Zhengzhou 450001, Henan, P.R. China.
(3)China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui
District, Zhengzhou 450008, Henan, P.R. China.
(4)Department of Bio & Medical Bigdata (BK4 Program), Gyeongsang National
University, Jinju 52828, Republic of Korea.
Soybean (Glycine max) is an important ingredient of cuisines worldwide. While

there is a wealth of evidence that soybean could be a good source of
macronutrients and phytochemicals with health-promoting effects, concerns
regarding adverse effects have been raised. In this work, we reviewed the
current clinical evidence focusing on the benefits and risks of soybean
ingredients. In breast, prostate, colorectal, ovarian, and lung cancer,
epidemiological studies showed an inverse association between soybean food
intake and cancer risks. Soybean intake was inversely correlated with risks of
type 2 diabetes mellitus (T2DM), and soy isoflavones ameliorated osteoporosis
and hot flashes. Notably, soybean was one of the dietary protein sources that
may reduce the risk of breast cancer and T2DM. However, soybean had adverse
effects on certain types of drug treatment and caused allergies. In sum, this
work provides useful considerations for planning clinical soybean research and
selecting dietary protein sources for human health.
DOI: 10.4014/jmb.2308.08016
PMCID: PMC10774093
Conflict of interest statement: Conflict of Interests The authors have no

financial conflicts of interest to declare.
32. J Adv Vet Anim Res. 2023 Jun 30;10(2):308-320. doi: 10.5455/javar.2023.j683.
eCollection 2023 Jun.
Autophagy characteristics of phytoestrogens in management and prevention of

diseases: A narrative review of in-vivo and in-vitro studies.
Khater SI(1), Shalabi M(1), Alammash BB(2), Alrais AI(2), Al-Ahmadi D(3),
Alqahtani LS(4), Khamis T(5), Abdelaziz S(6), Aldawy K(1).
Author information:
(1)Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig
University, Zagazig, Egypt.
(2)King Fahad Hospital, Ministry of Health, Medina, Saudi Arabia.
(3)Maternity and Children Hospital (MCH), Ministry of Health, Medina, Saudi
Arabia.
(4)Department of Biochemistry, College of Science, University of Jeddah, Jeddah
(5)Department of Pharmacology, Laboratory of Biotechnology, Faculty of
Veterinary Medicine, Zagazig University, Zagazig, Egypt.
(6)Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University,
Zagazig, Egypt.
Phytoestrogens are non-steroid polyphenolic materials present in 300 plants.

Regarding their structural similarities to estradiol, phytoestrogens attach to
estrogen receptors and display anti- or pro-estrogenic activities. This review
explored phytoestrogens' potential advantages and autophagy properties in light
of their future application for disease management, highlighting how
phytoestrogens could modulate autophagy. Research has examined the prospective
benefits of phytoestrogens for the anticipation and management of various
conditions, including signs of menopause, tumors, skin deterioration,
osteoporosis, heart disease, neurodegenerative conditions, disorders of the
immune system, and metabolic syndrome, owing to their therapeutic effects. As
phytoestrogens can activate or inhibit autophagy, which has antioxidant,
apoptotic, anti-mutagenic, anticancer, transcriptional, and genomic impacts on
cancer and aging illnesses, phytoestrogens could influence diseases through the
modulation of autophagy. The collaborative research on animal models,
utilization of genetic techniques, and administration of pharmacologically
active substances has indicated the possible therapeutic benefits of autophagy
modulation in various illnesses. Further research is required to illustrate the
pathways by which phytoestrogens modulate autophagy and the possible therapeutic
effects on these diseases.
Copyright: © Journal of Advanced Veterinary and Animal Research.

DOI: 10.5455/javar.2023.j683
PMCID: PMC10390686
PMID: 37534069
Conflict of interest statement: The authors declare no conflict of interests
33. Phytochemistry. 2023 Oct;214:113789. doi: 10.1016/j.phytochem.2023.113789. Epub

2023 Jul 21.
DESIGNER fraction concept unmasks minor bioactive constituents in red clover

(Trifolium pratense L.).
Hitzman R(1), Malca-Garcia GR(1), Howell C(1), Park HY(1), Friesen JB(2), Dong
H(1), Dunlap T(1), McAlpine JB(1), Vollmer G(3), Bosland MC(4), Nikolić D(1),
Lankin DC(1), Chen SN(1), Bolton JL(1), Pauli GF(5), Dietz BM(6).
Author information:
(1)UIC Center for Botanical Dietary Supplements Research and Center for Natural
Product Technologies, Pharmacognosy Institute, and Department of Pharmaceutical
Sciences, College of Pharmacy, University of Illinois Chicago, 833 S. Wood
Street, Chicago, IL, 60612, USA.
Street, Chicago, IL, 60612, USA; Physical Sciences Department, Rosary College of
Arts and Sciences, Dominican University, 7900 Division Street, River Forest, IL,
60305, USA.
Street, Chicago, IL, 60612, USA; Technische Universität Dresden, Faculty of
Biology, Chair for Molecular Cell Physiology & Endocrinology, D-01062, Dresden,
Germany.
(4)Department of Pathology, College of Medicine, University of Illinois Chicago,
840 S. Wood Street, Chicago, IL, 60612, USA.
Street, Chicago, IL, 60612, USA. Electronic address: gfp@uic.edu.
Street, Chicago, IL, 60612, USA. Electronic address: birgitd@uic.edu.
In botanical extracts, highly abundant constituents can mask or dilute the

effects of other, and often, more relevant biologically active compounds. To
facilitate the rational chemical and biological assessment of these natural
products with wide usage in human health, we introduced the DESIGNER approach of
Depleting and Enriching Selective Ingredients to Generate Normalized Extract
Resources. The present study applied this concept to clinical Red Clover Extract
(RCE) and combined phytochemical and biological methodology to help rationalize
the utility of RCE supplements for symptom management in postmenopausal women.
Previous work has demonstrated that RCE reduces estrogen detoxification pathways
in breast cancer cells (MCF-7) and, thus, may serve to negatively affect
estrogen metabolism-induced chemical carcinogenesis. Clinical RCE contains ca.
30% of biochanin A and formononetin, which potentially mask activities of less
abundant compounds. These two isoflavonoids are aryl hydrocarbon receptor (AhR)
agonists that activate P450 1A1, responsible for estrogen detoxification, and
P450 1B1, producing genotoxic estrogen metabolites in female breast cells.
Clinical RCE also contains the potent phytoestrogen, genistein, that
downregulates P450 1A1, thereby reducing estrogen detoxification. To identify
less abundant bioactive constituents, countercurrent separation (CCS) of a
clinical RCE yielded selective lipophilic to hydrophilic metabolites in six
enriched DESIGNER fractions (DFs 01-06). Unlike solid-phase chromatography, CCS
prevented any potential loss of minor constituents or residual complexity (RC)
and enabled the polarity-based enrichment of certain constituents. Systematic
analysis of estrogen detoxification pathways (ERα-degradation, AhR activation,
CYP1A1/CYP1B1 induction and activity) of the DFs uncovered masked bioactivity of
minor/less abundant constituents including irilone. These data will allow the
optimization of RCE with respect to estrogen detoxification properties. The DFs
revealed distinct biological activities between less abundant bioactives. The
present results can inspire future carefully designed extracts with
phytochemical profiles that are optimized to increase in estrogen detoxification
pathways and, thereby, promote resilience in women with high-risk for breast
cancer. The DESIGNER approach helps to establish links between complex chemical
makeup, botanical safety and possible efficacy parameters, yields candidate DFs
for (pre)clinical studies, and reveals the contribution of minor
phytoconstituents to the overall safety and bioactivity of botanicals, such as
resilience promoting activities relevant to women's health.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.phytochem.2023.113789
PMCID: PMC10528883

paper.
34. Eur J Pharmacol. 2023 Oct 5;956:175898. doi: 10.1016/j.ejphar.2023.175898. Epub

2023 Jul 20.
Targeting beta-catenin signaling for prevention of colorectal cancer -

Nutraceutical, drug, and dietary options.
Iloki Assanga SB(1), Lewis Luján LM(2), McCarty MF(3).
Author information:
(1)Departamento de Ciencias Químico Biológicas, Universidad de Sonora, Blvd Luis
Encinas y Rosales S/N Col. Centro, Hermosillo, Sonora, C.P. 83000, Mexico.
Electronic address: ilokiassanga@gmail.com.
(2)Technological Institute of Hermosillo (ITH), Ave. Tecnológico y Periférico
Poniente S/N, Col. Sahuaro, Hermosillo, Sonora, C.P. 83170, México. Electronic
address: lidianys1@yahoo.es.
(3)Catalytic Longevity, San Diego, CA, 92109, USA. Electronic address:
markfmccarty@gmail.com.
Progressive up-regulation of β-catenin signaling is very common in the

transformation of colorectal epithelium to colorectal cancer (CRC). Practical
measures for opposing such signaling hence have potential for preventing or
slowing such transformation. cAMP/PKA activity in colon epithelium, as
stimulated by COX-2-generated prostaglandins and β2-adrenergic signaling, boosts
β-catenin activity, whereas cGMP/PKG signaling has the opposite effect.
Bacterial generation of short-chain fatty acids (as supported by unrefined
high-carbohydrate diets, berberine, and probiotics), dietary calcium, daily
aspirin, antioxidants opposing cox-2 induction, and nicotine avoidance, can
suppress cAMP production in colonic epithelium, whereas cGMP can be boosted via
linaclotides, PDE5 inhibitors such as sildenafil or icariin, and likely
high-dose biotin. Selective activation of estrogen receptor-β by soy
isoflavones, support of adequate vitamin D receptor activity with UV exposure or
supplemental vitamin D, and inhibition of CK2 activity with flavanols such as
quercetin, can also oppose β-catenin signaling in colorectal epithelium.
Secondary bile acids, the colonic production of which can be diminished by
low-fat diets and berberine, can up-regulate β-catenin activity by
down-regulating farnesoid X receptor expression. Stimulation of PI3K/Akt via
insulin, IGF-I, TLR4, and EGFR receptors boosts β-catenin levels via inhibition
of glycogen synthase-3β; plant-based diets can down-regulate insulin and IGF-I
levels, exercise training and leanness can keep insulin low, anthocyanins and
their key metabolite ferulic acid have potential for opposing TLR4 signaling,
and silibinin is a direct antagonist for EGFR. Partially hydrolyzed phytate can
oppose growth factor-mediated down-regulation of β-catenin by inhibiting Akt
activation. Multifactorial strategies for safely opposing β-catenin signaling
can be complemented with measures that diminish colonic mutagenesis and DNA
hypomethylation - such as avoidance of heme-rich meat and charred or processed
meats, consumption of phase II-inductive foods and nutraceuticals (e.g.,
Crucifera), and assurance of adequate folate status.
DOI: 10.1016/j.ejphar.2023.175898
Conflict of interest statement: Declaration of competing interest Mark F.

McCarty is co-inventor and co-owner of a US patent on nutraceutical uses of
phycocyanobilin-containing oligopeptides derived from spirulina. The other
authors have no conflicts of interest to declare.
35. Foods. 2023 Jul 7;12(13):2629. doi: 10.3390/foods12132629.
The Role of Nutraceuticals and Functional Foods in Skin Cancer: Mechanisms and
Therapeutic Potential.
Peterle L(1), Sanfilippo S(2), Borgia F(1), Li Pomi F(1), Vadalà R(3), Costa
R(3), Cicero N(3)(4), Gangemi S(2).
Author information:
(1)School and Operative Unit of Dermatology, Department of Clinical and
Experimental Medicine, University of Messina, Via Consolare Valeria-Gazzi, 98125
Messina, Italy.
(2)School and Operative Unit of Allergy and Clinical Immunology, Department of
Clinical and Experimental Medicine, University of Messina, Via Consolare
Valeria-Gazzi, 98125 Messina, Italy.
(3)Department of Biomedical and Dental Sciences and Morphofunctional Imaging,
University of Messina, 98168 Messina, Italy.
(4)Science4life srl, University of Messina, 98168 Messina, Italy.
Skin cancer is a prevalent type of cancer worldwide and has a high growth rate
compared to other diseases. Although modern targeted therapies have improved the
management of cutaneous neoplasms, there is an urgent requirement for a safer,
more affordable, and effective chemoprevention and treatment strategy for skin
cancer. Nutraceuticals, which are natural substances derived from food, have
emerged as a potential alternative or adjunctive treatment option. In this
review, we explore the current evidence on the use of omega-3 fatty acids and
polyphenols (curcumin, epigallocatechin gallate, apigenin, resveratrol, and
genistein) for the treatment of melanoma and non-melanoma skin cancer (NMSC), as
well as in their prevention. We discuss the mechanisms of action of the
aforementioned nutraceuticals and their probable therapeutic benefits in skin
cancer. Omega-3 fatty acids, curcumin, epigallocatechin gallate, apigenin,
resveratrol, and genistein have several properties, among which are
anti-inflammatory and anti-tumor, which can help to prevent and treat skin
cancer. However, their effectiveness is limited due to poor bioavailability.
Nanoparticles and other delivery systems can improve their absorption and
targeting. More research is needed to evaluate their safety and effectiveness as
a natural approach to skin cancer prevention and treatment. These compounds
should not replace conventional cancer treatments, but may be used as
complementary therapy under the guidance of a healthcare professional.
DOI: 10.3390/foods12132629
PMCID: PMC10341090
PMID: 37444367
36. Brain Sci. 2023 Jun 2;13(6):902. doi: 10.3390/brainsci13060902.
Phytochemicals and Glioma: Results from Dietary Mixed Exposure.
Zhang W(1), Wang C(1), Chen F(1), He Y(1), Yin S(1), Peng Y(1), Li W(1).
Author information:
(1)Department of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital,
Capital Medical University, Beijing 100070, China.
The information about phytochemicals' potential to prevent cancer is

encouraging, including for glioma. However, most studies on phytochemicals and
glioma mainly focused on preclinical studies. Their epidemiological studies were
not sufficient, and the evidence on the dose-response relationship is usually
limited. Therefore, this investigation examined the association between dietary
phytochemical intake and glioma in Chinese adults. This case-control study was
carried out in a hospital in China. Based on the dietary information obtained
from the food frequency questionnaire, the researchers estimated the
phytochemical intake of 506 patients with glioma and 506 controls. Compared with
participants in the lowest tertile, the highest intakes of carotene, flavonoids,
soy isoflavones, anthocyanin, and resveratrol were associated with a reduced
risk of glioma. The WQS and BKMR models suggested that anthocyanin and carotene
have a greater influence on glioma. The significant nonlinear dose-response
associations between dietary phytochemicals and glioma were suggested using the
restricted cubic spline function. According to this study on phytochemicals and
glioma, higher intakes of carotene, flavonoids, soy isoflavones, anthocyanins,
and resveratrol are linked to a lower risk of glioma. So, we might not be able
to ignore how phytochemicals affect gliomas.
DOI: 10.3390/brainsci13060902
PMCID: PMC10296340
PMID: 37371380
37. Naunyn Schmiedebergs Arch Pharmacol. 2023 Nov;396(11):2893-2910. doi:

10.1007/s00210-023-02550-1. Epub 2023 Jun 10.
Genistein: a promising modulator of apoptosis and survival signaling in cancer.
Joshi H(1), Gupta DS(2), Abjani NK(2), Kaur G(2), Mohan CD(3), Kaur J(4),
Aggarwal D(5), Rani I(6), Ramniwas S(7), Abdulabbas HS(8), Gupta M(9), Tuli
HS(10).
Author information:
(1)School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067,
India.
(2)Department of Pharmacology, Shobhaben Pratapbhai Patel School of Pharmacy &
Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai,
400056, India.
(3)Department of Studies in Molecular Biology, University of Mysore,
Manasagangotri, Mysore-570006, India.
(4)Graduate School of Biomedical Engineering, Faculty of Engineering, The
University of New South Wales, Sydney, 2052, Australia.
(5)Department of Biotechnology, Maharishi Markandeshwar Engineering College,
Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, 133207,
India.
(6)Department of Biochemistry, Maharishi Markandeshwar College of Medical
Sciences and Research (MMCMSR), Sadopur, 134007, Ambala, India.
(7)University Centre for Research and Development, University Institute of
Pharmaceutical Sciences, Chandigarh University, Gharuan, Mohali, 140413, India.
(8)Continuous Education Department, Faculty of Dentistry, University of
Al-Ameed, Karbala, 56001, Iraq.
(9)Department of Pharmaceutics, School of Pharmaceutical Sciences, Delhi
Pharmaceutical Sciences and Research University, New Delhi, 110017, India.
(10)Department of Biotechnology, Maharishi Markandeshwar Engineering College,
Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala, 133207,
India. hardeep.biotech@gmail.com.
Genistein, a commonly occurring isoflavone, has recently gained popularity owing

to its ever-expanding spectrum of pharmacological benefits. In addition to
health benefits such as improved bone health and reduced postmenopausal
complications owing to its phytoestrogen properties, it has been widely
evaluated for its anti-cancer potential. Several studies have established the
potential for its usage in the management of breast, lung, and prostate cancers,
and its usage has significantly evolved from early applications in traditional
systems of medicine. This review offers an insight into its current status of
usage, the chemistry, and pharmacokinetics of the molecule, an exploration of
its apoptotic mechanisms in cancer management, and opportunities for synergism
to improve therapeutic outcomes. In addition to this, the authors have presented
an overview of recent clinical trials, to offer an understanding of contemporary
studies and explore prospects for a greater number of focused trials, moving
forward. Advancements in the application of nanotechnology as a strategy to
improve safety and efficacy have also been highlighted, with a brief discussion
of results from safety and toxicology studies.
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany,

part of Springer Nature.
DOI: 10.1007/s00210-023-02550-1
38. Phytother Res. 2023 Jul;37(7):3097-3120. doi: 10.1002/ptr.7861. Epub 2023 May
29.
A review on phytoestrogens: Current status and future direction.
Patra S(1), Gorai S(2), Pal S(1), Ghosh K(1), Pradhan S(3), Chakrabarti S(1).
Author information:
(1)Department of Biological Sciences, Midnapore City College, Paschim Medinipur,
India.
(2)Department of Neurological Science, Rush University Medical Center, Chicago,
Illinois, USA.
(3)Department of Paramedical Sciences, Midnapore City College, Paschim
Medinipur, India.
Phytoestrogens are plant secondary metabolite that is structurally and

functionally similar to mammalian estrogens, which have been shown to have
various health benefits in humans. Isoflavones, coumestans, and lignans are the
three major bioactive classes of phytoestrogens. It has a complicated mechanism
of action involving an interaction with the nuclear estrogen receptor isoforms
ERα and ERβ, with estrogen agonist and estrogen antagonist effects. Depending on
their concentration and bioavailability in various plant sources, phytoestrogens
can act as estrogen agonist or antagonists. Menopausal vasomotor symptoms,
breast cancer, cardiovascular disease, prostate cancer, menopausal symptoms, and
osteoporosis/bone health have all been studied using phytoestrogens as an
additional standard hormone supplemental remedy. The botanical sources,
techniques of identification, classification, side effects, clinical
implications, pharmacological and therapeutic effects of their proposed mode of
action, safety issues, and future directions for phytoestrogens have all been
highlighted in this review.
© 2023 John Wiley & Sons Ltd.
DOI: 10.1002/ptr.7861
39. Nutrients. 2023 May 21;15(10):2402. doi: 10.3390/nu15102402.
Isoflavone Consumption and Risk of Breast Cancer: An Updated Systematic Review

with Meta-Analysis of Observational Studies.
Yang J(1), Shen H(1), Mi M(2), Qin Y(1).
Author information:
(1)Research Center for Nutrition and Food Safety, Institute of Military
Preventive Medicine, Third Military Medical University (Army Medical
University), Chongqing 400038, China.
(2)Chongqing Medical Nutrition Research Center, Chongqing 400038, China.
RATIONALE: Epidemiological studies that focus on the relationship between

dietary isoflavone intake and the risk of breast cancer still lead to
inconsistent conclusions. Herein, we conducted a meta-analysis of the latest
studies to explore this issue.
METHOD: We performed a systematic search using Web of Science, PubMed, and
Embase from inception to August 2021. The robust error meta-regression (REMR)
model and generalized least squares trend (GLST) model were used to establish
dose-response relationships between isoflavones and breast cancer risk.
RESULTS: Seven cohort studies and 17 case-control studies were included in the
meta-analysis, and the summary OR for breast cancer was 0.71 (95% CI 0.72-0.81)
when comparing the highest to the lowest isoflavone intake. A subgroup analysis
further showed that neither menopausal status nor ER status has a significant
influence on the association between isoflavone intake and breast cancer risk,
while the isoflavone intake doses and study design does. When the isoflavones
exposure was less than 10 mg/day, no effects on breast cancer risk were
detected. The inverse association was significant in the case-control studies
but not in the cohort studies. In the dose-response meta-analysis of the cohort
studies, we observed an inverse association between isoflavone intake and breast
cancer: a 10 mg/day increase in isoflavone intake was related to reductions of
6.8% (OR = 0.932, 95% CI 0.90-0.96) and 3.2% (OR = 0.968, 95% CI 0.94-0.99) in
breast cancer risk when using REMR and GLST, respectively. In the dose-response
meta-analysis of the case-control studies, the inverse association for every 10
mg/day isoflavone intake was associated with breast cancer risk reductions by
11.7%.
CONCLUSION: present evidence demonstrated that taking in dietary isoflavone is
helpful in reducing the breast cancer risk.
DOI: 10.3390/nu15102402
PMCID: PMC10224089
40. Cell Mol Biol (Noisy-le-grand). 2023 Jan 31;69(1):36-43. doi:

10.14715/cmb/2022.69.1.7.
Effects of Curcumin and Soy Isoflavones on Genomic Instability of Human Colon

Cells NCM460 and SW620.
Yu C(1), Jianying L(2), Han W(3), Xu W(4), Juan N(5).
Author information:
(1)School of Life Sciences, The Engineering Research Center of Sustainable
Development and Utilization of Biomass Energy, Yunnan Normal University, Kunming
650500, China. xswdxzl@yeah.net.
650500, China. 83469143@qq.com.
650500, China. wanghan9215@163.com.
650500, China. wangxu@fudan.edu.cn.
650500, China. gt_gg30@163.com.
Curcumin (CUR) and soy isoflavones (SIs) are two plant-based polyphenols that
have attracted much attention, because of their extensive anticancer and health
maintenance effects. However, the relevant molecular mechanisms are still
uncertain. Genomic instability (GIN) refers to a combination of gene abnormal
amplification, sequence deletion, ectopic, and other types of gene damage in
cells, and it is one of the main factors causing cells to lose normal
physiological functions. Therefore, we used the cytokinesis-block micronucleus
cytome (CBMN-Cyt) assay as the main research method to analyze the effects of
CUR and SIs on the GIN of human normal colon cells NCM460 and colon cancer cells
SW620. Results show that CUR (12.5 μM) could reduce the apoptosis of NCM460 and
maintain its genomic stability while inhibiting the proliferation of SW620 and
promoting its apoptosis. There was no difference in the promoting effect of GIN
between SW620 and NCM460 using SIs (3.125-50 μM). When the two polyphenols (v/v
= 1/1, 1.5625-6.25 μM) were mixed, they could promote the proliferation and GIN
of the NCM460 and SW620 cells, but we did not find that combining the two
produced a better effect on the cells. In conclusion, CUR has more prominent
health and anticancer effects, and it may become a dietary recommendation for
daily health maintenance and a potential adjuvant drug for cancer treatment.
DOI: 10.14715/cmb/2022.69.1.7
41. Endocr Metab Immune Disord Drug Targets. 2023;23(13):1599-1610. doi:

10.2174/1871530323666230516103420.
Antidiabetic Effects of Genistein: Mechanism of Action.
Abbasi E(1), Khodadadi I(1).
Author information:
(1)Department of Clinical Biochemistry, Hamadan University of Medical Sciences,
Hamadan, Iran.
Diabetes mellitus is a metabolic disease recognized by abnormal glucose level

due to defects in insulin action, insulin secretion, or both. Administration of
soybean and isoflavones are accompanied by a lower risk of diabetes. The present
review analyzed the previous published papers related to genistein. This
isoflavone, which has been used for the prevention of some chronic diseases can
inhibit hepatic glucose production, increase β-cell proliferation, reduce β-cell
apoptosis, and show potential antioxidant and anti-diabetic effects. Therefore,
genistein may be useful in the management of diabetes. The beneficial effects of
this isoflavone on metabolic syndrome, diabetes, cardiovascular disease,
osteoporosis, and cancer have been reported in animal and human studies.
Moreover, genistein reduces hepatic glucose production, normalizes
hyperglycemia, and gut microbiota and exhibits potential anti-oxidative,
anti-apoptotic, and hypolipidemic effects. However, studies on the underlying
mechanisms of the action of genistein are very limited. Therefore, the present
study reviews multifaceted aspects of genistein to reveal a possible
anti-diabetic mechanism of this agent. Genistein by regulating several signaling
pathways can be used for the prevention and management of diabetes.

DOI: 10.2174/1871530323666230516103420
PMID: 37194227
42. Plants (Basel). 2023 Apr 29;12(9):1840. doi: 10.3390/plants12091840.
An In Vitro and In Vivo Assessment of Antitumor Activity of Extracts Derived

from Three Well-Known Plant Species.
Gligor O(1), Clichici S(2), Moldovan R(2), Decea N(2), Vlase AM(1), Fizeșan
I(3), Pop A(3), Virag P(4), Filip GA(2), Vlase L(5), Crișan G(1).
Author information:
(1)Department of Pharmaceutical Botany, Iuliu Hatieganu University of Medicine
and Pharmacy, 8 Victor Babes Street, 400347 Cluj-Napoca, Romania.
(2)Department of Physiology, Iuliu Hatieganu University of Medicine and
Pharmacy, 8 Victor Babes Street, 400347 Cluj-Napoca, Romania.
(3)Department of Toxicology, Faculty of Pharmacy, Iuliu Hatieganu University of
Medicine and Pharmacy, 8 Victor Babes Street, 400347 Cluj-Napoca, Romania.
(4)Department of Radiobiology and Tumor Biology, Oncology Institute "Prof. Dr.
Ion Chiricuță", 34-36 Republicii Street, 400015 Cluj-Napoca, Romania.
(5)Department of Pharmaceutical Technology and Biopharmaceutics, University of
Medicine and Pharmacy, 8 Victor Babes Street, 400347 Cluj-Napoca, Romania.
One of the objectives of this study consists of the assessment of the antitumor
activity of several extracts from three selected plant species: Xanthium
spinosum L., Trifolium pratense L., and Coffea arabica L. and also a comparative
study of this biological activity, with the aim of establishing a superior
herbal extract for antitumor benefits. The phytochemical profile of the extracts
was established by HPLC-MS analysis. Further, the selected extracts were
screened in vitro for their antitumor activity and antioxidant potential on two
cancer cell lines: A549-human lung adenocarcinoma and T47D-KBluc-human breast
carcinoma and on normal cells. One extract per plant was selected for in vivo
assessment of antitumor activity in an Ehrlich ascites mouse model. The extracts
presented high content of antitumor compounds such as caffeoylquinic acids in
the case of X. spinosum L. (7.22 µg/mL-xanthatin, 4.611 µg/mL-4-O-caffeoylquinic
acid) and green coffee beans (10.008 µg/mL-cafestol, 265.507
µg/mL-4-O-caffeoylquinic acid), as well as isoflavones in the case of T.
pratense L. (6806.60 ng/mL-ononin, 102.78 µg/mL-biochanin A). Concerning the in
vitro results, the X. spinosum L. extracts presented the strongest anticancerous
and antioxidant effects. In vivo, ascites cell viability decreased after T.
pratense L. and green coffee bean extracts administration, whereas the oxidative
stress reduction potential was important in tumor samples after T. pratense L.
Cell viability was also decreased after administration of cyclophosphamide
associated with X. spinosum L. and T. pratense L. extracts, respectively. These
results suggested that T. pratense L. or X. spinosum L. extracts in combination
with chemotherapy can induce lipid peroxidation in tumor cells and decrease the
tumor viability especially, T. pratense L. extract.
DOI: 10.3390/plants12091840
PMCID: PMC10180766
PMID: 37176897
43. Nutr Hosp. 2023 Oct 6;40(5):1056-1067. doi: 10.20960/nh.04372.
[Soy beverages and women's health: evidence review and experts opinion].
[Article in Spanish; Abstract available in Spanish from the publisher]
Bailón-Uriza R(1), Ayala-Méndez JA(2), Celis-González C(3), Chávez-Brambila

J(4), Hernández Marín I(5), Maldonado-Alvarado JD(6), Montoya-Cossío J(7),
Molina-Segui F(8), May-Hau A(8), Riobó Serván P(9), Neri-Ruz E(10),
Peralta-Sánchez A(11), Reyes E(12), Rosado-López R(13), Santa Rita-Escamilla
MT(14), Tena Alavez G(15), Laviada Molina H(8).
Author information:
(1)Fundación Clínica Médica Sur.
(2)Servicio de Ginecología y Obstetricia. Medicina Materno-Fetal. Hospital
Médica Sur.
(3)Unidad Médica de Alta Especialidad (UMAE). Hospital de Ginecología y
Obstetricia.
(4)Hospital de Ginecología y Obstetricia "Luis Castelazo Ayala". Instituto
Mexicano del Seguro Social.
(5)Hospital Juárez de México.
(6)Ejercicio profesional privado.
(7)Hospital Henri Dunant.
(8)Escuela de Ciencias de la Salud. Universidad Marista de Mérida.
(9)Servicio de Endocrinología y Nutrición. Hospital Fundación Jiménez Díaz.
(10)Colegio Mexicano de Especialistas en Ginecología y Obstetricia.
(11)Práctica profesional privada.
(12)Departamento de Atención a la Salud. Universidad Autónoma Metropolitana
Unidad Xochimilco.
(13)Centro Médico de las Américas.
(14)Hospital Médica Sur.
(15)Hospital Ángeles del Pedregal.
Soy drinks are an increasingly consumed option within the Western diet. However,
there are concerns about potential endocrine disruptor effects and possible
impact on women's reproductive health. This review evaluates scientific
documents in gynecology and obstetrics under an evidence-based medicine
approach. All methods adhered to PRISMA 2020 declaration guidelines. The
evaluated studies do not support a positive association between soy intake and
early puberty or breast cancer; instead, a protective effect against such
neoplasm was observed. Transplacental passage of soy isoflavones and their
presence in breast milk has been reported without any maternal-fetal
complications nor congenital malformations. Exposure to soy-derived products
appears to have a neutral effect on body weight and bone health. Studies
performed in adults indicate that soy may promote a minimal increase in
thyrotropin (TSH) in subjects with subclinical hypothyroidism. The impact of
soy-based foods on gut microbiota appears favorable, especially when consuming
fermented products. Many of the human studies have been conducted with
isoflavones supplements, isolated or textured soy proteins. Therefore, the
results and conclusions should be interpreted cautiously, as these are not
entirely applicable to commercial soy beverages.
Publisher: Las bebidas vegetales de soja constituyen una alternativa dentro de

la dieta habitual. Sin embargo, existe la preocupación de potenciales efectos en
la salud reproductiva de la mujer por mecanismos de disrupción endócrina. En
esta revisión se evalúan documentos científicos en el área de la Ginecología y
la Obstetricia bajo el tamiz de la medicina basada en la evidencia, respondiendo
preguntas estructuradas. La metodología se apegó a las guías establecidas por la
declaración PRISMA 2020. Los estudios evaluados descartan un riesgo incrementado
de pubertad precoz o cáncer de mama; incluso se aprecia un efecto protector
frente a dicha neoplasia. Se ha reportado el paso transplacentario de
isoflavonas de soja y su presencia en la leche materna, sin que ello implique
una relación con complicaciones materno-fetales o malformaciones congénitas. La
exposición a productos de soja no parece influir sobre el peso corporal y la
salud ósea de la mujer. Los estudios en adultos indican que la soja favorece un
mínimo incremento de tirotropina (TSH) en personas con antecedente de
hipotiroidismo subclínico. El impacto de los alimentos basados en soja sobre la
microbiota intestinal parece ser favorable para su diversidad, particularmente
al consumir productos fermentados. Muchos de los estudios en humanos han sido
realizados con suplementos de isoflavonas o con productos que contienen
proteínas aisladas o texturizadas de soja. Por tanto, los resultados y las
conclusiones deben interpretarse con cautela ya que no son totalmente
extrapolables a las bebidas comerciales de soja.
DOI: 10.20960/nh.04372
44. Nutrients. 2023 Apr 19;15(8):1959. doi: 10.3390/nu15081959.
Soy and Gastrointestinal Health: A Review.
Belobrajdic DP(1), James-Martin G(1), Jones D(1), Tran CD(1).
Author information:
(1)Human Health, Health and Biosecurity, CSIRO, Adelaide, SA 5000, Australia.
Soybean is the most economically important legume globally, providing a major

source of plant protein for millions of people; it offers a high-quality,
cost-competitive and versatile base-protein ingredient for plant-based meat
alternatives. The health benefits of soybean and its constituents have largely
been attributed to the actions of phytoestrogens, which are present at high
levels. Additionally, consumption of soy-based foods may also modulate
gastrointestinal (GI) health, in particular colorectal cancer risk, via effects
on the composition and metabolic activity of the GI microbiome. The aim of this
narrative review was to critically evaluate the emerging evidence from clinical
trials, observational studies and animal trials relating to the effects of
consuming soybeans, soy-based products and the key constituents of soybeans
(isoflavones, soy proteins and oligosaccharides) on measures of GI health. Our
review suggests that there are consistent favourable changes in measures of GI
health for some soy foods, such as fermented rather than unfermented soy milk,
and for those individuals with a microbiome that can metabolise equol. However,
as consumption of foods containing soy protein isolates and textured soy
proteins increases, further clinical evidence is needed to understand whether
these foods elicit similar or additional functional effects on GI health.
DOI: 10.3390/nu15081959
PMCID: PMC10144768
Soy Isoflavones Induce Cell Death by Copper-Mediated Mechanism: Understanding

Its Anticancer Properties.
Farhan M(1), El Oirdi M(1), Aatif M(2), Nahvi I(1), Muteeb G(3), Alam MW(4).
Author information:
(1)Department of Basic Sciences, Preparatory Year Deanship, King Faisal
University, Al Ahsa 31982, Saudi Arabia.
(2)Department of Public Health, College of Applied Medical Sciences, King Faisal
(3)Department of Nursing, College of Applied Medical Sciences, King Faisal
(4)Department of Physics, College of Science, King Faisal University, Al Ahsa
Cancer incidence varies around the globe, implying a relationship between food
and cancer risk. Plant polyphenols are a class of secondary metabolites that
have recently attracted attention as possible anticancer agents. The subclass of
polyphenols, known as isoflavones, includes genistein and daidzein, which are
present in soybeans and are regarded as potent chemopreventive agents. According
to epidemiological studies, those who eat soy have a lower risk of developing
certain cancers. Several mechanisms for the anticancer effects of isoflavones
have been proposed, but none are conclusive. We show that isoflavones suppress
prostate cancer cell growth by mobilizing endogenous copper. The copper-specific
chelator neocuproine decreases the apoptotic potential of isoflavones, whereas
the iron and zinc chelators desferroxamine mesylate and histidine do not,
confirming the role of copper. Reactive oxygen species (ROS) scavengers reduce
isoflavone-induced apoptosis in these cells, implying that ROS are cell death
effectors. Our research also clearly shows that isoflavones interfere with the
expression of the two copper transporter genes, CTR1 and ATP7A, in cancerous
cells. Copper levels are widely known to be significantly raised in all
malignancies, and we confirm that isoflavones can target endogenous copper,
causing prooxidant signaling and, eventually, cell death. These results
highlight the importance of copper dynamics within cancer cells and provide new
insight into the potential of isoflavones as cancer-fighting nutraceuticals.
PMCID: PMC10095714
Effects on Serum Hormone Concentrations after a Dietary Phytoestrogen

Intervention in Patients with Prostate Cancer: A Randomized Controlled Trial.
Ahlin R(1), Nørskov NP(2), Nybacka S(3), Landberg R(4), Skokic V(1)(5)(6),
Stranne J(7)(8), Josefsson A(9)(10)(11), Steineck G(1), Hedelin M(1)(12).
Author information:
(1)Department of Oncology, Division of Clinical Cancer Epidemiology, Institute
of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 40530
Gothenburg, Sweden.
(2)Department of Animal and Veterinary Sciences, Aarhus University, AU-Foulum,
8830 Tjele, Denmark.
(3)Department of Molecular and Clinical Medicine, Institute of Medicine,
Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden.
(4)Department of Life Sciences, Division of Food and Nutrition Science, Chalmers
University of Technology, 41296 Gothenburg, Sweden.
(5)Department of Molecular Medicine and Surgery, Karolinska Institute, 17176
Stockholm, Sweden.
(6)Department of Pelvic Cancer, Karolinska University Hospital, 17176 Stockholm,
Sweden.
(7)Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy,
University of Gothenburg, 40530 Gothenburg, Sweden.
(8)Region Västra Götaland, Department of Urology, Sahlgrenska University
Hospital, 41345 Gothenburg, Sweden.
(9)Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical
Sciences, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg,
Sweden.
(10)Wallenberg Center for Molecular Medicine, Umeå University, 90187 Umeå,
Sweden.
(11)Department of Urology and Andrology, Institute of Surgery and Perioperative
Sciences, Umeå University, 90187 Umeå, Sweden.
(12)Regional Cancer Center West, Sahlgrenska University Hospital, Region Västra
Götaland, 41345 Gothenburg, Sweden.
Phytoestrogens have been suggested to have an anti-proliferative role in

prostate cancer, potentially by acting through estrogen receptor beta (ERβ) and
modulating several hormones. We primarily aimed to investigate the effect of a
phytoestrogen intervention on hormone concentrations in blood depending on the
ERβ genotype. Patients with low and intermediate-risk prostate cancer, scheduled
for radical prostatectomy, were randomized to an intervention group provided
with soybeans and flaxseeds (∼200 mg phytoestrogens/d) added to their diet until
their surgery, or a control group that was not provided with any food items.
Both groups received official dietary recommendations. Blood samples were
collected at baseline and endpoint and blood concentrations of different
hormones and phytoestrogens were analyzed. The phytoestrogen-rich diet did not
affect serum concentrations of testosterone, insulin-like growth factor 1, or
sex hormone-binding globulin (SHBG). However, we found a trend of decreased risk
of increased serum concentration of estradiol in the intervention group compared
to the control group but only in a specific genotype of ERβ (p = 0.058). In
conclusion, a high daily intake of phytoestrogen-rich foods has no major effect
on hormone concentrations but may lower the concentration of estradiol in
patients with prostate cancer with a specific genetic upset of ERβ.
DOI: 10.3390/nu15071792
PMCID: PMC10097251

interpretation of data; in the writing of the manuscript; or in the decision to
47. Front Oncol. 2023 Mar 1;12:800562. doi: 10.3389/fonc.2022.800562. eCollection

2022.
The role of isoflavones in augmenting the effects of radiotherapy.
Ivashkevich A(1)(2).
Author information:
(1)Faculty of Engineering and Information Sciences, University of Wollongong,
Wollongong, NSW, Australia.
(2)Noxopharm, Gordon, NSW, Australia.
Cancer is one of the major health problems and the second cause of death
worldwide behind heart disease. The traditional soy diet containing isoflavones,
consumed by the Asian population in China and Japan has been identified as a
protective factor from hormone-related cancers. Over the years the research
focus has shifted from emphasizing the preventive effect of isoflavones from
cancer initiation and promotion to their efficacy against established tumors
along with chemo- and radiopotentiating effects. Studies performed in mouse
models and results of clinical trials emphasize that genistein or a mixture of
isoflavones, containing in traditional soy diet, could be utilized to both
potentiate the response of cancer cells to radiotherapy and reduce
radiation-induced toxicity in normal tissues. Currently ongoing clinical
research explores a potential of another significant isoflavone, idronoxil, also
known as phenoxodiol, as radiation enhancing agent. In the light of the recent
clinical findings, this article reviews the accumulated evidence which support
the clinically desirable interactions of soy isoflavones with radiation therapy
resulting in improved tumor treatment. This review discusses important aspects
of the development of isoflavones as anticancer agents, and mechanisms
potentially relevant to their activity in combination with radiation therapy of
cancer. It gives a critical overview of studies characterizing isoflavone
targets such as topoisomerases, ENOX2/PMET, tyrosine kinases and ER receptor
signaling, and cellular effects on the cell cycle, DNA damage, cell death, and
immune responses.
Copyright © 2023 Ivashkevich.
DOI: 10.3389/fonc.2022.800562
PMCID: PMC10016616
PMID: 36936272
Conflict of interest statement: AI is/was employed by Noxopharm Limited.
48. Chemphyschem. 2023 May 16;24(10):e202300056. doi: 10.1002/cphc.202300056. Epub

2023 Mar 2.
Exploring Glycosylated Soy Isoflavones Affinities toward G-tetrads as Studied by

Survival Yield Method.
Stężycka O(1), Frańska M(1), Beszterda-Buszczak M(2).
Author information:
(1)Institute of Chemistry and Technical Electrochemistry, Poznań University of
Technology, Berdychowo 4, 60-965, Poznań, Poland.
(2)Poznań University of Life Sciences, Department of Food Biochemistry and
Analysis, Mazowiecka 48, 60-623, Poznań, Poland.
Taking soy-based food supplements for menopausal symptoms by women may reduce
the risk of cancer. Therefore, the interaction between nucleic acids (or their
constituents) and ingredients of the supplements, e. g., isoflavone glucosides,
on the molecular level, has been of interest with respect to cancer therapy. In
this work, the interaction between isoflavone glucosides and G-tetrads, namely
[4G+Na]+ ions (G stands for guanosine or deoxyguanosine), were analyzed by using
electrospray ionization-collision induced dissociation-mass spectrometry
(ESI-CID-MS) and survival yields method. The strength of isoflavone
glucosides-[4G+Na]+ interaction in the gas phase was determined from Ecom50 -
the energy required to fragment 50 % of selected precursor ions.
Glycitin-[4G+Na]+ interaction was found to be the strongest, and the interaction
between isoflavone glucosides and guanosine tetrad was established to be
stronger than that between isoflavone glucosides and deoxyguanosine tetrad.
© 2023 Wiley-VCH GmbH.
DOI: 10.1002/cphc.202300056
49. Cells. 2023 Feb 12;12(4):593. doi: 10.3390/cells12040593.
Evaluation of Possible Neobavaisoflavone Chemosensitizing Properties towards

Doxorubicin and Etoposide in SW1783 Anaplastic Astrocytoma Cells.
Maszczyk M(1), Banach K(1), Rok J(1), Rzepka Z(1), Beberok A(1), Wrześniok D(1).
Author information:
(1)Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences in
Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland.
Flavonoids exert many beneficial properties, such as anticancer activity. They

were found to have chemopreventive effects hindering carcinogenesis, and also
being able to affect processes important for cancer cell pathophysiology
inhibiting its growth or promoting cell death. There are also reports on the
chemosensitizing properties of flavonoids, which indicate that they could be
used as a support of anticancer therapy. It gives promise for a novel
therapeutic approach in tumors characterized by ineffective treatment, such as
high-grade gliomas. The research was conducted on the in vitro culture of human
SW1783 anaplastic astrocytoma cells incubated with neobavaisoflavone (NEO),
doxorubicin, etoposide, and their combinations with NEO. The analyses involved
the WST-1 cell viability assay and image cytometry techniques including cell
count assay, Annexin V assay, the evaluation of mitochondrial membrane
potential, and the cell-cycle phase distribution. We found that NEO affects the
activity of doxorubicin and etoposide by reducing the viability of SW1783 cells.
The combination of NEO and etoposide caused an increase in the apoptotic and low
mitochondrial membrane potential subpopulations of SW1783 cells. Changes in the
cell cycle were observed in all combined treatments. These findings indicate a
potential chemosensitizing effect exerted by NEO.
DOI: 10.3390/cells12040593
PMCID: PMC9953891
50. Antioxidants (Basel). 2023 Feb 3;12(2):368. doi: 10.3390/antiox12020368.
The Role of Isoflavones in the Prevention of Breast Cancer and Prostate Cancer.
Pejčić T(1)(2), Zeković M(3), Bumbaširević U(1)(2), Kalaba M(4), Vovk I(5),
Bensa M(6), Popović L(7)(8), Tešić Ž(9).
Author information:
(1)Faculty of Medicine, University of Belgrade, dr Subotića 8, 11000 Belgrade,
Serbia.
(2)Clinic of Urology, University Clinical Center of Serbia, Pasterova 2, 11000
Belgrade, Serbia.
(3)Centre of Research Excellence in Nutrition and Metabolism, Institute for
Medical Research, National Institute of Republic of Serbia, University of
Belgrade, Tadeusa Koscuska 1, 11000 Belgrade, Serbia.
(4)Institute of General and Physical Chemistry, Studentski trg 12-16, 11158
Belgrade, Serbia.
(5)Laboratory for Food Chemistry, National Institute of Chemistry, Hajdrihova
19, 1000 Ljubljana, Slovenia.
(6)Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, 1000
Ljubljana, Slovenia.
(7)Department of Medical Oncology, Oncology Institute of Vojvodina, Put Doktora
Goldmana 4, 21204 Sremska Kamenica, Serbia.
(8)Faculty of Medicine Novi Sad, University of Novi Sad, Hajduk Veljkova 3,
21000 Novi Sad, Serbia.
(9)Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11158
Belgrade, Serbia.
This narrative review summarizes epidemiological studies on breast cancer and

prostate cancer with an overview of their global incidence distribution to
investigate the relationship between these diseases and diet. The biological
properties, mechanisms of action, and available data supporting the potential
role of isoflavones in the prevention of breast cancer and prostate cancer are
discussed. Studies evaluating the effects of isoflavones in tissue cultures of
normal and malignant breast and prostate cells, as well as the current body of
research regarding the effects of isoflavones attained through multiple
modifications of cellular molecular signaling pathways and control of oxidative
stress, are summarized. Furthermore, this review compiles literature sources
reporting on the following: (1) levels of estrogen in breast and prostate
tissue; (2) levels of isoflavones in the normal and malignant tissue of these
organs in European and Asian populations; (3) average concentrations of
isoflavones in the secretion of these organs (milk and semen). Finally,
particular emphasis is placed on studies investigating the effect of isoflavones
on tissues via estrogen receptors (ER).
DOI: 10.3390/antiox12020368
PMCID: PMC9952119
PMID: 36829927
51. Exp Dermatol. 2023 Jun;32(6):722-730. doi: 10.1111/exd.14777. Epub 2023 Mar 8.
Nutraceutical strategies for alleviation of UVB phototoxicity.
McCarty MF(1), Benzvi C(2), Vojdani A(3), Lerner A(2)(4).
Author information:
(1)Catalytic Longevity Foundation, San Diego, California, USA.
(2)Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune
Diseases, Tel Hashomer, Israel.
(3)Immunosciences Lab., Inc., Los Angeles, California, USA.
(4)Ariel University, Ariel, Israel.
Ultraviolet B exposure to keratinocytes promotes carcinogenesis by inducing

pyrimidine dimer lesions in DNA, suppressing the nucleotide excision repair
mechanism required to fix them, inhibiting the apoptosis required for the
elimination of initiated cells, and driving cellular proliferation. Certain
nutraceuticals - most prominently spirulina, soy isoflavones, long-chain omega-3
fatty acids, the green tea catechin epigallocatechin gallate (EGCG) and
Polypodium leucotomos extract - have been shown to oppose photocarcinogenesis,
as well as sunburn and photoaging, in UVB-exposed hairless mice. It is proposed
that spirulina provides protection in this regard via phycocyanobilin-mediated
inhibition of Nox1-dependent NADPH oxidase; that soy isoflavones do so by
opposing NF-κB transcriptional activity via oestrogen receptor-beta; that the
benefit of eicosapentaenoic acid reflects decreased production of prostaglandin
E2; and that EGCG counters UVB-mediated phototoxicity via inhibition of the
epidermal growth factor receptor. The prospects for practical nutraceutical
down-regulation of photocarcinogenesis, sunburn, and photoaging appear
favourable.
© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.
DOI: 10.1111/exd.14777
52. Food Nutr Res. 2023 Jan 31;67. doi: 10.29219/fnr.v67.9024. eCollection 2023.
Inhibition of castration-resistant prostate cancer growth by genistein through

suppression of AKR1C3.
Yu X(1), Yan J(2), Li Y(3), Cheng J(2), Zheng L(2), Fu T(2), Zhu Y(2).
Author information:
(1)School of Medicine and Nursing, Chengdu University, Chengdu, China.
(2)School of Public Health, Chengdu Medical College, Chengdu, China.
(3)National Institute for Occupational Health and Poison Control, Chinese Center
for Disease Control and Prevention, Beijing, China.
BACKGROUND: Prostate cancer is the second leading cause of cancer-related death

among males in America. The patients' survival time is significantly reduced
after prostate cancer develops into castration-resistant prostate cancer (CRPC).
It has been reported that AKR1C3 is involved in this progression, and that its
abnormal expression is directly correlated with the degree of CRPC malignancy.
Genistein is one of the active components of soy isoflavones, and many studies
have suggested that it has a better inhibitory effect on CRPC.
OBJECTIVE: This study aimed to investigate the antitumor effect of genistein on
CRPC and the potential mechanism of action.
DESIGN: A xenograft tumor mouse model established with 22RV1 cells was divided
into the experimental group and the control group, and the former was given 100
mg/kg.bw/day of genistein, with 22RV1, VCaP, and RWPE-1 cells cultured in a
hormone-free serum environment and treated with different concentrations of
genistein (0, 12.5, 25, 50, and 100 μmol/L) for 48 h. Molecular docking was used
to elucidate the molecular interactions between genistein and AKR1C3.
RESULTS: Genistein inhibits CRPC cell proliferation and in vivo tumorigenesis.
The western blot analysis confirmed that the genistein significantly inhibited
prostate-specific antigen production in a dose-dependent manner. In further
results, AKR1C3 expression was decreased in both the xenograft tumor tissues and
the CRPC cell lines following genistein gavage feeding compared to the control
group, with the reduction becoming more obvious as the concentration of
genistein was increased. When the genistein was combined with AKR1C3 small
interfering ribonucleic acid and an AKR1C3 inhibitor (ASP-9521), the inhibitory
effect on the AKR1C3 was more pronounced. In addition, the molecular docking
results suggested that the genistein had a strong affinity with the AKR1C3, and
that it could be a promising AKR1C3 inhibitor.
CONCLUSION: Genistein inhibits the progression of CRPC via the suppression of
AKR1C3.
© 2023 Xiaoping Yu et al.
DOI: 10.29219/fnr.v67.9024
PMCID: PMC9899042
PMID: 36794010
Conflict of interest statement: The authors declare that there are no conflicts
of interest. The authors have not received any funding or benefits from industry
or elsewhere to conduct this study.
53. Am J Clin Nutr. 2023 Jan;117(1):130-140. doi: 10.1016/j.ajcnut.2022.10.019.

Epub
2022 Dec 20.
Dietary phytoestrogens and total and cause-specific mortality: results from 2

prospective cohort studies.
Chen Z(1), Qian F(2), Hu Y(3), Voortman T(4), Li Y(3), Rimm EB(5), Sun Q(6).
Author information:
(1)Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston,
MA, USA; Department of Epidemiology, Erasmus MC, University Medical Center
Rotterdam, Rotterdam, the Netherlands.
MA, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA, USA.
MA, USA.
(4)Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam,
Rotterdam, the Netherlands; Division of Human Nutrition and Health, Wageningen
University & Research, Wageningen, the Netherlands.
MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard
T.H. Chan School of Public Health, Boston, MA, USA.
MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard
T.H. Chan School of Public Health, Boston, MA, USA; Joslin Diabetes Center,
Boston, Massachusetts, USA. Electronic address: qisun@hsph.harvard.edu.
BACKGROUND: Evidence regarding dietary phytoestrogens in relation to mortality

remains limited.
OBJECTIVES: The objective of the study is to examine the associations of intake
of isoflavones, lignans, and coumarins with total and cause-specific mortality
in US males and females.
METHODS: We followed 75,981 females in the Nurses' Health Study (1984-2018) and
44,001 males in the Health Professionals Follow-up Study (1986-2018), who were
free of cardiovascular disease (CVD), diabetes, or cancer at baseline. Their
diet was repeatedly assessed using validated food frequency questionnaires every
2-4 y. Associations with mortality were assessed using time-dependent Cox models
with adjustments for demographics, dietary and lifestyle factors, and medical
history.
RESULTS: During 3,427,156 person-years of follow-up, we documented 50,734
deaths, including 12,492 CVD deaths, 13,726 cancer deaths, and 24,516 other
non-CVD and noncancer deaths. After multivariable adjustment, the higher total
phytoestrogen intake was associated with lower risk of total CVD and other
non-CVD and noncancer mortality: comparing extreme quintiles, the pooled HRs
(95% CIs) were 0.89 (0.87, 0.92), 0.90 (0.85, 0.96), and 0.86 (0.82, 0.90),
respectively. We did not find a significant association with cancer mortality
[0.97 (0.92, 1.03)]. For individual phytoestrogens in relation to total
mortality, the pooled HRs (95% CIs) comparing extreme quintiles were 0.90 (0.87,
0.92) for isoflavones, 0.93 (0.90, 0.96) for lignans, and 0.93 (0.90, 0.95) for
coumarins. Individual phytoestrogens were also significantly associated with
lower risk of CVD mortality and other types of mortality. Primary food sources
of phytoestrogens, including tofu, soy milk, whole grains, tea, and flaxseed,
were also inversely associated with total mortality.
CONCLUSIONS: A higher intake of total phytoestrogens, including isoflavones,
lignans, and coumarins, and foods rich in these compounds was associated with
lower risk of total and certain cause-specific mortality in generally healthy US
adults. These data suggest that these phytochemicals and their dietary sources
may be integrated into an overall healthy diet to achieve a longer life span.
Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1016/j.ajcnut.2022.10.019
PMCID: PMC10196593
54. Prev Med. 2023 Mar;168:107446. doi: 10.1016/j.ypmed.2023.107446. Epub 2023 Feb
10.
Maternal lifestyle and nutrient intakes during pregnancy and exclusive

breastfeeding in relation to risk factors for breast cancer: The Japan
Environment and Children's Study.
Minami Y(1), Miyashita M(2), Ishida T(2), Fujita M(3), Hamada H(4), Saito M(4),
Arima T(5), Yaegashi N(4); Japan Environment and Children's Study Group.
Author information:
(1)Department of Health Sciences, Tohoku University Graduate School of Medicine,
2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Center for Preventive
Medicine, Osaki Citizen Hospital, 2-3-15 Senjuji-machi, Furukawa, Osaki, Miyagi
989-6174, Japan. Electronic address: adym@med.tohoku.ac.jp.
(2)Department of Breast and Endocrine Surgical Oncology, Tohoku University
Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575,
Japan.
(3)Department of Nursing, Yamagata University Graduate School of Medical
Science, 2-2-2 Iida-Nishi, Yamagata-shi, Yamagata 990-9585, Japan.
(4)Department of Obstetrics and Gynecology, Tohoku University Graduate School of
Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
(5)Department of Informative Genetics, Environment and Genome Research Center,
Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku,
Sendai, Miyagi 980-8575, Japan.
Breastfeeding has many benefits for infant growth and maternal health, such as
reducing breast cancer risk. However, data on maternal factors influencing
breastfeeding are insufficient. To clarify the associations between maternal
lifestyle and diet during pregnancy and exclusive breastfeeding (EBF), we
conducted a prospective study of pregnant women within the framework of the
Japan Environment and Children's Study (a nationwide birth cohort study). Of
97,413 pregnant women recruited between January 2011 and March 2014, 27,775 with
a singleton first live birth whose dietary data during pregnancy and lactation
data were complete were eligible. Using logistic regression, we evaluated the
associations between lifestyle factors including smoking and prepregnancy body
mass index and intake of nutrients (macronutrients, isoflavones, and dietary
fiber), some of which are known risk factors of breast cancer, and EBF for one
month postpartum (initiation of EBF). To investigate the associations of these
factors with EBF for 6 months (continuation of EBF), 9582 women who had
successfully completed one-month EBF were further followed up. Smoking and
prepregnancy obesity were inversely associated with the initiation and
continuation of EBF. Intakes of protein, fat, isoflavone, and dietary fiber were
positively associated (p trend = 0.0001 for dietary fiber), and carbohydrate
intake was inversely associated with the initiation of EBF. Dietary fiber intake
was also associated with the continuation of EBF (p trend = 0.048). These
findings indicate that maternal lifestyles during pregnancy affect lactation
performance. Lifestyle adjustments during pregnancy may have favorable effects
on maternal and children's health through successful breastfeeding.
Copyright © 2023 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ypmed.2023.107446

have no conflicts of interest to declare.
55. Plants (Basel). 2023 Jan 26;12(3):564. doi: 10.3390/plants12030564.
Effects of Isoflavone-Rich NADES Extract of Pueraria lobata Roots and

Astaxanthin-Rich Phaffia rhodozyma Extract on Prostate Carcinogenesis in Rats.
Semenov AL(1), Tyndyk ML(1), Von JD(1), Ermakova ED(1)(2), Dorofeeva AA(1),
Tumanyan IA(1), Radetskaya EA(1), Yurova MN(1), Zherebker A(3), Gorbunov AY(4),
Fedoros EI(1), Panchenko AV(1), Anisimov VN(1).
Author information:
(1)N.N. Petrov National Medical Research Center of Oncology, 197758 Saint
Petersburg, Russia.
(2)Institute of Biomedical Systems and Biotechnology, Peter the Great St.
Petersburg Polytechnic University, 195251 Saint Petersburg, Russia.
(3)Skolkovo Institute of Science and Technology, 121205 Moscow, Russia.
(4)Research Institute of Hygiene, Occupational Pathology and Human Ecology,
188663 Saint Petersburg, Russia.
Prostate cancer (PCa) is one of the most common male malignancies worldwide. In
the current study, we evaluated the effects of a natural deep eutectic solvent
(NADES) extract of Pueraria lobata roots rich in isoflavones (ISF) and Phaffia
rhodozyma extract rich in astaxanthin (ASX) on an N-methyl-N-nitrosourea plus
testosterone PCa model in rats. ISF consisted of puerarin, daidzein, genistein,
formononetin and other polyphenols, while ASX contained lipids and unsaturated
species in addition to astaxanthin. Extracts were administered through a whole
promotion period in daily doses shown by our group to successfully inhibit
benign prostate hyperplasia (BPH) development - 200 mg/kg for ISF and 25 mg/kg
for ASX. Though a similar effect was found for BPH processes accompanying PCa
induction, the incidence of PCa in animals treated with placebo, ISF and ASX was
37%, 37% and 41%, respectively, showing no chemopreventive activity of ISF and
ASX. PCa development was associated with a decrease in the Ca/Mg ratio in serum
and an increase in prostate tissue. Treatment with both extracts produced a
normalization effect on Ca balance in serum, which, combined with a decrease in
the prostatic index, suggests some positive health effects of ISF and ASX.
DOI: 10.3390/plants12030564
PMCID: PMC9920470
PMID: 36771648
Conflict of interest statement: The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of
the manuscript, or in the decision to publish the results.
56. Nutrients. 2023 Jan 9;15(2):317. doi: 10.3390/nu15020317.
Phytoestrogens and Health Effects.
Canivenc-Lavier MC(1), Bennetau-Pelissero C(2).
Author information:
(1)Centre des Sciences du Goût et de l'Alimentation, CNRS, INRAE, Institut Agro,
Université de Bourgogne, Franche-Comté, 21000 Dijon, France.
(2)Arna U1212 Inserm, 5320 CNRS, UB Université de Bordeaux, 33000 Bordeaux,
France.
Phytoestrogens are literally estrogenic substances of plant origin. Although

these substances are useful for plants in many aspects, their estrogenic
properties are essentially relevant to their predators. As such, phytoestrogens
can be considered to be substances potentially dedicated to plant-predator
interaction. Therefore, it is not surprising to note that the word phytoestrogen
comes from the early discovery of estrogenic effects in grazing animals and
humans. Here, several compounds whose activities have been discovered at
nutritional concentrations in animals and humans are examined. The substances
analyzed belong to several chemical families, i.e., the flavanones, the
coumestans, the resorcylic acid lactones, the isoflavones, and the
enterolignans. Following their definition and the evocation of their role in
plants, their metabolic transformations and bioavailabilities are discussed. A
point is then made regarding their health effects, which can either be
beneficial or adverse depending on the subject studied, the sex, the age, and
the physiological status. Toxicological information is given based on official
data. The effects are first presented in humans. Animal models are evoked when
no data are available in humans. The effects are presented with a constant
reference to doses and plausible exposure.
DOI: 10.3390/nu15020317
PMCID: PMC9864699
A Randomized Controlled Trial of Soy Isoflavone Intake on Mammographic Density

among Malaysian Women.
Rajaram N(1), Yap B(1), Eriksson M(2), Mariapun S(1), Tan LM(1), Sa'at H(3), Ho
ELM(4), Taib NAM(3), Khor GL(5), Yip CH(1)(6), Ho WK(1)(7), Hall P(2)(8), Teo
SH(1)(3).
Author information:
(1)Cancer Research Malaysia, Subang Jaya 47500, Malaysia.
(2)Karolinska Institutet, 171 77 Stockholm, Sweden.
(3)University of Malaya Cancer Research Institute, Kuala Lumpur 50603, Malaysia.
(4)ParkCity Medical Centre, Ramsay Sime Darby Healthcare, Kuala Lumpur 52200,
Malaysia.
(5)Department of Nutrition and Dietetics, Universiti Putra Malaysia, Serdang
43400, Malaysia.
(6)Subang Jaya Medical Centre, Ramsay Sime Darby Healthcare, Subang Jaya 47500,
Malaysia.
(7)Department of Applied Mathematics, Faculty of Engineering, University of
Nottingham Malaysia, Semenyih 43500, Malaysia.
(8)Södersjukhuset, 118 83 Stockholm, Sweden.
Soy intake is associated with lower breast cancer risk in observational studies
concerning Asian women, however, no randomized controlled trials (RCT) have been
conducted among Asian women living in Asia. This three-armed RCT assessed the
effects of one-year soy isoflavone (ISF) intervention on mammographic density
(MD) change among healthy peri- and postmenopausal Malaysian women. This study
was registered at ClinicalTrials.gov (NCT03686098). Participants were randomized
into the 100 mg/day ISF Supplement, 50 mg/day ISF Diet, or control arm, and
assessed for change in absolute and relative dense area from digital mammograms
conducted at enrolment and after 12 months, compared over time across study arms
using Kruskal-Wallis tests. Out of 118 women enrolled, 91 women completed the
intervention, while 27 women (23%) were lost in follow up. The ISF supplement
arm participants observed a larger decline in dense area (−1.3 cm2), compared to
the ISF diet (−0.5 cm2) and control arm (−0.8 cm2), though it was not
statistically significant (p = 0.48). Notably, among women enrolled within 5
years of menopause; dense area declined by 6 cm2 in the ISF supplement arm,
compared to <1.0 cm2 in the control arm (p = 0.13). This RCT demonstrates a
possible causal association between soy ISF intake and MD, a biomarker of breast
cancer risk, among Asian women around the time of menopause, but these findings
require confirmation in a larger trial.
DOI: 10.3390/nu15020299
PMCID: PMC9862880
58. Int J Mol Sci. 2022 Dec 23;24(1):247. doi: 10.3390/ijms24010247.
Molecular Mechanisms of Flavonoids against Tumor Gamma-Herpesviruses and Their

Correlated Cancers-A Focus on EBV and KSHV Life Cycles and Carcinogenesis.
Hassan STS(1), Šudomová M(2).
Author information:
(1)Department of Applied Ecology, Faculty of Environmental Sciences, Czech
University of Life Sciences Prague, Kamýcká 129, 165 00 Prague, Czech Republic.
(2)Museum of Literature in Moravia, Klášter 1, 664 61 Rajhrad, Czech Republic.
Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are

cancer-causing viruses that belong to human gamma-herpesviruses. They are DNA
viruses known to establish lifelong infections in humans, with the ability to
develop various types of cancer. Drug resistance remains the main barrier to
achieving effective therapies for viral infections and cancer. Thus, new
medications with dual antiviral and anticancer actions are highly needed.
Flavonoids are secondary metabolites biosynthesized by plants with diverse
therapeutic effects on human health. In this review, we feature the potential
role of flavonoids (flavones, protoflavones, isoflavones, flavanones, flavonols,
dihydroflavonols, catechins, chalcones, anthocyanins, and other flavonoid-type
compounds) in controlling gamma-herpesvirus-associated cancers by blocking EBV
and KSHV infections and inhibiting the formation and growth of the correlated
tumors, such as nasopharyngeal carcinoma, Burkitt's lymphoma, gastric cancer,
extranodal NK/T-cell lymphoma, squamous cell carcinoma, Kaposi sarcoma, and
primary effusion lymphoma. The underlying mechanisms via targeting EBV and KSHV
life cycles and carcinogenesis are highlighted. Moreover, the effective
concentrations or doses are emphasized.
DOI: 10.3390/ijms24010247
PMCID: PMC9820319
59. Phytomedicine. 2023 Jan;109:154550. doi: 10.1016/j.phymed.2022.154550. Epub

2022
Nov 15.
Crystal structure of tubulin-barbigerone complex enables rational design of

potent anticancer agents with isoflavone skeleton.
Yan W(1), Li Y(1), Liu Y(1), Wen Y(1), Pei H(1), Yang J(2), Chen L(3).
Author information:
(1)Laboratory of Natural and targeted small molecule drugs, State Key Laboratory
of Biotherapy and Cancer Center, National Clinical Research Center for
Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation
Center of Biotherapy, Chengdu 610041, China.
Center of Biotherapy, Chengdu 610041, China. Electronic address:
yjh1988@scu.edu.cn.
Center of Biotherapy, Chengdu 610041, China. Electronic address:
chenlijuan125@163.com.
BACKGROUND: Isoflavones possess many biological activities, including

anti-inflammatory and anticancer effects. Microtubules (composed of αβ-tubulin
heterodimers) are described as one possible cellular target of some of these
isoflavones. However, the binding of tubulin to isoflavones has not been
extensively studied, and until now, no crystal structure of the
tubulin-isoflavone complex has been solved, and details of the
isoflavone-tubulin interaction remain elusive.
PURPOSE: Barbigerone is an isoflavone mainly found in the genus Milletti, such
as the edible leguminous plant Millettia ferruginea, with anticancer activity.
This study aims to confirm the cellular target of barbigerone and to study its
anticancer mechanism.
METHOD: Surface plasmon resonance assays and X-ray crystallography were used to
study the interaction of barbigerone with tubulin protein. Immunofluorescence,
in-cell and in vitro tubulin polymerization assays were employed to investigate
the mechanism. MTT assays, cell clonal formation assays, wound healing assays,
tube formation assays and H460 xenograft models were conducted to evaluate the
in vitro and in vivo anticancer activities of barbigerone and one of its
derivatives, 0412.
RESULTS: Here, we found that barbigerone binds to tubulin to inhibit tubulin
polymerization. Moreover, we solved the X-ray crystal structure of the
tubulin-barbigerone complex at 2.33 Å resolution, which unambiguously determined
the orientation and position of barbigerone in the colchicine-binding site.
Illuminated by the X-ray data, we synthetized and obtained a more active
isoflavone, 0412. Both barbigerone and 0412 inhibit cancer cell proliferation,
tubulin polymerization, migration of HeLa cells and capillary-like tube
formation of HUVECs, induce G2/M phase cell cycle arrest and apoptosis, and
exhibit anticancer activity in an H460 xenograft model.
CONCLUSION: In all, through biochemical and X-ray crystal structure results, we
identified tubulin as the cellular target of one isoflavone, barbigerone, and
proved that the tubulin-barbigerone complex plays a guiding role in obtaining a
more active compound, 0412. These studies provide a crucial research basis for
the development of isoflavones as anticancer candidate compounds.
Copyright © 2022 Elsevier GmbH. All rights reserved.
DOI: 10.1016/j.phymed.2022.154550
Conflict of interest statement: Declaration of Competing Interest There are no

competing interests to declare for all authors.
Chickpea and Lupin Sprouts, Stimulated by Different LED Lights, As Novel

Examples of Isoflavones-Rich Functional Food, and Their Impact on Breast and
Prostate Cells.
Galanty A(1), Zagrodzki P(2), Miret M(3), Paśko P(2).
Author information:
(1)Department of Pharmacognosy, Faculty of Pharmacy, Medical College
Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland.
(2)Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Medical
College Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland.
(3)Faculty of Pharmacy and Food Science, University of Barcelona, Campus
Diagonal, Av. de Joan XXIII 27-31, 08028 Barcelona, Spain.
Among all legumes sprouts' active compounds, isoflavones seem to be the most
important; nevertheless, their high content is not always associated with
beneficial effects. These compounds may prevent or stimulate hormone-dependent
cancers due to their estrogen-like activity. Different LED light quality can
change the synthesis of active compounds and significantly influence the
biological activity of the sprouts. This study aimed to evaluate the effects of
LED light (red, blue, green, yellow), as well as total darkness, and natural
light conditions (as reference), on isoflavones content, determined by
HPLC-UV-VIS, during 10 days of harvesting of chickpea and lupin sprouts. Due to
the ambiguous estrogenic potential of isoflavones, the impact of these sprouts
on normal and cancer prostate and breast cells was evaluated. Yellow LED light
resulted in the highest sum of isoflavones in chickpea sprouts (up to 1 g/100 g
dw), while for green LED light, the isoflavones sum was the lowest. The exact
opposite effect was noted for lupin sprouts, with the predominance of green over
the yellow LED light. The examined sprouts were of high safety to non-neoplastic
breast and prostate cells, with interesting cytotoxic effects on breast MCF7 and
prostate DU145 cancer cells. No clear relationship was observed between the
activity and isoflavones content.
PMCID: PMC9781113
Health Effects of Soy Isoflavones and Green Tea Catechins on Cancer and
Cardiovascular Diseases Based on Urinary Biomarker Levels.
Ohishi T(1)(2), Miyoshi N(3), Mori M(4)(5)(6), Sagara M(6)(7), Yamori Y(6).
Author information:
(1)Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry
Research Foundation, Shizuoka 410-0301, Japan.
(2)Laboratory of Oncology, Institute of Microbial Chemistry (BIKAKEN), Microbial
Chemistry Research Foundation, Tokyo 141-0021, Japan.
(3)Graduate School of Integrated Pharmaceutical and Nutritional Sciences,
University of Shizuoka, Shizuoka 422-8526, Japan.
(4)Department of Health Management, School of Health Studies, Tokai University,
Kanagawa 259-1292, Japan.
(5)NPO World Health Frontier Institute, Nishinomiya 663-8143, Japan.
(6)Institute for World Health Development, Mukogawa Women's University,
Nishinomiya 663-8143, Japan.
(7)Disease Model Cooperative Research Association, Kyoto 606-0805, Japan.
Plant polyphenols have various health effects. Genistein, which is abundant in

soybeans, and epigallocatechin-3-gallate, which is abundant in green tea, are
major flavonoids, a subclass group of polyphenols. Several epidemiological
studies have shown that these flavonoids have beneficial effects against cancer
and cardiovascular diseases. However, other studies did not show such effects.
Several confounding factors, including recall bias, are related to these
inconsistent findings, and the determination of metabolites in the urine may be
useful in reducing the number of confounding factors. Equipment, which can be
used by research participants to collect samples from a portion of voided urine
within 24 h without the help of medical workers, has been developed for
epidemiological investigations. Previous studies, in which flavonoid metabolites
in these urine samples were measured, revealed that soy intake was correlated
with a reduced risk of certain types of cancer and cardiovascular diseases
worldwide. Although soybeans and green tea consumption may have protective
effects against cancer and cardiovascular diseases, further clinical studies
that consider different confounding factors are required to provide evidence for
the actual impact of dietary flavonoids on human diseases, including cancer and
cardiovascular diseases. One possible mechanism involved is discussed in
relation to the downregulation of reactive oxygen species and the upregulation
of 5'-adenosine monophosphate-activated protein kinase elicited by these
flavonoids.
PMCID: PMC9781513
62. Cancers (Basel). 2022 Dec 14;14(24):6163. doi: 10.3390/cancers14246163.
Phytoestrogens and Breast Cancer: Should French Recommendations Evolve?
Mauny A(1), Faure S(1)(2), Derbré S(1)(3).
Author information:
(1)Department Pharmacy, Faculty of Health Sciences, University of Angers,
F-49000 Angers, France.
(2)Inserm, CNRS, MINT, SFR ICAT, University of Angers, F-49000 Angers, France.
(3)SONAS, SFR QUASAV, University of Angers, F-49000 Angers, France.
Breast cancer (BC) occurs less frequently in Asia, where there is high soy
consumption. It has been hypothesized that soy isoflavones could be protective
against BC recurrence and mortality. At the same time, health organizations in
several countries have differing recommendations for soy consumption (soy foods
or dietary supplements) in BC survivors. The objective of this review is to
analyze the literature and to determine whether it is justified to advise
avoiding soy in dietary supplements and/or food in women with a history of BC.
We conducted a systematic literature search with the Medline/Pubmed and Web of
Science databases. Only prospective cohort studies published since 2009 were
retained. The endpoint of studies was BC recurrence and/or mortality, and the
association with soy isoflavone intake was specifically targeted. Seven studies
were included. None of these studies found statistically significant adverse
effects of soy consumption on BC recurrence or mortality (specific or
all-cause). Overall, only one study was not able to find beneficial effects of
soy intake on BC patients. The other studies concluded that there were positive
associations but in very variable ways. Two studies found a decrease in BC
recurrence associated with a higher isoflavone intake only for post-menopausal
women. The other four studies concluded that there were positive associations
regardless of menopausal status. Four studies showed better results on women
with hormonal-sensitive cancer and/or patients receiving hormonal treatment.
Only one found a stronger association for patients with ER-negative BC. No
adverse effects of soy isoflavones on BC mortality/recurrence were found. Soy
isoflavones may exert beneficial effects. These results coincide with other
recent works and suggest that soy isoflavone intake is safe for BC survivors.
Thus, these data no longer seem to coincide with the French recommendations,
which could then be brought to evolve. However, in order to confirm the current
results, larger studies are needed.
DOI: 10.3390/cancers14246163
PMCID: PMC9776930
PMID: 36551648
63. Sci Bull (Beijing). 2022 Apr 30;67(8):813-824. doi: 10.1016/j.scib.2022.01.011.

Epub 2022 Jan 17.
Long-term exposure to genistein inhibits the proliferation of gallbladder cancer

by downregulating the MCM complex.
Geng Y(1), Chen S(2), Yang Y(3), Miao H(3), Li X(3), Li G(3), Ma J(4), Zhang
T(5), Ren T(6), Li Y(3), Li L(3), Liu L(3), Yang J(3), Wang Z(3), Zou L(3), Liu
K(3), Li Y(3), Yan S(3), Cui X(3), Sun X(3), Yang B(3), Zhang L(3), Han X(6),
Wang C(7), Chen B(7), Yue X(8), Liang W(5), Ren J(5), Jia J(9), Gu J(10), Li
Z(11), Zhao T(12), Wang P(13), Wei D(2), Qiu S(3), Xiang D(3), Xu X(3), Chen
W(3), He M(3), Yang L(3), Wang H(3), Chen T(3), Hua R(3), Wang X(3), Wu X(6),
Gong W(2), Wang G(7), Li M(14), Zhang W(15), Shao R(16), Wu W(17), Liu Y(18).
Author information:
(1)Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai 200127, China; Department of General
Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of
Medicine, Shanghai 200092, China.
(2)Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao
Tong University School of Medicine, Shanghai 200092, China; Shanghai Key
Laboratory of Biliary Tract Disease Research, Shanghai 200127, China.
(3)Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai 200127, China.
(4)Department of Hepatobiliary Surgery, Affiliated Hospital of Jining Medical
University, Jining 272129, China.
(5)Department of General Surgery, The Affiliated Hospital of Inner Mongolia
Medical University, Hohhot 010050, China.
Tong University School of Medicine, Shanghai 200092, China.
(7)Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of
Jilin University, Changchun 130021, China.
(8)Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People's
Hospital, Zhengzhou 450003, China.
(9)Department of Surgical Oncology, First Affiliated Hospital of Bengbu Medical
College, Bengbu 233099, China.
(10)Department of General Surgery, Changshu No. 1 People's Hospital Affiliated
to Soochow University, Changshu 215500, China.
(11)Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital,
Shanghai 200433, China.
(12)Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute
and Hospital, Tianjin 300060, China.
(13)Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong
University, Nantong 226001, China.
Laboratory of Biliary Tract Disease Research, Shanghai 200127, China. Electronic
address: limaolan6@163.com.
(15)State Key Laboratory of Oncogene and Related Genes and Department of
Epidemiology, Shanghai Cancer Institute, Shanghai 200127, China. Electronic
address: zhangwei2004@126.com.
(16)Department of Pharmacology, Shanghai Jiao Tong University School of
Medicine, Shanghai 200025, China. Electronic address: rongshao@sjtu.edu.cn.
(17)Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao
Tong University School of Medicine, Shanghai 200127, China. Electronic address:
wuwenguang08@126.com.
(18)Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao
Laboratory of Biliary Tract Disease Research, Shanghai 200127, China; State Key
Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai
200127, China. Electronic address: laoniulyb@shsmu.edu.cn.
Soy isoflavones are natural tyrosine kinase inhibitors closely associated with
decreased morbidity and mortality of various tumors. The activation of tyrosine
kinases such as ERBB2 is the mechanism by which cholecystitis transforms into
gallbladder cancer (GBC), therefore, it is important to investigate the
relationship between long-term exposure to soy isoflavones and the occurrence
and progression of GBC. This case-control study (n = 85 pairs) found that the
high level of plasma soy isoflavone-genistein (GEN) was associated with a lower
risk of gallbladder cancer (≥326.00 ng/mL compared to ≤19.30 ng/mL, crude odds
ratio 0.15, 95% CI 0.04-0.59; P for trend = 0.016), and that the level of GEN
exposure negatively correlated with Ki67 expression in GBC tissue (n = 85).
Consistent with these results, the proliferation of GBC cells was inhibited in
the long-term exposure models of GEN in vitro and in vivo. The long-term
exposure to GEN reduced the tyrosine kinase activity of ERBB2 and impaired the
function of the PTK6-AKT-GSK3β axis, leading to downregulation of the MCM
complex in GBC cells. In summary, long-term exposure to GEN associated with soy
products intake might play a certain role in preventing GBC and even inhibiting
the proliferation of GBC cells.
Copyright © 2022 Science China Press. Published by Elsevier B.V. All rights
reserved.
DOI: 10.1016/j.scib.2022.01.011
Conflict of interest statement: Conflict of interest The authors declare that

they have no conflict of interest.
64. Clin Nutr ESPEN. 2022 Dec;52:158-168. doi: 10.1016/j.clnesp.2022.10.007. Epub

2022 Oct 26.
Soy isoflavones decrease fibroglandular breast tissue measured by magnetic

resonance imaging in premenopausal women: A 2-year randomized double-blind
placebo controlled clinical trial.
Lu LW(1), Chen NW(2), Brunder DG(3), Nayeem F(4), Nagamani M(5), Nishino TK(6),
Anderson KE(7), Khamapirad T(8).
Author information:
(1)Department of Preventive Medicine and Community Health, The University of
Texas Medical Branch, Galveston, TX 77555-1109, USA. Electronic address:
llu@utmb.edu.
naiwei.chen@health.missouri.edu.
(3)Academic Computing, The University of Texas Medical Branch, Galveston, TX
77555-1035, USA.
Texas Medical Branch, Galveston, TX 77555-1109, USA.
(5)Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston,
TX 77555, USA.
(6)Radiology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
Electronic address: tnishino@mdanderson.org.
kanderso@utmb.edu.
(8)Radiology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
BACKGROUND & AIMS: Populations consuming soy have reduced risk for breast
cancer, but the mechanisms are unclear. We tested the hypothesis that soy
isoflavones, which have ovarian hormone-like effects, can reduce fibroglandular
breast tissue (FGBT, 'breast density'), a strong risk marker for breast cancer.
METHODS: Premenopausal women (age 30-42 years) were randomized to consume
isoflavones (136.6 mg as aglycone equivalents, n = 99) or placebo (n = 98) for 5
days per week up to 2 years, and changes in breast composition measured by
magnetic resonance imaging at baseline and yearly intervals were compared after
square root transformation using linear mixed effects regression models.
RESULTS: By intention-to-treat analyses (n = 194), regression coefficients (β
estimates) of the interaction of time and isoflavone treatment were -0.238
(P = 0.06) and -0.258 (P < 0.05) before and after BMI adjustment, respectively
for FGBT, 0.620 (P < 0.05) and 0.248 (P = 0.160), respectively for fatty breast
tissue (FBT), and -0.155 (P < 0.05) and -0.107 (P < 0.05), respectively for FGBT
as percent of total breast (FGBT%). β Estimates for interaction of treatment
with serum calcium were -2.705 for FBT, and 0.588 for FGBT% (P < 0.05, before
but not after BMI adjustment). BMI (not transformed) was related to the
interaction of treatment with time (β = 0.298) or with calcium (β = -1.248)
(P < 0.05). Urinary excretion of isoflavones in adherent subjects (n = 135)
significantly predicted these changes in breast composition. Based on the
modeling results, after an average of 1.2, 2.2 and 3.3 years of supplementation,
a mean decrease of FGBT by 5.3, 12.1, and 19.3 cc, respectively, and a mean
decrease of FGBT% by 1.37, 2.43, and 3.50%, respectively, were estimated for
isoflavone exposure compared to placebo treatment. Subjects with maximum
isoflavone excretion were estimated to have 38 cc less FGBT (or ∼3.13% less
FGBT%) than subjects without isoflavone excretion. Decrease in FGBT and FGBT%
was more precise with daidzein than genistein.
CONCLUSIONS: Soy isoflavones can induce a time- and concentration-dependent
decrease in FGBT, a biomarker for breast cancer risk, in premenopausal women,
and moderate effects of calcium on BMI and breast fat, suggesting a beneficial
effect of soy consumption.
TRIAL REGISTRATION: www.
CLINICALTRIALS: gov identifier: NCT00204490.
TRIAL REGISTRATION: www.
CLINICALTRIALS: gov identifier: NCT00204490.
Copyright © 2022 European Society for Clinical Nutrition and Metabolism.
Published by Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.clnesp.2022.10.007
PMCID: PMC9825101
Conflict of interest statement: Financial and non-financial competing interests:

Fatima Nayeem, Nai-Wei Chen, Donald G. Brunder, Manubai Nagamani, Thomas K.
Nishino, Karl E. Anderson, Tuenchit Khamapirad, and Lee Jane Lu declare that
65. Mol Immunol. 2023 Jan;153:126-134. doi: 10.1016/j.molimm.2022.11.019. Epub 2022

Dec 7.
Anti-inflammation of hydrogenated isoflavones in LPS-stimulated RAW264.7 cells

via inhibition of NF-κB and MAPK signaling pathways.
Li K(1), Hu W(1), Yang Y(1), Wen H(1), Li W(2), Wang B(3).
Author information:
(1)School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023,
PR China.
PR China. Electronic address: liwaii@njucm.edu.cn.
PR China. Electronic address: bwang@njucm.edu.cn.
Isoflavones are commonly found in diets, such as soybean and clover. Their
anti-inflammatory effects are due to the inhibition of the transcriptional
regulation of NF-κB. Hydrogenated isoflavones are metabolites of isoflavones
with higher bioavailability, however, there have been few studies on their
anti-inflammatory effects. In this work, by using the LPS-stimulated RAW264.7
cell model, we investigated the anti-inflammatory effect and the underlying
mechanism of hydrogenated isoflavones. Hydrogenated isoflavones reduced the
production of LPS-stimulated pro-inflammatory mediators and enzymes, including
TNF-α, IL-6, NO, iNOS and COX-2. The level of ROS was also diminished in
LPS-stimulated RAW264.7 cells. Further mechanistic studies showcase that
hydrogenated isoflavones block NF-κB and MAPK pathways via attenuation of p65
nuclear translocation and JNK, ERK, and p38 phosphorylation, respectively. In
addition, we found that hydrogenated isoflavones display anti-proliferation
effect in human colon cancer cells with wild-type p53. Together, hydrogenated
isoflavones could be used as an adjuvant for the treatment of inflammation and
cancer.
DOI: 10.1016/j.molimm.2022.11.019

paper.
66. J Prev Med Hyg. 2022 Oct 17;63(2 Suppl 3):E21-E27. doi:
10.15167/2421-4248/jpmh2022.63.2S3.2743. eCollection 2022 Jun.
Foods of the Mediterranean diet: citrus, cucumber and grape.
Naureen Z(1), Dhuli K(2), Donato K(1), Aquilanti B(3), Velluti V(3), Matera
G(3), Iaconelli A(3), Bertelli M(1)(2)(4).
Author information:
(1)MAGI Euregio, Bolzano, Italy.
(2)MAGI's Lab, Rovereto (TN), Italy.
(3)UOSD Medicina Bariatrica, Fondazione Policlinico Agostino Gemelli IRCCS,
Rome, Italy.
(4)MAGISNAT, Peachtree Corners (GA), USA.
Fruit and vegetables are excellent sources of health-promoting bioactive

compounds and nutraceuticals. Regular consumption of fruit and vegetables helps
prevent the onset and progression of many non-communicable diseases. The
Mediterranean diet envisages consumption of healthy vegetables and fruit on a
daily basis for maximum health benefits. Traditional use envisages
vegetable-based and fruit-based diets, and many studies scientifically proved
the beneficial effects of Mediterranean vegetables and fruits. Rich in bioactive
phytochemicals, citrus, cucumbers and grapes have antioxidant,
anti-inflammatory, antimicrobial, cardioprotective, anti-ageing and anti-cancer
properties. Studies indicate that intake of citrus, cucumbers and grapes reduces
hypertension, hyperlipidemia, skin problems and infections and improves the
health of the cardiovascular and nervous systems. These beneficial effects are
mediated by several bioactive molecules present in Mediterranean diet vegetables
and fruits, such as citrus, cucumbers and grapes. Indeed, they contains
flavones, isoflavones, tannins, polyphenols and many beneficial natural
molecules. This review focuses on the bioactive ingredients in citrus fruit,
cucumbers and grapes, all components of the Mediterranean diet, and their health
effects. A deep understanding of Mediterranean diet's components, as well as
clinical trials to test natural molecules beneficial effects, will permit to
further explore the therapeutic potential of the Mediterranean diet in several
pathological conditions.
©2022 Pacini Editore SRL, Pisa, Italy.
DOI: 10.15167/2421-4248/jpmh2022.63.2S3.2743
PMCID: PMC9710412
67. Br J Nutr. 2023 Sep 14;130(5):750-764. doi: 10.1017/S0007114522003877. Epub

2022
Dec 7.
Association of urinary phytoestrogens with hormone-related cancers and cancer

biomarkers: NHANES 1999-2010.
Liu F(1), Peng Y(1), Qiao Y(1), Wang P(1), Si C(1), Wang X(1), Zhang M(2), Song
F(1).
Author information:
(1)Department of Epidemiology and Biostatistics, Key Laboratory of Molecular
Cancer Epidemiology, Tianjin, Key Laboratory of Breast Cancer Prevention and
Therapy, Tianjin Medical University, Ministry of Education, National Clinical
Research Center for Cancer, Tianjin's Clinical Research Center for Cancer,
Tianjin Medical University Cancer Institute and Hospital, Tianjin300060,
People's Republic of China.
(2)Comprehensive Management Department of Occupational Health, Shenzhen
Prevention and Treatment Center for Occupational Diseases, Shenzhen518020,
Phytoestrogens may have potential effects on hormone-related cancers (HRC) and

cancer biomarkers, but the findings have been inconsistent so far. Participants
from the National Health and Nutrition Examination Survey 1999-2010 with
information on the levels of urinary phytoestrogens, serum cancer biomarkers and
cancer history were included. Sampling-weighted logistic regression models
examined the association between urinary phytoestrogens concentrations
(creatinine-standardised and log-transformed) and HRC, followed by stratified
analyses by race/ethnicity, age and menopausal status for different gender.
Correlation analyses between phytoestrogens and cancer biomarkers were
performed. Of the total 8844 participants, there were 373 with HRC. We observed
total isoflavone and enterodiol excretion were positively associated with HRC,
especially in non-Hispanic white female subpopulations (Ptrend < 0·05). Similar
association also existed in the total isoflavones and enterodiol levels with
breast cancer. Whereas the highest concentration of total isoflavones was
significantly linked to a reduced prevalence of HRC (OR = 0·40, 95 % CI: 0·19,
0·84) in white males and of prostate cancer (OR = 0·40, 95 % CI: 0·18, 0·86).
Among twenty-four participants with HRC, urinary equol concentration was
positively correlated with CA15.3. Also, an inverse correlation of total
prostate-specific antigens (PSA) and positive correlation of the PSA ratio with
urinary enterolactone were detected in thirteen prostate cancer patients. Our
findings indicated that higher concentrations of total isoflavones and
enterodiol were positively associated with HRC. Urinary certain phytoestrogen
excretion may affect serum cancer biomarker levels in cancer patients. But
further prospective studies are needed to provide stronger evidence.
DOI: 10.1017/S0007114522003877
68. Rev Assoc Med Bras (1992). 2022 Nov 28;68(11):1487-1489. doi:
10.1590/1806-9282.2EDITR11. eCollection 2022.
May isoflavones prevent breast cancer risk?
Carbonel AAF(1)(2), Simões RS(3), Sasso GDS(1), Vieira RR(1), Lima PA(4), Simões
MJ(1)(3), Soares Júnior JM(3).
Author information:
(1)Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of
Morphology and Genetics - São Paulo (SP), Brazil.
(2)Universidade Federal de São Paulo, Escola Paulista de Medicina, Department of
Gynecology - São Paulo (SP), Brazil.
(3)Universidade de São Paulo, School of Medicine, Hospital das Clínicas,
Department of Gynecology and Obstetrics - São Paulo (SP), Brazil.
(4)Department of Medicine, Queen's Cardio-Pulmonary Unit - Kingston (ON),
Canada.
DOI: 10.1590/1806-9282.2EDITR11
PMCID: PMC9720771
Conflict of interest statement: Conflicts of interest: the authors declare there

is no conflicts of interest.
69. J Vet Pharmacol Ther. 2023 May;46(3):185-194. doi: 10.1111/jvp.13106. Epub 2022
Nov 30.
Modulation of monepantel secretion into milk by soy isoflavones.
Gunes Y(1), Okyar A(2), Krajcsi P(3), Fekete Z(4), Ustuner O(1).
Author information:
(1)Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine,
Istanbul University-Cerrahpasa, Istanbul, Turkey.
(2)Department of Pharmacology, Faculty of Pharmacy, Istanbul University,
Istanbul, Turkey.
(3)Solvo Biotechnology, A Charles River Company, Faculty of Health Sciences,
Semmelweis University, Budapest, Hungary.
(4)Solvo Biotechnology, Szeged, Hungary.
Monepantel (MNP), a novel anthelmintic drug from amino-acetonitrile derivatives,

is a substrate for breast cancer resistance protein (BCRP). BCRP-mediated milk
secretion of drugs can be altered by isoflavones. In this study, we aimed to
show how soy isoflavones and BCRP inhibitors genistein (GEN) and daidzein (DAI)
can modulate the secretion of MNP into milk. Moreover, we observed that the
expression of BCRP in the lactating mammary gland of sheep was significantly
higher than in non-lactating sheep using Western blot analysis. These properties
of MNP and MNPSO2 (monepantel sulfone, the major active metabolite of MNP),
identified as a BCRP substrate in determining the interaction with BCRP, were
examined by vesicular transport (VT) inhibition assays. In pharmacokinetic
studies, we demonstrated the transport of MNP into milk in three experimental
groups: G1 fed standard forage; G2 fed soy-enriched forage; G3 fed standard
forage paired with orally administered exogenous GEN and DAI. The concentrations
of MNP and MNPSO2 were analyzed by high-performance liquid chromatography.
Compared to the control group (3.27 ± 1.13 vs. 5.46 ± 2.23), the AUC (0-840 h)
milk/plasma ratio decreased by 40% in the soy-enriched diet group. The
concentrations of GEN and DAI were determined using liquid chromatography
coupled with tandem mass spectrometry in soy. A VT inhibition assay was
conducted to determine the IC50 values for MNP and MNPSO2 as BCRP inhibitors.
This study showed that milk excretion of a BCRP substrate, such as monepantel,
can be diminished by the presence of isoflavones in the diet.
DOI: 10.1111/jvp.13106
70. Arch Pharm Res. 2022 Dec;45(12):849-864. doi: 10.1007/s12272-022-01417-y. Epub

2022 Nov 28.
Effects of phytoestrogens on reproductive organ health.
Swathi Krishna S(1), Kuriakose BB(2), Lakshmi PK(3)(4).
Author information:
(1)Department of Pharmacy Practice, Amrita School of Pharmacy, AIMS Health
Science Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India.
(2)Department of Basic Medical Sciences, College of Applied Medical Sciences,
King Khalid University, Khamis Mushayt, Kingdom of Saudi Arabia.
(3)Department of Pharmacy Practice, Amrita School of Pharmacy, AIMS Health
Science Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India.
lakshmipk@pharmacy.aims.amrita.edu.
(4)Department of Pharmacognosy, Amrita School of Pharmacy, AIMS Health Science
Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682 041, India.
lakshmipk@pharmacy.aims.amrita.edu.
Phytoestrogens are non-steroidal, polyphenolic compounds that are derived from

plants and have biological properties similar to those of human estrogens. Their
bioactivity, which is based on the core ring system, is caused by their
structural resemblance to estrogen. Flavonoids, coumestans, lignans, and
stilbenes are the four major categories into which they can be divided. They are
structurally and functionally related to ovarian and placental estrogens, which
are essential in female reproductive processes. Phytoestrogens are present in
numerous dietary supplements and find application in hormone replacement therapy
as an alternative to synthetic hormones. In addition, they provide health
benefits for osteoporosis, heart disease, breast cancer, and prostate cancer.
There is a growing interest in using phytoestrogen as preventative medicine in
the form of nutraceuticals. This literature provides comprehensive information
about the types, sources, and biological actions of phytoestrogens in the
reproductive system.
© 2022. The Pharmaceutical Society of Korea.
DOI: 10.1007/s12272-022-01417-y
71. Int J Mol Sci. 2022 Nov 17;23(22):14228. doi: 10.3390/ijms232214228.
Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with

Isoflavones Reveals a Chemical Scaffold with Potential to Develop New
Therapeutics for the Treatment of Cancer.
Pugh L(1), Pancholi A(1), Purat PC(1), Agudo-Alvarez S(2), Benito-Arenas R(2),
Bastida A(2), Bolanos-Garcia VM(1).
Author information:
(1)Department of Biological and Medical Sciences, Faculty of Health and Life
Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UK.
(2)Departamento de Química Bio-Orgánica, IQOG, c/Juan de la Cierva 3, E-28006
Madrid, Spain.
The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the

Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system
of higher organisms that monitors the proper bipolar attachment of all
chromosomes to the mitotic spindle during cell division. Defects in the
catalytic activity and the transcription regulation of Mps1 are associated with
genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and
frameshift mutations have been reported in a wide range of types of cancer of
different tissue origin. Due to these features, Mps1 arises as one promising
drug target for cancer therapy. In this contribution, we developed a
computational biology approach to study the dynamics of human Mps1 kinase
interaction with isoflavones, a class of natural flavonoids, and compared their
predicted mode of binding with that observed in the crystal structure of Mps1 in
complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We
concluded that isoflavones define a chemical scaffold that can be used to
develop new Mps1 inhibitors for the treatment of cancer associated with Mps1
amplification and aberrant chromosome segregation. In a broader context, the
present report illustrates how modern chemoinformatics approaches can accelerate
drug development in oncology.
DOI: 10.3390/ijms232214228
PMCID: PMC9692432
72. Iran Biomed J. 2022 Nov 1;26(5):380-8. doi: 10.52547/ibj.3711.
Evaluation of Anticancer and Cytotoxic Effects of Genistein on PC3 Prostate Cell

Line under Three-Dimensional Culture Medium.
Khamesi SM(1), Salehi Barough M(1), Zargan J(2), Shayesteh M(3), Banaee N(1),
Haji Noormohammadi A(2), Keshavarz Alikhani H(2), Mousavi M(2).
Author information:
(1)Department of Medical Radiation Engineering, Central Tehran Branch, Islamic
Azad University, Tehran, Iran.
(2)Department of Biology, Faculty of Basic Science, Imam Hossein University,
Tehran, Iran.
(3)Department of Physics, Imam Hossein University, Tehran, Iran.
BACKGROUND: Prostate cancer is a major cause of disease and mortality among men.
Genistein (GNT) is an isoflavone found naturally in legumes. Isoflavones, a
subset of phytoestrogens, are structurally similar to mammalian estrogens. This
study aimed to evaluate the anticancer and cytotoxic effects of GNT on PC3 cell
line under three dimensional (3D) culture medium.
METHODS: The 3D culture was created by encapsulating the PC3 cells in alginate
hydrogel. MTT assay, neutral red uptake, comet assay, and cytochrome C assay
were used to study the anticancer and cytotoxic effects of GNT at 120, 240, and
480 μM concentrations. Also, nitric oxide (NO), catalase, and glutathione assay
levels were determined to evaluate the effect of GNT on the cellular stress. The
culture medium was used as the negative control.
RESULTS: GNT reduced the production of cellular NO and increased the production
of catalase and glutathione, confirming the results of the NO test. Evaluation
of the toxicity effect of GNT at the concentrations of 120, 240, and 480 μM
using comet assay showed that this chemical agent induces apoptosis in PC3 cells
in a dose-dependent manner. As the level of cytochrome C in PC3 cells treated
with different concentrations of GNT was not significantly different from that
of the control, GNT could induce apoptosis in PC3 cells through the
non-mitochondrial pathway.
CONCLUSION: The findings of this study disclose that the anticancer effect of
GNT on PC3 cells under 3D culture conditions could increase the effectiveness of
treatment. Also, the cell survival rate is dependent on GNT concentration.
DOI: 10.52547/ibj.3711
PMCID: PMC9763873
Conflict of interest statement: The authors declare that they have no conflicts
interest.
73. Food Funct. 2022 Nov 28;13(23):12268-12277. doi: 10.1039/d2fo02106d.
Soy isoflavone ameliorated the alterations in circulating adipokines and

microRNAs of mice fed a high-fat diet.
Lee HB(1), Lee AY(1), Jang Y(1), Kwon YH(1)(2).
Author information:
(1)Department of Food and Nutrition, Seoul National University, Seoul, Korea.
hye0414@snu.ac.kr.
(2)Research Institute of Human Ecology, Seoul National University, Seoul, Korea.
Soy protein, containing isoflavones and bioactive peptides, is shown to have

anti-obesity effects, but the main contributor and underlying mechanisms remain
unclear. Recent studies have demonstrated that circulating microRNAs (miRNAs)
act as important mediators in obesity and metabolic processes. In this study, we
investigated whether soy protein components have distinctive effects on
adiposity and circulating miRNA profiles in obese mice. C57BL/6J mice were
divided into 4 groups, and each group was fed with a control, high-fat (HF), HF
with low-isoflavone soy protein (HF/S), or HF with high-isoflavone soy protein
(HF/SI) diet for 16 weeks. In the HF/SI group, changes in the serum adipokine
levels, adipocyte diameter, and the number of crown-like structures (CLS) were
alleviated compared to those of the HF group. In the HF/S group, the number of
CLS was reduced. Decreases in body and adipose tissue weights were not observed
in both HF/S and HF/SI groups. Through microarray analysis of serum miRNAs, we
identified 23 differentially expressed miRNAs (DEMs) among the groups. The
levels of most circulating DEMs were correlated with body weight, serum
biochemical parameters, and adipose tissue histology. Functional analysis of
predicted target genes of DEMs from both HF vs. CON and HF/S vs. CON comparisons
revealed several cancer-related pathways. Only 2 DEMs were identified in the
HF/SI vs. CON comparison. In conclusion, the present study confirmed that soy
isoflavones are the main contributor to the health-beneficial effects of soy
protein in diet-induced obesity. Notably, the extent of serum miRNA
dysregulation coincided with obesity and altered the circulating adipokine
levels. These findings provide additional insights into the role of soy protein
in the regulation of circulating miRNAs in diet-induced obesity. Further work is
required to validate the proposed functions of miRNAs in target tissues.
DOI: 10.1039/d2fo02106d
74. Phytochem Rev. 2023;22(1):275-308. doi: 10.1007/s11101-022-09845-w. Epub 2022

Nov 3.
Millettia isoflavonoids: a comprehensive review of structural diversity,

extraction, isolation, and pharmacological properties.
Desta KT(1)(2), Abd El-Aty AM(3)(4)(5).
Author information:
(1)Department of Applied Chemistry, Adama Science and Technology University,
P.O. Box: 1888, Adama, Ethiopia.
(2)National Agrobiodiversity Center, National Institute of Agricultural
Sciences, Rural Development Administration, Jeonju, 54874 Republic of Korea.
(3)State Key Laboratory of Biobased Material and Green Papermaking, Qilu
University of Technology, Shandong Academy of Sciences, Jinan, 250353 China.
(4)Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University,
Giza, 12211 Egypt.
(5)Department of Medical Pharmacology, Medical Faculty, Ataturk University,
25240 Erzurum, Turkey.
There are approximately 260 known species in the genus Millettia, many of which
are used in traditional medicine to treat human and other animal ailments in
various parts of the world. Being in the Leguminosae (Fabaceae) family,
Millettia species are rich sources of isoflavonoids. In the past three decades
alone, several isoflavonoids originating from Millettia have been isolated, and
their pharmacological activities have been evaluated against major diseases,
such as cancer, inflammation, and diabetes. Despite such extensive research, no
recent and comprehensive review of the phytochemistry and pharmacology of
Millettia isoflavonoids is available. Furthermore, the structural diversity of
isoflavonoids in Millettia species has rarely been reported. In this review, we
comprehensively summarized the structural diversity of Millettia isoflavonoids,
the methods used for their extraction and isolation protocols, and their
pharmacological properties. According to the literature, 154 structurally
diverse isoflavonoids were isolated and reported from the various tissues of
nine well-known Millettia species. Prenylated isoflavonoids and rotenoids were
the most dominant subclasses of isoflavonoids reported. Other subclasses of
reported isoflavonoids include isoflavans, aglycone isoflavones, glycosylated
isoflavones, geranylated isoflavonoids, phenylcoumarins, pterocarpans and
coumaronochromenes. Although some isolated molecules showed promising
pharmacological properties, such as anticancer, anti-inflammatory, estrogenic,
and antibacterial activities, others remained untested. In general, this review
highlights the potential of Millettia isoflavonoids and could improve their
utilization in drug discovery and medicinal use processes.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material
available at 10.1007/s11101-022-09845-w.
© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer
Nature or its licensor (e.g. a society or other partner) holds exclusive rights
to this article under a publishing agreement with the author(s) or other
rightsholder(s); author self-archiving of the accepted manuscript version of
this article is solely governed by the terms of such publishing agreement and
applicable law.
DOI: 10.1007/s11101-022-09845-w
PMCID: PMC9630821
PMID: 36345415
Conflict of interest statement: Conflict of interestThe authors declare they

have no conflicts of interest.
75. Int J Mol Sci. 2022 Oct 15;23(20):12360. doi: 10.3390/ijms232012360.
The Effects of Genistein at Different Concentrations on MCF-7 Breast Cancer

Cells and BJ Dermal Fibroblasts.
Pawlicka MA(1), Zmorzyński S(1), Popek-Marciniec S(1), Filip AA(1).
Author information:
(1)Department of Cancer Genetics with Cytogenetic Laboratory, Medical University
of Lublin, Radziwiłłowska 11 Street, 20-080 Lublin, Poland.
This study aimed to evaluate the safety and potential use of soy isoflavones in
the treatment of skin problems, difficult-to-heal wounds and postoperative scars
in women after the oncological treatment of breast cancer. The effects of
different concentrations of genistein as a representative of soy isoflavonoids
on MCF-7 tumor cells and BJ skin fibroblasts cultured in vitro were assessed.
Genistein affects both healthy dermal BJ fibroblasts and cancerous MCF-7 cells.
The effect of the tested isoflavonoid is closely related to its concentration.
High concentrations of genistein destroy MCF-7 cancer cells, regardless of the
exposure time, with a much greater effect on reducing cancer cell numbers at
longer times (48 h). Lower concentrations of genistein (10 and 20 μM) increase
the abundance of dermal fibroblasts. However, higher concentrations of genistein
(50 μM and higher) are detrimental to fibroblasts at longer exposure times (48
h). Our studies indicate that although genistein shows high potential for use in
the treatment of skin problems, wounds and surgical scars in women during and
after breast cancer treatment, it is not completely safe. Introducing
isoflavonoids to treatment requires further research into their mechanisms of
action at the molecular level, taking into account genetic and immunological
aspects. It is also necessary to conduct research in in vivo models, which will
allow for eliminating adverse side effects of therapy.
DOI: 10.3390/ijms232012360
PMCID: PMC9604460
76. J Midlife Health. 2022 Apr-Jun;13(2):175-184. doi: 10.4103/jmh.jmh_190_21. Epub

2022 Sep 16.
The Impact of Soy Isoflavone Supplementation on the Menopausal Symptoms in

Perimenopausal and Postmenopausal Women.
Khapre S(1), Deshmukh U(2), Jain S(1).
Author information:
(1)Department of Obstetrics and Gynaecology, NKP Salve Institute of Medical
Sciences and Lata Mangeshkar Hospital and Research Centre, Nagpur, Maharashtra,
India.
(2)Dr. Deshmukh Shree Clinic Nursing Home, Nagpur, Maharashtra, India.
INTRODUCTION: Approximately one-third of a woman's life is spent in the

menopausal phase. The unpleasant menopausal symptoms are unacceptable as a part
of routine life. Indications of menopausal hormone therapy (MHT) are for
alleviation of vasomotor symptoms, prevention of osteoporosis, and genitourinary
symptoms associated with menopause. MHT is associated with an increased risk of
breast cancer, cerebrovascular accidents, and coronary heart disease. Soy
isoflavones have been extensively used as an alternative treatment in patients
who cannot take MHT. The evidence of the efficacy of isoflavones in the
literature is equivocal.
AIM: The aim of the study was to evaluate the efficacy of soy isoflavone
supplementation on menopausal symptoms in perimenopausal and postmenopausal
women and to evaluate the effect on blood pressure (BP) and body mass index
(BMI).
MATERIALS AND METHODS: A questionnaire-based prospective observational study was
undertaken involving 39 perimenopausal and 61 postmenopausal women, who were
prescribed 40 mg soy isoflavone supplements twice daily for 12 weeks. Menopause
Rating Scale questionnaire was given to the patients before starting soy
isoflavone therapy and at the end of the treatment; BP and BMI were also noted.
RESULTS: The total score of both the groups was comparable at baseline. Among
perimenopausal and postmenopausal women, the highest score was noted in symptoms
of somatic domain. At the completion of our study, the total scores improved
significantly by 38.6% and 33.3% in perimenopausal and postmenopausal women,
respectively. The greatest improvement was seen in somatic subscale (42.5%) and
psychological subscale (42.5%) and the least in urogenital subscale (16.1%) for
perimenopausal women. For postmenopausal women, the greatest improvement was
seen in psychological subscale (40.0%) and the least in urogenital subscale
(14.2%).
CONCLUSION: Soy isoflavone supplementation is beneficial in both perimenopausal
and postmenopausal women, more so in perimenopausal women. There is no
beneficial effect of soy isoflavone supplementation on lowering systolic BP and
BMI.
Copyright: © 2022 Journal of Mid-life Health.
DOI: 10.4103/jmh.jmh_190_21
PMCID: PMC9583364
PMID: 36276627
Conflict of interest statement: There are no conflicts of interest.
77. J Food Sci Technol. 2022 Oct;59(10):3723-3732. doi: 10.1007/s13197-021-05249-4.

Epub 2021 Aug 23.
Harmful compounds of soy milk: characterization and reduction strategies.
Mollakhalili-Meybodi N(1)(2), Arab M(1), Zare L(1).
Author information:
(1)Department of Food Sciences and Technology, School of Public Health, Shahid
Sadoughi University of Medical Sciences, Yazd, Iran.
(2)Research Center for Food Hygiene and Safety, Shahid Sadoughi University of
Medical Sciences, Yazd, Iran.
Soymilk is a plant based product which is a rich source of nutrients. However,

various harmful compounds including allergens, anti-nutritional factors, and
biogenic amines (BAs) exist in soybeans that may be transferred into soymilk.
These compounds cause difficulties for consumers from mild to severe symptoms.
Soymilk production is considered as a critical step in quantity of harmful
compounds in final product. Common steps in soy milk manufacturing include
soaking, grinding, and heating process. Allergens contents could be decreased by
heating alone or in combination with structural modifiers and fermentation. BAs
could be reduced by optimizing fermentation process and using suitable strains,
especially BAs degradable types. Soaking, grinding and heating of soybeans in
water are considered as effective methods for inactivation of antinutritional
factors. Isoflavones are soy phytochemicals, which potentially leads to breast
cancer in some women, can be converted to less bioavailable forms during
processing. Other treatments such as high hydrostatic pressure and irradiation
are also effective in harmful compounds reduction. Combination of the processes
is more effective in harmful compounds removal. Considering the increasing
trends in soymilk consumption, this review is focused on introduction of harmful
compounds in soymilk and investigating the effects of processing condition on
their concentration.
© Association of Food Scientists & Technologists (India) 2021.
DOI: 10.1007/s13197-021-05249-4
PMCID: PMC9525506
PMID: 36193379
Conflict of interest statement: Conflict of interestThe authors have no conflict

of interest to declare that are relevant to the content of this article.
78. Exp Ther Med. 2022 Sep 19;24(5):676. doi: 10.3892/etm.2022.11612. eCollection
2022 Nov.
Properties of flavonoids in the treatment of bladder cancer (Review).
Lv Y(1), Liu Z(1), Jia H(1), Xiu Y(1), Liu Z(1), Deng L(2).
Author information:
(1)Department of Urology, The First Affiliated Hospital, Harbin Medical
University, Harbin, Heilongjiang 150000, P.R. China.
(2)Department of Ultrasound Medicine, The First Affiliated Hospital of Nanchang
University, Nanchang, Jiangxi 330006, P.R. China.
Given its high recurrence and rapid progress, bladder cancer (BLCA) treatment
has become a major problem for clinicians. BLCA is difficult to control even
with surgical resection and extensive use of chemotherapeutic drugs. The
non-toxicity and ease of accessibility of natural compounds have attracted much
attention in recent years. Flavonoids serve an essential role given their
antioxidant, antibacterial, anticancer and cardiovascular properties. They are
mainly divided into several subclasses; flavones, flavanones, flavonols,
flavanols, anthocyanins isoflavones and chalcones. Over the years, the role of
flavonoids in BLCA has been extensively studied. The present review provided a
comprehensive overview of the classification of flavonoids and substantiate the
role of epithelial-mesenchymal transition, cancer stem cells, angiogenesis,
epigenetic regulation and programmed cell death in BLCA. The present review
emphasized that flavonoids for BLCA treatment are worthy of further study and
anti-BLCA drugs have huge prospects for clinical use.
Copyright: © Lv et al.
DOI: 10.3892/etm.2022.11612
PMCID: PMC9522619
PMID: 36185766
Conflict of interest statement: The authors declare that they have no competing
interests.
79. Phytochemistry. 2022 Dec;204:113440. doi: 10.1016/j.phytochem.2022.113440. Epub

2022 Sep 18.
Rotenoids and isoflavones from the leaf and pod extracts of Millettia
brandisiana Kurz.
Meesakul P(1), Suthiphasilp V(2), Teerapongpisan P(1), Rujanapun N(3),

Chaiyosang B(4), Tontapha S(5), Phukhatmuen P(1), Maneerat T(6), Charoensup
R(7), Duangyod T(7), Patrick BO(8), Andersen RJ(9), Laphookhieo S(10).
Author information:
(1)Center of Chemical Innovation for Sustainability (CIS) and School of Science,
Mae Fah Luang University, Chiang Rai, 57100, Thailand.
Mae Fah Luang University, Chiang Rai, 57100, Thailand; Department of Industrial
Technology and Innovation Management, Faculty of Science and Technology,
Pathumwan Institute of Technology, Bangkok, 10330, Thailand.
(3)Medicinal Plant Innovation Center of Mae Fah, Luang University, Chiang Rai,
57100, Thailand.
(4)Natural Products Research Unit, Department of Chemistry and Center of
Excellence for Innovation in Chemistry, Faculty of Science, Khon Kaen
University, Khon Kaen, 40002, Thailand.
(5)Institute of Nanomaterials Research and Innovation for Energy, Khon Kaen
University, Khon Kaen, 40002, Thailand.
Mae Fah Luang University, Chiang Rai, 57100, Thailand; Medicinal Plant
Innovation Center of Mae Fah, Luang University, Chiang Rai, 57100, Thailand.
(7)Medicinal Plant Innovation Center of Mae Fah, Luang University, Chiang Rai,
57100, Thailand; School of Integrative Medicine, Mae Fah Luang University,
Chiang Rai, 57100, Thailand.
(8)Department of Chemistry, University of British Columbia, 2036 Main Mall,
Vancouver, BC V6T 1Z1, Canada; Department of Earth, Ocean & Atmospheric
Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1,
Canada.
(9)Department of Chemistry, University of British Columbia, 2036 Main Mall,
Vancouver, BC V6T 1Z1, Canada; Department of Earth, Ocean & Atmospheric
Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1,
Canada. Electronic address: raymond.andersen@ubc.ca.
(10)Center of Chemical Innovation for Sustainability (CIS) and School of
Science, Mae Fah Luang University, Chiang Rai, 57100, Thailand; Medicinal Plant
Innovation Center of Mae Fah, Luang University, Chiang Rai, 57100, Thailand.
Electronic address: surat.lap@mfu.ac.th.
Phytochemical investigations of the leaf and pod extracts of Millettia

brandisiana Kurz led to the isolation and identification of four previously
undescribed rotenoids, (-)-(6aS,12aS)-millettiabrandisins A-C and
(-)-(6aS,12aS)-6-deoxyclitoriacetal, two previously undescribed isoflavones,
millettiabrandisins D and E, and 20 known compounds. The structures of
previously undescribed compounds were determined on the basis of NMR and MS
data. The absolute configurations of (-)-(6aS,12aS)-millettiabrandisins A-C were
determined from the comparison of their experimental and calculated ECD spectra.
(-)-(6aR,12aR)-12a-Hydroxy-α-toxicarol was also confirmed by X-ray
crystallographic data. Some isolated compounds were evaluated for their
cytotoxicity against three cancer cell lines, including lung cancer (A549),
colorectal cancer (SW480), and leukemic cells (K562). Of these, α-toxicarol
displayed the best cytotoxicity against lung cancer (A549) and leukemic cells
(K562) with the IC50 values of 104.4 and 67.5 μM, respectively.
6″,6″-Dimethylchromene-[2″,3″:7,8]-flavone showed the highest cytotoxicity
against colorectal cancer (SW480) with an IC50 value of 97.2 μM.
DOI: 10.1016/j.phytochem.2022.113440
PMID: 36130672

paper.
80. Yakugaku Zasshi. 2022;142(9):977-991. doi: 10.1248/yakushi.22-00043.
[Studies on the Isolation and Molecular Mechanisms of Bioactive Phytochemicals].
[Article in Japanese]
Kaneda N(1).
Author information:
(1)Faculty of Pharmacy, Meijo University.
Studies on the isolation and molecular mechanisms of phytochemicals with
anti-tumor or anti-inflammatory properties are important to developing new drugs
for cancer and neurodegenerative disorders such as Alzheimer's disease and
Parkinson's disease. In the course of a study to screen bioactive isoflavones
from Erythrina poeppigiana (Leguminosae), we isolated an isoflavone with potent
apoptosis-inducing activity against human leukemia HL-60 cells. It was
designated erypoegin K. The studies demonstrated an enantiomer, (S)-erypoegin K,
displayed selective cytotoxic activity, was a novel inhibitor of topoisomerase
II, and possessed anti-tumor activity both in vitro and in vivo. We identified
other apoptosis-inducing isoflavones with the ability to inhibit glyoxalase I.
Dimeric acridone alkaloids, carbazole alkaloids, and coumarin and quinoline
derivatives-all obtained mainly from plants in the family Rutaceae-induced
apoptosis of HL-60 cells via the production of reactive oxygen species and
mitochondrial dysfunction. We also identified terpenoid coumarins, carbazole
quinones, rotenoid derivatives, and quinolone alkaloids with anti-inflammatory
activities. These compounds reduced nitric oxide (NO) production from RAW264.7
macrophage cells stimulated with lipopolysaccharides and interferon-γ. Some of
the compounds displayed neuroprotective activity by reducing NO production. This
review primarily describes our recent studies on erypoegin K, and other
compounds with apoptosis-inducing and anti-inflammatory activities.
DOI: 10.1248/yakushi.22-00043
81. Front Nutr. 2022 Aug 11;9:970364. doi: 10.3389/fnut.2022.970364. eCollection

2022.
The health effects of soy: A reference guide for health professionals.
Messina M(1), Duncan A(2), Messina V(3), Lynch H(4), Kiel J(5), Erdman JW Jr(6).
Author information:
(1)Soy Nutrition Institute Global, Washington, DC, United States.
(2)Department of Human Health and Nutritional Sciences, University of Guelph,
Guelph, ON, Canada.
(3)Nutrition Matters, Inc, Pittsfield, MA, United States.
(4)Kinesiology Department, Point Loma Nazarene University, San Diego, CA, United
States.
(5)Scientific and Clinical Affairs, Medifast Inc., Baltimore, MD, United States.
(6)Division of Nutritional Sciences and Beckman Institute, Department of Food
Science and Human Nutrition, University of Illinois at Urbana/Champaign, Urbana,
IL, United States.
Soy is a hotly debated and widely discussed topic in the field of nutrition.
However, health practitioners may be ill-equipped to counsel clients and
patients about the use of soyfoods because of the enormous, and often
contradictory, amount of research that has been published over the past 30
years. As interest in plant-based diets increases, there will be increased
pressure for practitioners to gain a working knowledge of this area. The purpose
of this review is to provide concise literature summaries (400-500 words) along
with a short perspective on the current state of knowledge of a wide range of
topics related to soy, from the cholesterol-lowering effects of soy protein to
the impact of isoflavones on breast cancer risk. In addition to the literature
summaries, general background information on soyfoods, soy protein, and
isoflavones is provided. This analysis can serve as a tool for health
professionals to be used when discussing soyfoods with their clients and
patients.
Copyright © 2022 Messina, Duncan, Messina, Lynch, Kiel and Erdman.
DOI: 10.3389/fnut.2022.970364
PMCID: PMC9410752
PMID: 36034914
Conflict of interest statement: MM was employed by the Soy Nutrition Institute

Global, an organization that receives funding from the United Soybean Board
(USB) and from industry members who are involved in the manufacture and/or sale
of soyfoods and/or soybean components. JK was employed by Medifast Inc., a
nutrition and weight-management company based in Baltimore, Maryland, that uses
soy protein in many of its products. JE and AD are scientific advisors to the
Soy Nutrition Institute Global. VM is married to MM, and employed by Nutrition
Matters, which receives no funding from the soy industry. The remaining author
declares that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of
interest.
82. Bioorg Chem. 2022 Nov;128:106101. doi: 10.1016/j.bioorg.2022.106101. Epub 2022

Aug 17.
Synthesis and evaluation of benzoylbenzofurans and isoflavone derivatives as

sirtuin 1 inhibitors with antiproliferative effects on cancer cells.
Selepe MA(1), Kunyane P(2), Seboletswe P(3), Nair S(4), Cele N(3), Engelbrecht
M(4), Joubert DF(5), Vandevoorde C(4), Singh P(6), Sonopo MS(7).
Author information:
(1)Department of Chemistry, University of Pretoria, Lynnwood Rd, Hatfield,
Pretoria 0002, South Africa. Electronic address: mamoalosi.selepe@up.ac.za.
(2)Department of Chemistry, University of Pretoria, Lynnwood Rd, Hatfield,
Pretoria 0002, South Africa.
(3)School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001,
Westville, Durban 4000, South Africa.
(4)Radiation Biophysics Division, Separated Sector Cyclotron Laboratory,
NRF-iThemba LABS, Cape Town 7131, South Africa.
(5)Department of Physiology, University of Pretoria, Lynnwood Rd, Hatfield,
Pretoria 0002, South Africa.
(6)School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001,
Westville, Durban 4000, South Africa. Electronic address: Singhp4@ukzn.ac.za.
(7)Radiochemistry, South African Nuclear Energy Corporation Ltd, Pelindaba,
Brits 0240, South Africa. Electronic address: Molahlehi.Sonopo@necsa.co.za.
Isoflavone derivatives were prepared from benzoylbenzofuran precursors. The

synthesized compounds were analyzed by 1D and 2D nuclear magnetic resonance
(NMR) spectroscopy, as well as high-resolution mass spectrometry (HRMS) to
confirm their structures. The benzoylbenzofuran and isoflavone analogues were
evaluated for inhibition of sirtuin 1 (SIRT1) and cell proliferation in
MDA-MB-231 triple-negative breast cancer (TNBC) cells. Several isoflavone and
benzoylbenzofuran derivatives exhibited potent antiproliferative effects against
the MDA-MB-231 cancer cell line. Most of the isoflavone derivatives attenuated
SIRT1 activity to below 50%. The most active compounds were the isoflavone
quinones 38, 39, and 40, at IC50 values of 5.58 ± 0.373, 1.62 ± 0.0720, and
7.24 ± 0.823 μM, respectively. Importantly, the most active compound,
6-methoxy-4',6'-dimethylisoflavone-2',5'-quinone (39) displayed SIRT1 inhibitory
activity comparable to that of the reference compound, suramin. The in silico
docking simulations in the active site of SIRT1 further substantiated the
experimental results and explored the binding orientations of potent compounds
in the active site of the target.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bioorg.2022.106101

paper.
83. Pharmaceuticals (Basel). 2022 Jun 28;15(7):806. doi: 10.3390/ph15070806.
In the Search for Novel, Isoflavone-Rich Functional Foods-Comparative Studies of

Four Clover Species Sprouts and Their Chemopreventive Potential for Breast and
Prostate Cancer.
Galanty A(1), Niepsuj M(1), Grudzińska M(1), Zagrodzki P(2), Podolak I(1), Paśko
P(2).
Author information:
(1)Department of Pharmacognosy, Faculty of Pharmacy, Jagiellonian University
Medical College, Medyczna 9, 30-688 Cracow, Poland.
(2)Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian
University Medical College, Medyczna 9, 30-688 Cracow, Poland.
Despite a significant amount of research, the relationship between a diet rich

in isoflavones and breast and prostate cancer risk is still ambiguous. The
purpose of the current study was to pre-select the potential candidate for
functional foods among red, white, crimson, and Persian clover sprouts, cultured
for different periods of time (up to 10 days), with respect to the isoflavone
content (determined by HPLC-UV-VIS), and to verify their impact on
hormone-dependent cancers in vitro. The red clover sprouts were the richest in
isoflavones (up to 426.2 mg/100 g dw), whereas the lowest content was observed
for the crimson clover. Each species produced isoflavones in different patterns,
which refer to the germination time. Hormone-insensitive MDA-MB-231 breast
cancer cells were more resistant to the tested extracts than estrogen-dependent
MCF7 breast cancer cells. Regarding prostate cancer, androgen-dependent LNCap
cells were most susceptible to the tested sprouts, followed by
androgen-insensitive, high metastatic PC3, and low metastatic DU145 cells. The
observed cytotoxic impact of the tested sprouts is not associated with
isoflavone content, as confirmed by chemometric analysis. Furthermore, the
sprouts tested revealed a high antioxidant potential, and were characterized by
high safety for normal breast and prostate cells.
DOI: 10.3390/ph15070806
PMCID: PMC9319781
PMID: 35890104
84. Bioorg Chem. 2022 Oct;127:105868. doi: 10.1016/j.bioorg.2022.105868. Epub 2022

Jul 2.
Discovery and evaluation of cytisine N-isoflavones as novel EGFR/HER2 dual

inhibitors.
Wang Y(1), Yin X(2), Chen L(1), Yin Z(3), Zuo Z(4).
Author information:
(1)College of Chemistry and Chemical Engineering, Shanghai University of
Engineering Science, Shanghai 201620, PR China.
Engineering Science, Shanghai 201620, PR China; Shanghai Frontiers Science
Research Center for Druggability of Cardiovascular noncoding RNA, Institute for
Frontier Medical Technology, Shanghai University of Engineering Science,
Shanghai 201620, PR China; Shanghai Engineering Research Center for
Pharmaceutical Intelligent Equipment, Shanghai University of Engineering
Science, Shanghai 201620, China. Electronic address: ncyxoy@163.com.
(3)School of Mathematics, Physics and Statistics, Shanghai University of
Engineering Science, Shanghai 201620, PR China.
Engineering Science, Shanghai 201620, PR China; Shanghai Frontiers Science
Research Center for Druggability of Cardiovascular noncoding RNA, Institute for
Frontier Medical Technology, Shanghai University of Engineering Science,
Shanghai 201620, PR China. Electronic address: ZhichengZuo@sues.edu.cn.
Aberrant signaling of EGFR (ErbB) family members, in particular epidermal growth

factor receptor (EGFR) and human epidermal growth factor 2 (HER2), is associated
with the occurrence and development of many types of human malignancies (e.g.,
breast, lung, and gastric cancers), and dual targeting of EGFR/HER2 by
small-molecular inhibitors has proven to be an effective therapeutic approach
for treating these cancers. Herein we extracted and isolated from the medicinal
plant Sophora alopecuroides L. a new natural product, dubbed Cytisine
N-methylene-(4',7-dihydroxy-3'-methoxy)-isoflavone (CNI1) that features a unique
molecular framework. Our biochemical kinase assay suggested that one of its
derivative CNI3 exhibited the best, micromolar (μM) inhibition activities
against the EGFR (IC50 of 1.1 μM; Ki of 0.6 μM) and HER2 (IC50 of 3.5 μM; Ki of
1.8 μM) kinases. By contrast, another derivative CNI4 was most potent in
inhibiting the EGFR-overexpressing A431 cancer cell line (IC50 of 45.5 μM) and
the HER2-overexpressing BT-474 cancer cell line (IC50 of 32.9 μM), while the
respective cellular activities of Lapatinib (a marketed drug) were 24.9 and
20.3 μM under the same assay condition. Moreover, both CNI3 and CNI4 showed
desirable anti-metastatic efficacy in another two breast cancer models (viz.,
MDA-MB-231 and 4T1). In addition, we explored the inhibitory mechanisms of the
CNIs against EGFR and HER2 by molecular dynamics simulation and revealed a novel
mode of action that engages the cytisine and chromone moieties in CNIs. By
combining structure- and ligand-based analysis, we further rationally engineered
a new CNI compound that exhibits considerably improved cytotoxicity against both
types of A431 and BT-474 cancer cells. Our study demonstrates the CNI compounds
as a new class of EGFR/HER2 dual inhibitors and paves a way for their further
development.
DOI: 10.1016/j.bioorg.2022.105868
85. Evid Based Complement Alternat Med. 2022 Jun 29;2022:5957378. doi:
10.1155/2022/5957378. eCollection 2022.
Genistein: Therapeutic and Preventive Effects, Mechanisms, and Clinical

Application in Digestive Tract Tumor.
Hou S(1).
Author information:
(1)School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Genistein is one of the numerous recognized isoflavones that may be found in a

variety of soybeans and soy products, including tofu and tofu products. The
chemical name for genistein is 4', 5, 7-trihydroxyisoflavone, and it is found in
plants. In recent years, the scientific world has become more interested in
genistein because of its possible therapeutic effects on many forms of cancer.
It has been widely investigated for its anticancer properties. The discovery of
genistein's mechanism of action indicates its potential for apoptosis induction
and cell cycle arrest in gastrointestinal cancer, especially gastric and
colorectal cancer. Genistein's pharmacological activities as determined by the
experimental studies presented in this review lend support to its use in the
treatment of gastrointestinal cancer; however, additional research is needed in
the future to determine its efficacy, safety, and the potential for using
nanotechnology to increase bioavailability and therapeutic efficacy.
Copyright © 2022 Shenglin Hou.
DOI: 10.1155/2022/5957378
PMCID: PMC9259214
PMID: 35815271
86. Molecules. 2022 Jun 22;27(13):3996. doi: 10.3390/molecules27133996.
Identification of Anti-Proliferative Compounds from Genista monspessulana Seeds

through Covariate-Based Integration of Chemical Fingerprints and Bioactivity
Datasets.
Díaz L(1), Cely-Veloza W(2), Coy-Barrera E(2).
Author information:
(1)Bioprospecting Research Group, School of Engineering, Universidad de La
Sabana, Chía 250001, Colombia.
(2)Bioorganic Chemistry Laboratory, Universidad Militar Nueva Granada, Cajicá
250247, Colombia.
Genista monspessulana (L.) L.A.S. Johnson (Fabaceae) is a Mediterranean plant

introduced to South America and other regions for ornamental purposes. However,
it is considered an invasive shrub due to its reproductive vigor in many areas.
Unlike other Genista plants, G. monspessulana has few studies disclosing its
biologically active components, particularly cytotoxic agents against cancer
cells. Thus, as part of our research on anti-proliferative bioactives, a set of
ethanolic seed extracts from ten accessions of G. monspessulana, collected in
the Bogotá plateau, were evaluated against four cell lines: PC-3 (prostate
adenocarcinoma), SiHa (cervical carcinoma), A549 (lung carcinoma), and L929
(normal mouse fibroblasts). Extracts were also analyzed through liquid
chromatography coupled with mass spectrometry (LC/MS) to record chemical
fingerprints and determine the composition and metabolite variability between
accessions. Using multiple covariate statistics, chemical and bioactivity
datasets were integrated to recognize patterns and identify bioactive compounds
among studied extracts. G. monspessulana seed-derived extracts exhibited
dose-dependent antiproliferative activity on PC-3 and SiHa cell lines (>500
µg/mL < IC50 < 26.3 µg/mL). Seven compounds (1−7) were inferred as the compounds
most likely responsible for the observed anti-proliferative activity and
subsequently isolated and identified by spectroscopic techniques. A tricyclic
quinolizidine (1) and a pyranoisoflavone (2) were found to be the most active
compounds, exhibiting selectivity against PC-3 cell lines (IC50 < 18.6 µM).
These compounds were used as precursors to obtain a
quinolizidine-pyranoisoflavone adduct via Betti reaction, improving the activity
against PC-3 and comparable to curcumin as the positive control. Results
indicated that this composition−activity associative approach is advantageous to
finding those bioactive principles efficiently within active extracts. This
correlative association can be employed in further studies focused on the
targeted isolation of anti-proliferative compounds from Genista plants and
accessions.
PMCID: PMC9268615
87. Pharmaceuticals (Basel). 2022 Jun 2;15(6):699. doi: 10.3390/ph15060699.
In Vitro Evaluation of the Antioxidant Activity and Chemopreventive Potential in

Human Breast Cancer Cell Lines of the Standardized Extract Obtained from the
Aerial Parts of Zigzag Clover (Trifolium medium L.).
Zgórka G(1), Maciejewska-Turska M(1), Makuch-Kocka A(2), Plech T(2).
Author information:
(1)Department of Pharmacognosy with the Medicinal Plant Garden, Faculty of
Pharmacy, Medical University of Lublin, 1 Chodźki Str., 20-093 Lublin, Poland.
(2)Department of Pharmacology, Chair of Pharmacology and Biology, Faculty of
Health Sciences, Medical University of Lublin, 20-093 Lublin, Poland.
The aboveground parts of Trifolium medium L. (zigzag clover), a little-known

representative of the family Fabaceae, collected during flowering in a wild
stand (Sławin-Szerokie district, Lublin, Poland), were used in this study. Our
previous investigations confirmed the higher content of phytoestrogenic
isoflavones (especially biochanin A and formononetin derivatives) in T. medium
compared to the closely related medicinal plant T. pratense (red clover) and the
involvement of these compounds in anti-osteoporotic effects in ovariectomized
female rats. The current study focused on evaluating other antibiodegenerative
(antioxidant, chemopreventive, and cytostatic) effects for the lyophilisate
(TML) obtained from wild zigzag clover. For this purpose, efficient
ultrasound-assisted extraction (UAE) was employed, followed by vacuum drying and
phytochemical standardization using a newly developed reversed-phase
high-performance liquid chromatography (RP-LC) coupled with a PDA detection.
Malonylglycosides of biochanin A and formononetin were the predominant compounds
and were found to contribute more than 54% to the total isoflavone content
determined in the standardized extract of zigzag clover. The antioxidant
potential of TML was examined in vitro using the Folin-Ciocalteu and cupric
ion-reducing (CUPRAC) methods in addition to the free radical (DPPH• and ABTS•+)
scavenging assays. The cytotoxic effects of TML, formononetin, and ononin were
evaluated on MCF-7 (estrogen-dependent) and MDA-MB-231 (estrogen-independent)
human breast cancer cell lines using the MTT assay. The important role of
malonyl isoflavone derivatives has been indicated both in chemoprevention and
potential cytotoxic effects of TML against certain types of breast cancer.
DOI: 10.3390/ph15060699
PMCID: PMC9229722
PMID: 35745618
88. Food Chem. 2022 Nov 1;393:133430. doi: 10.1016/j.foodchem.2022.133430. Epub

2022
Jun 8.
FT-IR and FT-Raman fingerprints of flavonoids - A review.
Krysa M(1), Szymańska-Chargot M(2), Zdunek A(3).
Author information:
(1)Institute of Agrophysics, Polish Academy of Sciences, Doświadczalna 4, 20-290
Lublin, Poland. Electronic address: m.krysa@ipan.lublin.pl.
Lublin, Poland. Electronic address: m.szymanska@ipan.lublin.pl.
Lublin, Poland. Electronic address: a.zdunek@ipan.lublin.pl.
Flavonoids are secondary metabolites commonly found in plants. They are known
for their antioxidant properties, are part of the defense mechanisms of plants
and are responsible for the pigmentation of fruit and flowers petals.
Consumption foods rich in flavonoids in the daily diet brings a number of
pro-health benefits - for example blood pressure regulation, delaying the aging
process or anti-cancer effect. These compounds in synthetic or natural form are
also used in pharmacy. The profile of flavonoid compounds can be quickly,
accurately and easy determine in the test sample by using the infrared and Raman
spectroscopy. Those methods are successfully used in the food and pharmaceutical
industries. Spectroscopy methods allow us to determine the chemical structure of
these compounds. This review describes and compares differences between the
spectroscopic spectra of individual compounds with the chemical structure for
the flavonoids subgroups: flavones, isoflavones, flavanones, flavonols and
anthocyanins.
DOI: 10.1016/j.foodchem.2022.133430
89. Front Oncol. 2022 May 6;12:866154. doi: 10.3389/fonc.2022.866154. eCollection

2022.
Research Advances on Anti-Cancer Natural Products.
Guo M(1), Jin J(1), Zhao D(2), Rong Z(1), Cao LQ(2), Li AH(3), Sun XY(1), Jia
LY(1), Wang YD(1), Huang L(1), Li YH(4), He ZJ(4), Li L(2), Ma RK(2), Lv YF(2),
Shao KK(2), Cao HL(1)(2)(3)(4).
Author information:
(1)College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China.
(2)Xi'an Key Laboratory of Basic and Translation of Cardiovascular Metabolic
Disease, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of
Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.
(3)Shaanxi Key Laboratory of Chinese Herb and Natural Drug Development, Medicine
Research Institute, Shaanxi Pharmaceutical Holding Group Co., LTD, Xi'an, China.
(4)College of Life Sciences, Northwest University, Xi'an, China.
Malignant tumors seriously threaten people's health and life worldwide. Natural
products, with definite pharmacological effects and known chemical structures,
present dual advantages of Chinese herbs and chemotherapeutic drug. Some of them
exhibit favorable anti-cancer activity. Natural products were categorized into
eight classes according to their chemical structures, including alkaloids,
terpenoids and volatile oils, inorganic salts, phenylpropanoids, flavonoids and
isoflavones, quinone, saponins and polysaccharides. The review focused on the
latest advances in anti-cancer activity of representative natural products for
every class. Additionally, anti-cancer molecular mechanism and derivatization of
natural products were summarized in detail, which would provide new core
structures and new insights for anti-cancer new drug development.
Copyright © 2022 Guo, Jin, Zhao, Rong, Cao, Li, Sun, Jia, Wang, Huang, Li, He,
Li, Ma, Lv, Shao and Cao.
DOI: 10.3389/fonc.2022.866154
PMCID: PMC9135452
PMID: 35646647
Conflict of interest statement: Author A-HL is employed by Shaanxi

Pharmaceutical Holding Group Co., LTD, China. Author H-LC previously acted as an
advisor for Shaanxi Pharmaceutical Holding Group Co., LTD, China. The remaining
authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of
interest.
90. Int J Mol Sci. 2022 May 17;23(10):5621. doi: 10.3390/ijms23105621.
Chemosensitization of U-87 MG Glioblastoma Cells by Neobavaisoflavone towards

Doxorubicin and Etoposide.
Maszczyk M(1), Banach K(1), Karkoszka M(1), Rzepka Z(1), Rok J(1), Beberok A(1),
Wrześniok D(1).
Author information:
(1)Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences in
Sosnowiec, Medical University of Silesia in Katowice, Jagiellońska 4, 41-200
Sosnowiec, Poland.
Glioblastoma (GB) is the most common type of glioma, which is distinguished by

high mortality. Due to the rapid progression of the tumor and drug resistance,
the treatment is often ineffective. The development of novel therapies in a big
part concerns the application of anti-cancer agents already used in clinical
practice, unfortunately often with limited effects. This could be overcome
through the use of compounds that possess chemosensitizing properties. In our
previous work, it has been shown that neobavaisoflavone (NBIF) enhances the in
vitro activity of doxorubicin in GB cells. The aim of this study was a further
investigation of the possible chemosensitizing effects of this isoflavone. The
experimental panel involving image cytometry techniques, such as count assay,
examination of mitochondrial membrane potential, Annexin V assay, and cell cycle
analysis, was performed in human glioblastoma U-87 MG cells and normal human
astrocytes (NHA) treated with NBIF, doxorubicin, etoposide, and their mixes with
NBIF. NBIF in co-treatment with etoposide or doxorubicin caused an increase in
the population of apoptotic cells and prompted alterations in the cell cycle.
NBIF enhances the pro-apoptotic activity of etoposide and doxorubicin in U-87 MG
cells, which could be a sign of the chemosensitizing properties of the
isoflavone.
DOI: 10.3390/ijms23105621
PMCID: PMC9144651
91. Antibiotics (Basel). 2022 May 13;11(5):657. doi: 10.3390/antibiotics11050657.
Metabolic Profile, Biotransformation, Docking Studies and Molecular Dynamics

Simulations of Bioactive Compounds Secreted by CG3 Strain.
Messaoudi O(1)(2)(3), Sudarman E(4)(5), Patel C(6), Bendahou M(3), Wink J(2).
Author information:
(1)Department of Biology, Faculty of Science, University of Amar Telidji,
Laghouat 03000, Algeria.
(2)Microbial Strain Collection, Helmholtz Centre for Infection Research GmbH
(HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany.
(3)Laboratory of Applied Microbiology in Food and Environment, Abou Bekr Belkaïd
University, Tlemcen 13000, Algeria.
(4)Department Microbial Drugs, Helmholtz Centre for Infection Research GmbH
(HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany.
(5)German Centre for Infection Research Association (DZIF), Partner Site
Hannover-Braunschweig, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
(6)Computer-Aided Drug Design Group, Chemical Biology Laboratory, Center for
Cancer Research, National Cancer Institute, National Institute of Health,
Frederick, MD 21702, USA.
Actinobacteria isolated from untapped environments and exposed to extreme

conditions such as saltpans are a promising source of novel bioactive compounds.
These microorganisms can provide new molecules through either the biosynthetic
pathway or the biotransformation of organic molecules. In the present study, we
performed a chemical metabolic screening of secondary metabolites secreted by
the new strain CG3, which was isolated from a saltpan located in the Sahara of
Algeria, via high-performance liquid chromatography coupled with high-resolution
mass spectrometry (HPLC-ESI-HRMS). The results indicated that this strain
produced five new polyene macrolactams, kenalactams A-E, along with two known
compounds, mitomycin C and 6″-hydroxy-4,2',3',4″ tetramethoxy-p-terphenyl.
Furthermore, the CG3 isolate could have excellent properties for converting the
aglycone isoflavone glycitein to the compounds
6,7-dimethoxy-3-(4-methoxyphenyl)chromen-4-one (50) and
6,7-dimethoxy-3-phenylchromen-4-one (54), and the isoflavone genistein can be
converted to 5,7-dimethoxy-3-(4-methoxyphenyl)chromen-4-one (52). Docking
studies and molecular dynamics simulations indicated that these three
isoflavones, generated via biotransformation, are potent inhibitors of the
target protein aromatase (CYP19A1); consequently, they can be used to prevent
breast cancer risk in postmenopausal women.
DOI: 10.3390/antibiotics11050657
PMCID: PMC9137728
PMID: 35625301
92. Vet Ital. 2022 Nov 17;58(1):35-39. doi: 10.12834/VetIt.1741.9188.2.

Effects of isoflavone supplementation on endometrial thickness, endometrial
hyperplasia, and cancer in ovariectomized cats.
Negadmonfared M(1), Narenji Sani R(2), Ghaffari Khaligh S(3), Hayati F(4).
Author information:
(1)Department of Clinical Sciences, Faculty of Veterinary Medicine, Semnan
University, Semnan, Iran
(2)Department of Clinical Sciences, Faculty of Veterinary Medicine, Semnan
University, Semnan, Iran. PO Box 35131-19111 Semnan, Iran. Telefax:
+98(23)33654215, e-mail: rezasani_vet@semnan.ac.ir
(3)Department of Pathobiology, Faculty of Veterinary Medicine, Semnan
University, Semnan, Iran
(4)Department of Surgery and Radiology, Faculty of Veterinary Medicine,
University of Tehran, Tehran, Iran
Ovariectomy is identified as a standard treatment in different European

countries. Isoflavones, as nonsteroidal compounds in plants, are common
constituents of soy and soy products. Some available cat diets contain different
concentrations of soy products. This study aimed to examine the effects of
isoflavone supplementation on endometrial hyperplasia and endometrial thickness
in ovariectomized cats. Fifteen neutered adult cats were divided into control,
estradiol, and isoflavone groups (five cats per group). Subcutaneous injection
of estradiol (0.5 μg) in sesame oil (100 μL) was done for 30 days in
estradiol-treated cats. Isoflavone-treated cats ingested a single oral tablet of
soy extract for 30 days, while the controls received subcutaneous injections of
the vehicle and oral placebo for 30 days. Histopathological findings of
hematoxylin and eosin-stained sections revealed a significant difference between
the estradiol group and other groups in terms of hyperplastic epithelium and
simple hyperplasia. Thickness of myometrium was greater in the estradiol group
compared to the isoflavone and control groups. Higher concentrations of estrogen
can affect the endometrium and myometrium, while 30-day ingestion of isoflavone
didn't have any uterine effect.
DOI: 10.12834/VetIt.1741.9188.2
93. Anticancer Agents Med Chem. 2022;22(20):3343-3369. doi:

10.2174/1871520622666220421094055.
Recent Insights into Therapeutic Potential of Plant-Derived Flavonoids against

Cancer.
Mohi-Ud-Din R(1), Mir RH(2)(3), Sabreen S(4), Jan R(5), Pottoo FH(6), Singh
IP(7).
Author information:
(1)Department of General Medicine, Sher-I-Kashmir Institute of Medical Sciences
(SKIMS), Srinagar, Jammu and Kashmir, 190001, India.
(2)Pharmaceutical Chemistry Division, Chandigarh College of Pharmacy, Landran,
Punjab-140301, India.
(3)Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences,
University of Kashmir, Srinagar, India.
(4)Department of pharmaceutical sciences, Pharmaceutical Chemistry Division,
University of Kashmir, India.
(5)Defence Research and Development Organisation (DRDO), Hospital, Khonmoh,
Srinagar 190001, Jammu & Kashmir, India.
(6)Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman
Bin Faisal University, P.O.BOX 1982, Dammam 31441, Saudi Arabia.
(7)Department of Natural Products, National Institute of Pharmaceutical
Education & Research (NIPER), S.A.S Nagar, Mohali-160062, Punjab, India.
Flavonoids, a class of polyphenolic secondary metabolites, are present in

fruits, vegetables, beverages such as wine and tea abundantly. Flavonoids
exhibit a diverse array of pharmacological activities, including anticancer
activity, and are toxic to cancer cells but not harmful to healthy cells.
Besides, humans and animals cannot synthesize flavonoids, which leads to a
dramatic increase in the consumption of plant flavonoids. Flavonoids consist of
a 15- carbon skeleton in C6-C3-C6 rings with divergent substitution patterns to
form a series of compounds. Due to their multi-faceted mechanism of action by
modulating various signaling pathways associated with apoptosis, cellular
proliferation, inflammation, differentiation, metastasis, angiogenesis, they
interrupt the initiation, promotion, and progression of cancer. The present
review highlights the Structural Activity Relationship (SAR) of flavonoids and
recent insights on the progress of natural flavonoids and their synthetic
analogs as prospective drug candidates against cancer, along with molecular
mechanisms of action.

DOI: 10.2174/1871520622666220421094055
94. Nutr J. 2022 May 11;21(1):27. doi: 10.1186/s12937-022-00778-w.
Consumption of flavonoids and risk of hormone-related cancers: a systematic

review and meta-analysis of observational studies.
Liu F(1)(2)(3), Peng Y(1)(2)(3), Qiao Y(1)(2)(3), Huang Y(1)(2)(3), Song

F(1)(2)(3), Zhang M(4), Song F(5)(6)(7).
Author information:
Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital,
Tianjin, 300060, China.
(2)Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University
Cancer Institute and Hospital, Tianjin, 300060, China.
(3)Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of
Education, National Clinical Research Center for Cancer, Tianjin's Clinical
Research Center for Cancer, Tianjin Medical University Cancer Institute and
Hospital, Tianjin, 300060, China.
(4)Shenzhen Prevention and Treatment Center for Occupational Diseases, Shenzhen,
518020, Guangdong, China. mingle1981@163.com.
Cancer Epidemiology, Tianjin Medical University Cancer Institute and Hospital,
Tianjin, 300060, China. double1980@163.com.
(6)Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University
Cancer Institute and Hospital, Tianjin, 300060, China. double1980@163.com.
(7)Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of
Education, National Clinical Research Center for Cancer, Tianjin's Clinical
Research Center for Cancer, Tianjin Medical University Cancer Institute and
Hospital, Tianjin, 300060, China. double1980@163.com.
BACKGROUND: Flavonoids seem to have hormone-like and anti-hormone properties so

that the consumption of flavonoids may have potential effects on hormone-related
cancers (HRCs), but the findings have been inconsistent so far. This
meta-analysis was aimed to explore the association between flavonoids intake and
HRCs risk among observational studies.
METHODS: Qualified articles, published on PubMed, EMBASE, and China National
Knowledge Infrastructure (CNKI) from January 1999 to March 2022 and focused on
relationships between flavonoids (total, subclass of and individual flavonoids)
and HRCs (breast, ovarian, endometrial, thyroid, prostate and testicular
cancer), were retrieved for pooled analysis. Random effects models were
performed to calculate the pooled odds ratios (ORs) and corresponding 95%
confidence intervals (CIs). Funnel plots and Begg's/Egger's test were used to
evaluate the publication bias. Subgroup analyses and sensitivity analyses were
conducted to explore the origins of heterogeneity.
RESULTS: All included studies were rated as medium or high quality. Higher
consumption of flavonols (OR = 0.85, 95% CI: 0.76-0.94), flavones (OR = 0.85,
95% CI: 0.77-0.95) and isoflavones (OR = 0.87, 95% CI: 0.82-0.92) was associated
with a decreased risk of women-specific cancers (breast, ovarian and endometrial
cancer), while the higher intake of total flavonoids was linked to a
significantly elevated risk of prostate cancer (OR = 1.11, 95% CI: 1.02-1.21). A
little evidence implied that thyroid cancer risk was augmented with the higher
intake of flavones (OR = 1.24, 95% CI: 1.03-1.50) and flavanones (OR = 1.31, 95%
CI: 1.09-1.57).
CONCLUSIONS: The present study suggests evidence that intake of total
flavonoids, flavonols, flavones, flavanones, flavan-3-ols and isoflavones would
be associated with a lower or higher risk of HRCs, which perhaps provides
guidance for diet guidelines to a certain extent.
TRIAL REGISTRATION: This protocol has been registered on PROSPERO with
registration number CRD42020200720 .
© 2022. The Author(s).
DOI: 10.1186/s12937-022-00778-w
PMCID: PMC9092883
Conflict of interest statement: The authors declare no potential competing

interests.
95. Prostate Int. 2022 Jun;10(2):96-107. doi: 10.1016/j.prnil.2022.03.004. Epub

2022
Mar 29.
Prostate diseases and microbiome in the prostate, gut, and urine.
Miyake M(1), Tatsumi Y(1), Ohnishi K(1), Fujii T(2), Nakai Y(1), Tanaka N(1)(3),
Fujimoto K(1).
Author information:
(1)Department of Urology, Kashihara, Nara, 634-8522, Japan.
(2)Department of Diagnostic Pathology, Kashihara, Nara, 634-8522, Japan.
(3)Department of Prostate Brachytherapy, Nara Medical University, Nara,
634-8522, Japan.
The microbiome in various organs involves a vast network that plays a key role
in the health and wellness of the human body. With recent advances in biological
technologies such as high-throughput sequencing, transcriptomics, and
metabolomics, it appears that the microbial signature varies dynamically among
individuals, creating various roles in metabolism, local and systemic
inflammation, and host immunity. Urinary and genital organs, including the
prostate, seminal vesicles, and urinary bladder, are reservoirs of several
bacterial, viral, and fungal communities. Accumulating evidence has suggested
profound roles for the gut, urinary, and intraprostate microbiomes in
genitourinary benign and malignant diseases. This review article addresses
microbiome-related evidence for three major diseases involved in prostate
cancer: chronic prostatitis (CP), benign prostatic hyperplasia (BPH), and
prostate cancer (PCa). Symptomatic CP is known as CP/chronic pelvic pain
syndrome. CP is one of the most common prostate diseases in young men,
accounting for 8% of all men visiting a urologic clinic. Although oral
medication is the gold standard therapy for patients with BPH, approximately 13%
of men present with clinical progression within 4 years after the initiation of
treatment, with 5% requiring surgical intervention. The identification of
proinflammatory cytokines and pathogens responsible for the clinical progression
of BPH is still underway. Several topics regarding the association between PCa
and the microbiome are discussed in this review as follows: i) intraprostatic
microbiome and the risk of PCa, ii) gut microbiome and PCa, iii) gut microbiome
and the risk of radiation-induced side effects, iv) isoflavone intake and
equol-producing intestinal flora on PCa, and v) the inhibitory effect of
daidzein and equol on tumor growth and progression of PCa. Further studies are
required for a comprehensive understanding between the urogenital microbiome and
prostate pathogenesis to facilitate the development of preventive and
therapeutic approaches for prostate diseases.
© 2022 Asian Pacific Prostate Society. Publishing services by Elsevier B.V.
DOI: 10.1016/j.prnil.2022.03.004
PMCID: PMC9052083
PMID: 35510078
Conflict of interest statement: The authors disclose no potential conflicts of

interest.
96. Cancer Epidemiol Biomarkers Prev. 2022 Jul 1;31(7):1334-1340. doi:

10.1158/1055-9965.EPI-22-0016.
Habitual Phytoestrogen Intake Is Associated with Breast Composition in Girls at

2 Years after Menarche Onset.
Lesser C(1), Mericq V(2), Reyes M(1), Garmendia ML(1), Shepherd JA(3), Michels
KB(4)(5), Corvalán C(1), Pereira A(1).
Author information:
(1)Institute of Nutrition and Food Technology, University of Chile, Santiago,
Chile.
(2)Institute of Maternal and Child Research (IDIMI), Faculty of Medicine,
University of Chile, Santiago, Chile.
(3)Population Sciences in the Pacific Program (Cancer Epidemiology), University
of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii.
(4)Department of Epidemiology, Fielding School of Public Health, University of
California, Los Angeles, California.
(5)Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and
Medical Center, University of Freiburg, Freiburg, Germany.
BACKGROUND: High phytoestrogen intake during adolescence is associated with a

reduced risk of breast cancer. Breast density (BD) is a strong predictor of
breast cancer and can be considered an early marker. We aim to assess the
association between the mean habitual intake of isoflavones, lignans, and total
phytoestrogens intake during puberty until 2 years after menarche onset and
absolute fibroglandular volume (AFGV) and percentage of fibroglandular volume
(%FGV) in Hispanic girls at the end of puberty.
METHODS: Longitudinal study set up in the Growth and Obesity Chilean Cohort
Study (GOCS). We included 329 girls with dietary data (multiple 24-hours
recalls) from puberty until 2 years after menarche onset (81% had 2-4 recalls).
Two international datasets were used to estimate isoflavones, lignans, and total
phytoestrogens in the diet. Breast composition was measured by dual energy X-ray
absorptiometry at 2 years after menarche. Multiple linear regression models were
used to assess the association between isoflavones, lignans, and total
phytoestrogens intake and AFGV and %FGV.
RESULTS: The average total phytoestrogen intake was 1 mg/day and %FGV was 50.7%
(SD = 15.2) and AFGV 218.8 cm3 (SD = 79.3). An inverse association was found
between consumption of isoflavones and AFGV, as well as, with total
phytoestrogens [Q4 vs. Q1 adjusted model ß = -49.2 cm3; 95% CI (-85.5 to
-13.0)].
CONCLUSIONS: Girls with a higher intake of total phytoestrogens and isoflavones
during puberty until 2 years after menarche onset had significantly lower AFGV.
IMPACT: Although the intake of phytoestrogens is low in Western populations,
higher consumption of them during a critical period of life like puberty could
be beneficial to reduce breast cancer during adulthood.
©2022 American Association for Cancer Research.
DOI: 10.1158/1055-9965.EPI-22-0016
PMCID: PMC9250624
Conflict of interest statement: Conflicts of interest The authors have no

conflicts of interest to declare.
97. J Food Sci. 2022 May;87(5):1961-1982. doi: 10.1111/1750-3841.16131. Epub 2022

Apr 11.
Occurrence of isoflavones in soybean sprouts and strategies to enhance their

content: A review.
Wang SY(1), Zhang YJ(1), Zhu GY(1), Shi XC(1), Chen X(1), Herrera-Balandrano
DD(1), Liu FQ(2), Laborda P(1).
Author information:
(1)School of Life Sciences, Nantong University, Nantong, China.
(2)Institute of Plant Protection, Jiangsu Key Laboratory for Food Quality and
Safety-State Key Laboratory Cultivation Base of Ministry of Science and
Technology, Jiangsu Academy of Agricultural Sciences, Nanjing, China.
Sprouting is a common strategy to enhance the nutritional value of seeds. Here,

all the reports regarding the occurrence of isoflavones in soybean sprouts have
been covered for the first time. Isoflavones were detected with concentrations
ranging from 1 × 10-2 to 1 × 101 g/kg in soybean sprouts. Isoflavone
concentration depends on the cultivar, germination time, part of the sprout,
light, and temperature. Aglycon isoflavones increased during germination,
especially in the hypocotyl, while 6″-O-malonyl-7-O-β-glucoside isoflavones
decreased in the hypocotyl and increased in the cotyledon and root. Cooking
reduced total isoflavone content. Regarding the strategies to enhance isoflavone
contents, fermentation with Aspergillus sojae and external irradiation with UV-A
or far-infrared were the methods that caused the greatest increases in aglycon,
7-O-β-glucoside, and total isoflavones. However, the largest increases in
6″-O-malonyl-7-O-β-glucoside and 6″-O-acetyl-7-O-β-glucosides isoflavones were
detected after treatment with chitohexaose and calcium chloride, respectively.
PRACTICAL APPLICATION: Soybean sprouts are widely consumed and provide essential
proteins, antioxidants, and minerals. They are rich in isoflavones, which
exhibit numerous health benefits, and have been studied as alternative therapies
for a range of hormone-dependent conditions, such as cancer, menopausal
symptoms, cardiovascular disease, and osteoporosis. Despite numerous reports
being published to date regarding the occurrence of isoflavones in soybean
sprouts, the publications in this field are highly dispersed, and a review has
not yet been published. This review aims to (1) highlight the particular
isoflavones that have been detected in soybean sprouts and their concentrations,
(2) compared the effects of temperature, light, cooking and soybean cultivar
affect the isoflavone levels on the different parts of the sprout, and (3)
discuss the efficacy of the methods to enhance isoflavone contents. This review
will provide a better understanding of the current state of this field of
research by comparing the general trends and the different treatments for
soybean sprouts.
© 2022 Institute of Food Technologists®.
DOI: 10.1111/1750-3841.16131
98. Molecules. 2022 Apr 3;27(7):2322. doi: 10.3390/molecules27072322.
Cytotoxicity of Callerya speciosa Fractions against Myeloma and Lymphoma Cell

Lines.
Lam VQ(1), Anh H(2), Quan NV(2), Xuan TD(2), Hanamura I(1), Uchino K(1), Karnan
S(3), Takami A(1).
Author information:
(1)Division of Hematology, Department of Internal Medicine, Aichi Medical
University School of Medicine, Nagakute 480-1195, Japan.
(2)Transdisciplinary Science and Engineering Program, Graduate School of
Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529,
Japan.
(3)Department of Biochemistry, Aichi Medical University, Nagakute 480-1195,
Japan.
Callerya speciosa is widely distributed in tropical and subtropical countries

and is traditionally used for preventing numerous disorders. In this study, a
bioguided fractionation of ethyl acetate extract (SE) from C. speciosa root was
carried out to target antioxidant and cytotoxic activities. Of the four
fractions (SE1-SE4) obtained by column chromatography, SE4 had the strongest
anti-radical ability in the DPPH and ABTS assays (IC50 = 0.05 and 0.17 mg/mL,
respectively), with results close to butylated hydroxytoluene (BHT), a common
antioxidant agent. The cytotoxic activities against the selected cells were
analyzed in this study by MTT assay. Accordingly, SE2, SE3, and SE4
significantly inhibited the viability of multiple myeloma cell lines, comprising
U266 (IC50 = 0.38, 0.09, and 0.11 mg/mL, respectively) and KMS11 (IC50 = 0.09,
0.17, and 0.15 mg/mL, respectively), mantle cell lymphoma Mino (IC50 = 0.08,
0.16, and 0.15 mg/mL, respectively), and the noncancerous cell line LCL (IC50 =
0.40, 0.32, and 0.21 mg/mL, respectively). At a concentration of 125 µg/mL, SE2,
SE3, and SE4 induced the cell apoptosis of U266 (32.2%, 53.2%, and 55.6%,
respectively), KMS11 (36.9%, 40.8%, and 47.9%, respectively), Mino (36.6%,
39.8%, and 22.0%, respectively), and LCL (12.4%, 17.5%, and 23.5%, respectively)
via annexin V assay. The dominant compounds detected in fractions by
high-performance liquid chromatography-electrospray ionization-tandem mass
spectrometry (HPLC-ESI-MS/MS), were identified as isoflavones. This is the first
report describing C. speciosa as a promising natural source of antileukemia and
antimyeloma agents, which may be useful for the development of blood cancer
treatments.
PMCID: PMC9000591
99. Plants (Basel). 2022 Mar 10;11(6):741. doi: 10.3390/plants11060741.
Antioxidant and Cytotoxic Activities of Kudzu Roots and Soy Molasses against
Pediatric Tumors and Phytochemical Analysis of Isoflavones Using
HPLC-DAD-ESI-HRMS.
Aboushanab SA(1)(2), Shevyrin VA(1)(2), Slesarev GP(1)(2), Melekhin VV(2)(3)(4),

Shcheglova AV(2)(3), Makeev OG(3)(4), Kovaleva EG(1)(2), Kim KH(5).
Author information:
(1)Institute of Chemical Engineering, Ural Federal University Named after the
First President of Russia B. N. Yeltsin, Mira 19, 620002 Yekaterinburg, Russia.
(2)Innovative Center of Chemical and Pharmaceutical Technologies, Laboratory of
Organic Synthesis, Ural Federal University Named after the First President of
Russia B. N. Yeltsin, Mira 19, 620002 Yekaterinburg, Russia.
(3)Department of Biology, Ural State Medical University, Repina 3, 620014
Yekaterinburg, Russia.
(4)Department of Gene and Cell Therapy, Institute for Medical Cell Technologies,
Karla Marksa 22a, 620026 Yekaterinburg, Russia.
(5)School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
Pediatric solid tumors (PSTs) are life-threatening and can lead to high
morbidity and mortality rates in children. Developing novel remedies to treat
these tumors, such as glioblastoma multiforme and sarcomas, such as
osteosarcoma, and rhabdomyosarcoma, is challenging, despite immense attempts
with chemotherapeutic or radiotherapeutic interventions. Soy (Glycine max) and
kudzu roots (KR) (Pueraria spp.) are well-known phytoestrogenic botanical
sources that contain high amounts of naturally occurring isoflavones. In the
present study, we investigated the antioxidant and cytotoxic effects of the
extracts of KR and soy molasses (SM) against PSTs. The green extraction of
isoflavones from KR and SM was performed using natural deep eutectic solvents.
The extracts were subsequently analyzed by high-performance liquid
chromatography (HPLC)-diode array detector (DAD) coupled with high-resolution
(HR) mass spectrometry (MS), which identified 10 isoflavones in KR extracts and
3 isoflavones in the SM extracts. Antioxidant and cytotoxic activities of KR and
SM extracts were assessed against glioblastoma multiforme (A-172), osteosarcoma
(HOS), and rhabdomyosarcoma (Rd) cancer cell lines. The KR and SM extracts
showed satisfactory cytotoxic effects (IC50) against the cancer cell lines
tested, particularly against Rd cancer cell lines, in a dose-dependent manner.
Antioxidant activity was found to be significantly (p ≤ 0.05) higher in KR than
in SM, which was consistent with the results of the cytotoxic activity observed
with KR and SM extracts against glioblastoma and osteosarcoma cells. The total
flavonoid content and antioxidant activities of the extracts were remarkably
attributed to the isoflavone content in the KR and SM extracts. This study
provides experimental evidence that HPLC-ESI-HRMS is a suitable analytical
approach to identify isoflavones that exhibit potent antioxidant and anticancer
potential against tumor cells, and that KR and SM, containing many isoflavones,
can be a potential alternative for health care in the food and pharmaceutical
industries.
DOI: 10.3390/plants11060741
PMCID: PMC8955742
PMID: 35336625
100. Nutrients. 2022 Mar 14;14(6):1225. doi: 10.3390/nu14061225.
Essential Elements and Isoflavonoids in the Prevention of Prostate Cancer.
Stanisławska IJ(1), Figat R(2), Kiss AK(3), Bobrowska-Korczak B(1).
Author information:
(1)Department of Bromatology, Medical University of Warsaw, Banacha 1, 02-097
Warsaw, Poland.
(2)Department of Environmental Health Sciences, Medical University of Warsaw,
Banacha 1, 02-097 Warsaw, Poland.
(3)Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical
University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
The intake of selected minerals, especially zinc, calcium and selenium, and high
consumption of dietary isoflavones are recognised as factors influencing
prostate cancer risk. Moreover, changes in levels of some essential elements are
characteristic of the disease. Here, we examined the combined effects of main
dietary isoflavonoids (genistein, daidzein and its metabolite, equol) and
minerals implicated in prostate cancer, namely zinc, selenium, copper, iron and
calcium, on LNCaP prostate cancer cells proliferation. Secondly, we evaluated
the influence of the combinations on genotoxicity of model mutagens,
4-nitroquinoline oxide (4NQO) and 2-aminoanthracene (2AA), in the umu test. All
combinations of isoflavonoids and minerals inhibited prostate cancer cells
growth. However, only mixtures with iron ions had significantly stronger effect
than the phytochemicals. Interestingly, we observed that only genistein
attenuated genotoxicity of 4NQO. The addition of any tested mineral abolished
this effect. All tested isoflavonoids had anti-genotoxic activity against 2AA,
which was significantly enhanced in the presence of copper sulphate. Our results
indicate that the tested minerals in physiological concentrations had minimal
influence on the anti-proliferative activity of isoflavonoids. However, they
significantly modulated the anti-genotoxic effects of isoflavonoids against both
metabolically activated and direct mutagens. Thus, the minerals intake and
nutritional status may modulate protective action of isoflavonoids.
DOI: 10.3390/nu14061225
PMCID: PMC8949525
101. Front Nutr. 2022 Mar 4;9:847421. doi: 10.3389/fnut.2022.847421. eCollection

2022.
Intake of Soy, Soy Isoflavones and Soy Protein and Risk of Cancer Incidence and
Mortality.
Fan Y(1)(2)(3), Wang M(3), Li Z(3), Jiang H(3), Shi J(3), Shi X(3), Liu S(3),
Zhao J(3), Kong L(3)(4), Zhang W(1), Ma L(3)(4)(5).
Author information:
(1)The First Affiliated Hospital, Xi'an Jiaotong University Health Science
Center, Xi'an, China.
(2)Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine
Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
(3)School of Public Health, Xi'an Jiaotong University Health Science Center,
Xi'an, China.
(4)Key Laboratory for Disease Prevention and Control and Health Promotion of
Shaanxi Province, Xi'an, China.
(5)Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong
University), Ministry of Education of China, Xi'an, China.
BACKGROUND AND AIMS: Associations between soy intake and risk of cancer have
been evaluated in prospective observational studies with inconsistent results.
Whether the potential anticancer effects offered by soy were attributed to soy
isoflavones and soy protein still needs to be elucidated. This study aimed to
comprehensively quantify the association of soy, soy isoflavones and soy protein
intake with risk of cancer incidence and cancer mortality by conducting a
meta-analysis of all available studies.
METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were
searched up to 16 September 2021. Prospective cohort studies that examined the
effect of soy, soy isoflavones and soy protein on cancer incidence and cancer
mortality were identified. Random-effects models were used to pool the
multivariable-adjusted relative risks (RRs) and corresponding 95% confidence
intervals (CIs). The potential dose-response relations were explored by using
generalized least-squares trend estimation.
RESULTS: Eighty one prospective cohort studies were included in the
meta-analysis. A higher intake of soy was significantly associated with a 10%
reduced risk of cancer incidence (RR, 0.90; 95% CI, 0.83-0.96). Each additional
25 g/d soy intake decreased the risk of cancer incidence by 4%. Intake of soy
isoflavones was inversely associated with risk of cancer incidence (RR, 0.94;
95% CI, 0.89-0.99), whereas no significant association was observed for soy
protein. The risk of cancer incidence was reduced by 4% with each 10 mg/d
increment of soy isoflavones intake. Similar inverse associations were also
found for soy in relation to site-specific cancers, particularly lung cancer
(RR, 0.67; 95%CI, 0.52-0.86) and prostate cancer (RR, 0.88; 95%CI, 0.78-0.99).
However, high intake of soy, soy isoflavones and soy protein were not associated
with cancer mortality.
CONCLUSIONS: Higher intake of soy and soy isoflavones were inversely associated
with risk of cancer incidence, which suggested that the beneficial role of soy
against cancer might be primarily attributed to soy isoflavones. These findings
support recommendations to include soy as part of a healthy dietary pattern for
the prevention of cancer.
Copyright © 2022 Fan, Wang, Li, Jiang, Shi, Shi, Liu, Zhao, Kong, Zhang and Ma.
DOI: 10.3389/fnut.2022.847421
PMCID: PMC8931954
PMID: 35308286
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
102. In Vivo. 2022 Mar-Apr;36(2):556-562. doi: 10.21873/invivo.12737.

Soy Isoflavones and Breast Cancer Risk: A Meta-analysis.
Boutas I(1), Kontogeorgi A(2), Dimitrakakis C(3), Kalantaridou SN(2).
Author information:
(1)Third Department of Obstetrics and Gynecology, National and Kapodistrian
University of Athens, Attikon Hospital, Athens, Greece;
ioannis.boutas@gmail.com.
(2)Third Department of Obstetrics and Gynecology, National and Kapodistrian
University of Athens, Attikon Hospital, Athens, Greece.
(3)First Department of Obstetrics and Gynecology, National and Kapodistrian
University of Athens, Alexandra Hospital, Athens, Greece.
BACKGROUND/AIM: Soy contains genistein and daidzein isoflavones. Isoflavones are

phytoestrogens, with a similarity in structure to human 17-β estradiol hormone.
They imitate the action of estrogen on organs by binding and activating estrogen
receptors. Numerous studies have examined the relationship between soy
consumption and breast cancer but not the amount of consumption itself. We
performed a systematic review of the literature in order to determine whether
the amount of soy and isoflavones consumed has a positive effect in pre- and
post-menopausal women.
MATERIALS AND METHODS: Data gathering was performed following PRISMA guidelines.
Narrowing down the result set for all relevant data was performed via title,
abstract, full-text evaluation and the snowball procedure. The selected articles
had all relevant data extracted. Analysis of the data was performed using
Cochrane's Review Manager statistical analysis tool in order to draw conclusions
regarding the positive effect for the amount of soy and isoflavones consumed.
RESULTS: Significant results were found when statistically analyzing data from
prospective studies which compared soy isoflavones consumption, breast cancer
risk and occurrence. The data were indicative of a clear inverse correlation
between the amount of isoflavones consumed and breast cancer occurrence in pre-
and post-menopausal women.
CONCLUSION: The consumption of soy isoflavones can reduce the risk of breast
cancer in pre-menopausal and post-menopausal women.
Copyright © 2022, International Institute of Anticancer Research (Dr. George J.

DOI: 10.21873/invivo.12737
PMCID: PMC8931889
Conflict of interest statement: The Authors declare no conflicts of interest.
103. Nutrients. 2022 Feb 13;14(4):784. doi: 10.3390/nu14040784.
Cytotoxicity of Fenugreek Sprout and Seed Extracts and Their Bioactive

Constituents on MCF-7 Breast Cancer Cells.
Khoja KK(1), Howes MR(2)(3), Hider R(3), Sharp PA(1), Farrell IW(2),
Latunde-Dada GO(1).
Author information:
(1)Department of Nutritional Sciences, School of Life Course Sciences, King's
College London, Franklin-Wilkins-Building, 150 Stamford Street, London SE1 9NH,
UK.
(2)Royal Botanic Gardens Kew, Richmond TW9 3DS, UK.
(3)Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine,
King's College London, Franklin-Wilkins-Building, 150 Stamford Street, London
SE1 9NH, UK.
Trigonella foenum-graecum L. (fenugreek), a member of the legume family

(Fabaceae), is a promising source of bioactive phytochemicals, which explains
its traditional use for a variety of metabolic disorders including cancer. The
current study aimed to evaluate extracts of fenugreek seeds and sprouts, and
some of their constituents, to compare their cytotoxic and antiproliferative
activities in MCF-7 breast cancer cells. The extracts were chemically
characterised using high-resolution accurate mass liquid chromatography-mass
spectrometry to reveal the detection of compounds assigned as flavone
C-glycosides including those derived from apigenin and luteolin, in addition to
isoflavones. Five different flavones or their glycosides (apigenin, vicenin-2,
vitexin, luteolin and orientin) and two isoflavones (daidzein and formononetin)
were quantified in the fenugreek extracts. The
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using MCF-7
cells treated with fenugreek methanolic extracts showed dose- and time-dependent
effects on cell viability. The MCF-7 cancer cells treated with the fenugreek
methanolic extracts also displayed increased relative mitochondrial DNA damage
as well as suppressed metastasis and proliferation. This study demonstrates the
potential anti-cancer effects of fenugreek seeds and sprouts and reveals
fenugreek sprouts as an untapped resource for bioactive compounds.
DOI: 10.3390/nu14040784
PMCID: PMC8879394
104. Front Pharmacol. 2022 Jan 24;13:820969. doi: 10.3389/fphar.2022.820969.

eCollection 2022.
Genistein: A Review on its Anti-Inflammatory Properties.
Goh YX(1), Jalil J(1), Lam KW(1), Husain K(1), Premakumar CM(2).
Author information:
(1)Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti
Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
(2)Centre for Quality Management of Medicines, Faculty of Pharmacy, Universiti
Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
Nowadays, non-resolving inflammation is becoming a major trigger in various

diseases as it plays a significant role in the pathogenesis of atherosclerosis,
asthma, cancer, obesity, inflammatory bowel disease, chronic obstructive
pulmonary disease, neurodegenerative disease, multiple sclerosis, and rheumatoid
arthritis. However, prolonged use of anti-inflammatory drugs is usually
accompanied with undesirable effects and hence more patients tend to seek for
natural compounds as alternative medicine. Considering the fact above, there is
an urgency to discover and develop potential novel, safe and efficacious natural
compounds as drug candidates for future anti-inflammatory therapy. Genistein
belongs to the flavonoid family, in the subgroup of isoflavones. It is a
phytoestrogen that is mainly derived from legumes. It is a naturally occurring
chemical constituent with a similar chemical structure to mammalian estrogens.
It is claimed to exert many beneficial effects on health, such as protection
against osteoporosis, reduction in the risk of cardiovascular disease,
alleviation of postmenopausal symptoms and anticancer properties. In the past,
numerous in vitro and in vivo studies have been conducted to investigate the
anti-inflammatory potential of genistein. Henceforth, this review aims to
summarize the anti-inflammatory properties of genistein linking with the
signaling pathways and mediators that are involved in the inflammatory response
as well as its toxicity profile. The current outcomes are analysed to highlight
the prospect as a lead compound for drug discovery. Data was collected using
PubMed, ScienceDirect, SpringerLink and Scopus databases. Results showed that
genistein possessed strong anti-inflammatory activities through inhibition of
various signaling pathways such as nuclear factor kappa-B (NF-κB),
prostaglandins (PGs), inducible nitric oxide synthase (iNOS), proinflammatory
cytokines and reactive oxygen species (ROS). A comprehensive assessment of the
mechanism of action in anti-inflammatory effects of genistein is included.
However, evidence for the pharmacological effects is still lacking. Further
studies using various animal models to assess pharmacological effects such as
toxicity, pharmacokinetics, pharmacodynamics, and bioavailability studies are
required before clinical studies can be conducted. This review will highlight
the potential use of genistein as a lead compound for future drug development as
an anti-inflammatory agent.
Copyright © 2022 Goh, Jalil, Lam, Husain and Premakumar.
DOI: 10.3389/fphar.2022.820969
PMCID: PMC8818956
PMID: 35140617
105. Phytother Res. 2022 Mar;36(3):1310-1325. doi: 10.1002/ptr.7388. Epub 2022 Feb
2.
The natural isoflavone Biochanin-A synergizes 5-fluorouracil anticancer activity

in vitro and in vivo in Ehrlich solid-phase carcinoma model.
Mahmoud M(1), Abdollah MRA(2)(3), Elsesy ME(4)(5), Abou El Ella DA(6), Zada
SK(7), Tolba MF(1)(8)(9).
Author information:
(1)Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams
University, Cairo, Egypt.
(2)Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British
University in Egypt, El-Sherouk City, Cairo, Egypt.
(3)The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The
British University in Egypt (BUE), El-Sherouk City, Cairo, Egypt.
(4)Pharmacology Unit, Cancer Biology Department, National Cancer Institute,
Cairo University, Cairo, Egypt.
(5)Department of Radiotherapy and Radiooncology, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany.
(6)Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams
University, Cairo, Egypt.
(7)Biology Department, School of Sciences and Engineering, the American
University in Cairo (AUC), New Cairo, Egypt.
(8)Center of Drug Discovery Research and Development, Ain Shams University,
Cairo, Egypt.
(9)School of Life and Medical Sciences, The University of Hertfordshire-hosted
by Global Academic Foundation, New Administrative Capital, Egypt.
Isoflavones are considered one of the most extensively studied plant-derived
phytoestrogenic compounds. Of these, Biochanin A (Bio-A), a natural isoflavone
abundant in cabbage, alfalfa, and red clover, has drawn a lot of attention. As
reported in multiple studies, Bio-A possesses a promising anticancer activity
against estrogen receptor-positive (ER+) breast cancer. The current study
investigated the working hypothesis that Bio-A could synergistically enhance the
potency of 5-fluorouracil (5-FU) in ER+ breast cancer. The hypothesis was tested
both in vitro on hormone receptor-positive (MCF-7) and triple-negative breast
cancer cells (MDA-MB231). Additionally, in vivo studies were performed in the
Ehrlich solid-phase carcinoma mouse model. The in vitro cytotoxicity studies
revealed that Bio-A synergistically increased the potency of 5-FU in both MCF-7
and MDA-MB231 cell lines. The synergistic effect of 5-FU/Bio-A combination was
verified in vivo. The combination therapy (where 5-FU was used at one fourth its
full dose) led to a significant 75% reduction in tumor volume after two
treatment cycles. This was in addition to producing a significant 2.1-fold
increase in tumor necrosis area% compared to mock-treated control. In
conclusion, the current study presents the first preclinical evidence for the
potential merit of 5-FU/Bio-A combination for the treatment of ER+ breast
cancer. The synergistic antitumor effect of Bio-A/ 5-FU combination can be, at
least partly, attributed to Bio-A-mediated suppression of ER-α/Akt axis and the
augmentation of 5-FU-mediated proapoptotic effects. © 2022 John Wiley & Sons,
Ltd.
DOI: 10.1002/ptr.7388
106. Microorganisms. 2021 Dec 31;10(1):91. doi: 10.3390/microorganisms10010091.
Legumes and Legume-Based Beverages Fermented with Lactic Acid Bacteria as a

Potential Carrier of Probiotics and Prebiotics.
Cichońska P(1), Ziarno M(1).
Author information:
(1)Department of Food Technology and Assessment, Institute of Food Science,
Warsaw University of Life Sciences-SGGW (WULS-SGGW), 02-787 Warsaw, Poland.
Fermentation is widely used in the processing of dairy, meat, and plant

products. Due to the growing popularity of plant diets and the health benefits
of consuming fermented products, there has been growing interest in the
fermentation of plant products and the selection of microorganisms suitable for
this process. The review provides a brief overview of lactic acid bacteria (LAB)
and their use in fermentation of legumes and legume-based beverages. Its scope
also extends to prebiotic ingredients present in legumes and legume-based
beverages that can support the growth of LAB. Legumes are a suitable matrix for
the production of plant-based beverages, which are the most popular products
among dairy alternatives. Legumes and legume-based beverages have been
successfully fermented with LAB. Legumes are a natural source of ingredients
with prebiotic properties, including oligosaccharides, resistant starch,
polyphenols, and isoflavones. These compounds provide a broad range of important
physiological benefits, including anti-inflammatory and immune regulation, as
well as anti-cancer properties and metabolic regulation. The properties of
legumes make it possible to use them to create synbiotic food, which is a source
of probiotics and prebiotics.
DOI: 10.3390/microorganisms10010091
PMCID: PMC8779895
PMID: 35056540
107. Inflammopharmacology. 2022 Feb;30(1):111-136. doi: 10.1007/s10787-021-00895-8.

Epub 2022 Jan 15.
Therapeutic benefits of flavonoids against neuroinflammation: a systematic

review.
Hamsalakshmi(1), Alex AM(1), Arehally Marappa M(2), Joghee S(3), Chidambaram

SB(4)(5).
Author information:
(1)Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher
Education & Research, Mysuru, 570015, Karnataka, India.
(2)Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher
(3)Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher
Education & Research, Mysuru, 570015, Karnataka, India. jsuresh@jssuni.edu.in.
(4)Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher
saravanababu.c@jssuni.edu.in.
(5)Centre for Experimental Pharmacology and Toxicology (CPT), Central Animal
Facility, JSS Academy of Higher Education & Research, Mysuru, 570015, Karnataka,
India. saravanababu.c@jssuni.edu.in.
Flavonoids are an important class of natural polyphenolic compounds reported to

exert beneficial effects in cardiovascular and metabolic diseases, cancer,
autoimmune and neurological disorders. Flavonoids possess potential antioxidant,
anti-inflammatory, antiapoptotic and immuno-modulation properties. Intriguingly,
the importance of flavonoids in different neurological disorders is gaining more
attention due to the safety, better pharmacokinetic profile and blood-brain
barrier penetration, cost-effectiveness and readiness for clinical uses/trials.
Many in vitro and in vivo research studies have established the neuroprotective
mechanism of flavonoids in the central nervous system (CNS) diseases. The
present review summarizes the benefits of various classes of flavonoids
(flavones, flavonols, flavanones, anthocyanidins, isoflavones, flavanols),
chemical nature, classification, their occurrence and distribution,
pharmacokinetics and bioavailability. The manuscript also presents available
evidences relating to the role of flavonoids in regulating key signaling
pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-κB) pathway, mitogen-activated protein kinase (MAPK) pathway, Janus kinase
and signal transducer and activator of transcription proteins (JAK/STAT)
pathway, Toll-like receptors (TLR) pathway, nuclear factor erythroid 2-related
factor 2 (Nrf2) pathway and cAMP response element-binding protein (CREB) pathway
involved in neuroinflammation associated with major neurological disorders.
Literature search was conducted using electronic databases like Google Scholar,
Scopus, PubMed central, Springer search and Web of science. Chemical structures
used in the present analysis were drawn using Chemdraw Professional 15.0
software. This collective information provides comprehensive knowledge on
disease pathways and therapeutic benefits of flavonoids in neurological
disorders, druggability and future scope for research.
© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland

AG.
DOI: 10.1007/s10787-021-00895-8
108. Turk J Pharm Sci. 2021 Dec 31;18(6):799-810. doi:

10.4274/tjps.galenos.2020.79106.
Isoflavones in Soybean as a Daily Nutrient: The Mechanisms of Action and How

They Alter the Pharmacokinetics of Drugs.
Soyata A(1), Hasanah AN(2), Rusdiana T(1).
Author information:
(1)Padjadjaran University Faculty of Pharmacy, Department of Pharmaceutics and
Pharmaceutical Technology, Sumedang, Indonesia.
(2)Padjadjaran University Faculty of Pharmacy, Department of Analysis of
Pharmaceutical and Medical Chemistry, Sumedang, Indonesia.
Soybeans [Glycine max (L.)] are a good source of isoflavones. The main
isoflavone components of soybean are daidzein, genistein, and glycitein. World
soybean production is very high. Because of its pharmacological activity, soy
isoflavone intake over a long period of time may result in interactions with the
drugs. This review summarizes soy isoflavone-drug interactions based on the
pharmacokinetic parameters. Soy isoflavones have pharmacokinetic interactions
with celecoxib, theophylline, paclitaxel, midazolam, imatinib, carbamazepine,
valproic acid, repaglinide, omeprazole and danofloxacin. This is due to the
changes in the area under the curve, maximum serum concentration, time that a
drug is present at the maximum concentration in serum, clearance and half-life
of the drugs when delivered together with soy isoflavones. The mechanisms of
pharmacokinetic interactions occurs through the inhibition/induction of drug
metabolizing cytochrome P450 (CYP450) enzymes such as CYP3A4, CYP2A1, and CYP2C9
or through the inhibition of drug transporters such as P-glycoprotein and breast
cancer resistance protein. Thus, the consumption of soybean, soy isoflavones or
soy products with drugs needs to be reconsidered.
DOI: 10.4274/tjps.galenos.2020.79106
PMCID: PMC8744443
PMID: 34979737
Conflict of interest statement: Conflict of interest: No conflict of interest

was declared by the authors. The authors alone are responsible for the content
and writing of this article.
Antioxidant Potential and Cytotoxic Effect of Isoflavones Extract from Thai

Fermented Soybean (Thua-Nao).
Kulprachakarn K(1)(2), Chaipoot S(3), Phongphisutthinant R(3)(4), Paradee N(5),

Prommaban A(5), Ounjaijean S(1)(2), Rerkasem K(2)(6), Parklak W(2), Prakit K(7),
Saengsitthisak B(7), Chansiw N(8), Pangjit K(9), Boonyapranai K(2).
Author information:
(1)School of Health Sciences Research, Research Institute for Health Sciences,
Chiang Mai University, Chiang Mai 50200, Thailand.
(2)Environmental and Occupational Health Sciences and Non Communicable Diseases
Research Group (EOHS and NCD Research Group), Research Institute for Health
Sciences, Chiang Mai University, Chiang Mai 50200, Thailand.
(3)Science and Technology Research Institute, Chiang Mai University, Chiang Mai
50200, Thailand.
(4)Center of Excellent in Microbial Diversity and Sustainable Utilization,
Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.
(5)Oxidative Stress Cluster, Department of Biochemistry, Faculty of Medicine,
Chiang Mai University, Chiang Mai 50200, Thailand.
(6)Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai
50200, Thailand.
(7)Faculty of Pharmacy, Payap University, Chiang Mai 50000, Thailand.
(8)School of Medicine, Mae Fah Luang University, Chiang Rai 57100, Thailand.
(9)College of Medicine and Public Health, Ubon Ratchathani University, Ubon
Ratchathani 34190, Thailand.
Thua-nao, or Thai fermented soybeans, is a traditional Lanna fermented food in

Northern Thailand. It is produced by using a specific bacterial species called
Bacillus subtilis var. Thua-nao. We investigated the antioxidant activity and
cytotoxic effect of isoflavones from Thua-nao. The phenolic compound contents
and total flavonoid contents were determined by spectrophotometry. The
antioxidant activity was examined using the ABTS, FRAP, and DPPH assays. The
isoflavone contents and phenolic compositions were examined by the
high-performance liquid chromatography (HPLC) and liquid chromatography-mass
spectrometry (LC-MS) techniques. The ability of isoflavones to inhibit human
cancer cell growth was assessed by the MTT assay. The total phenolic content,
total flavonoid content, and antioxidant activities of the isoflavones were
49.00 ± 0.51 mg GAE/g of dry extract (DE), 10.76 ± 0.82 mg QE/g of DE, 61.03 ±
0.97 µmol Trolox/g of DE, 66.54 ± 3.97 µM FeSO4/g of DE, and 22.47 ± 1.92% of
DPPH inhibition, respectively. Additionally, the isoflavone extracts from
Thua-nao had high isoflavone contents and polyphenolic compound compositions,
especially daidzein and genistein. The isoflavone demonstrated a weak inhibition
of MCF-7 and HEK293 cancer cell growth. It has a high antioxidant component,
which is beneficial and can be developed for new therapeutic uses. However,
further studies on the benefits of Thua-nao should be performed for realizing
better and more effective uses soon.
PMCID: PMC8705088
110. Antioxidants (Basel). 2021 Dec 20;10(12):2027. doi: 10.3390/antiox10122027.
A Correlation Study on In Vitro Physiological Activities of Soybean Cultivars,

19 Individual Isoflavone Derivatives, and Genetic Characteristics.
Chu HN(1), Lee SJ(1), Wang X(2), Lee SH(1), Yoon HM(2), Hwang YJ(1), Jung ES(1),
Kwon Y(1), Wee CD(1), Jang KA(1), Kim HR(1).
Author information:
(1)Department of Agro-Food Resources, National Institute of Agricultural
Sciences, Wanju 55365, Korea.
(2)National Agrobiodiversity Center, National Institute of Agricultural
Sciences, Jeonju 54874, Korea.
The functionality of soybeans is an important factor in the selection and

utilization of excellent soybean cultivars, and isoflavones are representative
functional substances in soybeans, which exhibit effects on antioxidants,
estrogen activity, and cancer, and prevent cardiovascular diseases. This study
analyzed ABTS, DPPH, estrogen, ER (ER) alpha, UCP-1, and NO inhibition
activities in 48 types of soybean cultivars, as well as the relationship with 19
isolated types of individual isoflavone derivatives. Statistical analysis was
conducted to find individual isoflavone derivatives affecting physiological
activities, revealing the high correlation of three types of derivatives:
genistein 7-O-(6″-O-acetyl)glucoside (6″-O-acetylgenistin), genistein
7-O-(2″-O-apiosyl)glucoside, and glycitein. Based on these results, 15 types of
soybean cultivars were selected (one control type, seven yellow types, six black
types, and one green type), which have both high physiological activities and a
high content of individual isoflavone derivatives. In addition, these high
correlations were further verified through a genome-wide association study
(GWAS) to determine the association between activities, substances, and genetic
characteristics. This study comprehensively describes the relationship between
the specific physiological activities of soybean resources, individual
isoflavone derivative substances, and SNPs, which will be utilized for in-depth
research, such as selection of excellent soybean resources with specific
physiological activities.
DOI: 10.3390/antiox10122027
PMCID: PMC8698514
PMID: 34943130
111. Antioxidants (Basel). 2021 Dec 19;10(12):2014. doi: 10.3390/antiox10122014.
Flavonoids Present in Propolis in the Battle against Photoaging and Psoriasis.
Rivera-Yañez CR(1), Ruiz-Hurtado PA(2), Mendoza-Ramos MI(3)(4), Reyes-Reali

J(3)(4), García-Romo GS(3)(4), Pozo-Molina G(3)(5), Reséndiz-Albor AA(6),
Nieto-Yañez O(3), Méndez-Cruz AR(3)(4), Méndez-Catalá CF(5)(7), Rivera-Yañez
N(3)(7).
Author information:
(1)Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de
Mexico, Tlalnepantla 54090, Mexico.
(2)Laboratorio de Toxicología de Productos Naturales, Departamento de Farmacia,
IPN, Escuela Nacional de Ciencias Biológicas, Av. Wilfrido Massieu, Gustavo A.
Madero 07738, Mexico.
(3)Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala,
Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico.
(4)Laboratorio de Inmunología, Unidad de Morfofisiología y Función, Facultad de
Estudios Superiores Iztacala, Universidad Nacional Autónoma de Mexico,
Tlalnepantla 54090, Mexico.
(5)Laboratorio de Genética y Oncología Molecular, Laboratorio 5, Edificio A4,
Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de
Mexico, Tlalnepantla 54090, Mexico.
(6)Laboratorio de Inmunidad de Mucosas, Sección de Estudios de Posgrado e
Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional,
Salvador Díaz Mirón y Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo
Tomas, Mexico City 11340, Mexico.
(7)División de Investigación y Posgrado, Facultad de Estudios Superiores
Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla 54090, Mexico.
The skin is the main external organ. It protects against different types of
potentially harmful agents, such as pathogens, or physical factors, such as
radiation. Skin disorders are very diverse, and some of them lack adequate and
accessible treatment. The photoaging of the skin is a problem of great relevance
since it is related to the development of cancer, while psoriasis is a chronic
inflammatory disease that causes scaly skin lesions and deterioration of the
lifestyle of people affected. These diseases affect the patient's health and
quality of life, so alternatives have been sought that improve the treatment for
these diseases. This review focuses on describing the properties and benefits of
flavonoids from propolis against these diseases. The information collected shows
that the antioxidant and anti-inflammatory properties of flavonoids play a
crucial role in the control and regulation of the cellular and biochemical
alterations caused by these diseases; moreover, flavones, flavonols, flavanones,
flavan-3-ols, and isoflavones contained in different worldwide propolis samples
are the types of flavonoids usually evaluated in both diseases. Therefore, the
research carried out in the area of dermatology with bioactive compounds of
different origins is of great relevance to developing preventive and therapeutic
approaches.
DOI: 10.3390/antiox10122014
PMCID: PMC8698766
PMID: 34943117
112. Mech Ageing Dev. 2021 Dec;200:111596. doi: 10.1016/j.mad.2021.111596. Epub

2021
Nov 10.
Lifelong soya consumption in males does not increase lifespan but increases
health span under a metabolic stress such as type 2 diabetes mellitus.
Borrás C(1), Abdelaziz KM(2), Díaz A(3), Gambini J(4), Jové M(5), López-Grueso
R(6), Mas-Bargues C(7), Monleón D(8), Pamplona R(9), Viña J(10).
Author information:
(1)Freshage Research Group, Department of Physiology, Faculty of Medicine,
University of Valencia, and CIBERFES, Insitute of Health Research-INCLIVA,
Spain. Electronic address: consuelo.borras@uv.es.
Spain. Electronic address: moabk@alumni.uv.es.
(3)Unidad Central de Investigación Biomédica (UCIM), Universidad de Valencia,
Valencia, Spain. Electronic address: ana.diaz@uv.es.
Spain. Electronic address: juan.gambini@uv.es.
(5)Department of Experimental Medicine, University of Lleida-Institute for
Research in Biomedicine of Lleida (UdL-IRBLleida), Lleida, Spain. Electronic
address: mariona.jove@udl.cat.
Spain. Electronic address: raul.lopez@uv.es.
Spain. Electronic address: cristina.mas@uv.es.
(8)Department of Pathology, Faculty of Medicine, University of Valencia,
CIBERFES, INCLIVA, Spain. Electronic address: daniel.monleon@uv.es.
(9)Department of Experimental Medicine, University of Lleida-Institute for
Research in Biomedicine of Lleida (UdL-IRBLleida), Lleida, Spain. Electronic
address: reinald.pamplona@udl.cat.
Spain. Electronic address: jose.vina@uv.es.
Soya consumption can decrease oxidative stress in animal models. Moreover,

phytoestrogens such as genistein, present in soya, can mimic some of the
beneficial effects of estrogens and are devoid of significant side effects, such
as cancer. In this study, we have performed a controlled lifelong study with
male OF1 mice that consumed either a soya-free diet or a soya-rich diet. We show
that, although we found an increase in the expression and activity of
antioxidant enzymes in soya-consuming mice, it did not increase lifespan. We
reasoned that the soya diet could not increase lifespan in a very healthy
population, but perhaps it could extend health span in stressed animals such as
type 2 diabetic Goto Kakizaki (GK) rats. Indeed, this was the case: we found
that male GK rats consuming a soya-rich diet developed the disease at a lower
rate and, therefore, lived longer than soya-free diet-consuming rats.
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.mad.2021.111596
113. Br J Nutr. 2022 Oct 28;128(8):1490-1498. doi: 10.1017/S0007114521004463. Epub

2021 Nov 12.
Metabolomics profiles of premenopausal women are different based on

O-desmethylangolensin metabotype.
Frankenfeld CL(1)(2), Maskarinec G(3), Franke AA(3).
Author information:
(1)George Mason University, Department of Global and Community Health, Fairfax,
VA, USA.
(2)George Mason University, MicroBiome Analysis Center, Manassas, VA, USA.
(3)Population Sciences in the Pacific, University of Hawaii Cancer Center,
Honolulu, Hawaii, USA.
Urinary O-desmethylangolensin (ODMA) concentrations provide a functional gut

microbiome marker of dietary isoflavone daidzein metabolism to ODMA. Individuals
who do not have gut microbial environments that produce ODMA have less
favourable cardiometabolic and cancer risk profiles. Urinary metabolomics
profiles were evaluated in relation to ODMA metabotypes within and between
individuals over time. Secondary analysis of data was conducted from the BEAN2
trial, which was a cross-over study of premenopausal women consuming 6 months on
a high and a low soya diet, each separated by a 1-month washout period. In all
of the 672 samples in the study, sixty-six of the eighty-four women had the same
ODMA metabotype at seven or all eight time points. Two or four urine samples per
woman were selected based on temporal metabotypes in order to compare within and
across individuals. Metabolomics assays for primary metabolism and biogenic
amines were conducted in sixty urine samples from twenty women. Partial
least-squares discriminant analysis was used to compare metabolomics profiles.
For the same ODMA metabotype across different time points, no profile
differences were detected. For changes in metabotype within individuals and
across individuals with different metabotypes, distinct metabolomes emerged.
Influential metabolites (variables importance in projection score > 2) included
several phenolic compounds, carnitine and derivatives, fatty acid and amino acid
metabolites and some medications. Based on the distinct metabolomes of producers
v. non-producers, the ODMA metabotype may be a marker of gut microbiome
functionality broadly involved in nutrient and bioactive metabolism and should
be evaluated for relevance to precision nutrition initiatives.
DOI: 10.1017/S0007114521004463
PMCID: PMC9095764
Conflict of interest statement: CONFLICT OF INTEREST The authors declare no

financial or personal conflicts of interest.
114. Am J Clin Nutr. 2022 Mar 4;115(3):643-651. doi: 10.1093/ajcn/nqab358.
Phytoestrogens and lung cancer risk: a nested case-control study in

never-smoking Chinese women.
Li M(1), Cai Q(1), Gao YT(2), Franke AA(3), Zhang X(4), Zhao Y(1), Wen W(1), Lan
Q(5), Rothman N(5), Shyr Y(6), Shu XO(1), Zheng W(1), Yang G(1).
Author information:
(1)Division of Epidemiology, Department of Medicine, Vanderbilt University
Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
(2)Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University
School of Medicine, Shanghai, China.
(3)University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu,
HI, USA.
(4)Tennessee Department of Health, Nashville, TN, USA.
(5)Division of Cancer Epidemiology and Genetics, Occupational and Environmental
Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA.
(6)Department of Biostatistics, Vanderbilt University Medical Center, Nashville,
TN, USA.
BACKGROUND: Since several lines of evidence suggest that estrogens may be

involved in lung carcinogenesis, it has been hypothesized that intake of
phytoestrogens, similar in molecular structure to mammalian estrogens, may be
associated with lung cancer development.
OBJECTIVE: The aim was to prospectively evaluate the association between
phytoestrogen exposure and lung cancer risk in never-smoking women.
METHODS: We conducted a nested case-control study within a population-based
prospective cohort study of women. A total of 478 incident lung cancer cases and
their individually matched controls were identified among never-smoking women
after a mean follow-up of 15.6 years. Habitual intake of and internal exposure
to phytoestrogens were assessed by repeated dietary surveys and urinary
biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in
conditional logistic regression models.
RESULTS: After adjustment for potential confounders, a moderate intake of
dietary isoflavones was inversely associated with lung cancer risk in
never-smoking women, with the OR for the second quartile vs. the lowest quartile
of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not
convey additional benefits, with ORs (95% CI) for the third and fourth quartiles
of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and
P-nonlinearity = 0.006). A similar association was seen when exposure to
isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second,
third, and fourth quartiles compared with the lowest quartile of urinary
isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41,
0.86), respectively. The inverse association reached a plateau beyond the second
quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of
gut-microbiota-derived metabolites of lignans was not related to lung cancer
risk.
CONCLUSIONS: This study suggests that moderately increasing intake of
isoflavone-rich foods is associated with lower risk of lung cancer in
never-smoking women.
© The Author(s) 2021. Published by Oxford University Press on behalf of the

American Society for Nutrition.
DOI: 10.1093/ajcn/nqab358
PMCID: PMC8895217
115. Environ Int. 2022 Jan;158:106940. doi: 10.1016/j.envint.2021.106940. Epub 2021

Oct 18.
Elucidation of xenoestrogen metabolism by non-targeted, stable isotope-assisted

mass spectrometry in breast cancer cells.
Flasch M(1), Bueschl C(2), Del Favero G(1), Adam G(3), Schuhmacher R(4), Marko
D(1), Warth B(5).
Author information:
(1)University of Vienna, Faculty of Chemistry, Department of Food Chemistry and
Toxicology, Währinger Str. 38, 1090 Vienna, Austria.
(2)University of Natural Resources and Life Sciences, Vienna (BOKU), Department
of Agrobiotechnology, IFA-Tulln, Institute of Bioanalytics and
Agro-Metabolomics, Konrad-Lorenz-Str. 20, 3430 Tulln, Austria; University of
Vienna, Faculty of Chemistry, Department of Analytical Chemistry, Währinger Str.
38, 1090 Vienna, Austria.
of Applied Genetics and Cell Biology, Institute of Microbial Genetics,
Konrad-Lorenz-Str. 24, 3430 Tulln, Austria.
of Agrobiotechnology, IFA-Tulln, Institute of Bioanalytics and
Agro-Metabolomics, Konrad-Lorenz-Str. 20, 3430 Tulln, Austria.
(5)University of Vienna, Faculty of Chemistry, Department of Food Chemistry and
Toxicology, Währinger Str. 38, 1090 Vienna, Austria. Electronic address:
benedikt.warth@univie.ac.at.
Environmental exposure to xenoestrogens, i.e., chemicals that imitate the

hormone 17β-estradiol, has the potential to influence hormone homeostasis and
action. Detailed knowledge of xenobiotic biotransformation processes in cell
models is key when transferring knowledge learned from in vitro models to in
vivo relevance. This study elucidated the metabolism of two naturally-occurring
phyto- and mycoestrogens; namely genistein and zearalenone, in an estrogen
receptor positive breast cancer cell line (MCF-7) with the aid of stable
isotope-assisted metabolomics and the bioinformatic tool MetExtract II.
Metabolism was studied in a time course experiment after 2 h, 6 h and 24 h
incubation. Twelve and six biotransformation products of zearalenone and
genistein were detected, respectively, clearly demonstrating the abundant
xenobiotic biotransformation capability of the cells. Zearalenone underwent
extensive phase-I metabolism resulting in α-zearalenol (α-ZEL), a molecule known
to possess a significantly higher estrogenicity, and several phase-II
metabolites (sulfo- and glycoconjugates) of the native compound and the major
phase I metabolite α-ZEL. Moreover, potential adducts of zearalenone with a
vitamin and several hydroxylated metabolites were annotated. Genistein
metabolism resulted in sulfation, combined sulfation and hydroxylation,
acetylation, glucuronidation and unexpectedly adduct formation with pentose- and
hexose sugars. Kinetics of metabolite formation and subsequent excretion into
the extracellular medium revealed a time-dependent increase in most
biotransformation products. The untargeted elucidation of biotransformation
products formed during cell culture experiments enables an improved and more
meaningful interpretation of toxicological assays and has the potential to
identify unexpected or unknown metabolites.
DOI: 10.1016/j.envint.2021.106940
116. J Food Biochem. 2021 Nov;45(11):e13972. doi: 10.1111/jfbc.13972. Epub 2021 Oct
19.
Cellular and molecular mechanisms of genistein in prevention and treatment of

diseases: An overview.
Nazari-Khanamiri F(1), Ghasemnejad-Berenji M(2)(3).
Author information:
(1)Student Research Committee, Urmia University of Medical Sciences, Urmia,
Iran.
(2)Experimental and Applied Pharmaceutical Research Center, Urmia University of
Medical Sciences, Urmia, Iran.
(3)Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia
University of Medical Sciences, Urmia, Iran.
Genistein is the simplest secondary metabolite in soybeans and belongs to a

group of compounds called isoflavones. It is a phytoestrogen and it makes up
more than 60% of soy isoflavones. Studies have shown the anti-inflammatory,
anti-apoptotic, and anti-angiogenic effects of genistein in addition to its
modulatory effects on steroidal hormone receptors. In this review, we discuss
the pharmacologic and therapeutic effects of genistein on various diseases.
PRACTICAL APPLICATIONS: In this review, we have discussed the therapeutic
effects of genistein as the main constituent of soybeans on health conditions.
Its antioxidant, anti-inflammatory, anti-apoptotic and, anti-angiogenic effects
need more attention. The pharmacological properties of genistein make this
natural isoflavone a potential treatment for various diseases such as
postmenopausal symptoms, cancer, bone, brain, and heart diseases. Special
emphasis should be given to it, resulting in using it in clinical as a safe,
potent, and bioactive molecule.
© 2021 Wiley Periodicals LLC.
DOI: 10.1111/jfbc.13972
117. Oxid Med Cell Longev. 2021 Sep 9;2021:6331630. doi: 10.1155/2021/6331630.
eCollection 2021.
Therapeutic Potential of Isoflavones with an Emphasis on Daidzein.
Alshehri MM(1), Sharifi-Rad J(2), Herrera-Bravo J(3)(4), Jara EL(3), Salazar

LA(4), Kregiel D(5), Uprety Y(6), Akram M(7), Iqbal M(8), Martorell M(9),
Torrens-Mas M(10), Pons DG(11), Daştan SD(12)(13), Cruz-Martins N(14)(15)(16),
Ozdemir FA(17), Kumar M(18), Cho WC(19).
Author information:
(1)Pharmaceutical Care Department, Ministry of National Guard-Health Affairs,
Riyadh, Saudi Arabia.
(2)Phytochemistry Research Center, Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
(3)Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo
Tomas, Chile.
(4)Center of Molecular Biology and Pharmacogenetics, Scientific and
Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230,
Chile.
(5)Department of Environmental Biotechnology, Lodz University of Technology,
Wolczanska 171/173, 90-924 Lodz, Poland.
(6)Amrit Campus, Tribhuvan University, Kathmandu, Nepal.
(7)Department of Eastern Medicine and Surgery, Directorate of Medical Sciences,
GC University Faisalabad, Pakistan.
(8)Institute of Health Management, Dow University of Health Sciences, Karachi,
Pakistan.
(9)Department of Nutrition and Dietetics, Faculty of Pharmacy and Centre for
Healthy Living, University of Concepción, 4070386 Concepción, Chile.
(10)Translational Research In Aging and Longevity (TRIAL Group), Health Research
Institute of the Balearic Islands (IdISBA), 07122 Palma, Spain.
(11)Grupo Multidisciplinar de Oncología Traslacional (GMOT), Institut
Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les
Illes Balears (UIB), Instituto de Investigación Sanitaria Illes Balears
(IdISBa), 07122 Palma, Spain.
(12)Department of Biology, Faculty of Science, Sivas Cumhuriyet University,
58140 Sivas, Turkey.
(13)Beekeeping Development Application and Research Center, Sivas Cumhuriyet
University, 58140 Sivas, Turkey.
(14)Faculty of Medicine, University of Porto, Alameda Professor Hernâni
Monteiro, 4200-319 Porto, Portugal.
(15)Institute for Research and Innovation in Health (i3S), University of Porto,
4200-135 Porto, Portugal.
(16)Institute of Research and Advanced Training in Health Sciences and
Technologies (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra, PRD,
Portugal.
(17)Department of Molecular Biology and Genetics, Faculty of Science and Art,
Bingol University, Bingol 1200, Turkey.
(18)Chemical and Biochemical Processing Division, ICAR-Central Institute for
Research on Cotton Technology, Mumbai 400019, India.
(19)Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong
Kong.
Daidzein is a phytoestrogen isoflavone found in soybeans and other legumes. The

chemical composition of daidzein is analogous to mammalian estrogens, and it
could be useful with a dual-directional purpose by substituting/hindering with
estrogen and estrogen receptor (ER) complex. Hence, daidzein puts forth
shielding effects against a great number of diseases, especially those
associated with the control of estrogen, such as breast cancer, diabetes,
osteoporosis, and cardiovascular disease. However, daidzein also has other
ER-independent biological activities, such as oxidative damage reduction acting
as an antioxidant, immune regulator as an anti-inflammatory agent, and apoptosis
regulation, directly linked to its potential anticancer effects. In this sense,
the present review is aimed at providing a deepen analysis of daidzein
pharmacodynamics and its implications in human health, from its best-known
effects alleviating postmenopausal symptoms to its potential anticancer and
antiaging properties.
Copyright © 2021 Mohammed M. Alshehri et al.

DOI: 10.1155/2021/6331630
PMCID: PMC8448605
Conflict of interest statement: The authors declare that they have no conflicts
of interest.
118. Int J Mol Sci. 2021 Aug 16;22(16):8783. doi: 10.3390/ijms22168783.
Anti-Cancer and Electrochemical Properties of Thiogenistein-New Biologically

Active Compound.
Stolarczyk EU(1), Strzempek W(2)(3), Łaszcz M(1), Leś A(4), Menaszek E(3),
Sidoryk K(5), Stolarczyk K(4).
Author information:
(1)Research Analytics Team, Analytical Department, Łukasiewicz Research
Network-Industrial Chemistry Institute, 8 Rydygiera Street, 01-793 Warsaw,
Poland.
(2)Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Street, 30-387
Krakow, Poland.
(3)Faculty of Pharmacy, Collegium Medicum, Jagiellonian University, 9 Medyczna
Street, 30-068 Krakow, Poland.
(4)Faculty of Chemistry, University of Warsaw, 1 Pasteura Street, 02-093 Warsaw,
Poland.
(5)Chemistry Group, Department of Pharmacy, Cosmetic Chemistry and
Biotechnology, Łukasiewicz Research Network-Industrial Chemistry Institute, 8
Rydygiera Street, 01-793 Warsaw, Poland.
Pharmacological and nutraceutical effects of isoflavones, which include

genistein (GE), are attributed to their antioxidant activity protecting cells
against carcinogenesis. The knowledge of the oxidation mechanisms of an active
substance is crucial to determine its pharmacological properties. The aim of the
present work was to explain complex oxidation processes that have been simulated
during voltammetric experiments for our new thiolated genistein analog (TGE)
that formed the self-assembled monolayer (SAM) on the gold electrode. The thiol
linker assured a strong interaction of sulfur nucleophiles with the gold
surface. The research comprised of the study of TGE oxidative properties,
IR-ATR, and MALDI-TOF measurements of SAM before and after electrochemical
oxidation. TGE has been shown to be electrochemically active. It undergoes one
irreversible oxidation reaction and one quasi-reversible oxidation reaction in
PBS buffer at pH 7.4. The oxidation of TGE results in electroactive products
composed likely from TGE conjugates (e.g., trimers) as part of polymer. The
electroactive centers of TGE and its oxidation mechanism were discussed using IR
supported by quantum chemical and molecular mechanics calculations. Preliminary
in-vitro studies indicate that TGE exhibits higher cytotoxic activity towards
DU145 human prostate cancer cells and is safer for normal prostate epithelial
cells (PNT2) than genistein itself.
DOI: 10.3390/ijms22168783
PMCID: PMC8395759
119. Int J Environ Res Public Health. 2021 Aug 4;18(16):8254. doi:
10.3390/ijerph18168254.
Soy and Frequent Dairy Consumption with Subsequent Equol Production Reveals
Decreased Gut Health in a Cohort of Healthy Puerto Rican Women.
Lacourt-Ventura MY(1), Vilanova-Cuevas B(2), Rivera-Rodríguez D(3),

Rosario-Acevedo R(1), Miranda C(4), Maldonado-Martínez G(4), Maysonet J(4)(5),
Vargas D(1), Ruiz Y(4)(5), Hunter-Mellado R(4)(5), Cubano LA(1), Dharmawardhane
S(6), Lampe JW(7), Baerga-Ortiz A(6), Godoy-Vitorino F(2), Martínez-Montemayor
MM(1).
Author information:
(1)Department of Biochemistry, School of Medicine, Universidad Central del
Caribe, Bayamón 00956, Puerto Rico.
(2)Department of Microbiology and Medical Zoology, Medical Sciences Campus,
University of Puerto Rico, San Juan 00921, Puerto Rico.
(3)Department of Biology, University of Puerto Rico, Bayamón 00959, Puerto Rico.
(4)Retrovirus Research Center, Internal Medicine Department, School of Medicine,
Universidad Central del Caribe, Bayamón 00956, Puerto Rico.
(5)Hematology and Oncology Group, HIMA-San Pablo Bayamón Hospital, Bayamón
00961, Puerto Rico.
(6)Department of Biochemistry, Medical Sciences Campus, University of Puerto
Rico, San Juan 00921, Puerto Rico.
(7)Fred Hutchinson Cancer Research Center, Division of Public Health Sciences,
Seattle, WA 98109, USA.
The U.S. Hispanic female population has one of the highest breast cancer (BC)
incidence and mortality rates, while BC is the leading cause of cancer death in
Puerto Rican women. Certain foods may predispose to carcinogenesis. Our previous
studies indicate that consuming combined soy isoflavones (genistein, daidzein,
and glycitein) promotes tumor metastasis possibly through increased protein
synthesis activated by equol, a secondary dietary metabolite. Equol is a
bacterial metabolite produced in about 20-60% of the population that harbor and
exhibit specific gut microbiota capable of producing it from daidzein. The aim
of the current study was to investigate the prevalence of equol production in
Puerto Rican women and identify the equol producing microbiota in this
understudied population. Herein, we conducted a cross-sectional characterization
of equol production in a clinically based sample of eighty healthy 25-50 year
old Puerto Rican women. Urine samples were collected and evaluated by GCMS for
the presence of soy isoflavones and metabolites to determine the ratio of equol
producers to equol non-producers. Furthermore, fecal samples were collected for
gut microbiota characterization on a subset of women using next generation
sequencing (NGS). We report that 25% of the participants were classified as
equol producers. Importantly, the gut microbiota from equol non-producers
demonstrated a higher diversity. Our results suggest that healthy women with soy
and high dairy consumption with subsequent equol production may result in gut
dysbiosis by having reduced quantities (diversity) of healthy bacterial
biomarkers, which might be associated to increased diseased outcomes (e.g.,
cancer, and other diseases).
DOI: 10.3390/ijerph18168254
PMCID: PMC8391519
120. Nat Prod Res. 2021 Aug;35(16):2744-2747. doi: 10.1080/14786419.2019.1660335.

Epub 2019 Sep 6.
Cytotoxicity of isoflavones from Millettia dura.
Buyinza D(1)(2), Yang LJ(3), Derese S(1), Ndakala A(1), Coghi P(3), Heydenreich
M(4), Wong VKW(3), Möller HM(4), Yenesew A(1).
Author information:
(1)Department of Chemistry, University of Nairobi, Nairobi, Kenya.
(2)Department of Chemistry, Kabale University, Kabale, Uganda.
(3)State Key Laboratory of Quality Research in Chinese Medicine, Macau
University of Science and Technology, Macau, China.
(4)Institut für Chemie, Universität Potsdam, Potsdam, Germany.
The first phytochemical investigation of the flowers of Millettia dura resulted

in the isolation of seven isoflavones, a flavonol and a chalcone. Eleven
isoflavones and a flavonol isolated from various plant parts from this plant
were tested for cytotoxicity against a panel of cell lines, and six of these
showed good activity with IC50 values of 6-14 μM. Durmillone was the most active
with IC50 values of 6.6 μM against A549 adenocarcinomic human alveolar basal
epithelial cancer cell line with low cytotoxicity against the non-cancerous cell
lines BEAS-2B (IC50 = 58.4 μM), LO2 hepatocytes (IC50 78.7 μM) and CCD19Lu
fibroblasts (IC50 >100 μM).
DOI: 10.1080/14786419.2019.1660335
121. Nutrients. 2021 Jul 5;13(7):2309. doi: 10.3390/nu13072309.
Effect of the Intake of Isoflavones on Risk Factors of Breast Cancer-A

Systematic Review of Randomized Controlled Intervention Studies.
Finkeldey L(1), Schmitz E(1), Ellinger S(1)(2).
Author information:
(1)Faculty of Nutrition and Food Sciences, Niederrhein, University of Applied
Sciences, Rheydter Street 277, 41065 Mönchengladbach, Germany.
(2)Department of Nutrition and Food Sciences, Human Nutrition, University of
Bonn, Meckenheimer Allee 166a, 53115 Bonn, Germany.
Epidemiological studies suggest that high intake of soy isoflavones may protect
against breast cancer, but causal relationships can only be established by
experimental trials. Thus, we aimed to provide a systematic review of randomized
controlled trials (RCTs) on the effect of an isoflavone intake on risk factors
of breast cancer in healthy subjects. After a systematic literature search in
PubMed, 18 different RCTs with pre- and/or postmenopausal women were included
and investigated for details according to the PRISMA guideline. In these
studies, isoflavones were provided by soy food or supplements in amounts between
36.5-235 mg/d for a period of 1-36 months. Breast density, estrogens including
precursors, metabolites, estrogen response such as length of menstrual cycle,
and markers of proliferation and inflammation were considered. However, in most
studies, differences were not detectable between isoflavone and control/placebo
treatment despite a good adherence to isoflavone treatment, irrespective of the
kind of intervention, the dose of isoflavones used, and the duration of
isoflavone treatment. However, the lack of significant changes in most studies
does not prove the lack of effects as a sample size calculation was often
missing. Taking into account the risk of bias and methodological limitations,
there is little evidence that isoflavone treatment modulates risk factors of
breast cancer in pre- and postmenopausal women. Future studies should calculate
the sample size to detect possible effects and consider methodological details
to improve the study quality.
DOI: 10.3390/nu13072309
PMCID: PMC8308688
122. Crit Rev Food Sci Nutr. 2023;63(2):261-287. doi:

10.1080/10408398.2021.1946006.
Epub 2021 Jul 12.
Isoflavones derived from plant raw materials: bioavailability, anti-cancer,

anti-aging potentials, and microbiome modulation.
Aboushanab SA(1), Khedr SM(2), Gette IF(1)(3), Danilova IG(1)(3), Kolberg NA(4),
Ravishankar GA(5), Ambati RR(6), Kovaleva EG(1).
Author information:
(1)Institute of Chemical Engineering, Ural Federal University named after the
first President of Russia B. N. Yeltsin, Yekaterinburg, Russia.
(2)Pharmaceutical and Fermentation Industries Development Center (PFIDC), City
of Scientific Research and Technological Applications, SRTA-City, Alexandria,
Egypt.
(3)Institute of Immunology and Physiology, Ural Branch of the Russian Academy of
Sciences, Yekaterinburg, Russia.
(4)Integrated Laboratory Complex, Ural State University of Economics,
Yekaterinburg, Russia.
(5)C. D. Sagar Centre for Life Sciences, Dayananda Sagar College of Engineering,
Dayananda Sagar Institutions, Bangalore, Karnataka, India.
(6)Department of Biotechnology, Vignan's Foundation of Science, Technology and
Research, Guntur, Andhra Pradesh, India.
Isoflavones are secondary metabolites that represent the most abundant category
of plant polyphenols. Dietary soy, kudzu, and red clover contain primarily
genistein, daidzein, glycitein, puerarin, formononetin, and biochanin A. The
structural similarity of these compounds to β-estradiol has demonstrated
protection against age-related and hormone-dependent diseases in both genders.
Demonstrative shreds of evidence confirmed the fundamental health benefits of
the consumption of these isoflavones. These relevant activities are complex and
largely driven by the source, active ingredients, dose, and administration
period of the bioactive compounds. However, the preclinical and clinical studies
of these compounds are greatly variable, controversial, and still with no
consensus due to the non-standardized research protocols. In addition,
absorption, distribution, metabolism, and excretion studies, and the safety
profile of isoflavones have been far limited. This highlights a major gap in
understanding the potentially critical role of these isoflavones as prospective
replacement therapy. Our general review exclusively focuses attention on the
crucial role of isoflavones derived from these plant materials and critically
highlights their bioavailability, possible anticancer, antiaging potentials, and
microbiome modulation. Despite their fundamental health benefits, plant
isoflavones reveal prospective therapeutic effects that worth further
standardized analysis.
DOI: 10.1080/10408398.2021.1946006
123. Am J Cancer Res. 2021 Jun 15;11(6):2590-2617. eCollection 2021.
A preclinical report of a cobimetinib-inspired novel anticancer small-molecule

scaffold of isoflavones, NSC777213, for targeting PI3K/AKT/mTOR/MEK in multiple
cancers.
Lawal B(1)(2), Lo WC(3)(4)(5), Mokgautsi N(1)(2), Sumitra MR(1)(2), Khedkar

H(1)(2), Wu AT(6)(7)(8)(9), Huang HS(1)(2)(10)(11).
Author information:
(1)PhD Program for Cancer Molecular Biology and Drug Discovery, College of
Medical Science and Technology, Taipei Medical University and Academia Sinica
Taipei 11031, Taiwan.
(2)Graduate Institute for Cancer Biology & Drug Discovery, College of Medical
Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
(3)Department of Surgery, Division of Neurosurgery, School of Medicine, College
of Medicine, Taipei Medical University Taipei 11031, Taiwan.
(4)Department of Neurosurgery, Taipei Medical University Hospital Taipei 11031,
Taiwan.
(5)Taipei Neuroscience Institute, Taipei Medical University Taipei 11031,
Taiwan.
(6)TMU Research Center of Cancer Translational Medicine, Taipei Medical
University Taipei 11031, Taiwan.
(7)The PhD Program of Translational Medicine, College of Science and Technology,
Taipei Medical University Taipei 11031, Taiwan.
(8)Clinical Research Center, Taipei Medical University Hospital, Taipei Medical
University Taipei 11031, Taiwan.
(9)Graduate Institute of Medical Sciences, National Defense Medical Center
(10)School of Pharmacy, National Defense Medical Center Taipei 11490, Taiwan.
(11)PhD Program in Biotechnology Research and Development, College of Pharmacy,
Taipei Medical University Taipei 11031, Taiwan.
Erratum in
Am J Cancer Res. 2021 Nov 15;11(11):5761.
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of

rapamycin (mTOR) and mitogen-activated protein kinase kinase/extracellular
signal-regulated kinase (MEK/ERK) signaling pathways are critical for normal
human physiology, and any alteration in their regulation leads to several human
cancers. These pathways are well interconnected and share a survival mechanism
for escaping the depressant effect of antagonists. Therefore, novel small
molecules capable of targeting both pathways with minimal or no toxicity are
better alternatives to current drugs, which are disadvantaged by their
accompanying resistance and toxicity. In this study, we demonstrate that the
PI3K/AKT/mTOR/MEK is a crucial oncoimmune signature in multiple cancers.
Moreover, we describe NSC777213, a novel isoflavone core and
cobimetinib-inspired small molecule, which exhibit both antiproliferative
activities against all panels of NCI60 human tumor cell lines (except COLO205
and HT29) and a selective cytotoxic preference for melanoma, non-small-cell lung
cancer (NSCLC), brain, renal, and ovarian cancer cell lines. Notably, for
NSC777213 treatment, chemoresistant ovarian cancer cell lines, including
SK-OV-3, OVCAR-3, OVCAR-4, and NCI/ADR-RES, exhibited a higher antiproliferative
sensitivity (total growth inhibition (TGI) = 7.62-31.50 µM) than did the
parental cell lines OVCAR-8 and IGROV1 (TGI > 100 µM). NSC777213 had a
mechanistic correlation with clinical inhibitors of PI3K/AKT/mTOR/MEK. NSC777213
demonstrates robust binding interactions and higher affinities for AKT and mTOR
than did isoflavone, and also demonstrate a higher affinity for human MEK-1
kinase than some MEK inhibitors under clinical developments. In addition,
treatment of U251 and U87MG cells with NSC777213 significantly downregulated the
expression levels of the total and phosphorylated forms of PI3K/AKT/mTOR/MEK.
Our study suggests that NSC777213 is a promising PI3K/AKT/mTOR/MEK inhibitor for
further preclinical and clinical evaluation as a chemotherapeutic agent,
particularly for the treatment of NSCLC, melanoma, and brain, renal, and ovarian
cancers.
AJCR Copyright © 2021.
PMCID: PMC8263676
PMID: 34249417
Conflict of interest statement: None.
124. Front Oncol. 2021 Jun 21;11:705903. doi: 10.3389/fonc.2021.705903. eCollection

2021.
Remodeling the Epigenetic Landscape of Cancer-Application Potential of

Flavonoids in the Prevention and Treatment of Cancer.
Jiang W(1), Xia T(1), Liu C(1), Li J(1), Zhang W(2), Sun C(3)(4).
Author information:
(1)College of First Clinical Medicine, Shandong University of Traditional
Chinese Medicine, Jinan, China.
(2)Clinical Medical Colleges, Weifang Medical University, Weifang, China.
(3)Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China.
(4)Qingdao Academy of Chinese Medical Sciences, Shandong University of
Traditional Chinese Medicine, Qingdao, China.
Epigenetics, including DNA methylation, histone modification, and noncoding RNA

regulation, are physiological regulatory changes that affect gene expression
without modifying the DNA sequence. Although epigenetic disorders are considered
a sign of cell carcinogenesis and malignant events that affect tumor progression
and drug resistance, in view of the reversible nature of epigenetic
modifications, clinicians believe that associated mechanisms can be a key target
for cancer prevention and treatment. In contrast, epidemiological and
preclinical studies indicated that the epigenome is constantly reprogrammed by
intake of natural organic compounds and the environment, suggesting the
possibility of utilizing natural compounds to influence epigenetics in cancer
therapy. Flavonoids, although not synthesized in the human body, can be consumed
daily and are common in medicinal plants, vegetables, fruits, and tea. Recently,
numerous reports provided evidence for the regulation of cancer epigenetics by
flavonoids. Considering their origin in natural and food sources, few side
effects, and remarkable biological activity, the epigenetic antitumor effects of
flavonoids warrant further investigation. In this article, we summarized and
analyzed the multi-dimensional epigenetic effects of all 6 subtypes of
flavonoids (including flavonols, flavones, isoflavones, flavanones, flavanols,
and anthocyanidin) in different cancer types. Additionally, our report also
provides new insights and a promising direction for future research and
development of flavonoids in tumor prevention and treatment via epigenetic
modification, in order to realize their potential as cancer therapeutic agents.
Copyright © 2021 Jiang, Xia, Liu, Li, Zhang and Sun.
DOI: 10.3389/fonc.2021.705903
PMCID: PMC8255972
PMID: 34235089
125. Antioxidants (Basel). 2021 Jun 30;10(7):1064. doi: 10.3390/antiox10071064.
Current Perspectives on the Beneficial Effects of Soybean Isoflavones and Their

Metabolites for Humans.
Kim IS(1).
Author information:
(1)Advanced Bio-Resource Research Center, Kyungpook National University, Daegu
41566, Korea.
Soybeans are rich in proteins and lipids and have become a staple part of the
human diet. Besides their nutritional excellence, they have also been shown to
contain various functional components, including isoflavones, and have
consequently received increasing attention as a functional food item.
Isoflavones are structurally similar to 17-β-estradiol and bind to estrogen
receptors (ERα and ERβ). The estrogenic activity of isoflavones ranges from a
hundredth to a thousandth of that of estrogen itself. Isoflavones play a role in
regulating the effects of estrogen in the human body, depending on the
situation. Thus, when estrogen is insufficient, isoflavones perform the
functions of estrogen, and when estrogen is excessive, isoflavones block the
estrogen receptors to which estrogen binds, thus acting as an estrogen
antagonist. In particular, estrogen antagonistic activity is important in the
breast, endometrium, and prostate, and such antagonistic activity suppresses
cancer occurrence. Genistein, an isoflavone, has cancer-suppressing effects on
estrogen receptor-positive (ER+) cancers, including breast cancer. It suppresses
the function of enzymes such as tyrosine protein kinase, mitogen-activated
kinase, and DNA polymerase II, thus inhibiting cell proliferation and inducing
apoptosis. Genistein is the most biologically active and potent isoflavone
candidate for cancer prevention. Furthermore, among the various physiological
functions of isoflavones, they are best known for their antioxidant activities.
S-Equol, a metabolite of genistein and daidzein, has strong antioxidative
effects; however, the ability to metabolize daidzein into S-equol varies based
on racial and individual differences. The antioxidant activity of isoflavones
may be effective in preventing dementia by inhibiting the phosphorylation of
Alzheimer's-related tau proteins. Genistein also reduces allergic responses by
limiting the expression of mast cell IgE receptors, which are involved in
allergic responses. In addition, they have been known to prevent and treat
various diseases, including cardiovascular diseases, metabolic syndromes,
osteoporosis, diabetes, brain-related diseases, high blood pressure,
hyperlipidemia, obesity, and inflammation. Further, it also has positive effects
on menstrual irregularity in non-menopausal women and relieving menopausal
symptoms in middle-aged women. Recently, soybean consumption has shown steep
increasing trend in Western countries where the intake was previously only
1/20-1/50 of that in Asian countries. In this review, I have dealt with the
latest research trends that have shown substantial interest in the biological
efficacy of isoflavones in humans and plants, and their related mechanisms.
DOI: 10.3390/antiox10071064
PMCID: PMC8301030
PMID: 34209224

126. Stroke. 2021 Aug;52(8):2661-2670. doi: 10.1161/STROKEAHA.120.032042. Epub 2021
Jun 23.
Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm.
Yokosuka K(#)(1), Rutledge C(#)(2), Kamio Y(#)(1), Kuwabara A(1), Sato H(1),
Rahmani R(1)(3), Purcell J(1), Eguchi S(4), Baranoski JF(1), Margaryan T(5),
Tovmasyan A(5), Ai J(1), Lawton MT(1)(6), Hashimoto T(1).
Author information:
(1)Barrow Aneurysm and AVM Research Center (K.Y., Y.K., A.K., H.S., R.R., J.P.,
J.F.B., J.A., M.T.L., T.H.), Barrow Neurological Institute, Phoenix, AZ.
(2)Department of Neurological Surgery, University of California, San Francisco
(C.R.).
(3)Department of Neurosurgery, University of Rochester Medical Center, NY
(R.R.).
(4)Cardiovascular Research Center, Lewis Katz School of Medicine at Temple
University, Philadelphia, PA (S.E.).
(5)Division of Neurobiology, Ivy Brain Tumor Center (T.M., A.T.), Barrow
Neurological Institute, Phoenix, AZ.
(6)Department of Neurosurgery (M.T.L.), Barrow Neurological Institute, Phoenix,
AZ.
(#)Contributed equally
BACKGROUND AND PURPOSE: The incidences of intracranial aneurysm and aneurysmal

subarachnoid hemorrhage are high in postmenopausal women. Although
population-based studies suggest that hormone replacement therapy is beneficial
for postmenopausal women with intracranial aneurysms, estrogen replacement may
no longer be recommended for the prevention of chronic diseases given its
association with adverse outcomes, such as cancer and ischemic stroke. The
isoflavone daidzein and its intestinal metabolite equol are bioactive
phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic
properties, we investigated whether the isoflavones daidzein and equol are
protective against the formation and rupture of intracranial aneurysms in a
mouse model of the postmenopausal state.
METHODS: We induced intracranial aneurysms in ovariectomized adult female mice
using a combination of induced systemic hypertension and a single injection of
elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free
diet with/without daidzein supplementation, or in a combination of
intraperitoneal equol, or oral vancomycin treatment. We also used estrogen
receptor beta knockout mice.
RESULTS: Both dietary daidzein and supplementation with its metabolite, equol,
were protective against aneurysm formation in ovariectomized mice. The
protective effects of daidzein and equol required estrogen receptor-β. The
disruption of the intestinal microbial conversion of daidzein to equol abolished
daidzein’s protective effect against aneurysm formation. Mice treated with equol
had lower inflammatory cytokines in the cerebral arteries, suggesting that
phytoestrogens modulate inflammatory processes important to intracranial
aneurysm pathogenesis.
CONCLUSIONS: Our study establishes that both dietary daidzein and its
metabolite, equol, protect against aneurysm formation in ovariectomized female
mice through the activation of estrogen receptor-β and subsequent suppression of
inflammation. Dietary daidzein’s protective effect required the intestinal
conversion to equol. Our results indicate the potential therapeutic value of
dietary daidzein and its metabolite, equol, for the prevention of the formation
of intracranial aneurysms and related subarachnoid hemorrhage.
DOI: 10.1161/STROKEAHA.120.032042
PMCID: PMC8366789
127. Breast Cancer. 2021 Nov;28(6):1283-1291. doi: 10.1007/s12282-021-01265-6. Epub

2021 Jun 13.
Association between dietary phytochemical index and breast cancer: a

case-control study.
Ghoreishy SM(1)(2), Aminianfar A(3), Benisi-Kohansal S(4), Azadbakht L(4),

Esmaillzadeh A(5)(6)(7).
Author information:
(1)Students' Scientific Research Center, Tehran University of Medical Sciences,
Tehran, Iran.
(2)Department of Clinical Nutrition, School of Nutritional Sciences and
Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
(3)Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan
University of Medical Sciences, Kashan, Iran.
(4)Department of Community Nutrition, School of Nutritional Sciences and
Dietetics, Tehran University of Medical Sciences, P.O. Box 14155-6117, Tehran,
Iran.
(5)Department of Community Nutrition, School of Nutritional Sciences and
Dietetics, Tehran University of Medical Sciences, P.O. Box 14155-6117, Tehran,
Iran. a-esmaillzadeh@sina.tums.ac.ir.
(6)Obesity and Eating Habits Research Center, Endocrinology and Metabolism
Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences,
Tehran, Iran. a-esmaillzadeh@sina.tums.ac.ir.
(7)Department of Community Nutrition, School of Nutrition and Food Science,
Isfahan University of Medical Sciences, Isfahan, Iran.
a-esmaillzadeh@sina.tums.ac.ir.
BACKGROUND: Dietary intake of isoflavones has been positively associated with

risk of breast cancer (BC) in some earlier studies. In addition, most studies on
diet-disease associations came from western countries and limited data are
available in the Middle-East.
METHODS: This case-control study was performed on 350 women with BC aged over
30 years who were recruited from hospitals or private clinics in Isfahan, Iran.
All patients were diagnosed with BC during the maximum of the last 6 months
using physical examination and mammography findings. Using cluster method
sampling, 700 apparently healthy age- and socioeconomic status-matched controls
were randomly selected from healthy women who had no relationship with BC
patients and had no familial history of BC. Data on dietary intakes were
collected using a validated food-frequency questionnaire. The DPI was calculated
based on dietary energy derived from foods rich in phytochemicals (kcal) divided
by total daily energy intake (kcal) of each participant.
RESULTS: Mean ± SD age and BMI in the study participants were 62.4 ± 10.8 years
and 24.3 ± 5.2 kg/m2, respectively. In the crude model, participants in the
highest quartile of DPI had 63% lower odds of breast cancer compared to those in
the lowest quartile (95% CI 0.26, 0.54; P-trend < 0.001). After adjustment for
potential confounders, this inverse association became strengthened (95% CI
0.22, 0.49; P-trend < 0.001). Further adjustment for BMI did not change the
association (OR for the highest quartile vs. the lowest quartile = 0.40, 95% CI
0.26, 0.60; P-trend < 0.001).
CONCLUSION: In conclusion, a protective association was observed between DPI and
BC in this case-control study. Therefore, high consumption of foods rich in
phytochemicals such as fruits, vegetables, and whole grains might help reducing
the odds of BC among women.
© 2021. The Japanese Breast Cancer Society.
DOI: 10.1007/s12282-021-01265-6
Pleiotropic Effects of Isoflavones in Inflammation and Chronic Degenerative

Diseases.
Bernatoniene J(1)(2), Kazlauskaite JA(2), Kopustinskiene DM(2).
Author information:
(1)Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy,
Medical Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13,
LT-50161 Kaunas, Lithuania.
(2)Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical
Academy, Lithuanian University of Health Sciences, Sukileliu pr. 13, LT-50161
Kaunas, Lithuania.
Isoflavones are phytoestrogens of plant origin, mostly found in the members of

the Fabaceae family, that exert beneficial effects in various degenerative
disorders. Having high similarity to 17-β-estradiol, isoflavones can bind
estrogen receptors, scavenge reactive oxygen species, activate various cellular
signal transduction pathways and modulate growth and transcription factors,
activities of enzymes, cytokines, and genes regulating cell proliferation and
apoptosis. Due to their pleiotropic activities isoflavones might be considered
as a natural alternative for the treatment of estrogen decrease-related
conditions during menopause. This review will focus on the effects of
isoflavones on inflammation and chronic degenerative diseases including cancer,
metabolic, cardiovascular, neurodegenerative diseases, rheumatoid arthritis and
adverse postmenopausal symptoms.
DOI: 10.3390/ijms22115656
PMCID: PMC8197878
Current Perspectives on the Physiological Activities of Fermented

Soybean-Derived Cheonggukjang.
Kim IS(1), Hwang CW(2), Yang WS(3), Kim CH(4)(5).
Author information:
(1)Advanced Bio-Resource Research Center, Kyungpook National University, Daegu
41566, Korea.
(2)Global Leadership School, Handong Global University, Pohang 37554, Korea.
(3)Nodaji Co., Ltd., Pohang 37927, Korea.
(4)Molecular and Cellular Glycobiology Unit, Department of Biological Sciences,
SungKyunKwan University, Suwon 16419, Korea.
(5)Samsung Advanced Institute of Health Science and Technology (SAIHST),
Sungkyunkwan University, Seoul 06351, Korea.
Cheonggukjang (CGJ, fermented soybean paste), a traditional Korean fermented
dish, has recently emerged as a functional food that improves blood circulation
and intestinal regulation. Considering that excessive consumption of refined
salt is associated with increased incidence of gastric cancer, high blood
pressure, and stroke in Koreans, consuming CGJ may be desirable, as it can be
made without salt, unlike other pastes. Soybeans in CGJ are fermented by
Bacillus strains (B. subtilis or B. licheniformis), Lactobacillus spp.,
Leuconostoc spp., and Enterococcus faecium, which weaken the activity of
putrefactive bacteria in the intestines, act as antibacterial agents against
pathogens, and facilitate the excretion of harmful substances. Studies on CGJ
have either focused on improving product quality or evaluating the bioactive
substances contained in CGJ. The fermentation process of CGJ results in the
production of enzymes and various physiologically active substances that are not
found in raw soybeans, including dietary fiber, phospholipids, isoflavones
(e.g., genistein and daidzein), phenolic acids, saponins, trypsin inhibitors,
and phytic acids. These components prevent atherosclerosis, oxidative
stress-mediated heart disease and inflammation, obesity, diabetes, senile
dementia, cancer (e.g., breast and lung), and osteoporosis. They have also been
shown to have thrombolytic, blood pressure-lowering, lipid-lowering,
antimutagenic, immunostimulatory, anti-allergic, antibacterial, anti-atopic
dermatitis, anti-androgenetic alopecia, and anti-asthmatic activities, as well
as skin improvement properties. In this review, we examined the physiological
activities of CGJ and confirmed its potential as a functional food.
DOI: 10.3390/ijms22115746
PMCID: PMC8198423
130. Molecules. 2021 May 16;26(10):2954. doi: 10.3390/molecules26102954.
The Potential Effects of Phytoestrogens: The Role in Neuroprotection.
Gorzkiewicz J(1), Bartosz G(2), Sadowska-Bartosz I(1).
Author information:
(1)Laboratory of Analytical Biochemistry, Institute of Food Technology and
Nutrition, College of Natural Sciences, Rzeszow University, 4 Zelwerowicza
Street, 35-601 Rzeszow, Poland.
(2)Department of Bioenergetics, Food Analysis and Microbiology, Institute of
Food Technology and Nutrition, College of Natural Sciences, Rzeszow University,
4 Zelwerowicza Street, 35-601 Rzeszow, Poland.
Phytoestrogens are naturally occurring non-steroidal phenolic plant compounds.

Their structure is similar to 17-β-estradiol, the main female sex hormone. This
review offers a concise summary of the current literature on several potential
health benefits of phytoestrogens, mainly their neuroprotective effect.
Phytoestrogens lower the risk of menopausal symptoms and osteoporosis, as well
as cardiovascular disease. They also reduce the risk of brain disease. The
effects of phytoestrogens and their derivatives on cancer are mainly due to the
inhibition of estrogen synthesis and metabolism, leading to antiangiogenic,
antimetastatic, and epigenetic effects. The brain controls the secretion of
estrogen (hypothalamus-pituitary-gonads axis). However, it has not been
unequivocally established whether estrogen therapy has a neuroprotective effect
on brain function. The neuroprotective effects of phytoestrogens seem to be
related to both their antioxidant properties and interaction with the estrogen
receptor. The possible effects of phytoestrogens on the thyroid cause some
concern; nevertheless, generally, no serious side effects have been reported,
and these compounds can be recommended as health-promoting food components or
supplements.
PMCID: PMC8156305
131. Food Funct. 2021 Jul 5;12(13):5770-5778. doi: 10.1039/d1fo00547b.
S-equol, a metabolite of dietary soy isoflavones, alleviates

lipopolysaccharide-induced depressive-like behavior in mice by inhibiting
neuroinflammation and enhancing synaptic plasticity.
Lu C(1), Gao R(2), Zhang Y(1), Jiang N(3), Chen Y(4), Sun J(1), Wang Q(1), Fan
B(1), Liu X(3), Wang F(2).
Author information:
(1)Institute of Food Science and Technology, Chinese Academy of Agricultural
Sciences (CAAS), Beijing 100193, China. wangfengzhong@sina.com.
Sciences (CAAS), Beijing 100193, China. wangfengzhong@sina.com and College of
Food Science and Technology, Nanjing Agricultural University, Nanjing 210095,
China.
(3)Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences
(CAMS) and Peking Union Medical College (PUMC), Beijing 100193, China.
liuxinmin@hotmail.com.
(4)Institute of Chinese Materia Medica, China Academy of Chinese Medical
Sciences (CACM), Beijing 100700, China.
Systemic injection with lipopolysaccharide can lead to depressive-like behavior

in experimental animals by inducing neuroinflammation and is considered to be a
classic model of depression. S-equol is a major metabolite of dietary soy
isoflavones with antioxidant and anti-inflammatory effects, and it has many
beneficial effects on human health, including alleviation of menopausal
symptoms, osteoporosis, cancer, obesity, chronic kidney disease, and cognitive
dysfunction. A recent study reported that S-equol inhibited
lipopolysaccharide-stimulated neuroinflammation in astrocytes. However, there is
no research on the antidepressant-like effects of S-equol. Therefore, the
present study was conducted to evaluate the antidepressant-like effects of
S-equol in a lipopolysaccharide-induced depression model in mice and explore its
underlying mechanisms. Our results demonstrated that treatment with S-equol (10,
20 and 40 mg kg-1) for 19 days markedly reversed the behavior of acute LPS (1.0
mg kg-1) treated mice in sucrose preference, tail suspension and forced swimming
tests, exerting antidepressant-like effects. In addition, S-equol administration
significantly decreased the levels of pro-inflammatory cytokines (tumor necrosis
factor, interleukin-6, interleukin-10, interleukin-1β), increased the levels of
5-hydroxytryptamine and norepinephrine, and normalized the release of tryptophan
and kynurenine in the hippocampi of lipopolysaccharide-treated mice. Moreover,
treatment with S-equol significantly up-regulated the expression of synaptic
plasticity-related proteins (phospho synapsin, synapsin, postsynaptic
density-95) and down-regulated the toll-like receptor 4/nuclear factor kappa B
signaling pathway in the hippocampi of lipopolysaccharide-treated mice. These
findings demonstrated that S-equol significantly alleviated the depressive-like
behavior induced by acute systemic injection of LPS, and its antidepressant
action was related to mediation of neuroinflammation via the TLR4/NF-κB
signaling pathway, normalization of the monoamine neurotransmitter levels,
reversal of tryptophan metabolism dysfunction, and enhancement of synaptic
plasticity. The current study provides insight into the potential of S-equol in
the prevention of depression.
DOI: 10.1039/d1fo00547b
132. J Sci Food Agric. 2021 Oct;101(13):5314-5324. doi: 10.1002/jsfa.11334. Epub

2021
Jun 16.
The association between soy-based food and soy isoflavone intake and the risk of
gastric cancer: a systematic review and meta-analysis.
Wang Y(1), Guo J(1), Yu F(1), Tian Y(1), Wu Y(1)(2), Cui L(1), Liu LE(1)(2).
Author information:
(1)College of Public Health, Zhengzhou University, Zhengzhou City, People's
Republic of China.
(2)Key Laboratory of Nanomedicine and Health Inspection of Zhengzhou, Zhengzhou
City, People's Republic of China.
Soy contains many bioactive phytochemicals, such as isoflavones, which have the
effect of preventing many cancers. Some studies have shown the beneficial effect
of soy-based food and isoflavone intake on gastric cancer (GC), while others
claimed no effect. Therefore, whether the beneficial effect of soy-based food is
related to its fermentation or whether its protective effect comes from
isoflavones still remains inconclusive. Our aim was to investigate the
relationship between total soybean, fermented soybean, non-fermented soybean and
isoflavone intake, and the risk of GC. Ten cohort studies and 21 case-control
studies involving 916 354 participants were included. The association between
soy-based food and isoflavone intake and the risk of GC was calculated with the
pooled relative risks (RRs) for the highest versus lowest intake categories. The
results showed that isoflavone intake might be a protective factor to GC, but
the result was not statistically significant (RR = 0.92; 95% CI: 0.79-1.07).
However, total soybean intake could significantly decrease the risk of GC by 36%
(RR = 0.64; 95% CI: 0.51-0.80), which might be credited to non-fermented soybean
products (RR = 0.79; 95% CI: 0.71-0.87). In contrast, high intake of fermented
soybean products could increase the risk of GC (RR = 1.19; 95% CI: 1.02-1.38).
High intake of total soybean and non-fermented soybean products could reduce the
risk of GC, and high intake of fermented soybean products could increase the
risk, which indicated that the beneficial effect of soy-based food might be
related to its non-fermentation. However, high intake of isoflavones may not be
associated with the incidence of GC. © 2021 Society of Chemical Industry.
© 2021 Society of Chemical Industry.
DOI: 10.1002/jsfa.11334
133. J Cancer. 2021 Apr 30;12(12):3686-3700. doi: 10.7150/jca.57776. eCollection

2021.
Phytochemicals in Chemoprevention: A Cost-Effective Complementary Approach.

Jain A(1), Madu CO(1), Lu Y(2).
Author information:
(1)Departments of Biological Sciences, University of Memphis, Memphis, TN 38152.
USA.
(2)Department of Pathology and Laboratory Medicine, University of Tennessee
Health Science Center, Memphis, TN 38163. USA.
Cancer is one of the leading causes of death across the world. Although
conventional cancer treatments such as chemotherapy and radiotherapy have
effectively decreased cancer progression, they come with many dose-limiting
side-effects. Phytochemicals that naturally occur in spices, fruits, vegetables,
grains, legumes, and other common foods are surprisingly effective complements
to conventional cancer treatments. These biologically active compounds
demonstrate anticancer effects via cell signaling pathway interference in
cancerous cells. In addition, phytochemicals protect non-cancerous cells from
chemotherapy-induced side-effects. This paper addresses the not only the
potential of phytochemicals quercetin, isoflavones, curcumin, catechins, and
hesperidin in terms of cancer treatment and protection against side-effects of
chemotherapy, but also methods for increasing phytochemical bioavailability.
© The author(s).
DOI: 10.7150/jca.57776
PMCID: PMC8120178
PMID: 33995644
Conflict of interest statement: Competing Interests: The authors have declared

that no competing interest exists.
134. Mol Nutr Food Res. 2021 Jun;65(12):e2100163. doi: 10.1002/mnfr.202100163. Epub
2021 May 10.
Disposition of Dietary Polyphenols in Breast Cancer Patients' Tumors, and Their

Associated Anticancer Activity: The Particular Case of Curcumin.
Ávila-Gálvez MÁ(1), González-Sarrías A(1), Martínez-Díaz F(2), Abellán B(3),

Martínez-Torrano AJ(2), Fernández-López AJ(3), Giménez-Bastida JA(1), Espín
JC(1).
Author information:
(1)Laboratory of Food & Health, Research Group on Quality, Safety and
Bioactivity of Plant Foods, CEBAS-CSIC, Campus de Espinardo, Murcia, 30100,
Spain.
(2)Anatomical Pathology Service, Reina Sofía University Hospital, Avda.
Intendente Jorge Palacios s/n, Murcia, 30003, Spain.
(3)Surgery Service, Reina Sofía University Hospital, Avda. Intendente Jorge
Palacios, Murcia, 30003, Spain.
SCOPE: Some polyphenol-derived metabolites reach human breast cancer (BC)

tissues at concentrations that induce cell senescence. However, this is unknown
for isoflavones, curcuminoids, and lignans. Here, their metabolic profiling in
normal (NT) and malignant (MT) mammary tissues of newly-diagnosed BC patients
and the tissue-occurring metabolites' anticancer activity are evaluated.
METHODS AND RESULTS: Patients (n = 26) consumed 3 capsules/day (turmeric, red
clover, and flaxseed extracts plus resveratrol; 296.4 mg phenolics/capsule) from
biopsy-confirmed diagnosis to surgery (5 ± 2 days) or did not consume capsules
(n = 13). NT and MT, blood, and urine are analyzed by UPLC-QTOF-MS using
targeted metabolomics. Anticancer activity was tested in MCF-7 and MDA-MB-231 BC
cells. Mainly phase-II metabolites were detected (108, 84, 49, and 47 in urine,
plasma, NT, and MT, respectively). Total metabolite concentrations reached
10.7 ± 11.1 and 2.5 ± 2.4 µmol L-1 in NT and MT, respectively. Free curcumin,
but not its glucuronide, was detected in the tissues (1.1 ± 1.8 and
0.2 ± 0.2 µmol L-1 in NT and MT, respectively). Breast tissue-occurring
metabolites' antiproliferation was mainly exerted in p53-wild-type MCF-7 cells
by curcuminoids through cell cycle arrest, senescence, and apoptosis induction
via p53/p21 induction, while isoflavone-derived metabolites exerted
estrogenic-like activity.
CONCLUSION: Curcuminoids could be coadjuvants that might help fight BC upon
regular consumption.
© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH
GmbH.
DOI: 10.1002/mnfr.202100163
Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor.
Goya-Jorge E(1)(2), Jorge Rodríguez ME(3), Veitía MS(4), Giner RM(1).
Author information:
(1)Departament de Farmacologia, Facultat de Farmàcia, Universitat de València.
Av. Vicente Andrés Estellés, s/n, Burjassot, 46100 Valencia, Spain.
(2)ProtoQSAR SL., CEEI (Centro Europeo de Empresas Innovadoras), Av. Benjamin
Franklin 12, Parque Tecnológico de Valencia, Paterna, 46980 Valencia, Spain.
(3)Departamento de Farmacia, Facultad de Química-Farmacia, Universidad Central
"Marta Abreu" de las Villas, C. Camajuaní km 5½, Santa Clara 54830, Villa Clara,
Cuba.
(4)Equipe de Chimie Moléculaire du Laboratoire Génomique, Bioinformatique et
Chimie Moléculaire (EA 7528), Conservatoire National des Arts et Métiers (Cnam),
2 Rue Conté, HESAM Université, 75003 Paris, France.
The aryl hydrocarbon receptor (AhR) is a transcription factor deeply implicated

in health and diseases. Historically identified as a sensor of xenobiotics and
mainly toxic substances, AhR has recently become an emerging pharmacological
target in cancer, immunology, inflammatory conditions, and aging. Multiple AhR
ligands are recognized, with plant occurring flavonoids being the largest group
of natural ligands of AhR in the human diet. The biological implications of the
modulatory effects of flavonoids on AhR could be highlighted from a
toxicological and environmental concern and for the possible pharmacological
applicability. Overall, the possible AhR-mediated harmful and/or beneficial
effects of flavonoids need to be further investigated, since in many cases they
are contradictory. Similar to other AhR modulators, flavonoids commonly exhibit
tissue, organ, and species-specific activities on AhR. Such cellular-context
dependency could be probably beneficial in their pharmacotherapeutic use.
Flavones, flavonols, flavanones, and isoflavones are the main subclasses of
flavonoids reported as AhR modulators. Some of the structural features of these
groups of flavonoids that could be influencing their AhR effects are herein
summarized. However, limited generalizations, as well as few outright
structure-activity relationships can be suggested on the AhR agonism and/or
antagonism caused by flavonoids.
PMCID: PMC8073824
Association between Soy Food and Dietary Soy Isoflavone Intake and the Risk of
Cardiovascular Disease in Women: A Prospective Cohort Study in Korea.
Im J(1), Park K(1).
Author information:
(1)Department of Food and Nutrition, Yeungnam University, Gyeongsan 38541,
Korea.
The association between soy food and soy isoflavone intake and cardiovascular
disease (CVD) risk is uncertain, especially in women. We aimed to investigate
this association in Korean women. We analyzed data from the Korean Genome and
Epidemiology Study, including 4713 Korean women aged 40-69 years with no CVD or
cancer at baseline. Dietary information was obtained using a validated
semi-quantitative food frequency questionnaire, and the incidence of CVD was
assessed using biennial self-reported questionnaires on medical history. The
mean follow-up time was 7.4 years, during which 82 premenopausal and 200
postmenopausal women reported CVD incidence. The highest tofu, total soy foods,
and dietary soy isoflavone intake groups were significantly associated with a
decreased CVD risk in premenopausal women (tofu: hazard ratio (HR) 0.39; 95%
confidence interval (CI), 0.19-0.80; total soy food: HR 0.36; 95% CI, 0.18-0.70;
dietary soy isoflavones: HR 0.44; 95% CI, 0.22-0.89), whereas no association was
observed in postmenopausal women. Other soy foods showed no association with CVD
incidence. Dietary soy isoflavones and total soy foods are associated with a
decreased CVD risk in premenopausal women. Among soy foods, only tofu showed
significant health benefits.
DOI: 10.3390/nu13051407
PMCID: PMC8143453
137. Pharmaceuticals (Basel). 2021 Apr 17;14(4):373. doi: 10.3390/ph14040373.
The Influence of Plant Isoflavones Daidzein and Equol on Female Reproductive

Processes.
Sirotkin AV(1), Alwasel SH(2), Harrath AH(2).
Author information:
(1)Department of Zoology and Anthropology, Constantine the Philosopher
University in Nitra, 949 01 Nitra, Slovakia.
(2)Department of Zoology, College of Science, King Saud University, Riyadh
In this review, we explore the current literature on the influence of the plant
isoflavone daidzein and its metabolite equol on animal and human physiological
processes, with an emphasis on female reproduction including ovarian functions
(the ovarian cycle; follicullo- and oogenesis), fundamental ovarian-cell
functions (viability, proliferation, and apoptosis), the pituitary and ovarian
endocrine regulators of these functions, and the possible intracellular
mechanisms of daidzein action. Furthermore, we discuss the applicability of
daidzein for the control of animal and human female reproductive processes, and
how to make this application more efficient. The existing literature
demonstrates the influence of daidzein and its metabolite equol on various
nonreproductive and reproductive processes and their disorders. Daidzein and
equol can both up- and downregulate the ovarian reception of gonadotropins,
healthy and cancerous ovarian-cell proliferation, apoptosis, viability, ovarian
growth, follicullo- and oogenesis, and follicular atresia. These effects could
be mediated by daidzein and equol on hormone production and reception, reactive
oxygen species, and intracellular regulators of proliferation and apoptosis.
Both the stimulatory and the inhibitory effects of daidzein and equol could be
useful for reproductive stimulation, the prevention and mitigation of cancer
development, and the adverse effects of environmental stressors in reproductive
biology and medicine.
DOI: 10.3390/ph14040373
PMCID: PMC8073550
PMID: 33920641
138. Int J Mol Sci. 2021 Apr 14;22(8):4054. doi: 10.3390/ijms22084054.
Physiologically Active Molecules and Functional Properties of Soybeans in Human

Health-A Current Perspective.
Kim IS(1), Kim CH(2)(3), Yang WS(4).
Author information:
(1)Advanced Bio-resource Research Center, Kyungpook National University, Daegu
41566, Korea.
(2)Molecular and Cellular Glycobiology Unit, Department of Biological Sciences,
SungKyunKwan University, Gyunggi-Do 16419, Korea.
(3)Samsung Advanced Institute of Health Science and Technology, Gyunggi-Do
16419, Korea.
(4)Nodaji Co., Ltd., Pohang, Gyeongsangbuk-Do 37927, Korea.
In addition to providing nutrients, food can help prevent and treat certain
diseases. In particular, research on soy products has increased dramatically
following their emergence as functional foods capable of improving blood
circulation and intestinal regulation. In addition to their nutritional value,
soybeans contain specific phytochemical substances that promote health and are a
source of dietary fiber, phospholipids, isoflavones (e.g., genistein and
daidzein), phenolic acids, saponins, and phytic acid, while serving as a trypsin
inhibitor. These individual substances have demonstrated effectiveness in
preventing chronic diseases, such as arteriosclerosis, cardiac diseases,
diabetes, and senile dementia, as well as in treating cancer and suppressing
osteoporosis. Furthermore, soybean can affect fibrinolytic activity, control
blood pressure, and improve lipid metabolism, while eliciting antimutagenic,
anticarcinogenic, and antibacterial effects. In this review, rather than to
improve on the established studies on the reported nutritional qualities of
soybeans, we intend to examine the physiological activities of soybeans that
have recently been studied and confirm their potential as a high-functional,
well-being food.
DOI: 10.3390/ijms22084054
PMCID: PMC8071044
139. Arch Biochem Biophys. 2021 Jun 15;704:108889. doi: 10.1016/j.abb.2021.108889.

Epub 2021 Apr 22.
Inhibition of calcitriol inactivating enzyme CYP24A1 gene expression by

flavonoids in hepatocellular carcinoma cells under normoxia and hypoxia.
Angeli-Terzidou AE(1), Gkotinakou IM(1), Pazaitou-Panayiotou K(2), Tsakalof

A(3).
Author information:
(1)Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly,
41500 Biopolis, Larissa, Greece.
(2)Division of Endocrinology, Interbalkan Medical Center, 55535 Thessaloniki,
Greece.
(3)Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly,
41500 Biopolis, Larissa, Greece. Electronic address: atsakal@med.uth.gr.
A vast number of epidemiological, preclinical and in vitro experimental data

strongly indicate the anticancer potential of calcitriol, the biologically
active form of vitamin D. However, for the implementation of a vitamin D based
cancer therapy the increased deactivation of calcitriol in cancer cells by
overexpressed CYP24A1 hydroxylase should be suppressed. Inhibition of this
enzyme expression or activity nowadays is considered as important aspect of
anticancer therapeutic strategies. Herein, we investigated the impact of
genistein, biochanin A, formonentin and kaempferol on the expression of the
CYP24A1 gene induced by calcitriol in hepatocellular cancer cells Huh7 under
normoxia (21%O2) or hypoxia (1%O2). We demonstrate that calcitriol induces
CYP24A1 under normoxia and hypoxia, but this induction is significantly more
potent under hypoxia, the typical microenvironment of solid tumors. In the
presence of isoflavones genistein, biochanin A and formononetin, this induction
is abrogated to the control levels under normoxia, while under hypoxia there is
some differentiation in suppression efficacy between these compounds with
genistein ≥ biochanin > formononetin. At the same time, kaempferol turned out to
be completely ineffective in the suppression of CYP24A1 gene expression.
DOI: 10.1016/j.abb.2021.108889
140. Nat Prod Res. 2022 Oct;36(19):4886-4891. doi: 10.1080/14786419.2021.1908280.

Epub 2021 Apr 5.
(±) Erysectin A, a new isoprenylated isoflavone with a rare acetonyl group from
Erythrina secundiflora Hassk.
Luo R(1), Li F(1), Zhuang H(1), Wang L(1).
Author information:
(1)Faculty of Chemistry and Chemical Engineering, Yunnan Normal University,
Kunming, P.R. China.
(±) Erysectin A (1), a new isoprenylated isoflavone with a rare acetonyl group,
along with 15 known compounds including eight isoprenylated isoflavones (2-9),
two isoprenylated flavanones (10-11), three flavanones (12-14), a flavone (15),
and a chalcone (16), was isolated from the twigs and leaves of Erythrina
secundiflora Hassk. Their structures were identified based on their 1 D and 2 D
NMR spectral data. All the compounds were isolated from this plant for the first
time. Compound 1 showed moderate cytotoxicity on several cancer cell
lines.[Formula: see text].
DOI: 10.1080/14786419.2021.1908280
141. Int J Pharm. 2021 May 15;601:120564. doi: 10.1016/j.ijpharm.2021.120564. Epub

2021 Apr 1.
Oral genistein-loaded phytosomes with enhanced hepatic uptake, residence and

improved therapeutic efficacy against hepatocellular carcinoma.
Komeil IA(1), El-Refaie WM(2), Gowayed MA(3), El-Ganainy SO(3), El Achy SN(4),
Huttunen KM(5), Abdallah OY(6).
Author information:
(1)Department of Pharmaceutics, Faculty of Pharmacy, Pharos University in
Alexandria, Alexandria, Egypt.
(2)Department of Pharmaceutics, Faculty of Pharmacy, Pharos University in
Alexandria, Alexandria, Egypt. Electronic address: wessamelrefaie@yahoo.com.
(3)Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos
University in Alexandria, Alexandria, Egypt.
(4)Department of Pathology, Faculty of Medicine, Alexandria University,
Alexandria, Egypt.
(5)School of Pharmacy, Faculty of Health Sciences, University of Eastern
Finland, Yliopistonranta 1C, Kuopio, Finland.
(6)Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University,
Alexandria, Egypt.
Genistein (Gen) is one of the most potent soy isoflavones used for
hepatocellular carcinoma (HCC) treatment. Low aqueous solubility and first-pass
metabolism are the main obstacles resulting in low Gen oral bioavailability. The
current study aims to introduce phytosomes as an approach to improve Gen
solubility, protect it from metabolism by complexation with phospholipids (PL),
and get used to PL in Gen lymphatic delivery. Different forms of PL namely:
Lipiod® S100, Phosal® 53 MCT, and Phosal®75 SA were used in phytosomes
preparation GP, GPM, and GPL respectively. The effect of formulation components
on Gen absorption, metabolism, and liver accumulation was evaluated following
oral administration to rats. Cytotoxicity and cellular uptake studies were
applied on HepG2 cells and in-vivo anti-tumor studies were applied to the
DEN-mice model. Results revealed that GP and GPL remarkably accumulated Gen
aglycone in hepatic cells and minimized the metabolic effect on Gen. They
significantly increased the intracellular accumulation of Gen in its complex
form in HepG2 cells. Their cytotoxicity is time-dependent according to the
complex stability. The enhanced in-vivo anti-tumor effect was observed for GP
and GPL compared to Gen suspension on DEN-induced HCC in mice. In conclusion,
Gen-phytosomes can represent a promising approach for liver cancer treatment.
DOI: 10.1016/j.ijpharm.2021.120564
142. Int J Mol Sci. 2021 Mar 22;22(6):3212. doi: 10.3390/ijms22063212.
Utilization of Isoflavones in Soybeans for Women with Menopausal Syndrome: An

Overview.
Chen LR(1)(2), Chen KH(3)(4).
Author information:
(1)Department of Physical Medicine and Rehabilitation, Mackay Memorial Hospital,
(2)Department of Mechanical Engineering, National YangMing ChiaoTung University,
Hsinchu 30010, Taiwan.
(3)Department of Obstetrics and Gynecology, Taipei Tzu-Chi Hospital, The
Buddhist Tzu-Chi Medical Foundation, Taipei 231, Taiwan.
(4)School of Medicine, Tzu-Chi University, Hualien 970, Taiwan.
Based on their nutrient composition, soybeans and related foods have been
considered to be nutritious and healthy for humans. Particularly, the biological
activity and subsequent benefits of soy products may be associated with the
presence of isoflavone in soybeans. As an alternative treatment for
menopause-related symptoms, isoflavone has gained much popularity for
postmenopausal women who have concerns related to undergoing hormone replacement
therapy. However, current research has still not reached a consensus on the
effects of isoflavone on humans. This overview is a summary of the current
literature about the processing of soybeans and isoflavone types (daidzein,
genistein, and S-equol) and supplements and their extraction and analysis as
well as information about the utilization of isoflavones in soybeans. The
processes of preparation (cleaning, drying, crushing and dehulling) and
extraction of soybeans are implemented to produce refined soy oil, soy lecithin,
free fatty acids, glycerol and soybean meal. The remaining components consist of
inorganic constituents (minerals) and the minor components of biologically
interesting small molecules. Regarding the preventive effects on diseases or
cancers, a higher intake of isoflavones is associated with a moderately lower
risk of developing coronary heart disease. It may also reduce the risks of
breast and colorectal cancer as well as the incidence of breast cancer
recurrence. Consumption of isoflavones or soy foods is associated with reduced
risks of endometrial and bladder cancer. Regarding the therapeutic effects on
menopausal syndrome or other diseases, isoflavones have been found to alleviate
vasomotor syndromes even after considering placebo effects, reduce bone loss in
the spine and ameliorate hypertension and in vitro glycemic control. They may
also alleviate depressive symptoms during pregnancy. On the other hand,
isoflavones have not shown definitive effects regarding improving cognition and
urogenital symptoms. Because of lacking standardization in the study designs,
such as the ingredients and doses of isoflavones and the durations and outcomes
of trials, it currently remains difficult to draw overall conclusions for all
aspects of isoflavones. These limitations warrant further investigations of
isoflavone use for women's health.
DOI: 10.3390/ijms22063212
PMCID: PMC8004126
143. Animals (Basel). 2021 Mar 8;11(3):735. doi: 10.3390/ani11030735.

Production of Bovine Equol-Enriched Milk: A Review.
Křížová L(1), Křešťáková V(2), Dadáková K(2), Kašparovský T(2).
Author information:
(1)Department of Animal Breeding, Animal Nutrition and Biochemistry, Faculty of
Veterinary Hygiene and Ecology, University of Veterinary and Pharmaceutical
Sciences, 61242 Brno, Czech Republic.
(2)Department of Biochemistry, Faculty of Science, Masaryk University, 61137
Brno, Czech Republic.
Milk and dairy products are important sources of nutrients in the human diet
because they contain a number of essential substances and other biologically
active components. Many of these substances can be modified, and thus offer
opportunities to use milk and dairy products as functional food. Isoflavones are
particularly important in human nutrition due to their diverse pharmacological
and antioxidant properties. The clinical effectiveness of isoflavone-rich
products is believed to be dependent on their ability to metabolize daidzein to
equol, which may directly exert cancer preventive effects. However, only
approximately 30-40% of humans are able to produce equol, while animals, in
general, produce equol. Equol is the predominant product of bacterial metabolism
of isoflavones and can be found in various amounts in some food of animal
origin, especially in milk. Therefore, milk and dairy products can be considered
to be sources of equol for humans who are not able to produce this metabolite.
When the content of isoflavones in milk is to be modified, two groups of factors
should be considered, i.e., dietary factors that include the source of
isoflavones and the processing effects on feedstuffs and animal factors that
include the intake of isoflavones, ruminal and postruminal changes, and the
health and physiological status of animals. The approximate content of
isoflavones in milk can be predicted using carry-over rates for different
dietary sources or using a formula that describes the relationship between equol
concentration in milk and formononetin intake. Processing and storage can affect
the content and profile of isoflavones in milk and dairy products.
DOI: 10.3390/ani11030735
PMCID: PMC7999515
PMID: 33800327

10.1080/10408398.2021.1895054. Epub 2021 Mar 27.
Neither soyfoods nor isoflavones warrant classification as endocrine disruptors:

a technical review of the observational and clinical data.
Messina M(1), Mejia SB(2), Cassidy A(3), Duncan A(4), Kurzer M(5), Nagato C(6),
Ronis M(7), Rowland I(8), Sievenpiper J(9), Barnes S(10).
Author information:
(1)Department of Nutrition, Loma Linda University, Loma Linda, California, USA.
(2)Department of Nutritional Sciences, University of Toronto, Toronto, Canada.
(3)Nutrition and Preventive Medicine, Queen's University, Belfast, Northern
Ireland, UK.
(4)College of Biological Sciences, University of Guelph, Guelph, Canada.
(5)Department of Food Science and Nutrition, University of Minnesota,
Minneapolis, Minnesota, USA.
(6)Graduate School of Medicine, Gifu University, Gifu, Japan.
(7)Health Sciences Center, Louisiana State University Health Sciences Center,
Baton Rouge, New Orleans, USA.
(8)Human Nutrition, University of Reading, Reading, England, UK.
(9)Nutritional Sciences, University of Toronto, Toronto, Canada.
(10)Department of Pharmacology and Toxicology, University of Alabama, Alabama,
USA.
Soybeans are a rich source of isoflavones, which are classified as

phytoestrogens. Despite numerous proposed benefits, isoflavones are often
classified as endocrine disruptors, based primarily on animal studies. However,
there are ample human data regarding the health effects of isoflavones. We
conducted a technical review, systematically searching Medline, EMBASE, and the
Cochrane Library (from inception through January 2021). We included clinical
studies, observational studies, and systematic reviews and meta-analyses (SRMA)
that examined the relationship between soy and/or isoflavone intake and
endocrine-related endpoints. 417 reports (229 observational studies, 157
clinical studies and 32 SRMAs) met our eligibility criteria. The available
evidence indicates that isoflavone intake does not adversely affect thyroid
function. Adverse effects are also not seen on breast or endometrial tissue or
estrogen levels in women, or testosterone or estrogen levels, or sperm or semen
parameters in men. Although menstrual cycle length may be slightly increased,
ovulation is not prevented. Limited insight could be gained about possible
impacts of in utero isoflavone exposure, but the existing data are reassuring.
Adverse effects of isoflavone intake were not identified in children, but
limited research has been conducted. After extensive review, the evidence does
not support classifying isoflavones as endocrine disruptors.
DOI: 10.1080/10408398.2021.1895054
145. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2011269118. doi:

10.1073/pnas.2011269118.
Estrogen receptor β and treatment with a phytoestrogen are associated with

inhibition of nuclear translocation of EGFR in the prostate.
Wu WF(1), Wang L(1), Spetsieris N(2), Boukovala M(2), Efstathiou E(2), Brössner
C(3), Warner M(1), Gustafsson JA(4)(5).
Author information:
(1)Center for Nuclear Receptors and Cell Signaling, Department of Biology and
Biochemistry, University of Houston, Houston, TX 77204.
(2)Department of Genitourinary Medical Oncology, University of Texas MD Anderson
Cancer Center, Houston, TX 77030.
(3)Department of Urology, Barmherzige Schwestern Hospital, 1060 Vienna, Austria.
(4)Center for Nuclear Receptors and Cell Signaling, Department of Biology and
Biochemistry, University of Houston, Houston, TX 77204; jgustafsson@uh.edu.
(5)Department of Biosciences and Nutrition, Karolinska Institutet, 14157
Huddinge, Sweden.
Knockout of ERβ in the mouse leads to nuclear expression of epidermal growth

factor receptor (EGFR) in the prostate. To examine whether ERβ plays a similar
role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of
normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men
with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor,
finasteride, and finasteride together with the ERβ agonists, soy isoflavones; 3)
men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation
therapy) and abiraterone (AA), the blocker of androgen synthesis for different
durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor)
blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment
induced EGFR nuclear expression, but, when finasteride was combined with
isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR
for 4 mo to 6 mo resulted in loss of ERβ and PTEN expression and increase in
patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of
adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of
increasing ERβ expression, but, on treatment longer than 8 mo, ERβ was lost and
EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in
PCa, addition of ERβ agonists together with abiraterone should be considered as
a treatment that might sustain expression of ERβ and offer some benefit to
patients.
DOI: 10.1073/pnas.2011269118
PMCID: PMC8020780
Conflict of interest statement: The authors declare no competing interest.
146. Cancer Treat Res Commun. 2021;27:100350. doi: 10.1016/j.ctarc.2021.100350.

Epub
2021 Mar 12.
Pre-diagnosis and early post-diagnosis dietary soy isoflavone intake and

survival outcomes: A prospective cohort study of early stage breast cancer
survivors.
Ho SC(1), Yeo W(2), Goggins W(3), Kwok C(4), Cheng A(4), Chong M(3), Lee R(5),
Cheung KL(6).
Author information:
(1)Division of Epidemiology, the Jockey Club School of Public Health and Primary
Care, the Chinese University of Hong Kong, New Territories, Hong Kong SAR,
China. Electronic address: suzanneho@cuhk.edu.hk.
(2)Department of Clinical Oncology, Prince of Wales Hospital, the Chinese
University of Hong Kong, New Territories, Hong Kong SAR, China; Hong Kong Cancer
Institute, State Key Laboratory in Oncology in South China, Faculty of Medicine,
the Chinese University of Hong Kong, New Territories, Hong Kong SAR, China.
(3)Division of Biostatistics, the Jockey Club School of Public Health and
Primary Care, the Chinese University of Hong Kong, New Territories, Hong Kong
SAR, China.
(4)Department of Clinical Oncology, Princess Margaret Hospital, Hong Kong SAR,
China.
(5)Division of Epidemiology, the Jockey Club School of Public Health and Primary
Care, the Chinese University of Hong Kong, New Territories, Hong Kong SAR,
China.
(6)Department of Clinical Oncology, Prince of Wales Hospital, the Chinese
University of Hong Kong, New Territories, Hong Kong SAR, China.
BACKGROUND: There is concern that the estrogen-like effects of soy isoflavones

may stimulate mammary tumor growth and interfere with the efficacy of breast
cancer treatment. This study aimed to examine prospectively the associations of
dietary soy isoflavone intake with all-cause mortality and breast cancer (BC)
specific mortality and recurrence among BC survivors.
DESIGN: The study included 1460 Chinese women with early-stage incident BC.
Pre-diagnosis and early post-diagnosis soy food intakes were assessed at study
entry, and at 18-month follow-up using validated soy food frequency
questionnaire. Associations of soy isoflavone intake with prognostic outcomes
within 48 months were examined using multivariable adjusted Cox proportional
hazards models.
RESULTS: We observed increasing pre-diagnosis and early post-diagnosis soy
isoflavone intakes up to the third quartile (Q3) were associated with reductions
for adverse prognostic outcomes. Relative to the lowest quartile (Q1), the
hazard ratios (HRs) for all-cause mortality for pre-diagnosis and post-diagnosis
Q3 intake were respectively 0.34 (95% CI, 0.16-0.74), and 0.44 (95% CI,
0.22-0.89). A similar risk reduction was observed for pre- and post-diagnosis
intakes and BC-specific mortality when comparing Q3 versus Q1 with the
respective HRs 0.36 (95% CI, 0.16-0.82), and 0.49 (95% CI, 0.23-1.01). Subgroup
analyses showed more favourable prognostic outcomes in association with moderate
soy intake among premenopausal women, those with triple negative cancer and
recipients of tamoxifen treatment.
CONCLUSION: Moderate soy isoflavone intake was associated with favourable
prognostic outcomes in Chinese early stage BC survivors.
DOI: 10.1016/j.ctarc.2021.100350

Mar 25.
Randomized, Placebo-Controlled Six-Month Intervention Study of Soy Protein

Isolate in Men with Biochemical Recurrence after Radical Prostatectomy: A Pilot
Study.
Bosland MC(1)(2)(3), Schmoll J(2), Watanabe H(2), Randolph C(2), Kato I(4).
Author information:
(1)Department of Pathology, University of Illinois at Chicago, Chicago,
Illinois, USA.
(2)Department of Environmental Medicine, New York University School of Medicine,
New York, New York, USA.
(3)Department of Urology, New York University School of Medicine, New York, New
York, USA.
(4)Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State
University, Detroit, Michigan, USA.
There is evidence to suggest that soy may be beneficial for prostate cancer
patients, but few randomized trials have addressed this. We examined the effect
of 6-8 mo soy protein supplementation on prostate specific antigen (PSA) serum
levels in men who recurred (PSA > 0.1 ng/ml) within three years of
prostatectomy. Sixteen men were randomized to 20 g soy protein (∼24-26/day
genistein; ∼40-43/day total isoflavones) or casein placebo. PSA was measured at
base line and at 1, 2, 4, and 6-8 mo. Serum genistein levels greatly increased
from baseline and cholesterol decreased in the soy group. In both treatment arms
PSA increased similarly and PSA doubling times were not different over the
6-8 mo study duration. Two subjects in each group had stable PSA. A literature
search for clinical studies of soy, isoflavones, and PSA revealed that
supplementation with soy or isoflavones did not affect PSA in virtually all
clinical studies identified. Although this study is too small to draw a
definitive conclusion on the effect of soy protein on PSA in men with
biochemical failure, the null finding in this study is consistent with the
results of virtually all reports of soy and soy isoflavones in the literature.
DOI: 10.1080/01635581.2021.1903949
PMCID: PMC8756455
148. Bioorg Med Chem Lett. 2021 May 15;40:127967. doi: 10.1016/j.bmcl.2021.127967.
Epub 2021 Mar 19.
A new anti-austerity agent, 4'-O-methylgrynullarin from Derris scandens induces

PANC-1 human pancreatic cancer cell death under nutrition starvation via
inhibition of Akt/mTOR pathway.
Sun S(1), Dibwe DF(1), Kim MJ(1), Omar AM(1), Phan ND(1), Fujino H(1),
Pongterdsak N(2), Chaithatwatthana K(2), Phrutivorapongkul A(2), Awale S(3).
Author information:
(1)Natural Drug Discovery Laboratory, Institute of Natural Medicine, University
of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
(2)Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.
(3)Natural Drug Discovery Laboratory, Institute of Natural Medicine, University
of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address:
suresh@inm.u-toyama.ac.jp.
An ethanolic extract of Derris scandens flowers showed potent preferential

cytotoxicity against PANC-1 human pancreatic cancer cells under
nutrient-deprived condition, with a PC50 value of 0.7 μg/mL. Phytochemical
investigation of this active extract led to the isolation of four prenylated
isoflavones (1-4) including a new compound named 4'-O-methylgrynullarin (1). The
structure elucidation of the new compound was achieved by HRFABMS and NMR
spectroscopic analysis. The isolated compounds exhibited potent anti-austerity
activity against four different human pancreatic cancer cell lines under
nutrient-deprived conditions. The new compound 4'-O-methylgrynullarin (1) was
also found to inhibit PANC-1 cell migration and colony formation under
nutrient-rich condition. Mechanistically, compound 1 inhibited key survival
proteins in the Akt/mTOR signaling pathway. Therefore, 4'-O-methylgrynullarin
(1) can be considered as a potential lead compound for the anticancer drug
development based on the anti-austerity strategy.
DOI: 10.1016/j.bmcl.2021.127967
149. Cancer. 2021 Jun 1;127(11):1758-1769. doi: 10.1002/cncr.33425. Epub 2021 Mar
11.
Prediction models for breast cancer prognosis among Asian women.
Fan R(1), Chen Y(1), Nechuta S(2), Cai H(3), Gu K(4), Shi L(4), Bao P(4), Shyr
Y(1), Shu XO(3), Ye F(1).
Author information:
(1)Department of Biostatistics, Vanderbilt University Medical Center, Nashville,
Tennessee.
(2)Department of Public Health, Grand Valley State University, Grand Rapids,
Michigan.
Medical Center, Nashville, Tennessee.
(4)Shanghai Municipal Center for Disease Control and Prevention, Shanghai,
China.
BACKGROUND: Robust and reliable prognosis prediction models have not been
developed and validated for Asian patients with breast cancer, a rapidly growing
yet understudied population in the United States.
METHODS: We used longitudinal data from the Shanghai Breast Cancer Survival
Study, a population-based prospective cohort study (n = 5042), to develop
prediction models for 5- and 10-year disease-free survival (DFS) and overall
survival (OS). The initial models considered age at diagnosis, tumor grade,
tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen
therapy, and estrogen receptor (ER), progesterone receptor (PR), and human
epidermal growth factor receptor 2 (HER2) status. We then evaluated whether the
addition of modifiable lifestyle factors (physical activity, soy isoflavones
intake, and postdiagnostic weight change) improved the models. All final models
have been validated internally and externally in the National Cancer Database
when applicable.
RESULTS: Our final models included age at diagnosis, tumor grade, tumor size,
number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, ER status,
PR status, 6-month postdiagnostic weight change, interaction between ER status
and tamoxifen therapy, and interaction between age and TNM stage. The internal
validation yielded C-statistics of 0.76, 0.74, 0.78, and 0.75 for 5-year DFS,
10-year DFS, 5-year OS, and 10-year OS, respectively. The external validation
yielded C-statistics of 5- and 10-year OS both at 0.78 for Chinese ethnicity,
0.79 for East Asian ethnicity, and 0.75 and 0.76 for all ethnic groups combined.
CONCLUSION: We developed prediction models for breast cancer prognosis from a
large prospective study. Our prognostic models performed very well in women from
the United States-particularly in Asian American women-and demonstrated high
prediction accuracy and generalizability.
© 2021 American Cancer Society.
DOI: 10.1002/cncr.33425
PMCID: PMC9443412
Conflict of interest statement: CONFLICT OF INTEREST DISCLOSURES The authors

made no disclosures.
150. Molecules. 2021 Feb 19;26(4):1105. doi: 10.3390/molecules26041105.
A Systematic Review of the Effects of Equol (Soy Metabolite) on Breast Cancer.
Hod R(1), Maniam S(1), Mohd Nor NH(1).
Author information:
(1)Department of Human Anatomy, Faculty of Medicine and Health Sciences,
University Putra Malaysia, Serdang 43400, Malaysia.
Equol is a soy isoflavone metabolite that can be produced by intestinal

bacteria. It is lipophilic and resembles natural oestrogens with an affinity to
oestrogen receptors. This review is focused on how equol affects breast cancer,
as evidenced by in vivo and in vitro studies. Equol is considered
chemoprotective in specific endocrine-related pathologies, such as breast
cancer, prostate cancer, cardiovascular diseases, and menopausal symptoms. In
humans, not everyone can produce equol from gut metabolism. It is postulated
that equol producers benefit more than non-equol producers for all the
endocrine-related effects. Equol exists in two enantiomers of R-equol and
S-equol. Earlier studies, however, did not specify which enantiomer was being
used. This review considers equol's type and concentration variations, pathways
affected, and its outcome in in vivo and in vitro studies.
PMCID: PMC7922416
151. Asian Pac J Cancer Prev. 2021 Feb 1;22(2):603-610. doi:

10.31557/APJCP.2021.22.2.603.
Daidzein Induces Intrinsic Pathway of Apoptosis along with ER α/β Ratio

Alteration and ROS Production.
Kumar V(1), Chauhan SS(1).
Author information:
(1)Department of Biochemistry, All India Institute of Medical Sciences, New
Delhi, India.
BACKGROUND: Low risk of breast cancer is observed among females consuming a

moderate quantity of soy throughout their life. The present study was conducted
to evaluate the anticancer potential of Daidzein, one of the major Isoflavones
in soy using Human breast cancer cells MCF-7.
METHODS: MCF-7 were subjected to various doses of Daidzein treatment to
determine the IC50 value. Onset of apoptosis was ascertained by AnnexinV assay
and caspase 3/7 activity post treatment. Expression of pro-apoptotic protein Bax
and anti-apoptotic protein Bcl2 was also assessed to further confirm apoptotic
mode of cell death. ROS production post treatment with Daidzein was assessed to
ascertain the apoptosis via intrinsic pathway. Expression of ER α and ER β was
evaluated by western blot analysis.
RESULTS: Human breast cancer cells MCF-7 were found to be sensitive to Daidzein
treatment, with an IC50 value of 50µM. Increased percentage of treated cells
stained with Annexin V confirmed apoptosis mediated cell death. Activity of
Caspase 3/7 activity was found to be 1.4-fold higher in Daidzein treated cells
than control cells, confirming apoptosis. Daidzein caused over expression of Bax
and down-regulated expression of Bcl2. There has been an outburst of ROS in
Daidzein treated cells indicating that Daidzein induces apoptosis via intrinsic
pathway. A decrease in the expression of ER α and increase in levels of ER β has
been observed which are conducive indicator of apoptosis.
CONCLUSIONS: In conclusion, the present study suggests that Daidzein induces
apoptosis in MCF-7 cells by mitochondrial pathway along with lowering the ratio
of ER α/β and an outburst of Reactive Oxygen Species(ROS).
DOI: 10.31557/APJCP.2021.22.2.603
PMCID: PMC8190374
152. Am J Clin Nutr. 2021 Apr 6;113(4):821-831. doi: 10.1093/ajcn/nqaa390.
Soy protein supplementation in men following radical prostatectomy: a 2-year

randomized, placebo-controlled clinical trial.
Bosland MC(1), Enk E(1), Schmoll J(2), Schlicht MJ(1), Randolph C(2), Deaton
RJ(1), Xie H(3), Zeleniuch-Jacquotte A(2), Kato I(2)(4).
Author information:
(1)Department of Pathology, College of Medicine, University of Illinois at
Chicago, Chicago, IL, USA.
(2)Department of Environmental Medicine, New York University School of Medicine,
New York, NY, USA.
(3)Division of Epidemiology and Biostatistics, School of Public Health,
University of Illinois at Chicago, Chicago, IL, USA.
(4)Departments of Oncology and Pathology, Wayne State University, Detroit, MI,
USA.
BACKGROUND: Many studies have addressed effects of dietary supplementation with

soy protein, but most have been inconsistent and few have been long-term studies
in men.
OBJECTIVES: This study was a secondary analysis of body weight, blood pressure,
thyroid hormones, iron status, and clinical chemistry in a 2-y trial of soy
protein supplementation in middle-aged to older men.
METHODS: Data were analyzed as secondary outcomes of a randomized controlled
trial of dietary supplementation with 20 g/d soy protein isolate, providing 41
mg/d total isoflavones and 23 mg/d genistein, in 44- to 75-y-old men who were at
risk of cancer recurrence following prostatectomy randomized to soy (n = 50) or
a casein-based placebo (n = 43). Weight, blood pressure, and blood samples were
collected at baseline, every 2 mo in year 1, and every 3 mo in year 2.
RESULTS: Compared with casein, soy supplementation did not affect body weight,
blood pressure, serum total cholesterol, calcium, phosphorus, and thyroid
hormones. Serum ferritin concentrations doubled over 2 y in both groups
(117-129%), whereas hemoglobin and hematocrit increased slightly. In an
exploratory subgroup analysis of soy group data, weight increased in subjects
producing equol but not in nonproducers. Blood pressure was reduced in nonequol
producers but not in producers. Other endpoints were not affected by equol
production status.
CONCLUSIONS: Soy protein supplementation for 2 y compared with a casein-based
placebo did not affect body weight, blood pressure, serum total cholesterol,
iron status parameters, calcium, phosphorus, and thyroid hormones. Exploratory
analysis suggests that equol production status of subjects on soy may modify
effects of soy on body weight and possibly blood pressure. This trial was
registered at clinicaltrials.gov as NCT00765479.

American Society for Nutrition.
DOI: 10.1093/ajcn/nqaa390
PMCID: PMC8024002
153. JNCI Cancer Spectr. 2021 Jan 22;5(1):pkaa125. doi: 10.1093/jncics/pkaa125.

eCollection 2021 Feb.
Chemoprevention Agents to Reduce Mammographic Breast Density in Premenopausal

Women: A Systematic Review of Clinical Trials.
Salazar AS(1), Rakhmankulova M(1), Simon LE(2), Toriola AT(1).
Author information:
(1)Department of Surgery, Division of Public Health Sciences, Washington
University School of Medicine, St Louis, MO, USA.
(2)Bernard Becker Medical Library, Washington University School of Medicine, St
Louis, MO, USA.
Comment in
JNCI Cancer Spectr. 2021 Jun 14;5(4):
JNCI Cancer Spectr. 2021 Jun 14;5(4):
BACKGROUND: Higher mammographic breast density (MBD) is associated with an

increased risk of breast cancer when compared with lower MBD, especially in
premenopausal women. However, little is known about the effectiveness of
chemoprevention agents in reducing MBD in premenopausal women without a history
of breast cancer. Findings from this review should provide insight on how to
target MBD in breast cancer prevention in premenopausal women with dense
breasts.
METHODS: We searched 9 electronic databases for clinical trials in English,
Spanish, French, or German published until January 2020. Articles evaluating the
association of pharmacological agents and MBD were included. Data were extracted
on methods, type and dose of intervention, outcomes, side effects, and follow
up. Quality of the studies was assessed using the US Preventive Services Task
Force criteria.
RESULTS: We identified 7 clinical trials evaluating the associations of 6
chemoprevention agents with changes in MBD in premenopausal women without
history of breast cancer. The studies evaluated selective estrogen-receptor
modulators (n = 1); gonadotropin-releasing hormone agonists (n = 2); isoflavones
(n = 1); vitamin D (n = 1); and Boswellia, betaine, and mayo-inositol compound
(n = 1). Hormonal interventions were associated with net reductions in percent
density (tamoxifen [13.4%], leuprolide acetate [8.9%], and goserelin [2.7%]),
whereas nonhormonal (vitamin D and isoflavone) interventions were not. However,
MBD returned to preintervention baseline levels after cessation of
gonadotropin-releasing hormone agonists.
CONCLUSIONS: A limited number of chemoprevention agents have been shown to
reduce MBD in premenopausal women. Identification of new and well-tolerated
chemoprevention agents targeting MBD and larger studies to confirm agents that
have been studied in small trials are urgent priorities for primary breast
cancer prevention in premenopausal women with dense breasts.
DOI: 10.1093/jncics/pkaa125
PMCID: PMC7853173
154. Nutr Res Pract. 2021 Feb;15(1):1-11. doi: 10.4162/nrp.2021.15.1.1. Epub 2020
Aug
5.
Validation of soy isoflavone intake and its health effects: a review of the
development of exposure biomarkers.
Jang HH(1)(2), Lee YM(3), Choe JS(1), Kwon O(2).
Author information:
(1)National Institute of Agricultural Sciences, Rural Development
Administration, Wanju 55365, Korea.
(2)Department of Nutritional Science and Food Management, Ewha Womans
University, Seoul 03765, Korea.
(3)Division of Applied Food System, Major of Food and Nutrition, Seoul Women's
University, Seoul 01797, Korea.
BACKGROUND/OBJECTIVES: It is difficult to consistently demonstrate the health

effects of soy isoflavones owing to the multitude of factors contributing to
their bioavailability. To accurately verify these health effects, dietary
isoflavone intake should be measured using a biologically active dose rather
than an intake dose. This concept has been expanded to the development of new
exposure biomarkers in nutrition research. This review aims to provide an
overview of the development of exposure biomarkers and suggest a novel research
strategy for identifying the health effects of soy isoflavone intake.
MATERIALS/METHODS: We cover recent studies on the health effects of soy
isoflavones focusing on isoflavone metabolites as exposure biomarkers.
RESULTS: Compared to non-fermented soy foods, fermented soy foods cause an
increased concentration of isoflavones in the biofluid immediately following
ingestion. The correlation between exposure biomarkers in blood and urine and
the food frequency questionnaire was slightly lower than that of corresponding
24-h dietary recalls. Urinary and blood isoflavone levels did not show a
consistent association with chronic disease and cancer risk.
CONCLUSION: It is crucial to understand the variable bioavailabilities of soy
isoflavones, which may affect evaluations of soy isoflavone intake in health and
disease. Further studies on the development of valid exposure biomarkers are
needed to thoroughly investigate the health effects of isoflavone.
©2021 The Korean Nutrition Society and the Korean Society of Community
Nutrition.
DOI: 10.4162/nrp.2021.15.1.1
PMCID: PMC7838478
PMID: 33542788
Conflict of interest statement: Conflict of Interest: The authors declare no

potential conflicts of interests.
155. Saudi J Biol Sci. 2021 Jan;28(1):1141-1146. doi: 10.1016/j.sjbs.2020.11.048.

Epub 2020 Nov 18.
Isoflavones from black chickpea (Cicer arietinum L) sprouts with antioxidant and
antiproliferative activity.
Dulce-María DA(1), Adrián CR(1)(2), Cuauhtémoc RM(1), Ada-Keila MN(1), Jorge

MC(1), Erika AS(2), Edith-Oliva CR(1).
Author information:
(1)Programa Regional de Posgrado en Biotecnología, Programa de Posgrado en
Ciencia y Tecnología de Alimentos, Facultad de Ciencias Químico Biológicas,
Universidad Autónoma de Sinaloa, Mexico.
(2)CIASaP, Programa de Posgrado en Ciencias en Biomedicina Molecular, Facultad
de Medicina, Universidad Autónoma de Sinaloa, 80246 Culiacán Sinaloa, Mexico.
Black chickpea is a good source of bioactive compounds, particularly

isoflavones. Sprouting improves nutraceutical value in chickpea seeds. This
study aimed to explore the role of sprouting of black chickpea seeds on the
synthesis of isoflavones and evaluate the impact of the soluble isoflavone on
cellular antioxidant activity (CAA) and antiproliferative activity in breast
cancer cells. Isoflavones were identified and quantified by HPLC-UV-MS. The CAA
and antiproliferative activity were determined in HepG2 cells and MDA-MB-231
cancer cells, correspondingly. In sprouted black chickpea, six isoflavones
(formononetin, biochanin-A, and its glycosides) were identified and the total
isoflavones content increased (0.31 to 35.72 µgBA/mg of extract). The CAA was
increased five times from 137.2 to 788.2 µMEQ/100 g of sample. The bioactive
compounds in sprouted chickpea decreased the proliferation of MDA-MB-231 cell
line. Also caused morphological changes such as cell shrinkage, rounding and
nuclear fragmentation. The results herein suggest that bioactive compounds, as
isoflavones, in sprouted black chickpea showed a potential antioxidant and
antiproliferative activity. Therefore, it may be considered as a value-added
product or ingredient for produce functional foods.
© 2020 The Author(s).
DOI: 10.1016/j.sjbs.2020.11.048
PMCID: PMC7783802
PMID: 33424409
156. Menopause. 2021 Jan 4;28(4):413-422. doi: 10.1097/GME.0000000000001715.
Serum isoflavones and lignans and odds of breast cancer in pre- and
postmenopausal Chinese women.
Feng XL(1), Ho SC(2), Zhan XX(3), Zuo LS(1), Mo XF(4), Zhang X(1), Abulimiti
A(1), Huang CY(1), Zhang CX(1).
Author information:
(1)Department of Epidemiology, School of Public Health, Sun Yat-sen University,
Guangzhou, People's Republic of China.
(2)Division of Epidemiology, The Jockey Club School of Public Health and Primary
Care, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of
China.
(3)Department of Laboratory Medicine, Sun Yat-sen University First Affiliated
Hospital, Guangzhou, People's Republic of China.
(4)Department of Thyroid and Breast Surgery, Sun Yat-sen University First
Affiliated Hospital, Guangzhou, People's Republic of China.
OBJECTIVE: Isoflavones and lignans are phytoestrogens present in plant-based

foods, which have a potential preventive effect on breast carcinogenesis. The
effects of phytoestrogens on breast cancer may differ according to the hormonal
environment. This case-control study aimed to investigate the association
between serum phytoestrogens and odds of breast cancer among Chinese pre- and
postmenopausal women.
METHODS: A total of 792 cases and 813 age-matched controls were included. Serum
isoflavone (daidzein, genistein, glycitein, equol, and formononetin) and lignan
(enterodiol and enterolactone) concentrations were measured using a liquid
chromatography-tandem mass spectrometry method.
RESULTS: Significant inverse associations were found between serum total soy
isoflavone precursors, daidzein, genistein, formononetin, total lignans,
enterodiol, enterolactone, and the odds of breast cancer in premenopausal but
not postmenopausal women. For premenopausal women, the adjusted odds ratios (95%
confidence intervals) for the highest versus the lowest serum concentration
groups were 0.60 (0.41-0.87) for total soy isoflavones precursors, 0.64
(0.44-0.93) for daidzein, 0.62 (0.43-0.90) for genistein, 0.49 (0.35-0.68) for
formononetin, 0.38 (0.25-0.57) for total lignans, 0.49 (0.33-0.73) for
enterodiol, and 0.49 (0.33-0.74) for enterolactone. However, the interaction
between serum phytoestrogens and menopausal status on odds of breast cancer was
statistically significant only for daidzein. No significant association was
found between serum equol or gycitein and the odds of breast cancer among either
pre- or postmenopausal women.
CONCLUSIONS: Higher levels of certain serum isoflavones and lignans were
associated with reduced odds of breast cancer in premenopausal women, but the
interaction was statistically significant only for daidzein.
Copyright © 2021 by The North American Menopause Society.
DOI: 10.1097/GME.0000000000001715
Conflict of interest statement: Financial disclosures/conflicts of interest:

None reported.
157. Climacteric. 2021 Feb;24(1):57-63. doi: 10.1080/13697137.2020.1863356. Epub

2021
Jan 4.
The effects of phytoestrogens on postmenopausal health.
Rowe IJ(1), Baber RJ(2).
Author information:
(1)Northern Clinical School, Sydney Medical Programme, Royal North Shore
Hospital, Sydney, Australia.
(2)University of Sydney Faculty of Medicine and Health, The Royal North Shore
Hospital Division of Women and Child Health, Sydney, Australia.
Phytoestrogens are a group of non-steroidal polyphenolic plant-based substances,

commonly used for the treatment of menopause-related conditions. They have both
genomic and non-genomic effects, displaying weak affinity for estrogen receptors
(ER) and preferentially binding to ER-B over ER-A. However, evidence for the
benefits of phytoestrogen consumption has been limited. We conducted a review of
recent literature, focusing on systematic reviews and meta-analyses reporting on
postreproductive health effects of phytoestrogens. While many trials concerning
dietary and supplementary phytoestrogens have been conducted, evidence of
clinical efficacy is heterogeneous and inconclusive. There appears to be
reduction in the vasomotor symptoms of menopause with phytoestrogen intake;
however, it is likely small and slow in onset. Phytoestrogens also appear to
improve bone mineral density and markers of cardiovascular risk; however, there
is inadequate research regarding long-term outcomes. There appear to be no
harmful effects of phytoestrogens on breast, endometrial cancer or colorectal
cancer and phytoestrogens intake may in fact be protective. Research regarding
the effect of phytoestrogens on cognition is mixed, with most studies reporting
no significant association. Overall, individual variations in the metabolism of
phytoestrogens and age-related genomic effects may account for the considerable
variability in the measured effects of phytoestrogens.
DOI: 10.1080/13697137.2020.1863356
158. J Nutr Sci Vitaminol (Tokyo). 2020;66(6):502-507. doi: 10.3177/jnsv.66.502.
Health Promotion Effects of Soy Isoflavones.
Nakai S(1), Fujita M(1), Kamei Y(1).
Author information:
(1)Graduate School of Life and Environmental Sciences, Kyoto Prefectural
University.
Soybeans contain several physiologically active ingredients, such as soy
phytosterol, soyasaponin, soy protein, and lecithin, and are therefore expected
to express the functionalities of said ingredients. Among them, soy isoflavones
have been studied in recent years for their various functions, including their
obesity-preventing effect, blood glucose level reducing effect, osteoporosis and
breast cancer risk reduction, and anti-oxidative effect, and several health
promoting effects and disease preventing effects are expected. For example, it
has been determined that soy isoflavones reduce body and fat weight in
experiments in which mice were fed a diet containing soy isoflavones in studies
on anti-obesity. Epidemiologic studies with humans have also shown that women
who consume more soybeans have lower BMI than those who consume less. We
previously found that soy isoflavones may have anti-obesity effects in myoblasts
through the activation of transcriptional coactivator PGC-1β, which increases
energy expenditure. In recent studies, a decrease in blood glucose level due to
soy isoflavone was seen in an experiment in which diabetic model mice were fed a
diet containing soy isoflavone. It has also been suggested that soy isoflavone
intake may increase bone mineral density in postmenopausal women and reduce the
risk of breast cancer. This review focuses on the actions of soy isoflavones
known to date, including their anti-obesity and anti-diabetic effects, bone loss
preventing effects, and cancer risk reduction effects, and introduces reports on
the health promotion and disease prevention effects of soy isoflavones.
DOI: 10.3177/jnsv.66.502
159. J Pers Med. 2020 Dec 19;10(4):292. doi: 10.3390/jpm10040292.
From Proteomics to Personalized Medicine: The Importance of Isoflavone Dose and

Estrogen Receptor Status in Breast Cancer Cells.
Ilieș M(1), Uifălean A(2), Pașca S(1)(3), Dhople VM(4), Lalk M(5), Iuga
CA(1)(2), Hammer E(4)(6).
Author information:
(1)MedFuture Research Center for Advanced Medicine, Department of Proteomics and
Metabolomics, "Iuliu Hațieganu" University of Medicine and Pharmacy, no. 4-6
Louis Pasteur st., 400349 Cluj-Napoca, Romania.
(2)Department of Pharmaceutical Analysis, Faculty of Pharmacy, "Iuliu Hațieganu"
University of Medicine and Pharmacy, Louis Pasteur Street 6, 400349 Cluj-Napoca,
Romania.
(3)Department of Hematology, "Iuliu Hațieganu" University of Medicine and
Pharmacy, 400012 Cluj-Napoca, Romania.
(4)Interfaculty Institute for Genetics and Functional Genomics, University
Medicine Greifswald, Felix-Hausdorff-Straße 8, 17475 Greifswald, Germany.
(5)Institute of Biochemistry, University of Greifswald, Felix-Hausdorff-Straße
4, 17489 Greifswald, Germany.
(6)DZHK (German Center for Cardiovascular Research), Partner Site Greifswald,
17475 Greifswald, Germany.
Continuing efforts are directed towards finding alternative breast cancer

chemotherapeutics, with improved safety and efficacy profiles. Soy isoflavones
represent promising agents but, despite extensive research, limited information
exists regarding their impact on the breast cancer cell proteome. The purpose of
this study was to compare the proteomic profiles of MCF-7 (estrogen responsive)
and MDA-MB-231 (estrogen non-responsive) breast cancer cells exposed to
different concentrations of genistein, daidzein, and a soy seed extract, using a
high throughput LC-UDMSE protein profiling approach. The
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay
confirmed the dual activity of soy isoflavones on MCF-7 cells and the inhibitory
effect on MDA-MB-231 cells. Proteome profiling of paramagnetic beads prepared
peptides by nano-LC UDMSE and pathway enrichment analysis revealed that
isoflavones affected distinct molecular pathways in MCF-7 and MDA-MB-231 cells,
such as tyrosine kinases signaling pathway, cytoskeleton organization, lipid and
phospholipid catabolism, extracellular matrix degradation and mRNA splicing.
Also, in MCF-7 cells, low and high isoflavone doses induced different changes of
the proteome, including cell cycle alterations. Therefore, the expression of
estrogen receptors and the isoflavone dose are determinant factors for the
molecular impact of isoflavones and must be taken into account when considering
adjuvant breast cancer therapy towards personalized medicine.
DOI: 10.3390/jpm10040292
PMCID: PMC7766658
PMID: 33352803
160. Nutrients. 2020 Dec 17;12(12):3853. doi: 10.3390/nu12123853.
Scientific Evidence Supporting the Beneficial Effects of Isoflavones on Human

Health.
Gómez-Zorita S(1)(2)(3), González-Arceo M(1), Fernández-Quintela A(1)(2)(3),

Eseberri I(1)(2)(3), Trepiana J(1)(2)(3), Portillo MP(1)(2)(3).
Author information:
(1)Nutrition and Obesity Group, Department of Pharmacy and Food Science,
University of the Basque Country (UPV/EHU) and Lucio Lascaray Research
Institute, 01006 Vitoria, Spain.
(2)CIBEROBN Physiopathology of Obesity and Nutrition, Institute of Health Carlos
III, 01006 Vitoria, Spain.
(3)Bioaraba Health Research Institute, 01002 Vitoria, Spain.
Isoflavones are phenolic compounds with a chemical structure similar to that of

estradiol. They are present in several vegetables, mainly in legumes such as
soy, white and red clover, alfalfa and beans. The most significant food source
of isoflavones in humans is soy-derived products. Isoflavones could be used as
an alternative therapy for pathologies dependent on hormonal disorders such as
breast and prostate cancer, cardiovascular diseases, as well as to minimize
menopausal symptoms. According to the results gathered in the present review, it
can be stated that there is scientific evidence showing the beneficial effect of
isoflavones on bone health and thus in the prevention and treatment of
osteoporosis on postmenopausal women, although the results do not seem entirely
conclusive as there are discrepancies among the studies, probably related to
their experimental designs. For this reason, the results should be interpreted
with caution, and more randomized clinical trials are required. By contrast, it
seems that soy isoflavones do not lead to a meaningful protective effect on
cardiovascular risk. Regarding cancer, scientific evidence suggests that
isoflavones could be useful in reducing the risk of suffering some types of
cancer, such as breast and endometrial cancer, but further studies are needed to
confirm these results. Finally, isoflavones could be useful in reducing hot
flushes associated with menopause. However, a limitation in this field is that
there is still a great heterogeneity among studies. Lastly, with regard to
isoflavone consumption safety, it seems that they are safe and that the most
common adverse effect is mild and occurs at the gastrointestinal level.
DOI: 10.3390/nu12123853
PMCID: PMC7766685
161. Curr Med Chem. 2021;28(39):8068-8082. doi: 10.2174/0929867327666201109122025.
mTOR Targeted Cancer Chemoprevention by Flavonoids.
Badar Ul Islam(1), Khan MS(2), Husain FM(3), Rehman MT(4), Zughaibi TA(5),
Abuzenadah AM(5), Urooj M(6), Kamal MA(5), Tabrez S(5).
Author information:
(1)Department of Biochemistry, J.N Medical College, Faculty of Medicine, Aligarh
Muslim University, Aligarh,, India.
(2)Protein Research Chair, Department of Biochemistry, College of Sciences, King
Saud University, Riyadh, Saudi Arabia.
(3)Department of Food Science and Nutrition, Faculty of Food and Agriculture
Sciences, King Saud University, Riyadh, Saudi Arabia.
(4)Department of Pharmacognosy, College of Pharmacy, King Saud University,
Riyadh, Saudi Arabia.
(5)King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi
Arabia.
(6)Independent Researcher, Yanbu, Saudi Arabia.
Over the past several decades, plant-derived products (phytochemicals) have been
suggested to possess immense therapeutic potential. Among these phytochemicals,
different flavonoids have been reported for their potent anticancer activity. To
exhibit their anticancer potential, these flavonoids modulate different
signaling pathways. Among these pathways, the mammalian target of rapamycin
(mTOR) and associated phosphatidyl-inositol 3-kinase (PI3K)/protein kinase B
(Akt) signaling cascade have been reported as a pivotal modulator of cell
survival, proliferation, and death/apoptosis. Hence, targeting this cascade
could be an ideal strategy to alleviate apoptosis and inhibit proliferation in
different forms of cancer. The targeting of PI3K/Akt/mTOR by flavonoids have
been well documented in the scientific literature. In the current study, we have
studied the anticancer potential of various flavonoids, especially flavones,
flavonols, and isoflavones that include apigenin, luteolin, baicalein,
tangeretin, epigallocatechin- 3-gallate, genistein, and daidzein especially
dealing with mTOR targeting.

DOI: 10.2174/0929867327666201109122025
162. Phytochemistry. 2021 Jan;181:112574. doi: 10.1016/j.phytochem.2020.112574.

Epub
2020 Nov 3.
The genus Genista L.: A rich source of bioactive flavonoids.
Grafakou ME(1), Barda C(1), Tomou EM(1), Skaltsa H(2).
Author information:
(1)Department of Pharmacognosy and Chemistry of Natural Products, School of
Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis,
Zografou, 15771, Athens, Greece.
(2)Department of Pharmacognosy and Chemistry of Natural Products, School of
Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis,
Zografou, 15771, Athens, Greece. Electronic address: skaltsa@pharm.uoa.gr.
The genus Genista L. (family Fabaceae, subfamily Papilionoideae), with its

cosmopolitan distribution, has attracted the human interest since ancient times,
as it is used in folk medicine and mainly in the Mediterranean area for the
treatment of respiratory diseases, rheumatic disorders, diabetes and ulcer,
while it is also well known for its yellow pigment. The chemical composition of
the Genista species revealed the presence of more than 108 flavonoids.
Isoflavones, belonging to the group of phytoestrogens, are important secondary
metabolites of the genus. The extracts of the Genista species may act as
important source of bioactive phytochemicals for the treatment of many human
ailments, mainly inflammation and pain, estrogen related pathology,
hyperglycaemia, cancer and microbial infections. Therefore, the present review
summarizes and discusses the flavonoid derivatives from the genus Genista,
together with their structural features and pharmacological properties, aiming
to highlight the recent advances in current knowledge on Genista species as a
source of bioactive flavonoids.
DOI: 10.1016/j.phytochem.2020.112574
163. Life Sci. 2020 Dec 15;263:118594. doi: 10.1016/j.lfs.2020.118594. Epub 2020
Oct
16.
Genistin attenuates cellular growth and promotes apoptotic cell death breast
cancer cells through modulation of ERalpha signaling pathway.
Hwang ST(1), Yang MH(2), Baek SH(3), Um JY(1), Ahn KS(4).
Author information:
(1)Department of Science in Korean Medicine, Kyung Hee University, 24
Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST
Department of Converging Science and Technology, Kyung Hee University, Seoul
02447, Republic of Korea.
(3)College of Korean Medicine, Dongguk University, 32 Dongguk-ro, Ilsandong-gu,
Goyang-si, Gyeonggi-do 10326, Republic of Korea.
Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; KHU-KIST
Department of Converging Science and Technology, Kyung Hee University, Seoul
02447, Republic of Korea. Electronic address: ksahn@khu.ac.kr.
Estrogen receptor alpha (ERα) is a vital molecular target in ER-positive breast

cancer. Genistin (GS) is one of isoflavones that can exert diverse
pharmacological effects including that of anti-proliferation, anti-tumor
angiogenesis, induce cell cycle arrest and apoptosis. Here, we examined the
efficacy of GS as an anti-cancer agent against breast cancer cells. We observed
that GS exhibited more cytotoxic activity against MCF-7 cells than
MDA-MB-231cells. We found that GS caused negative regulation of ERα. It also
effectively down-modulated ER nuclear translocation as well DNA binding activity
in breast cancer cells. Moreover, GS effectively induced apoptosis and
suppressed levels of oncogenic markers in MCF-7 cells. Interestingly, in ERα
knocked-down MCF-7 cells, cell viability was found to be increased and the
levels of cleaved PARP was abolished. We found completely contrasting results in
ERα overexpressed MDA-MB-231 cells, where cell viability was decreased and
expression level of apoptotic markers was enhanced. Our results demonstrate that
GS can suppress ERα signaling and can be useful for prevention and therapy of
ER-positive breast cancer.
Copyright © 2020. Published by Elsevier Inc.
DOI: 10.1016/j.lfs.2020.118594
164. Breast Cancer Res Treat. 2020 Nov;184(2):615-626. doi:

10.1007/s10549-020-05875-0. Epub 2020 Oct 17.
Isoflavone intake on the risk of overall breast cancer and molecular subtypes in
women at high risk for hereditary breast cancer.
Sim EJ(1)(2)(3), Ko KP(4), Ahn C(1)(2)(3)(5), Park SM(5)(6), Surh YJ(3)(7)(8),

An S(2)(3)(5), Kim SW(9), Lee MH(10), Lee JW(11), Lee JE(12), Kim KS(13), Yom
CK(14), Kim HA(15), Park SK(16)(17)(18).
Author information:
(1)Interdisciplinary Program in Cancer Biology, Seoul National University
College of Medicine, Seoul, South Korea.
(2)Department of Preventive Medicine, Seoul National University College of
Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
(3)Cancer Research Institute, Seoul National University, Seoul, Korea.
(4)Department of Preventive Medicine, Gachon University College of Medicine,
Incheon, Korea.
(5)Department of Biomedical Science, Seoul National University Graduate School,
Seoul, Korea.
(6)Department of Family Medicine, Seoul National University Hospital, Seoul
National University College of Medicine, Seoul, South Korea.
(7)Tumor Microenvironment Global Core Research Center, College of Pharmacy,
Seoul National University, Seoul, Korea.
(8)Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate
School of Convergence Sciences and Technology, Seoul National University, Seoul,
Korea.
(9)Department of Surgery, Daerim St. Mary's Hospital, Seoul, Korea.
(10)Department of Surgery, College of Medicine, Soonchunhyang University, Seoul,
Korea.
(11)Department of Surgery, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, Korea.
(12)Department of Surgery, Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, Korea.
(13)Department of Breast Surgery, Gosin University Gospel Hospital, Pusan,
Korea.
(14)Yom Breast Clinic, Seoul, Korea.
(15)Department of Surgery, Korea Cancer Center Hospital, Korea Institute of
Radiological and Medical Sciences, Seoul, Korea.
(16)Interdisciplinary Program in Cancer Biology, Seoul National University
College of Medicine, Seoul, South Korea. suepark@snu.ac.kr.
Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
suepark@snu.ac.kr.
(18)Cancer Research Institute, Seoul National University, Seoul, Korea.
suepark@snu.ac.kr.
PURPOSE: We investigated the association between isoflavone (ISF) intake and

hereditary breast cancer (BC) risk, particularly by molecular subtype, in
East-Asian BRCA1/2 mutation carriers and non-carriers at a high risk of
hereditary breast cancer (i.e., family history of BC (FHBC) and early-onset BC
[EOBC, age < 40 years]).
METHODS: The association between ISF intake and BC risk by molecular subtypes
was assessed in 1709 participants (407 BRCA1/2 carriers, 585 FHBC non-carriers,
586 EOBC non-carriers, and 131 unaffected non-carriers) from the Korean
Hereditary Breast Cancer Study using hazard ratios (HRs) and 95% confidence
intervals (CIs) in weighted Cox regression models. Daily ISF intake was assessed
using a validated food frequency questionnaire. We evaluated gene-environment
interactions between BRCA1/2 mutation and ISF intake in 1604 BC cases by
calculating the case-only odds ratios (CORs) and 95% CIs in logistic regression
models.
RESULTS: ISF intake was inversely associated with luminal A BC risk in BRCA2
mutation carriers and FHBC non-carriers (HR = 0.14, 95% CI = 0.04-0.50 for high
intake [ISF intake ≥ 15.50 mg/day]; HR = 0.27, 95% CI = 0.11-0.69 for high
intake, respectively). We observed a reduced risk of triple negative BC (TNBC)
in BRCA1 carriers and FHBC non-carriers (HR = 0.09, 95% CI = 0.02-0.40 for high
intake; HR = 0.19, 95% CI = 0.05-0.69 for high intake, respectively). In the
case-only design, an interaction between BRCA1 mutation carrier status and ISF
intake emerged in TNBC patients (COR = 0.39, 95% CI = 0.16-0.95).
CONCLUSIONS: This study suggests that ISF intake is inversely associated with BC
risk in women at high risk of hereditary BC and that the effect could differ by
molecular subtypes.
DOI: 10.1007/s10549-020-05875-0
165. Molecules. 2020 Oct 14;25(20):4712. doi: 10.3390/molecules25204712.
Antiangiogenic Activity of Flavonoids: A Systematic Review and Meta-Analysis.
Khater M(1)(2), Greco F(1), Osborn HMI(1).
Author information:
(1)School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK.
(2)Therapeutic Chemistry Department, Pharmaceutical & Drug Industries Research
Division, National Research Centre, Cairo 12622, Egypt.
Abstract: An imbalance of angiogenesis contributes to many pathologies such as

cancer, arthritis and retinopathy, hence molecules that can modulate
angiogenesis are of considerable therapeutic importance. Despite many reports on
the promising antiangiogenic properties of naturally occurring flavonoids, no
flavonoids have progressed to the clinic for this application. This systematic
review and meta-analysis therefore evaluates the antiangiogenic activities of a
wide range of flavonoids and is presented in two sections. The first part of the
study (Systematic overview) included 402 articles identified by searching
articles published before May 2020 using ScienceDirect, PubMed and Web of
Science databases. From this initial search, different classes of flavonoids
with antiangiogenic activities, related pathologies and use of in vitro and/or
in/ex vivo angiogenesis assays were identified. In the second part
(Meta-analysis), 25 studies concerning the antiangiogenic evaluation of
flavonoids using the in vivo chick chorioallantoic membrane (CAM) assay were
included, following a targeted search on articles published prior to June 2020.
Meta-analysis of 15 out of the 25 eligible studies showed concentration
dependent antiangiogenic activity of six compared subclasses of flavonoids with
isoflavones, flavonols and flavones being the most active (64 to 80% reduction
of blood vessels at 100 µM). Furthermore, the key structural features required
for the antiangiogenic activity of flavonoids were derived from the pooled data
in a structure activity relationship (SAR) study. All in all, flavonoids are
promising candidates for the development of antiangiogenic agents, however
further investigations are needed to determine the key structural features
responsible for their activity.
PMCID: PMC7594036
166. Breast Cancer Res Treat. 2021 Jan;185(2):307-316. doi:

10.1007/s10549-020-05957-z. Epub 2020 Oct 9.
Effect of isoflavones on breast cancer cell development and their impact on

breast cancer treatments.
Hatono M(1), Ikeda H(2), Suzuki Y(1), Kajiwara Y(1), Kawada K(1), Tsukioki T(1),
Kochi M(1), Suzawa K(1), Iwamoto T(1), Yamamoto H(1), Shien T(1), Yamane M(1),
Taira N(1), Doihara H(1), Toyooka S(1).
Author information:
(1)Department of General Thoracic Surgery and Breast and Endocrine Surgery,
Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical
Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
(2)Department of General Thoracic Surgery and Breast and Endocrine Surgery,
Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical
Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
yashima_hirokuni@msn.com.
PURPOSE: Epidemiological studies have suggested that intake of soy isoflavones

is associated with a reduced risk of development of breast cancer and an
improved prognosis in patients with breast cancer. In addition, basic research
has demonstrated the antitumor effects of these compounds on breast cancer cell
lines. However, the detailed effects of the intake of equol, which is one of the
metabolites of the soy isoflavones, are yet to be clarified on the risk of
development and recurrence of breast cancer and its interactions with drugs used
for treating breast cancer. This study aimed to determine the antitumor effects
of equol and investigate the impact of adding equol to therapeutic agents for
breast cancer using breast cancer cell lines.
METHODS: We examined the antitumor effect of equol on breast cancer cell lines
using MTS assay. We also studied the combined effect of equol and the existing
hormonal or chemotherapeutic agents using combination index. We evaluated the
expressions of the related proteins by Western blot analysis and correlated the
findings with the antitumor effect.
RESULTS: Equol showed bi-phasic protumor and antitumor effects; at a low
concentration, it promoted the tumor growth in hormone receptor-positive cell
lines, whereas antitumor effects were generally observed when an excessive
amount of dose unexpected in the blood and the tissue was administered. When
used with tamoxifen, equol might have some antagonistic effect, although it
depends on equol concentration and the type of cancer cells.
CONCLUSIONS: We confirmed that equol has dual action, specifically a tumor
growth-promoting effect and an antitumor effect. Although the results suggested
that equol might exert an antagonistic effect against tamoxifen depending on the
concentration, equol did not exert an antagonistic effect on other therapeutic
agents.
DOI: 10.1007/s10549-020-05957-z
Dietary Factors and Supplements Influencing Prostate Specific-Antigen (PSA)

Concentrations in Men with Prostate Cancer and Increased Cancer Risk: An
Evidence Analysis Review Based on Randomized Controlled Trials.
Grammatikopoulou MG(1), Gkiouras K(1)(2), Papageorgiou SΤ(2), Myrogiannis I(2),

Mykoniatis I(3)(4), Papamitsou T(5), Bogdanos DP(1)(6), Goulis DG(7).
Author information:
(1)Department of Rheumatology and Clinical Immunology, Faculty of Medicine,
School of Health Sciences, University of Thessaly, Biopolis, GR-41334 Larissa,
Greece.
(2)Medical School, Faculty of Health Sciences, Aristotle University of
Thessaloniki, University Campus, GR-54124 Thessaloniki, Greece.
(3)Institute for the Study of Urological Diseases (ISUD), 33 Nikis Avenue,
GR-54622 Thessaloniki, Greece.
(4)1st Department of Urology and Center for Sexual and Reproductive Health, G.
Gennimatas-Aghios Demetrius General Hospital, 41 Ethnikis Amynis Street,
Aristotle University of Thessaloniki, GR-54635 Thessaloniki, Greece.
(5)Laboratory of Histology and Embryology, Medical School, Faculty of Health
Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
(6)Division of Transplantation, Immunology and Mucosal Biology, MRC Centre for
Transplantation, King's College London Medical School, London SE5 9RS, UK.
(7)Unit of Reproductive Endocrinology, 1st Department of Obstetrics and
Gynecology, Medical School, Faculty of Health Sciences, Aristotle University of
Thessaloniki, GR-56429 Thessaloniki, Greece.
The quest for dietary patterns and supplements efficient in down-regulating

prostate-specific antigen (PSA) concentrations among men with prostate cancer
(PCa) or increased PCa risk has been long. Several antioxidants, including
lycopene, selenium, curcumin, coenzyme Q10, phytoestrogens (including
isoflavones and flavonoids), green tea catechins, cernitin, vitamins (C, E, D)
and multivitamins, medicinal mushrooms (Ganoderma lucidum), fruit extracts (saw
palmetto, cranberries, pomegranate), walnuts and fatty acids, as well as
combined supplementations of all, have been examined in randomized controlled
trials (RCTs) in humans, on the primary, secondary, and tertiary PCa prevention
level. Despite the plethora of trials and the variety of examined interventions,
the evidence supporting the efficacy of most dietary factors appears inadequate
to recommend their use.
DOI: 10.3390/nu12102985
PMCID: PMC7600271
168. Int J Epidemiol. 2020 Oct 1;49(5):1553-1561. doi: 10.1093/ije/dyaa177.

Soy and isoflavone consumption and subsequent risk of prostate cancer mortality:
the Japan Public Health Center-based Prospective Study.
Sawada N(1), Iwasaki M(1), Yamaji T(1), Shimazu T(1), Inoue M(1), Tsugane S(1);
Japan Public Health Center-based Prospective Study Group.
Author information:
(1)Epidemiology and Prevention Group, Center for Public Health Sciences,
National Cancer Center, Tokyo, Japan.
BACKGROUND: Although many epidemiological studies have reported the preventive

effects of soy products and isoflavones on prostate cancer, our previous studies
reported that the association between soy and isoflavones and prostate cancer
incidence differed according to stage. It is more important to identify
modifiable risk factors related to lethal prostate cancer. Here, we investigated
the association between soy, soy products and isoflavones intake and prostate
cancer mortality, in a prospective study in Japan.
METHODS: We conducted a population-based prospective study in 43 580 Japanese
men with no history of cancer or cardiovascular disease (aged 45-74 years).
Participants completed a validated questionnaire which included 138 food items.
We followed participants from 1995 to 2016. Hazard ratios (HRs) and 95%
confidence intervals (CIs) of prostate cancer mortality were calculated
according to quintiles of soy products and isoflavones intake, using Cox hazard
proportional hazards regression.
RESULTS: During 16.9 years follow-up, we registered 221 deaths from prostate
cancer. Isoflavones and soy products intake was associated with an increased
risk of prostate cancer death, with multivariate HRQ5 vs. Q1=1.39, 95%
CI = 0.87-2.20, p for trend = 0.04 for isoflavones and multivariate HRQ5 vs.
Q1=1.76, 95% CI = 1.10-2.82, p for trend = 0.04 for soy food.
CONCLUSIONS: Our study suggested that high intake of soy and isoflavones might
increase the risk of prostate cancer mortality.
© The Author(s) 2020; all rights reserved. Published by Oxford University Press
on behalf of the International Epidemiological Association.
DOI: 10.1093/ije/dyaa177
169. Food Chem Toxicol. 2020 Nov;145:111743. doi: 10.1016/j.fct.2020.111743. Epub

2020 Sep 11.
Dietary isoflavone-induced, estrogen receptor-β-mediated proliferation of Caco-2

cells is modulated by gallic acid.
Ye H(1), Shaw IC(2).
Author information:
(1)Human Toxicology Research Group, School of Physical & Chemical Sciences,
University of Canterbury, Christchurch, New Zealand. Electronic address:
hye88@uic.edu.
(2)Human Toxicology Research Group, School of Physical & Chemical Sciences,
University of Canterbury, Christchurch, New Zealand.
Dietary isoflavones and their biotransformation products (from food

fermentation) are estrogen mimics which activate estrogen receptors (ER)α and
ERβ. In silico molecular modelling is used to determine theoretical binding
energies of genistein, daidzein and hydroxylated biotransformation products, and
to investigate structure-binding energy relationships with ERβ. Results suggest
that ligand hydroxyl arrangement determines binding energy and influences
binding affinity. Caco-2 cells (ERβ expressing) are used to study the
proliferative effect of genistein, daidzein and their hydroxylated
biotransformation products. Isoflavones/biotransformation products showed weaker
enhancement of Caco-2 proliferation than 17β-estradiol. The EC50s of
isoflavones/biotransformation products agreed with in silico-predicted binding
affinity order. Hydroxylated biotransformation products studied showed greater
Caco-2 proliferative effects than the parent isoflavones except
8-hydroxygenistein, probably due to unfavourable ERβ interactions caused by
8-hydroxygenistein's extra hydroxyl. Caco-2 pre-treatment with UDP-glucose
dehydrogenase inhibitor gallic acid promoted
genistein/8-hydroxygenistein-mediated proliferation. This is probably due to a
reduced isoflavone glucuronidation to form low estrogenicity glucuronides.
Findings are discussed in the context of dietary isoflavones/gallic acid and
effects on proliferation of ERβ-expressing gut cancer cells.
DOI: 10.1016/j.fct.2020.111743
170. Eur J Clin Nutr. 2021 Jun;75(6):890-901. doi: 10.1038/s41430-020-00744-x. Epub

2020 Sep 11.
Soy intake and chronic disease risk: findings from prospective cohort studies in
Japan.
Nagata C(1).
Author information:
(1)Department of Epidemiology & Preventive Medicine, Gifu University Graduate
School of Medicine, Gifu, Japan. chisato@gifu-u.ac.jp.
There has been much interest in the potential role of soy in reducing the risk
of chronic diseases. Soy foods are uniquely rich in isoflavones, a fact that has
triggered much research including intervention studies. However, there have been
few long-term prospective observational studies that include disease itself as
an outcome. High intake of soy foods is intrinsic to the Japanese diet, which
can be advantageous for conducting such studies in Japan. The present report
reviews the findings from Japanese prospective cohort studies on soy intake and
the risk of cardiovascular diseases, cancer, type 2 diabetes, osteoporosis,
menopausal symptoms, and dementia. The results suggest a beneficial role of soy
in several chronic diseases, but they are not without controversy. Discrepancies
have been observed in the findings of studies of Japanese or other Asians as
compared to those of non Asians. This review discusses the issues to be explored
in future studies.
DOI: 10.1038/s41430-020-00744-x
171. Nan Fang Yi Ke Da Xue Xue Bao. 2020 Jun 30;40(6):876-883. doi:
10.12122/j.issn.1673-4254.2020.06.16.
[Preparation of warangalone-loaded liposomes and its inhibitory effect on breast

cancer cells].
[Article in Chinese]
Mao L(1), Liu H(2), Liu H(1), Bian Z(1), Zhang Q(1), Liao W(1), Sun S(1).
Author information:
(1)Department of Nutrition and Food Hygiene, School of Public Health, Southern
Medical University, Guangzhou 510515, China.
(2)ERA (Shenzhen) Biotechonology, Shenzhen 518000, China.
OBJECTIVE: To prepare warangalone-loaded thermosensitive liposomes (WLTSL) and

evaluate its inhibitory effect on breast cancer cells in vitro.
METHODS: MTT assay was used to assess the changes in proliferation of 3 breast
cancer cell lines (MDA-MB-231, MCF7, and SKBR3) following treatment with
warangalone, soy isoflavone and genistein. Colony-forming assay and wound
healing assay was used to assess colony forming activity and migration of
MDA-MB-231 cells treated with warangalone. The effect of warangalone on the
expression of MMP2 and MMP9 in MDA-MB-231 cells was examined with Western
blotting. The thermosensitive liposomes (TSL) and WLTSL were prepared using a
thin film hydration method, and the morphology, size, encapsulation efficiency
and stability of the prepared liposomes were characterized using transmission
electron microscopy, dynamic light scattering scanning and UV spectrophotometry.
MTT assay was used to examine the inhibitory effect of WLTSL on mouse breast
cancer cells (4T1) in vitro.
RESULTS: Warangalone showed stronger anti-proliferation effects than soy
isoflavones and genistein in the 3 human breast cancer cell lines and
significantly inhibited colony formation by MDA-MB-231 cells. Treatment with
warangalone significantly inhibited migration of the breast cancer cells and
down-regulated the cellular expressions of MMP2 and MMP9. The prepared TSL and
WLTSL presented with a homogeneous, irregular spherical morphology, with a mean
particle size of 56.23±0.61 nm, a polymer dispersity index of 0.241±0.014, a
Zeta potential of -40.40±0.46 mV, and an encapsulation efficiency was
87.68±2.41%. WLTSL showed a good stability at 4 ℃ and 37 ℃ and a stronger
inhibitory effect than warangalone in 4T1 cells.
CONCLUSIONS: Warangalone inhibits the proliferation, migration and invasion of
breast cancer cells, and the prepared WLTSL possesses good physical properties
and strong anti-breast cancer activity.
目的: 制备和鉴定攀登鱼藤异黄酮温敏脂质体并研究其抗乳腺癌作用。
方法:
MTT 法检测攀登鱼藤异黄酮、大豆异黄酮和金雀异黄酮对人乳腺癌细胞（MDA-MB-231、MCF7、SKBR3）增殖活
性影响；克隆形成实验探讨攀登鱼藤异黄酮对三阴性乳腺癌细胞（MDA-MB-231）克隆形成的影响；细胞划痕实
验检测 MDA-MB-231 细胞迁移；蛋白印迹法检测 MDA-MB-231 细胞迁移和侵袭蛋白 MMP2，MMP9 表达量；薄膜
水化法制备温敏脂质体及攀登鱼藤异黄酮温敏脂质体；透射电子显微镜、动态光散射扫描仪以及紫外分光光度计
分别鉴定攀登鱼藤异黄酮温敏脂质体形貌、粒径、包封率及稳定性，并用 MTT 法检测攀登鱼藤异黄酮温敏脂质体
抗小鼠乳腺癌细胞（4T1）增殖活性。
结果:
攀登鱼藤异黄酮可显著抑制人乳腺癌细胞（MDA-MB-231、MCF7、SKBR3）增殖，且效果优于大豆异黄酮和金雀
异黄酮；攀登鱼藤异黄酮显著减少三阴性乳腺癌细胞（MDA-MB-231）克隆形成量，降低其划痕面积的愈合速度，
并下调 MMP2 和 MMP9 的表达。薄膜水化法制备得到的温敏脂质体呈均质不规则球形，其粒径为 56.23±0.61
nm、聚合物分散指数为 0.241±0.014、Zeta 电位为-40.40±0.46
mV、包封率为（87.68±2.41）%、稳定性较好，且抗小鼠乳腺癌增殖活性增强。
结论: 攀登鱼藤异黄酮通过抑制乳腺癌细胞增殖、转移和侵袭发挥其抗癌活性，攀登鱼藤异黄酮温敏脂质体具有
较好的物理性能及抗乳腺癌活性。
DOI: 10.12122/j.issn.1673-4254.2020.06.16
PMCID: PMC7321263
172. Eur J Clin Nutr. 2021 Jun;75(6):954-968. doi: 10.1038/s41430-020-00732-1. Epub

2020 Sep 4.
Fermented soy products intake and risk of cardiovascular disease and total
cancer incidence: The Japan Public Health Center-based Prospective study.
Nozue M(1)(2), Shimazu T(3), Charvat H(2), Mori N(2), Mutoh M(2), Sawada N(2),
Iwasaki M(2), Yamaji T(2), Inoue M(2), Kokubo Y(4), Yamagishi K(5), Iso H(6),
Tsugane S(2).
Author information:
(1)Department of Health and Nutritional Sciences, Faculty of Health Promotional
Sciences, Tokoha University, Hamamatsu, Japan.
National Cancer Center, Tokyo, Japan. tshimazu@ncc.go.jp.
(4)Department of Preventive Cardiology, National Cerebral and Cardiovascular
Center, Suita, Japan.
(5)Department of Public Health Medicine, Faculty of Medicine, Health Services
Research and Development Center, University of Tsukuba, Tsukuba, Japan.
(6)Public Health, Department of Social Medicine, Osaka University Graduate
School of Medicine, Suita, Japan.
BACKGROUND/OBJECTIVES: The association of fermented soy products, separately

from total soy products, with cardiovascular disease (CVD) and total cancer has
not been reported. We examined this association in a population-based
prospective cohort study in Japan.
SUBJECTS/METHODS: We studied 79,648 participants (42,788 women; 36,860 men) aged
45-74 years without a history of cancer, myocardial infarction, or stroke.
Participants completed a food frequency questionnaire (1995-1998) and were
followed to 2009-2012. Cox proportional hazards regression analysis was used to
calculate the hazard ratios (HR) and 95% confidence intervals (CI) of incidence
of CVD and total cancer according to quartiles of total soy products,
nonfermented soy products, fermented soy products, miso soup, natto, total
isoflavones from soy products, isoflavones from nonfermented soy products, and
isoflavones from fermented soy products.
RESULTS: In women, we observed a significant inverse association between
fermented soy product intake and the risk of CVD (multivariate HR in the highest
compared with the lowest quartile of fermented soy product intake: 0.80; 95% CI:
0.68, 0.95; P for trend = 0.010), and also found significant inverse
associations for natto and isoflavones among fermented soy products. In
site-specific analysis, we observed a similar, significant inverse association
between fermented soy product intake and the risk of stroke in women. We found
no significant association between any soy product and risk of CVD in men or
total cancer in both sexes.
CONCLUSIONS: Intake of fermented soy products such as natto was inversely
associated with the risk of CVD in women.
DOI: 10.1038/s41430-020-00732-1
173. Plants (Basel). 2020 Aug 16;9(8):1043. doi: 10.3390/plants9081043.
Effect of Ultraviolet C Irradiation on Isoflavone Concentrations in Different

Cultivars of Soybean (Glycine max).
Karki KB(1), Mishra AK(2), Choi SJ(3), Baek KH(2).
Author information:
(1)Research and Development Society, Kathmandu 4179, Nepal.
(2)Department of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 38541,
Korea.
(3)Department of Biotechnology, Catholic University of Daegu, Gyeongsan 38430,
Korea.
Phytoestrogens are naturally occurring plant polyphenolic compounds present in

high concentrations in soybean products. Phytoestrogens are divided into three
classes: lignans, isoflavones, and coumestans. Nine types of glycoside
isoflavones and three types of aglycoside isoflavones are reported in soybean.
Soy isoflavones can reduce the risk of a certain type of cancer, cardiovascular
problems, osteoporosis, and menopausal symptoms. We irradiated the leaves of
five cultivars of soybean with UV-C (260 nm) and determined the effect on
concentrations of isoflavone compounds using liquid chromatography-mass
spectrometry (LC-MS). Isoflavone concentrations were significantly higher
following irradiation, particularly in the cultivar Daepung, which was selected
as the best cultivar for high isoflavone induction with UV-C irradiation.
Further experimentation with the cultivar Daepung revealed that 20 min UV-C
irradiation was the best treatment for the induction of aglycone compounds, and
5 min with the dorsal surface facing the UV-C irradiation source was the best
treatment for the induction of glycoside isoflavone compounds.
DOI: 10.3390/plants9081043
PMCID: PMC7464170
PMID: 32824390
174. Eur J Med Chem. 2020 Nov 15;206:112677. doi: 10.1016/j.ejmech.2020.112677.

Epub
2020 Aug 1.
Design and synthesis of novel Flavone-based histone deacetylase inhibitors

antagonizing activation of STAT3 in breast cancer.
Wei M(1), Xie M(1), Zhang Z(1), Wei Y(1), Zhang J(2), Pan H(3), Li B(1), Wang
J(1), Song Y(1), Chong C(1), Zhao R(1), Wang J(4), Yu L(5), Yang G(6), Yang
C(7).
Author information:
(1)The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy,
Nankai University, Tianjin, 300071, PR China.
(2)Department of Hematology and Oncology, International Cancer Center, Shenzhen
University General Hospital, Shenzhen University Health Science Center, Xueyuan
AVE 1098, Nanshan District, Shenzhen, Guangdong, 518000, PR China.
(3)Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment,
Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital,
Tianjin, PR China.
(4)Tianjin Medical University Cancer Institute and Hospital, National Clinical
Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key
Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China.
Electronic address: jwang05@tmu.edu.cn.
(5)Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment,
Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital,
Tianjin, PR China. Electronic address: liyu301@vip.163.com.
Nankai University, Tianjin, 300071, PR China. Electronic address:
Guang.yang@nankai.edu.cn.
Nankai University, Tianjin, 300071, PR China. Electronic address:
Cheng.yang@nankai.edu.cn.
Histone deacetylases (HDACs) inhibitors have demonstrated a great clinical

achievement in hematological malignancies. However, the efficacy of HDACs
inhibitors in treating solid tumors remains limited due to the complicated tumor
microenvironment. In this study, we designed and synthesized a class of novel
HDACs inhibitors based on the structure of flavones and isoflavones, followed by
biological evaluation. To be specific, a lead compound 15a was discovered with
strong anti-proliferative effects on a variety of solid tumor cells, especially
for breast cancer cells with resistance to SAHA. Studies demonstrated that 15a
could significantly inhibit the activity of HDAC 1, 2, 3 (class I) and 6 (class
IIB), leading to a dose-dependent accumulation of acetylated histones and
α-Tubulin, cell cycle arrest (G1/S phase) and apoptosis in breast cancer cells.
Furthermore, the lead compound 15a could also antagonize the activation of STAT3
induced by HDACs inhibition in some breast cancer cells, which further reduced
the level of pro-survive proteins in tumor cells and enhanced anti-tumor
activity regulated by STAT3 signaling in vivo. Overall, our findings
demonstrated that the novel compound 15a might be a HDACs inhibitor candidate,
which could be used as promising chemotherapeutic agent for breast cancer.
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.ejmech.2020.112677

paper.
Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and

Future Perspectives.
Ávila-Gálvez MÁ(1), Giménez-Bastida JA(1), Espín JC(1), González-Sarrías A(1).
Author information:
(1)Laboratory of Food and Health, Research Group on Quality, Safety and
Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O.
Box 164, Campus de Espinardo, 30100 Murcia, Spain.
Breast cancer (BC) is the most common malignancy and the leading cause of
cancer-related death in adult women worldwide. Over 85% of BC cases are
non-hereditary, caused by modifiable extrinsic factors related to lifestyle,
including dietary habits, which play a crucial role in cancer prevention.
Although many epidemiological and observational studies have inversely
correlated the fruit and vegetable consumption with the BC incidence, the
involvement of their phenolic content in this correlation remains contradictory.
During decades, wrong approaches that did not consider the bioavailability,
metabolism, and breast tissue distribution of dietary phenolics persist behind
the large currently existing gap between preclinical and clinical research. In
the present review, we provide comprehensive preclinical and clinical evidence
according to physiologically relevant in vitro and in vivo studies. Some dietary
phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin
gallate (EGCG), lignans, and curcumin are gaining attention for their
chemopreventive properties in preclinical research. However, the clinical
evidence of dietary phenolics as BC chemopreventive compounds is still
inconclusive. Therefore, the only way to validate promising preclinical results
is to conduct clinical trials in BC patients. In this regard, future
perspectives on dietary phenolics and BC research are also critically discussed.
DOI: 10.3390/ijms21165718
PMCID: PMC7461055
176. J Nutr. 2020 Sep 1;150(9):2442-2450. doi: 10.1093/jn/nxaa194.
Soy Intake and Colorectal Cancer Risk: Results from a Pooled Analysis of
Prospective Cohort Studies Conducted in China and Japan.
Khankari NK(1), Yang JJ(1), Sawada N(2), Wen W(1), Yamaji T(2), Gao J(3), Goto
A(2), Li HL(3), Iwasaki M(2), Yang G(1), Shimazu T(2), Xiang YB(3), Inoue M(2),
Shu XO(1), Tsugane S(2), Zheng W(1).
Author information:
(1)Division of Epidemiology, Vanderbilt University Medical Center, Nashville,
Tennessee, USA.
National Cancer Center, Chuo-ku, Tokyo, Japan.
(3)Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital,
Shanghai Jiaotong University School of Medicine, Shanghai, China.
BACKGROUND: Soy is commonly consumed in east Asian countries and is suggested to

reduce colorectal cancer (CRC) risk. However, results from epidemiologic studies
are inconsistent, despite the anti-inflammatory and antiproliferative properties
of soy isoflavones and soy protein.
OBJECTIVE: We evaluated the association between soy isoflavones and soy protein
and CRC risk using 4 prospective cohort studies from China and Japan.
METHODS: Data were pooled from the Shanghai Women's Health Study (SWHS),
Shanghai Men's Health Study (SMHS), Japan Public Health Center-based Prospective
Study Cohort 1 (JPHC1), and Cohort 2 (JPHC2). Cox proportional hazards models
estimated HRs and corresponding 95% CIs for the association of soy protein and
isoflavone intake with CRC risk. The study included 205,060 individuals, among
whom 2971 were diagnosed with incident CRC over an average follow-up of 12.7 y.
RESULTS: No statistically significant associations with CRC risk were observed
for soy protein or isoflavone intake. No association was observed among ever
smokers consuming higher isoflavones (HRisoflavones: 0.83; 95% CI: 0.68, 1.00)
and soy protein (HRsoy protein: 0.81; 95% CI: 0.39, 1.10). However, risk
reductions were observed among premenopausal women with a body mass index [BMI
(kg/m2)] <23.0 at baseline for higher isoflavone (HRisoflavones: 0.58, 95% CI:
0.34, 0.98).
CONCLUSIONS: No evidence for an overall reduction in CRC risk by increasing soy
food intake (i.e., protein or isoflavones) was observed. However, the
association between soy and CRC risk may vary by BMI, smoking, and menopausal
status among women. Future investigations are needed to further understand the
biologic mechanisms observed.
Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.
DOI: 10.1093/jn/nxaa194
PMCID: PMC7762761
177. Acta Biomater. 2020 Sep 15;114:407-420. doi: 10.1016/j.actbio.2020.07.006.

Epub
2020 Jul 8.
Controlled release of soy isoflavones from multifunctional 3D printed bone

tissue engineering scaffolds.
Sarkar N(1), Bose S(2).
Author information:
(1)W. M. Keck Biomedical Materials Research Laboratory, School of Mechanical and
Materials Engineering, Washington State University, Pullman, Washington 99164,
United States.
(2)W. M. Keck Biomedical Materials Research Laboratory, School of Mechanical and
Materials Engineering, Washington State University, Pullman, Washington 99164,
United States. Electronic address: sbose@wsu.edu.
Recent challenges in post-surgical bone tumor management have elucidated the

need for a multifunctional scaffold, which can be used for residual tumor-cell
suppression, defect repair, and simultaneous bone regeneration. In this
perspective, 3D printing allows to create a wide variety of patient-specific
implant with complex porous architecture and compatible mechanical strength to
that of cancellous bone. Here, a multifunctional bone graft substitute is
designed by incorporating the three primary soy isoflavones: genistein,
daidzein, and glycitein onto a 3D printed (3DP) tricalcium phosphate (TCP)
scaffolds with designed pores, endowing them with in vitro chemopreventive,
bone-cell proliferating and immune-modulatory potential. The interconnected
porosity and biodegradability of 3DP TCP ceramics have allowed controlled
release kinetics of genistein, daidzein and glycitein in acidic and
physiological buffer medium for 16 days, which is fitted with Korsmeyer-Peppas
model. Presence of genistein, a well-known natural biomolecule shows a 90%
reduction in vitro osteosarcoma (MG-63) cell viability and proliferation after
11 days. Meanwhile, daidzein, the other primary isoflavone, promotes in vitro
cellular attachment and enhances viability and proliferation of human fetal
osteoblast cell (hFOB). Furthermore, controlled release of genistein, daidzein,
and glycitein from 3DP TCP scaffold demonstrates improved hFOB cell
proliferation, viability, and differentiation in a dynamic flow-perfusion
bioreactor, which is utilized to better simulate the clinical microenvironment.
Finally, in vivo H&E staining confirms controlled co-delivery of
genistein-daidzein-glycitein from 3DP scaffold carefully modulated neutrophil
recruitment to the surgery site after 24 h of implantation in a rat distal femur
model. These results advance our understanding towards multipronged therapeutic
approaches utilizing synthetic bone graft substitutes as a drug delivery
vehicle, and more importantly, demonstrate the feasibility of localized tumor
cell suppression and bone cell proliferation for post-surgical defect repair
application. STATEMENT OF SIGNIFICANCE: Designed multimodal porosity of 3D
printed TCP scaffold allows a controlled and sustained release of soy
isoflavones, genistein, daidzein and glycitein in both physiological and acidic
pH. Presence of genistein shows 90% reduction in vitro bone cancer cell
viability and proliferation. Meanwhile, controlled release of genistein,
daidzein, and glycitein from 3DP TCP scaffolds demonstrate improved osteoblast
cell proliferation, viability, and differentiation in static and dynamic
flow-perfusion bioreactor. Furthermore, H&E staining at 24 h post-surgical
specimens from rat distal femur model shows neutrophil recruitment at the
surgery site is significantly decreased, suggesting the anti-inflammatory
property of soy isoflavones. This work provides deeper understanding on the
design of a multifunctional 3D printed patient-specific scaffold with enhanced
in vitro chemopreventive, osteogenic and in vivo anti-inflammatory ability.
Copyright © 2020. Published by Elsevier Ltd.
DOI: 10.1016/j.actbio.2020.07.006
PMCID: PMC8009492

paper.
178. Nutr Rev. 2021 Jan 1;79(1):42-65. doi: 10.1093/nutrit/nuaa043.
Dietary phytoestrogens and biomarkers of their intake in relation to cancer

survival and recurrence: a comprehensive systematic review with meta-analysis.
Micek A(1), Godos J(2), Brzostek T(3), Gniadek A(1), Favari C(4), Mena P(4),
Libra M(5), Del Rio D(6), Galvano F(5), Grosso G(5).
Author information:
(1)Department of Nursing Management and Epidemiology Nursing, Faculty of Health
Sciences, Jagiellonian University Medical College, Krakow, Poland.
(2)Oasi Research Institute - IRCCS, Troina, Italy.
(3)Department of Internal Medicine and Community Nursing, Faculty of Health
Sciences, Jagiellonian University Medical College, Krakow, Poland.
(4)Department of Food and Drugs, Human Nutrition Unit, University of Parma,
Parma, Italy.
(5)Department of Biomedical and Biotechnological Sciences, University of
Catania, Catania, Italy.
(6)School of Advanced Studies on Food and Nutrition and Department of Veterinary
Science, University of Parma, Parma, Italy.
CONTEXT: Recent studies have outlined the potential role of dietary factors in
patients who have survived cancer.
OBJECTIVE: The aim of this study was to summarize the evidence of the relation
between dietary intake of phytoestrogens and their blood biomarkers and,
overall, cancer-specific mortality and recurrence in patients with cancer.
DATA SOURCES: A systematic search of PubMed, EMBASE, and Web of Science
databases of studies published up to September 2019 was performed. Databases
were searched for prospective and retrospective cohort studies reporting on
dietary phytoestrogen intake and/or blood biomarkers and the outcomes
investigated.
DATA EXTRACTION: Data were extracted from each identified study using a
standardized form.
DATA ANALYSIS: Twenty-eight articles on breast, lung, prostate, and colorectal
cancer, and glioma were included for systematic review. Given the availability
of studies, a quantitative meta-analysis was performed solely for breast cancer
outcomes. A significant inverse association among higher dietary isoflavone
intake, higher serum/plasma enterolactone concentrations, and overall mortality
and cancer recurrence was found. Among other cancer types, 2 studies reported
that higher serum enterolactone and higher intake of lignans were associated
with cancer-specific survival for colorectal cancer and glioma, respectively.
CONCLUSIONS: Dietary phytoestrogens may play a role in survival from breast
cancer ; evidence regarding other cancers is too limited to draw any
conclusions.

International Life Sciences Institute. All rights reserved. For permissions,
please e-mail: journals.permissions@oup.com.
DOI: 10.1093/nutrit/nuaa043
179. Chin Herb Med. 2020 Jul 6;12(3):326-335. doi: 10.1016/j.chmed.2020.02.002.

eCollection 2020 Jul.
Phytochemicals and antioxidant activity of alcoholic/hydroalcoholic extract of

Trifolium pratense.
Akbaribazm M(1), Khazaei MR(1), Khazaei M(1).
Author information:
(1)Fertility and Infertility Research Center, Health Technology Institute,
Kermanshah University of Medical Sciences, Kermanshah 6714869914, Iran.
OBJECTIVE: Trifolium pratense has many healing properties, including fewer

complications of menopause, cancer cell suppression, reducing blood glucose and
lipids, as well as cardiovascular beneficial effects. The purpose of this study
was to identify the phytochemical and mineral composition of T. pratense.
METHODS: Plant aerial parts were harvested and dried, and then hydroalcoholic
and alcoholic extracts were prepared. Gas chromatography-mass spectrometry
(GC-MS) analytical method was used to identify volatile compounds then liquid
chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) was used to
identify polyphenols and the mineral elements were identify by inductively
coupled plasma atomic emission spectrometer/ICP-AES and scanning electron
microscope-energy-dispersive X-ray spectroscopy (SEM-EDS) methods. Total
phenolic content (TPC) was determined based on colorimetric method, and total
flavonoid content (TFC) was established based on the folin-chiocalteau reagent.
Furthermore, two assays (DPPH and FRAP) were used to measure the antioxidant
capacity of T. pratense ethanolic extract.
RESULTS: A total of 37 polyphenols and 107 peaks were identified by LC-ESI-MS
analysis, and the GC/MS method also detected 21 volatile compounds, the most
important of which were methylcyclopentane, dimethylpentanal and hexadecanol. A
total of 18 mineral elements, including K, Mg, Al, Si, Zn, Ni, Cu, Se, Co, Fe,
Mn, and Ca in the plant, were identified ICP-AES and SEM-EDS analysis.
CONCLUSION: T. pratense has many therapeutic compounds such as polyphenol
(isoflavone and flavonoids), volatile compounds, and essential mineral elements,
which can be formulated purely and used in the pharmaceutical and traditional
medicine industries.
© 2020 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.
DOI: 10.1016/j.chmed.2020.02.002
PMCID: PMC9476498
PMID: 36119012

10.1080/10408398.2020.1763910. Epub 2020 Jun 1.
Targeting epigenetics in cancer: therapeutic potential of flavonoids.
Khan H(1), Belwal T(2), Efferth T(3), Farooqi AA(4), Sanches-Silva A(5)(6),
Vacca RA(7), Nabavi SF(8), Khan F(9), Prasad Devkota H(10), Barreca D(11),
Sureda A(12), Tejada S(13), Dacrema M(14), Daglia M(14), Suntar İ(15), Xu S(16),
Ullah H(1), Battino M(17)(18)(19), Giampieri F(17)(18)(20), Nabavi SM(8).
Author information:
(1)Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan.
(2)College of Biosystems Engineering and Food Science, Zhejiang University,
Hangzhou, China.
(3)Department of Pharmaceutical Biology, Institute of Pharmaceutical and
Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
(4)Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif
Medical College, Lahore, Pakistan.
(5)National Institute for Agricultural and Veterinary Research (INIAV), Porto,
Portugal.
(6)Center for Study in Animal Science (CECA), ICETA, University of Porto, Porto,
Portugal.
(7)Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies,
National Council of Research, Bari, Italy.
(8)Applied Biotechnology Research Center, Baqiyatallah University of Medical
(9)Department of Toxicology and Pharmacology, The Institute of Pharmaceutical
Sciences (TIPS), School of Pharmacy, International Campus, Tehran University of
Medical Sciences, Tehran, Iran.
(10)Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto,
Japan.
(11)Department of Chemical, Biological, Pharmaceutical and Environmental
Sciences, University of Messina, Messina, Italy.
(12)Research Group on Community Nutrition and Oxidative Stress (NUCOX), Health
Research Institute of the Balearic Islands (IdISBa) and CIBEROBN
(Physiopathology of Obesity and Nutrition), University of Balearic Islands,
Palma de Mallorca, Balearic Islands, Spain.
(13)Laboratory of neurophysiology, Biology Department, Health Research Institute
of the Balearic Islands (IdISBa) and CIBEROBN (Physiopathology of Obesity and
Nutrition), University of the Balearic Islands, Palma de Mallorca, Spain.
(14)Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical
Technology Section, University of Pavia, Pavia, Italy.
(15)Deparment of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler,
Ankara, Turkey.
(16)Aab Cardiovascular Research Institute, University of Rochester, Rochester,
New York, USA.
(17)Nutrition and Food Science Group, Department of Analytical and Food
Chemistry, CITACA, CACTI, University of Vigo, Vigo Campus, Vigo, Spain.
(18)Department of Clinical Sciences, Università Politecnica delle Marche,
Ancona, Italy.
(19)International Research Center for Food Nutrition and Safety, Jiangsu
University, Zhenjiang, China.
(20)College of Food Science and Technology, Northwest University, Xi'an,
Shaanxi, China.
Irrespective of sex and age, cancer is the leading cause of mortality around the
globe. Therapeutic incompliance, unwanted effects, and economic burdens imparted
by cancer treatments, are primary health challenges. The heritable features in
gene expression that are propagated through cell division and contribute to
cellular identity without a change in DNA sequence are considered epigenetic
characteristics and agents that could interfere with these features and are
regarded as potential therapeutic targets. The genetic modification accounts for
the recurrence and uncontrolled changes in the physiology of cancer cells. This
review focuses on plant-derived flavonoids as a therapeutic tool for cancer,
attributed to their ability for epigenetic regulation of cancer pathogenesis.
The epigenetic mechanisms of various classes of flavonoids including flavonols,
flavones, isoflavones, flavanones, flavan-3-ols, and anthocyanidins, such as
cyanidin, delphinidin, and pelargonidin, are discussed. The outstanding results
of preclinical studies encourage researchers to design several clinical trials
on various flavonoids to ascertain their clinical strength in the treatment of
different cancers. The results of such studies will define the clinical fate of
these agents in future.
DOI: 10.1080/10408398.2020.1763910
181. Fitoterapia. 2020 Oct;146:104640. doi: 10.1016/j.fitote.2020.104640. Epub 2020

May 28.
Plant natural products with anti-thyroid cancer activity.
Sharifi-Rad J(1), Rajabi S(2), Martorell M(3), López MD(4), Toro MT(5), Barollo
S(6), Armanini D(6), Fokou PVT(7), Zagotto G(8), Ribaudo G(9), Pezzani R(10).
Author information:
(1)Phytochemistry Research Center, Shahid Beheshti University of Medical
Sciences, Tehran, Iran. Electronic address: javad.sharifirad@gmail.com.
(2)Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti
University of Medical Sciences, Tehran, Iran.
(3)Department of Nutrition and Dietetics, Faculty of Pharmacy, University of
Concepcion, Concepcion, Chile; Centre for Healthy Living, University of
Concepción, Concepción, Chile; Unidad de Desarrollo Tecnológico, Universidad de
Concepción UDT, Concepcion, Chile. Electronic address: martorellpons@gmail.com.
(4)Department of Plant Production, Faculty of Agronomy, Universidad de
Concepción, Avenida Vicente Mendez, 595, Chillán 3812120, Chile.
(5)Department of Plant Production, Faculty of Agronomy, Universidad de
Concepción, Avenida Vicente Mendez, 595, Chillán 3812120, Chile. Electronic
address: mlopezb@udec.cl.
(6)Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via
Ospedale 105, 35128 Padova, Italy.
(7)Faculty of Science, University of Bamenda, Bambili, Po. Box 39, Bamenda,
Cameroon. Electronic address: ptsouh@gmail.com.
(8)Department of Pharmaceutical and Pharmacological Sciences, University of
Padova, via Marzolo 5, 35131 Padova, Italy. Electronic address:
giuseppe.zagotto@unipd.it.
(9)Department of Molecular and Translational Medicine, University of Brescia,
Viale Europa 11, 25123 Brescia, Italy. Electronic address:
giovanni.ribaudo@unibs.it.
(10)Endocrinology Unit, Department of Medicine (DIMED), University of Padova,
via Ospedale 105, 35128 Padova, Italy; AIROB, Associazione Italiana per la
Ricerca Oncologica di Base, Padova, Italy. Electronic address:
raffaele.pezzani@unipd.it.
Thyroid cancer is the most frequent endocrine malignancy, with more than 500,000
cases per year worldwide. Differentiated thyroid cancers are the most common
forms with best prognosis, while poorly/undifferentiated ones are rare (2% of
all thyroid cancer), aggressive, frequently metastasize and have a worse
prognosis. For aggressive, metastatic and advanced thyroid cancer novel
antitumor molecules are urgently needed and phytochemical products can be a
rational and extensive source, since secondary plant metabolites can guarantee
the necessary biochemical variability for therapeutic purpose. Among bioactive
molecules that present biological activity on thyroid cancer, resveratrol,
curcumin, isoflavones, glucosinolates are the most common and used in
experimental model. Most of them have been studied both in vitro and in vivo on
this cancer, but rarely in clinical trial. This review summarizes
phytochemicals, phytotherapeutics and plant derived compounds used in thyroid
cancer.
DOI: 10.1016/j.fitote.2020.104640

declare no conflict of interest.
182. Rev Assoc Med Bras (1992). 2020 May 15;66(2):174-179. doi:
10.1590/1806-9282.66.2.174.
The influence of phytoestrogens or estrogens on the proliferation of the rat

endocervical mucosa.
Franco PC(1), Simões RS(2), Carbonel AAF(1), Sasso GRDS(3), Florencio-Silva

R(1), Baracat EC(2), Girão MBC(3), Soares Júnior JM(2), Simões MJ(1).
Author information:
(1). Departamento de Morfologia e Genética - Escola Paulista de
Medicina/Universidade Federal de São Paulo - EPM/Unifesp - São Paulo, SP,
Brasil.
(2). Departamento de Obstetrícia e Ginecologia - Faculdade de Medicina da
Universidade de São Paulo - FMUSP - São Paulo, SP, Brasil.
(3). Departamento de Ginecologia - Escola Paulista de Medicina/Universidade
Federal de São Paulo - EPM/Unifesp - São Paulo, SP, Brasil.
OBJECTIVE: Although estrogen therapy is widely used against post-menopausal

symptoms, it can present adverse effects, including endometrial cancer. Soy
isoflavones are considered a possible alternative to estrogen therapy. However,
there are still concerns whether isoflavones exert trophic effects on the
uterine cervix. To evaluate the histomorphometric and immunohistochemical
alterations in the uterine cervix of ovariectomized rats treated with soy
isoflavones (Iso).
METHODS: Fifteen adult Wistar rats were ovariectomized (Ovx) and divided into
three groups: Group I (Ovx), administered with vehicle solution; Group II
(OVX-Iso), administered with concentrated extract of Iso (150 mg/kg) by gavage;
and Group III (OVX-E2), treated with 17β-estradiol (10 µg/kg), subcutaneously.
After 30 days of treatments, the uterine cervix was fixed in 10% formaldehyde
and processed for paraffin-embedding. Sections were stained with Hematoxylin and
eosin for morphological and morphometric studies or subjected to
immunohistochemistry for detections of Ki-67 and vascular endothelial growth
factor-A (Vegf-A). The data obtained were subjected to statistical analysis (p ≤
0.05).
RESULTS: We noted an atrophic uterine cervix in GI, whereas it was more
voluminous in GII and even more voluminous in GIII. The thickness of the
cervical mucosa was significantly higher in GIII, as compared to GI and GII. The
cell proliferation (Ki-67) was significantly elevated in the estradiol and
isoflavones treated groups, whereas Vegf-A immunoexpression was significantly
higher in GIII, as compared to groups GII and GI.
CONCLUSIONS: Soy isoflavones cause less trophic and proliferative effects in the
uterine cervix of rats as compared to estrogen.
DOI: 10.1590/1806-9282.66.2.174
183. J Anal Methods Chem. 2020 Jan 20;2020:2359397. doi: 10.1155/2020/2359397.

eCollection 2020.
A Simple and Rapid LC-MS/MS Method for Quantification of Total Daidzein,

Genistein, and Equol in Human Urine.
Saha S(1), Kroon PA(1).
Author information:
(1)Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK.
Isoflavones and isoflavandiols have shown many health benefits, such as reducing
cardiovascular disease, cancer, age-related disease, and osteoporosis. However,
to investigate the relationships between consumption of isoflavones and their
health benefits, it is important to be able to accurately quantify exposure in
the large numbers of samples typically produced in association studies (i.e.,
several thousands). Current methods rely on solid-phase extraction protocols for
sample cleanup, resulting in protracted extraction and analysis times. Here, we
describe a fast and easy sample preparation method of human urine samples for
subsequent quantification of daidzein, genistein (isoflavones), and equol
(isoflavandiol) using LC-MS/MS. Sample preparation involves only the addition of
dimethylformamide (DMF) and formic acid (FA) after enzymatic hydrolysis of their
metabolites by a β-glucuronidase and sulfatase mixture. The method was validated
by precision, linearity, accuracy, recoveries, limit of detection (LOD), and
limit of quantification (LOQ). Linear calibration curves have been shown by
daidzein, genistein, and equol. The correlation coefficients values are r
2 > 0.99 for daidzein, genistein, and equol. LOD for daidzein and genistein was
1 ng/ml and equol was 2 ng/ml. Recoveries were >90%, and the relative standard
deviation for intraday (<10%) and interday (≤20% over 10 days) was good. This
method is suitable for quantification of isoflavones and the microbial
metabolite equol in human urine and is particularly useful where large numbers
of samples require analysis.
Copyright © 2020 Shikha Saha and Paul A Kroon.
DOI: 10.1155/2020/2359397
PMCID: PMC7201686
PMID: 32399306

Apr 29.
Can Isoflavones Influence Prostate Specific Antigen Serum Levels in Localized

Prostate Cancer? A Systematic Review.
Ratha P(1), Neumann T(1), Schmidt CA(1), Schneidewind L(2).
Author information:
(1)Department of Haematology/Oncology, University Medicine Greifswald,
Greifswald, Germany.
(2)Department of Urology, University Medicine Rostock, Rostock, Germany.
Low risk prostate cancer does not always necessitate aggressive or invasive
intervention and is best monitored through active surveillance, but in daily
practice a majority of men seek a more proactive approach. Therefore, tertiary
chemoprevention is an attractive option for men seeking a way to slow disease
progression. Several natural anti-carcinogens have been identified in soy beans,
especially isoflavones. Case series have been published, demonstrating a
positive influence of isoflavones on PSA serum levels in prostate cancer.
Consequently, we decided to perform a systematic review about the effect of
isoflavones compared to placebo on PSA levels in localized prostate cancer
following the recommendations provided in the Cochrane Handbook of systematic
Reviews. On the whole, the primary aim of this review is to summarize the
evidence for the use of isoflavones in localized prostate cancer in terms of PSA
response. As a result, in all randomized controlled trials identified for this
review, isoflavones seem to have no influence on PSA levels in localized
prostate cancer. The influence of isoflavones on overall survival in localized
prostate cancer remains unclear. Furthermore, isoflavones are interesting
substances for further research, for example in lipid metabolism and
cholesterol.
DOI: 10.1080/01635581.2020.1759660

10.2174/1871520620666200423071759.
Flavonoid-Based Cancer Therapy: An Updated Review.
Hosseinzadeh E(1), Hassanzadeh A(2), Marofi F(2), Alivand MR(1), Solali S(3).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine, Tabriz University of
Medical Sciences, Tabriz, Iran.
(2)Department of Immunology, Division of Hematology, Faculty of Medicine, Tabriz
University of Medical Sciences, Tabriz, Iran.
(3)Molecular Medicine Research Center, Tabriz University of Medical Sciences,
Tabriz, Iran.
As cancers are one of the most important causes of human morbidity and mortality
worldwide, researchers try to discover novel compounds and therapeutic
approaches to decrease survival of cancer cells, angiogenesis, proliferation and
metastasis. In the last decade, use of special phytochemical compounds and
flavonoids was reported to be an interesting and hopeful tactic in the field of
cancer therapy. Flavonoids are natural polyphenols found in plant, fruits,
vegetables, teas and medicinal herbs. Based on reports, over 10,000 flavonoids
have been detected and categorized into several subclasses, including flavonols,
anthocyanins, flavanones, flavones, isoflavones and chalcones. It seems that the
anticancer effect of flavonoids is mainly due to their antioxidant and anti
inflammatory activities and their potential to modulate molecular targets and
signaling pathways involved in cell survival, proliferation, differentiation,
migration, angiogenesis and hormone activities. The main aim of this review is
to evaluate the relationship between flavonoids consumption and cancer risk, and
discuss the anti-cancer effects of these natural compounds in human cancer
cells. Hence, we tried to collect and revise important recent in vivo and in
vitro researches about the most effective flavonoids and their main mechanisms
of action in various types of cancer cells.

DOI: 10.2174/1871520620666200423071759
186. Res Vet Sci. 2020 Aug;131:87-91. doi: 10.1016/j.rvsc.2020.04.013. Epub 2020
Apr
13.
Changes in steroid hormone profile and tumour progression after genistein

treatment of canine inflammatory mammary cancer xenotransplanted mice.
Martín-Ruiz A(1), Peña L(2), González-Gil A(1), Silvan G(1), Caceres S(1),
Illera JC(3).
Author information:
(1)Department of Animal Physiology, Veterinary Medicine School, Complutense
University of Madrid, Madrid, Spain.
(2)Department of Animal Medicine, Surgery and Pathology, Veterinary Medicine
School, Complutense University of Madrid, Madrid, Spain.
(3)Department of Animal Physiology, Veterinary Medicine School, Complutense
University of Madrid, Madrid, Spain. Electronic address: jcillera@ucm.es.
Isoflavones, such as genistein, have been proposed to have beneficial effects on

health, including preventive or therapeutic actions in carcinogenesis. Their
structural similarity to oestrogens allows them to bind at the cellular level
with oestrogen receptors. Therefore, this study attempted to determine the
antitumoural effects of genistein administered in a canine inflammatory mammary
cancer xenograft model, in terms of tumour proliferation, appearance of
metastases and steroid hormone regulation. Using histology and
immunohistochemical analyses as well as the EIA technique for hormonal
determinations, the antitumoural effects of genistein on an inflammatory mammary
cancer xenograft model were assessed for 3 weeks. Mice treated with genistein
showed higher Ki-67 levels than the control group. There were significantly more
distant metastases in the genistein-treated xenografts versus the control group.
Intratumoural and serum progesterone, androstenedione and oestrogen levels in
treated mice were elevated, whereas intratumoural testosterone levels were
decreased compared to the control group. These results revealed that genistein
ingestion promotes tumour proliferation and elevates metastatic rates by
increasing intratumoural and circulating oestrogen levels in a mammary cancer
xenograft model.
DOI: 10.1016/j.rvsc.2020.04.013
Conflict of interest statement: Declaration of Competing Interest None of the

authors of this paper has a financial or personal relationship with other people
or organizations that could inappropriately influence or bias the content of the
paper.
187. Phytochemistry. 2020 Jul;175:112376. doi: 10.1016/j.phytochem.2020.112376.
Epub
2020 Apr 15.
Three isoflavones from Derris scandens (Roxb.) Benth and their cancer
chemopreventive activity and in vitro antiproliferative effects.
Ito C(1), Matsui T(2), Miyabe K(1), Hasan CM(3), Rashid MA(3), Tokuda H(4),
Itoigawa M(5).
Author information:
(1)Faculty of Pharmacy, Meijo University, Tempaku, Nagoya, 468-8503, Japan.
(2)Faculty of Pharmacy, Meijo University, Tempaku, Nagoya, 468-8503, Japan;
Department of Physiology, School of Medicine, Aichi Medical University, 1-1
Yazakokarimata, Nagakute, Aichi, 480‒1195, Japan. Electronic address:
tmatsui@aichi-med-u.ac.jp.
(3)Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh.
(4)Organic Chemistry in Life Science, Division of Food Science and
Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto,
606‒8502, Japan.
(5)School of Sport and Health Science, Tokai Gakuen University, 21-233
Nishinohora, Ukigai, Miyoshi, Aichi, 470-0207, Japan.
Three undescribed isoflavones, derriscandenon A, B, and C, together with seven

known isoflavones were isolated and structurally characterized during a study of
the chemical constituents in the leaves of Derris scandens (Roxb.) Benth
(Leguminosae, Fabaceae) collected in Bangladesh. The inhibitory activity of the
compounds against activation of Epstein-Barr virus antigen (EBV-EA) by
12-O-tetradecanoylphorbo-13-acetate (TPA) was measured to identify possible
chemopreventive agents. Mild inhibitory effects (IC50 278-290 mol ratio/32 pmol
TPA) against EBV-EA induction compared with curcumin (IC50 341 mol ratio/32 pmol
TPA) were observed for four known compounds (lupalbigenin, isopalbigenin,
glyurallin, and isangustone A). Next, we focused on antitumor effects and
investigated cell viability, cell proliferation, and mitochondria membrane
potential by using an MTT assay, a live cell monitoring system, and fluorescence
staining. Of the seven isoflavones tested for cell viability, a dose-dependent
decrease in cell viability was observed for four isoflavones (derriscandenon B
and C, derrubone, and glyurallin) in KB cells and two compounds (derriscandenon
B and isochandaisone) in NALM6-MSH+ cells. In addition, the proliferation of KB
cells was significantly inhibited by these four compounds at a concentration of
5 μM. The mitochondria membrane potentials of KB cells treated with
derriscandenon C, derrubone, and glyurallin at the IC50 concentration were
decreased by about 55%, whereas undescribed compound derriscandenon B had no
effect. Our results show that some of the compounds isolated from D. scandens
may be suitable as seed compounds for cancer prevention and therapy.
DOI: 10.1016/j.phytochem.2020.112376

declare no conflicts of interest.
188. Oncotarget. 2020 Apr 7;11(14):1218-1234. doi: 10.18632/oncotarget.27529.

eCollection 2020 Apr 7.
A phase II randomized clinical trial using aglycone isoflavones to treat
patients with localized prostate cancer in the pre-surgical period prior to
radical prostatectomy.
Kumar NB(1), Pow-Sang J(2), Spiess P(2), Dickinson S(3), Schell MJ(4).
Author information:
(1)Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute,
Inc., Tampa, FL, USA.
(2)Department of Urology, H. Lee Moffitt Cancer Center and Research Institute,
(3)Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute,
(4)Department of Biostatistics, H. Lee Moffitt Cancer Center and Research
Institute, Inc., Tampa, FL, USA.
Prostate cancer (PCa) is the most common cancer in American men. Additionally,
African American Men (AAM) are 60% more likely to be diagnosed with PCa and 2.4
times more likely to die from this disease compared to Caucasian men (CM). To
date, there are few strategies effective for chemoprevention for men with
localized PCa. There is thus a need to continue to evaluate agents and
strategies for chemoprevention of prostate cancer. Epidemiological, laboratory
and early phase clinical trials have shown that the isoflavones modulates
several biomarkers implicated in prostate carcinogenesis. The goal of this phase
II randomized clinical trial was to explore the comparative effectiveness and
safety of 40 mgs of aglycone isoflavones in AAM and CM with localized PCa in the
pre-surgical period prior to radical prostatectomy. Thirty six participants (25
CM, 6AAM) were randomized to the isoflavone arm and 34 (25 CM, 7AAM) to the
placebo arm, with 62 completing the intervention. Results indicated that
isoflavones at a dose of 20 mgs BID for 3-6 weeks was well tolerated but did not
reduce tissue markers of proliferation. A significant reduction in serum PSA was
observed with isoflavone supplementation in CM compared to the placebo arm, but
not observed in AAM. We observed no changes in serum steroid hormones with
isoflavone supplementation. In AAM, a reduction in serum IGF-1 concentrations
and IGF1: IGFBP-3 ratios were observed with isoflavone supplementation.
Well-powered studies for longer duration of intervention may inform future
trials with isoflavones, for chemoprevention of PCa.
DOI: 10.18632/oncotarget.27529
PMCID: PMC7147089
PMID: 32292572
Conflict of interest statement: CONFLICTS OF INTEREST None.
189. Breast Cancer Res Treat. 2020 May;181(1):167-180. doi:

10.1007/s10549-020-05616-3. Epub 2020 Apr 1.
The association between soy isoflavone intake and menopausal symptoms after
breast cancer diagnosis: a prospective longitudinal cohort study on Chinese
breast cancer patients.
Lei YY(1), Ho SC(2), Cheng A(3), Kwok C(3), Cheung KL(1), He YQ(1), Lee R(1),
Yeo W(4)(5).
Author information:
(1)Department of Clinical Oncology, Prince of Wales Hospital, The Chinese
University of Hong Kong, New Territories, Hong Kong, SAR, China.
Care, The Chinese University of Hong Kong, New Territories, Hong Kong, SAR,
China.
(3)Department of Clinical Oncology, Princess Margaret Hospital, Hong Kong SAR,
China.
(4)Department of Clinical Oncology, Prince of Wales Hospital, The Chinese
University of Hong Kong, New Territories, Hong Kong, SAR, China.
winnieyeo@cuhk.edu.hk.
(5)Hong Kong Cancer Institute, State Key Laboratory in Oncology in South China,
Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong
Kong, SAR, China. winnieyeo@cuhk.edu.hk.
PURPOSE: This study investigated the association between soy isoflavone intake
and menopausal symptoms (MPS) among Chinese women with early stage breast cancer
in a prospective cohort study.
METHODS: In an on-going prospective cohort study that involved 1462 Chinese
women with early stage breast cancer, MPS were assessed at 18, 36 and 60 months
after cancer diagnosis using the validated menopausal rating scale (MRS)
questionnaire. Daily soy food intake for the previous 12 months was assessed at
the same time using a validated food frequency questionnaire. The associations
between MPS and soy isoflavone intake were evaluated in multivariable logistic
regression analyses.
RESULTS: The prevalence of MPS was almost the same during the first 60 months
after cancer diagnosis, which were 64.5%, 65.2%, and 63.9% at 18, 36, and
60 months, respectively. Patients with MPS tended to be younger than those
without MPS. The intake of soy isoflavones was not associated with the total
score of MRS at 18-month follow-up [highest vs lowest tertile, odds ratio
(OR) = 1.00, 95% CI 0.75-1.34]. Similarly, no significant association was noted
at 36-month (OR = 1.25, 95% CI 0.92-1.69) and 60-month (OR = 1.21, 95% CI
0.84-1.74) follow-up. With regards to specific domain within MRS, the risk of
symptoms presenting in somatic domain was higher among breast cancer patients
who were in the highest tertile of soy isoflavone intake at 36 months
post-diagnosis (OR = 1.44, 95% CI 1.07-1.94, P-trend = 0.02), compared with the
lowest tertile, where a stronger significant association was noted among
patients who were younger than 60 years (OR = 1.52, 95% CI 1.05-2.20,
P-trend = 0.03) and pre-menopausal (OR = 3.81, 95% CI 1.85-8.11,
P-trend < 0.01).
CONCLUSION: The present study provided further evidence that soy isoflavone
consumption was not associated with MPS among Chinese breast cancer patients. In
fact, patients with higher intake of soy isoflavone have increased risk of
experiencing somatic symptoms.
DOI: 10.1007/s10549-020-05616-3
190. Microorganisms. 2020 Mar 25;8(4):469. doi: 10.3390/microorganisms8040469.
Soy Metabolism by Gut Microbiota from Patients with Precancerous Intestinal

Lesions.
Polimeno L(1), Barone M(2), Mosca A(3), Viggiani MT(2), Joukar F(4),
Mansour-Ghanaei F(4), Mavaddati S(4), Daniele A(5), Debellis L(6), Bilancia
M(7), Santacroce L(8), Di Leo A(2).
Author information:
(1)Polypheno Academic Spin Off, University of Bari "A. Moro", 70124 Bari, Italy.
(2)Gastroenterology Unit, Department of Emergency and Organ Transplantation,
University of Bari, 70124 Bari, Italy.
(3)Interdisciplinary Department of Medicine (DIM), University of Bari "Aldo
Moro", Policlinico, Piazza G. Cesare 11, 70124 Bari, Italy.
(4)Gastrointestinal and Liver Diseases Research Center, Guilan University of
Medical Sciences, Rasht 41448-95655, Iran.
(5)Experimental Oncology, Scientific Institute for Cancer Care and Research
IRCCS "G. Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
(6)Department of Biosciences, Biotechnologies and Biopharmaceuticals, University
of Bari "Aldo Moro", Via E. Orabona 4, 70124 Bari, Italy.
(7)Ionian Department (DJSGEM), University of Bari "Aldo Moro", 74123 Taranto,
Italy.
(8)Ionian Department (DJSGEM), University of Bari "Aldo Moro", Microbiology and
Virology Lab., Policlinico University Hospital of Bari, 70124 Bari, Italy.
BACKGROUND: Colorectal cancer (CRC) requires the presence of a variety of

factors predisposing a tumorigenic milieu. Excluding familial clustering and
hereditary CRC syndromes, the development of sporadic CRC from precancerous
lesions is influenced by tissue inflammation, modulation of intestinal immunity,
hormones, dietary habits and gut microbiota composition. As concerning the last
two aspects, the intestinal presence of equol, the most biologically active
metabolite of the soy isoflavone daidzein and the presence of a genetic
determinant of gut microbiota able to metabolize daidzein, seem to lower the CRC
risk. It has been hypothesized that the anaerobic microorganisms of the
Bacteroides genus play a role in equol production.
AIM: To evaluate the presence of (i) anaerobic gut microbiota and (ii) the
urinary levels of soy isoflavones (daidzein, genistein and equol) in patients
with and without precancerous lesions, challenged with a daidzein-rich soy
extract.
METHODS: Consecutive subjects undergoing colonoscopy participated to the study.
Feces were collected from all patients one week before colonoscopy for gut
microbiota studies. After the endoscopy examination and the histological
evaluation, 40 subjects, 20 with sporadic colorectal adenomas (SCA/P group) and
20 without proliferative lesions (control group) were enrolled for the study.
Urine levels of soy isoflavones daidzein, genistein and their metabolite equol,
were determined by high performance liquid chromatographic (HPLC) analysis and
gut microbiota analysis was performed by Matrix Assisted Laser Desorption
Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) procedure.
RESULTS: Seventeen different bacterial species were identified in the fecal
samples of the forty subjects participating to the study. Ten bacterial species
resulted anaerobic Gram-negative bacteria, all belonging to the Bacteroides
genus. A significant difference of bacteria species was evidenced in the fecal
samples of the two groups of subjects. Particularly important was the evidence
of Parabacteroides distasonis, Clostridium clostridioforme and Pediococcus
pentasaceus only in control fecal samples, such as the presence of Bacteroides
fragilis and Prevotella melaningenica only in SCA/P fecal samples. Concerning
the soy isoflavones levels, no statistically significant differences were
revealed in the genistein and daidzein urinary levels between the two groups of
subjects. On the contrary, urinary equol levels were undetectable in ten SCA/P
subjects and in two controls; moreover, when present, the levels of urinary
equol were significantly lower in SCA/P subjects compared to controls (0.24 ±
0.27 mg/24 hrs vs. 21.25 ± 4.3 mg/24 hrs, respectively, p = 1.12 × 10-6).
CONCLUSIONS: Our results suggest that the presence of anaerobic Bacteroides in
the colon, and the production of equol from soy, could determine a milieu able
to contrast the development of colonic mucosa proliferative lesions.
DOI: 10.3390/microorganisms8040469
PMCID: PMC7232402
PMID: 32218321

191. Circulation. 2020 Apr 7;141(14):1127-1137. doi:
10.1161/CIRCULATIONAHA.119.041306. Epub 2020 Mar 23.
Isoflavone Intake and the Risk of Coronary Heart Disease in US Men and Women:
Results From 3 Prospective Cohort Studies.
Ma L(1)(2)(3), Liu G(4), Ding M(2), Zong G(2), Hu FB(5)(2)(6), Willett

WC(5)(2)(6), Rimm EB(5)(2)(6), Manson JE(5)(6)(7), Sun Q(2)(6).
Author information:
(1)School of Public Health, Xi'an Jiaotong University Health Science Center,
China (L.M.).
(2)Department of Nutrition (L.M., M.D., G.Z., F.B.H., W.C.W., E.B.R., Q.S.),
Harvard T.H. Chan School of Public Health, Boston, MA.
(3)Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong
University), Ministry of Education of China (L.M.).
(4)Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food
Nutrition and Safety, Ministry of Education Key Lab of Environment and Health,
School of Public Health, Tongji Medical College, Huazhong University of Science
and Technology, Wuhan, China (G.L.).
(5)Department of Epidemiology (F.B.H., W.C.W., E.B.R., J.E.M.), Harvard T.H.
Chan School of Public Health, Boston, MA.
(6)Channing Division of Network Medicine (F.B.H., W.C.W., E.B.R., J.E.M.,
Q.S.)Department of Medicine, Brigham and Women's Hospital and Harvard Medical
School, Boston, MA.
(7)Division of Preventive Medicine (J.E.M.), Department of Medicine, Brigham and
Women's Hospital and Harvard Medical School, Boston, MA.
Comment in
Circulation. 2020 Apr 7;141(14):1138-1140.
BACKGROUND: Whether soy products confer health benefits related to coronary

heart disease (CHD) remains controversial because of inconsistent evidence.
METHODS: A total of 74 241 women from the NHS (Nurses' Health Study; 1984-2012),
94 233 women from the NHSII (Nurses' Health Study II; 1991-2013), and 42 226 men
from the Health Professionals Follow-Up Study (1986-2012), who were free of
cardiovascular disease and cancer at baseline, were included in the present
analysis. Dietary data were updated every 2 to 4 years using a validated food
frequency questionnaire. Nonfatal myocardial infarction and CHD deaths were
adjudicated through reviewing medical records, death certificates, and other
medical documents.
RESULTS: In these cohorts, 8359 incident CHD cases were documented during 4 826
122 person-years of follow-up. In multivariable-adjusted analyses, isoflavone
intake was inversely associated with CHD (pooled hazard ratio [HR] comparing the
extreme quintiles: 0.87 [95% CI, 0.81-0.94]; P=0.008). Consumption of tofu, but
not soy milk, was inversely associated with the risk of CHD, with pooled HRs
(95% CIs) of 0.82 (0.70-0.95; P=0.005) and 0.87 (0.69-1.10; P=0.41),
respectively, comparing ≥1 serving/week with <1 serving/month. Further analyses
showed that, in women, the favorable association of tofu was primarily driven by
stronger inverse association of tofu intake observed in younger women before
menopause and postmenopausal women without hormone use (Pinteraction=0.002).
CONCLUSIONS: Higher intake of isoflavones and tofu was associated with a
moderately lower risk of developing CHD, and in women the favorable association
of tofu were more pronounced in young women or postmenopausal women without
hormone use.
DOI: 10.1161/CIRCULATIONAHA.119.041306
PMCID: PMC7138725
Conflict of interest statement: Disclosures All authors have no conflict of

interest to disclose.
192. Immunol Lett. 2020 Jun;222:67-72. doi: 10.1016/j.imlet.2020.03.004. Epub 2020

Mar 18.
Daidzein-rich isoflavones aglycone inhibits lung cancer growth through

inhibition of NF-κB signaling pathway.
Guo S(1), Wang Y(2), Li Y(3), Li Y(4), Feng C(5), Li Z(6).
Author information:
(1)Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan
Medical University, Ganzhou, 341000, Jiangxi, China.
(2)Department of Respiratory Medicine, First Affiliated Hospital of Gannan
Medical University, Ganzhou, 341000, Jiangxi, China.
(3)Department of Thoracic Surgery, Zhaoyuan People's Hospital, Shandong 265400,
China.
(4)Department of Thoracic Surgery, PLA General Hospital, Beijing 100853, China.
(5)Department of Thoracic Surgery, PLA General Hospital, Beijing 100853, China.
Electronic address: fengchangjiang301@126.com.
(6)Department of Cardiothoracic Surgery, First Affiliated Hospital of Gannan
Medical University, Ganzhou, 341000, Jiangxi, China. Electronic address:
gzlizhh@163.com.
To develop anti-tumor agents for lung cancer, we aim to characterize a herbal

compound, daidzein-rich isoflavones aglycone (DRIA), in inhibiting the
proliferation and NF-κB signaling pathway of lung cancer. MTT and colony
formation assays were used to analyze the proliferation of lung cancer cells in
presence of DRIA treatment, which showed that DRIA dose-dependently inhibited
the proliferation and colony formation of lung cancer cells. Enzyme-linked
immunosorbent assay revealed that interleukin-6 (IL6) and interleukin-8 (IL-8)
levels were reduced by DRIA. p65-NFκB expression and activation, which was
enhanced by TNF-α and C/EBPβ treatment, were attenuated by DRIA. Exogenous tumor
necrosis factor-α (TNF-α) and CCAAT/enhancer binding protein (C/EBPβ) were used
to enhance NF-κB signaling in cells, and the effects of DRIA in attenuating
NF-κB signaling were assessed by analyzing p65-NFκB expression in mRNA and
protein levels, using quantitative real-time PCR (qRT-PCR), western blot and
immunofluorescence staining. immunohistochemical staining revealed that Ki-67
and p65-NF-κB levels in A594 tumor xenografts of A594 tumors were also reduced
by DRIA treatment in mice. Our data indicates that DRIA is effective in
inhibiting the proliferation and NFκB signaling of lung cancer both in vitro and
in vivo.
Copyright © 2020 European Federation of Immunological Societies. Published by

Elsevier B.V. All rights reserved.
DOI: 10.1016/j.imlet.2020.03.004
193. Biol Pharm Bull. 2020 Jun 1;43(6):976-984. doi: 10.1248/bpb.b20-00004. Epub
2020
Mar 19.
Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the
Natural Anticancer Active Compound Cytisine N-Isoflavones Combined with Computer
Simulation.
Chen F(1), Yin X(1), Wang Y(1), Lv Y(2), Sheng S(1), Ouyang S(2), Zhong Y(2).
Author information:
Engineering Science.
(2)College of Pharmacy, Jiangxi University of Traditional Chinese Medicine.
Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new

compound isolated from the Chinese herbal medicine Sophora alopecuroides.
Preliminary pharmacodynamic studies demonstrated its activity in inhibiting
breast cancer cell metastasis. This study examined the pharmacokinetics,
absolute bioavailability, and tissue distribution of CNF2 in rats, and combined
computer-aided technology to predict the druggability of CNF2. The binding site
of CNF2 and the breast cancer target human epidermal growth factor receptor-2
(HER2) were examined with molecular docking technology. Next, ACD/Percepta
software was used to predict the druggability of CNF2 based on the quantitative
structure-activity relationship (QSAR). Finally, a simple and effective HPLC
method was used to determine plasma pharmacokinetics and tissue distribution of
CNF2 in rats. Prediction and experimental results show that compared with the
positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity
with HER2, suggesting that its efficacy is stronger; and the structure of CNF2
complies with the Lipinski's Rule of Five and has good drug-likeness. The
residence time of CNF2 in rats is less than 4 h, and the metabolic rate is
relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%,
mainly distributed in the stomach, intestine, and lung tissues, where the CNF2
contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study
constructed rapid screening and preliminary evaluation of active compounds,
which provided important references for the development and further research of
such compounds.
DOI: 10.1248/bpb.b20-00004
194. Nutrients. 2020 Mar 13;12(3):761. doi: 10.3390/nu12030761.
Flavonoids and Other Polyphenols Act as Epigenetic Modifiers in Breast Cancer.
Selvakumar P(1), Badgeley A(1), Murphy P(1), Anwar H(1), Sharma U(1), Lawrence
K(1), Lakshmikuttyamma A(1).
Author information:
(1)Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas
Jefferson University, Philadelphia, PA 19107, USA.
Breast cancer is a common cancer that occurs due to different epigenetic

alterations and genetic mutations. Various epidemiological studies have
demonstrated an inverse correlation between breast cancer incidence and
flavonoid intake. The anti-cancer action of flavonoids, a class of polyphenolic
compounds that are present in plants, as secondary metabolites has been a major
topic of research for many years. Our review analysis demonstrates that
flavonoids exhibit anti-cancer activity against breast cancer occurring in
different ethnic populations. Breast cancer subtype and menopausal status are
the key factors in inducing the flavonoid's anti-cancer action in breast cancer.
The dose is another key factor, with research showing that approximately 10
mg/day of isoflavones is required to inhibit breast cancer occurrence. In
addition, flavonoids also influence the epigenetic machinery in breast cancer,
with research demonstrating that epigallocatechin, genistein, and resveratrol
all inhibited DNA methyltransferase and altered chromatin modification in breast
cancer. These flavonoids can induce the expression of different tumor suppressor
genes that may contribute to decreasing breast cancer progression and
metastasis. Additional studies are required to confirm the contribution of
epigenetic modifications by flavonoids to breast cancer prevention.
DOI: 10.3390/nu12030761
PMCID: PMC7146477
195. Ann Transl Med. 2020 Feb;8(4):86. doi: 10.21037/atm.2019.12.141.
Identification of hub genes and potential molecular mechanisms of chickpea

isoflavones on MCF-7 breast cancer cells by integrated bioinformatics analysis.
Wang J(1)(2), Yu H(1), Yili A(3), Gao Y(3), Hao L(1), Aisa HA(3), Liu S(1)(4).
Author information:
(1)College of Animal Science, Jilin University, Changchun 130062, China.
(2)Xinjiang Tefeng Pharmaceutical Company, Ltd., Urumqi 830054, China.
(3)State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource
Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Urumqi 830011, China.
(4)Five-Star Animal Health Pharmaceutical Factory of Jilin Province, Changchun
130062, China.
BACKGROUND: Chickpea isoflavones have been demonstrated to play an inhibitory

role in breast cancer cells. In this study, we aimed to explore the mechanism of
chickpea isoflavones inhibiting the formation and development of breast
carcinoma through the integration of wet and dry experiments.
METHODS: Chickpea isoflavones were added to the MCF-7 cells for 48 hours, and
the subsequent morphological changes of cells were observed using an inverted
microscope, while apoptosis was quantified by flow cytometry. The mRNA and
LncRNA expression profiles were detected by RNA-sequencing (RNA-Seq) technology.
The protein-protein interaction (PPI) network was constructed from the STRINGdb
database. To identify the co-expressed long non-coding RNA and messenger RNA
(lncRNA-mRNA) pairs, Pearson's correlation coefficients were calculated based on
the expression value between every differentially expressed lncRNA and mRNA
pair. The hub gene expression was verified by quantitative reverse transcription
polymerase chain reaction (qRT-PCR), and survival analysis results were provided
by The Human Protein Atlas website.
RESULTS: Microscopic observation and flow cytometry results confirmed that
chickpea isoflavones with a final concentration of 32.8 µg/mL could cause
apoptosis of the MCF-7 cells. Transcriptome results showed that a total of 1,094
mRNAs and 378 lncRNAs were differentially expressed in isoflavone-treated cells.
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that
inhibition of cell proliferation was mainly due to the up-regulation of genes in
the apoptosis signaling pathway and the down-regulation of genes in mRNA
splicing pathway. The co-expressed genes of the top 10 down-regulated lncRNAs
were mainly heterogeneous nuclear ribonucleoproteins (HNRNP) family genes, which
interacted with apoptosis-related genes through ubiquitin C (UBC). The abnormal
expression of 11 hub genes (degree >10) of PPI networks were beneficial to
improve the overall survival time of breast cancer patients.
CONCLUSIONS: Our results reveal a potential mechanism for chickpea isoflavones
to inhibit MCF-7 breast cancer cell proliferation and provide a reference for
the development of new anti-cancer drugs used in breast cancer.
2020 Annals of Translational Medicine. All rights reserved.
DOI: 10.21037/atm.2019.12.141
PMCID: PMC7048992
PMID: 32175379
Conflict of interest statement: Conflicts of Interest: The authors have no

conflicts of interest to declare.

10.2174/1871520620666200227091811.
A Critical Review on Anticancer Mechanisms of Natural Flavonoid Puerarin.
Murahari M(1), Singh V(2), Chaubey P(3), Suvarna V(2).
Author information:
(1)Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ramaiah
University of Applied Sciences, Bangalore 560054, Karnataka, India.
(2)SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V.L. Mehta Road, Vile Parle
(West), Mumbai 400056, Maharashtra, India.
(3)College of Pharmacy, Shaqra University, Al-Dawadmi, Saudi Arabia.
Cancer is one of the prominent global causes of death and the foremost worldwide
health concern. Despite unprecedented progress in cancer chemoprevention, a vast
number of cancers, however, remain an undefeatable challenge for treatment
modalities. Immense therapeutic activities of puerarin contribute to its use in
various health disorders. In this review, we explored the potential molecular
mechanisms and targets of puerarin, proving its potential as a novel anticancer
agent, for future cancer therapy and chemoprevention. Several mechanisms account
for anticancer activity of puerarin which includes downregulation of NF-kB
signalling pathway, mTOR signalling pathway, PI3K and BCl-2 proteins and
upregulation of miR-16, caspase proteins, c- Jun N terminal kinase and
extracellular signal-regulated kinase 1/2. These alterations result in
inhibition of cancer cell proliferation and/or induction of apoptosis.
Understanding the molecular mechanisms involved in chemotherapy and
chemoprevention could aid in the more pronounced exploration of puerarin in
effective cancer treatment.

DOI: 10.2174/1871520620666200227091811
197. J Ethnopharmacol. 2020 Aug 10;258:112690. doi: 10.1016/j.jep.2020.112690. Epub

2020 Feb 24.
Glycyrrhiza glabra (Licorice) root extract attenuates doxorubicin-induced

cardiotoxicity via alleviating oxidative stress and stabilising the cardiac
health in H9c2 cardiomyocytes.
Upadhyay S(1), Mantha AK(1), Dhiman M(2).

Author information:
(1)Department of Zoology, School of Basic and Applied Sciences, Central
University of Punjab, Bathinda, 151001, Punjab, India.
(2)Department of Microbiology, School of Basic and Applied Sciences, Central
University of Punjab, Bathinda, 151001, Punjab, India. Electronic address:
monisha.dhiman@cup.edu.in.
ETHNOPHARMACOLOGICAL RELEVANCE: Doxorubicin (DOX) is an effective

anti-neoplastic drug, however; it has downside effects on cardiac health and
other vital organs. The herbal remedies used in day to day life may have a
beneficial effect without disturbing the health of the vital organs. Glycyrrhiza
glabra L. is a ligneous perennial shrub belonging to
Leguminosae/Fabaceae/Papilionaceae family growing in Mediterranean region and
Asia and widespread in Turkey, Italy, Spain, Russia, Syria, Iran, China, India
and Israel. Commonly known as mulaithi in north India, G. glabra has
glycyrrhizin, glycyrrhetic acid, isoliquiritin, isoflavones, etc., which have
been reported for several pharmacological activities such as anti-demulcent,
anti-ulcer, anti-cancer, anti-inflammatory and anti-diabetic.
AIM OF THE STUDY: The objective of the present study is to investigate the
interaction between the molecular factors like PPAR-α/γ and SIRT-1 during
cardiac failure arbitrated by DOX under in vitro conditions and role of
Glycyrrhiza glabra (Gg) root extract in alleviating these affects.
MATERIALS AND METHODS: In the present study, we have examined the DOX induced
responses in H9c2 cardiomyocytes and investigated the role of phytochemical
Glycyrrhiza glabra in modulating these affects. MTT assay was done to evaluate
the cell viability, Reactive Oxygen Species (ROS)/Reactive Nitrogen Species
(RNS) levels, mitochondrial ROS, mitochondrial membrane potential was estimated
using fluorescent probes. The oxidative stress in terms of protein
carbonylation, lipid peroxidation and DNA damage was detected via
spectrophotometric methods and immune-fluorescence imaging. The cardiac markers
and interaction between SIRT-1 and PPAR-α/γ was measured using Real-Time PCR,
Western blotting and Co-immunoprecipitation based studies.
RESULTS: The Glycyrrhiza glabra (Gg) extracts maintained the membrane integrity
and improved the lipid homeostasis and stabilized cytoskeletal element actin. Gg
phytoextracts attenuated aggravated ROS level, repaired the antioxidant status
and consequently, assisted in repairing the DNA damage and mitochondrial
function. Further, the expression of hypertrophic markers in the DOX treated
cardiomyocytes reconciled the expression factors both at the transcriptional and
translational levels after Gg treatment. SIRT-1 mediated pathway and its
downstream activator PPARs are significant in maintaining the cellular
functions. It was observed that the Gg extract allows regaining the nuclear
SIRT-1 and PPAR-γ level which was otherwise reduced with DOX treatment in H9c2
cardiomyocytes. The co-immunoprecipitation (Co-IP) documented that SIRT-1
interacts with PPAR-α in the untreated control H9c2 cardiomyocytes whereas DOX
treatment interferes and diminishes this interaction however the Gg treatment
maintains this interaction. Knocking down SIRT-1 also downregulated expression
of PPAR-α and PPAR-γ in DOX treated cells and Gg treatment was able to enhance
the expression of PPAR-α and PPAR-γ in SIRT-1 knocked down cardiomyocytes.
CONCLUSIONS: The antioxidant property of Gg defend the cardiac cells against the
DOX induced toxicity via; 1) reducing the oxidative stress, 2) maintaining the
mitochondrial functions, 3) regulating lipid homeostasis and cardiac metabolism
through SIRT-1 pathway, and 4) conserving the cardiac hypertrophy and hence
preserving the cardiomyocytes health. Therefore, Gg can be recommended as a
healthy supplement with DOX towards cancer therapeutics associated
cardiotoxicity.

DOI: 10.1016/j.jep.2020.112690

declare that they have no conflict of interest.
198. Int J Epidemiol. 2020 Oct 1;49(5):1526-1537. doi: 10.1093/ije/dyaa007.
Dairy, soy, and risk of breast cancer: those confounded milks.
Fraser GE(1), Jaceldo-Siegl K(1), Orlich M(1), Mashchak A(1), Sirirat R(1),
Knutsen S(1).
Author information:
(1)Center for Nutrition, Healthy Lifestyle, and Disease Prevention, School of
Public Health, Loma Linda University, Loma Linda, CA, USA.
Comment in
Int J Epidemiol. 2020 Oct 1;49(5):1537-1539.
BACKGROUND: Associations between soy, dairy intakes and breast cancer risk are
inconsistent. No studies exist with large numbers of dairy consumers and soy
consumers to assess mutual confounding.
METHODS: The study cohort contains 52 795 North American women, initially free
of cancer, followed for 7.9 years (29.7% were Black). Dietary intakes were
estimated from food frequency questionnaires and, for 1011 calibration study
subjects, from six structured 24-h dietary recalls. Incident invasive breast
cancers were detected mainly by matching with cancer registries. Analyses used
multivariable proportional hazards regression.
RESULTS: The participants (mean age of 57.1 years) experienced 1057 new breast
cancer cases during follow-up. No clear associations were found between soy
products and breast cancer, independently of dairy. However, higher intakes of
dairy calories and dairy milk were associated with hazard ratios (HRs) of 1.22
[95% confidence interval (CI): 1.05-1.40] and 1.50 (95% CI 1.22-1.84),
respectively, comparing 90th to 10th percentiles of intakes. Full fat and
reduced fat milks produced similar results. No important associations were noted
with cheese and yogurt. Substituting median intakes of dairy milk users by those
of soy milk consumers was associated with HR of 0.68 (95% CI: 0.55-0.85).
Similar-sized associations were found among pre- and post-menopausal cases, with
CIs also excluding the null in estrogen receptor (ER+, ER-), and progesterone
receptor (PR+) cancers. Less biased calibrated measurement-error adjusted
regressions demonstrated yet stronger, but less precise, HRs and CIs that still
excluded the null.
CONCLUSIONS: Higher intakes of dairy milk were associated with greater risk of
breast cancer, when adjusted for soy intake. Current guidelines for dairy milk
consumption could be viewed with some caution.
© The Author(s) 2020; all rights reserved. Published by Oxford University Press
on behalf of the International Epidemiological Association.
DOI: 10.1093/ije/dyaa007
PMCID: PMC8453418
199. Food Waterborne Parasitol. 2019 Mar 14;15:e00040. doi:

10.1016/j.fawpar.2019.e00040. eCollection 2019 Jun.
The importance of being parasiticidal… an update on drug development for the
treatment of alveolar echinococcosis.
Lundström-Stadelmann B(1), Rufener R(1), Ritler D(1), Zurbriggen R(1), Hemphill

A(1).
Author information:
(1)Institute of Parasitology, Department of Infectious Diseases and
Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012
Bern, Switzerland.
Erratum in
Food Waterborne Parasitol. 2020 Dec 15;21:e00105.
The lethal disease alveolar echinococcosis (AE) is caused by the metacestode

stage of the fox tapeworm Echinococcus multilocularis. Current
chemotherapeutical treatment of AE relies on albendazole and mebendazole, with
the caveat that these compounds are not parasiticidal. Drugs have to be taken
for a prolonged period of time, often life-long, which can cause adverse effects
and reduces the patients' quality of life. In some individuals, benzimidazoles
are inactive or cause toxicity, leading to treatment discontinuation.
Alternatives to benzimidazoles are urgently needed. Over the recent years, in
vivo and in vitro models for low-to-medium throughput drug discovery against AE
have been set in place. In vitro drug tests include the phosphoglucose-isomerase
(PGI) assay to measure physical damage induced to metacestodes, and viability
assays to assess parasiticidal activity against metacestodes and stem cells. In
vitro models are also employed for studies on mechanisms of action. In vivo
models are thus far based on rodents, mainly mice, and benefits could be gained
in future by comparative approaches in naturally infected dogs or captive
monkeys. For the identification of novel drugs against AE, a rare disease with a
low expected market return, drug-repurposing is the most promising strategy. A
variety of chemically synthesized compounds as well as natural products have
been analyzed with respect to in vitro and/or in vivo activities against AE. We
here review and discuss the most active of these compounds including
anti-infective compounds (benzimidazoles, nitazoxanide, amphotericin B,
itraconazole, clarithromycin, DB1127, and buparvaquone), the anti-infective
anti-malarials (artemisinin, ozonids, mefloquine, and MMV665807) and anti-cancer
drugs (isoflavones, 2-methoxyestradiol, methotrexate, navelbine, vincristine,
kinase inhibitors, metallo-organic ruthenium complexes, bortezomib, and
taxanes). Taking into account the efficacy as well as the potential availability
for patients, the most promising candidates are new formulations of
benzimidazoles and mefloquine. Future drug-repurposing approaches should also
target the energy metabolism of E. multilocularis, in particular the
understudied malate dismutation pathway, as this offers an essential target in
the parasite, which is not present in mammals.
DOI: 10.1016/j.fawpar.2019.e00040
PMCID: PMC7034016
PMID: 32095613
200. iScience. 2020 Feb 21;23(2):100821. doi: 10.1016/j.isci.2020.100821. Epub 2020

Jan 9.
Estrogen Induces Mammary Ductal Dysplasia via the Upregulation of Myc Expression
in a DNA-Repair-Deficient Condition.
Itou J(1), Takahashi R(2), Sasanuma H(3), Tsuda M(4), Morimoto S(3), Matsumoto
Y(5), Ishii T(5), Sato F(6), Takeda S(3), Toi M(5).
Author information:
(1)Laboratory of Molecular Life Science, Institute for Biomedical Research and
Innovation, Foundation for Biomedical Research and Innovation at Kobe (FBRI),
2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan; Department of Breast
Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho,
Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: junji-itou@umin.ac.jp.
(2)Graduate School of Pharmaceutical Sciences and Faculty of Pharmaceutical
Sciences, Doshisha Women's College of Liberal Arts, 97-1 Kodo, Kyotanabe
610-0395, Japan.
(3)Department of Radiation Genetics, Graduate School of Medicine, Kyoto
University, Yoshida-Konoe-cho, Kyoto 606-8501, Japan.
(4)Department of Radiation Genetics, Graduate School of Medicine, Kyoto
University, Yoshida-Konoe-cho, Kyoto 606-8501, Japan; Program of Mathematical
and Life Science, Graduate School of Integrated Sciences for Life, Hiroshima
University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan.
(5)Department of Breast Surgery, Graduate School of Medicine, Kyoto University,
54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
(6)Department of Breast Surgery, Graduate School of Medicine, Kyoto University,
54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan; Department of Breast
Surgery, Kansai Electric Power Hospital & Kansai Electric Power Medical Research
Institute, 2-1-7 Fukushima, Fukushima-ku, Osaka 553-0003, Japan.
Mammary ductal dysplasia is a phenotype observed in precancerous lesions and

early-stage breast cancer. However, the mechanism of dysplasia formation remains
elusive. Here we show, by establishing a novel dysplasia model system, that
estrogen, a female hormone, has the potential to cause mammary ductal dysplasia.
We injected estradiol (E2), the most active form of estrogen, daily into scid
mice with a defect in non-homologous end joining repair and observed dysplasia
formation with cell proliferation at day 30. The protooncogene Myc is a
downstream target of estrogen signaling, and we found that its expression is
augmented in mammary epithelial cells in this dysplasia model. Treatment with a
Myc inhibitor reduced E2-induced dysplasia formation. Moreover, we found that
isoflavones inhibited E2-induced dysplasia formation. Our dysplasia model system
provides insights into the mechanistic understanding of breast tumorigenesis and
the development of breast cancer prevention.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.isci.2020.100821
PMCID: PMC6976935
PMID: 31978754
Conflict of interest statement: Declaration of Interests J.I. was an employee of

Kyoto University's Sponsored Research Program funded by Taiho Pharmaceutical.
R.T., H.S., M. Tsuda, S.M., Y.M., T.I., F.S., S.T., and M. Toi have no conflict
of interest. The funding source had no role in the study design, experiment,
analysis, interpretation, or writing the manuscript.
The Effects of Trifolium pratense L. Sprouts' Phenolic Compounds on Cell Growth

and Migration of MDA-MB-231, MCF-7 and HUVEC Cells.
Zakłos-Szyda M(1), Budryn G(2).

Author information:
(1)Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology
and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924
Lodz, Poland.
(2)Institute of Food Technology and Analysis, Faculty of Biotechnology and Food
Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz,
Poland.
Uncontrolled growth and migration and invasion abilities are common for cancer
cells in malignant tumors with low therapeutic effectiveness and high mortality
and morbidity. Estrogen receptor β (ERβ), as a member of the nuclear receptor
superfamily, shows potent tumor suppressive activities in many cancers.
Phytoestrogens' structural resemblance to 17 β-estradiol allows their binding to
ERβ isoform predominantly, and therefore, expression of genes connected with
elevated proliferation, motility and invasiveness of cancer cells may be
downregulated. Among polyphenolic compounds with phytoestrogenic activity, there
are isoflavones from Trifolium pratense L. (red clover) sprouts, containing high
amounts of formononetin and biochanin A and their glycosides. To determine the
source of the most biologically active isoflavones, we obtained four extracts
from sprouts before and after their lactic fermentation and/or β-glucosidase
treatment. Our previous results of ITC (isothermal titration calorimetry)
modelling and a docking simulation showed clover isoflavones' affinity to ERβ
binding, which may downregulate cancer cell proliferation and migration. Thus,
the biological activity of T. pratense sprouts' extracts was checked under in
vitro conditions against highly invasive human breast cancer cell line
MDA-MB-231 and non-invasive human breast cancer cell line MCF-7 cells. To
compare extracts' activities acquired for cancer cells with those activities
against normal cells, as a third model we choose human umbilical vein
endothelial cells (HUVEC), which, due to their migration abilities, are involved
in blood vessel formation. Extracts obtained from fermented sprouts at IC0
dosages were able to inhibit migration of breast cancer cells through their
influence on intracellular ROS generation; membrane stiffening; adhesion;
regulation of MMP-9, N-cadherin and E-cadherin at transcriptional level; or VEGF
secretion. Simultaneously, isolated phenolics revealed no toxicity against
normal HUVEC cells. In the manuscript, we proposed a preliminary mechanism
accounting for the in vitro activity of Trifolium pratense L. isoflavones. In
this manner, T. pratense sprouts, especially after their lactic fermentation,
can be considered a potent source of biological active phytoestrogens and a
dietary supplement with anti-cancer and anti-invasion properties.
DOI: 10.3390/nu12010257
PMCID: PMC7020047
202. Molecules. 2020 Jan 3;25(1):207. doi: 10.3390/molecules25010207.
Isoflavones Isolated from the Seeds of Millettia ferruginea Induced Apoptotic

Cell Death in Human Ovarian Cancer Cells.
Wang YY(1), Kwak JH(1), Lee KT(1), Deyou T(2), Jang YP(1)(3), Choi JH(1)(3).
Author information:
(1)Department of Life and Nanopharmaceutical Sciences, Kyung Hee University,
Seoul 02447, Korea.
(2)Department of Chemistry, College of Natural Sciences, Salale University,
Fitche, P.O. Box 245, Ethiopia.
(3)Department of Oriental Pharmaceutical Sciences, College of Pharmacy, Kyung
Hee University, Seoul 02447, Korea.
The seeds of Millettia ferruginea are used in fishing, pesticides, and folk
medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from
M. ferruginea were evaluated in human ovarian cancer cells. We found that
isoflavone ferrugone and
6,7-dimethoxy-3',4'-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had
potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone
and DMI treatment increased the sub-G1 cell population in a dose-dependent
manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was
associated with the induction of apoptosis, as shown by an increase in annexin
V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk,
a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced
apoptosis, suggesting that cell death stimulated by the isoflavones is mediated
by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was
found to be caspase-8-dependent, while DMI-induced apoptosis was
caspase-9-dependent. Notably, DMI, but not ferrugone, increased the
intracellular levels of reactive oxygen species (ROS), and antioxidant
N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These
data suggest that DMI induced apoptotic cell death through the intrinsic pathway
via ROS production, while ferrugone stimulated the extrinsic pathway in human
ovarian cancer cells.
PMCID: PMC6983189
203. Cancers (Basel). 2020 Jan 9;12(1):167. doi: 10.3390/cancers12010167.
Divergent Effects of Daidzein and its Metabolites on Estrogen-Induced Survival

of Breast Cancer Cells.
Montalesi E(1), Cipolletti M(1), Cracco P(1), Fiocchetti M(1), Marino M(1).
Author information:
(1)Department of Science, University Roma Tre, Viale Guglielmo Marconi 446,
I-00146 Roma, Italy.
Although soy consumption is associated with breast cancer prevention, the low
bioavailability and the extensive metabolism of soy-active components limit
their clinical application. Here, the impact of daidzein (D) and its metabolites
on estrogen-dependent anti-apoptotic pathway has been evaluated in breast cancer
cells. In estrogen receptor α-positive breast cancer cells treated with D and
its metabolites, single or in mixture, ERα activation and Neuroglobin (NGB)
levels, an anti-apoptotic estrogen/ERα-inducible protein, were evaluated.
Moreover, the apoptotic cascade activation, as well as the cell number after
stimulation was assessed in the absence/presence of paclitaxel to determine the
compound effects on cell susceptibility to a chemotherapeutic agent. Among the
metabolites, only D-4'-sulfate maintains the anti-estrogenic effect of D,
reducing the NGB levels and rendering breast cancer cells more prone to the
paclitaxel treatment, whereas other metabolites showed estrogen mimetic effects,
or even estrogen independent effects. Intriguingly, the co-stimulation of D and
gut metabolites strongly reduced D effects. The results highlight the important
and complex influence of metabolic transformation on isoflavones physiological
effects and demonstrate the need to take biotransformation into account when
assessing the potential health benefits of consumption of soy isoflavones in
cancer.
DOI: 10.3390/cancers12010167
PMCID: PMC7017042
PMID: 31936631
204. Front Pharmacol. 2019 Dec 6;10:1336. doi: 10.3389/fphar.2019.01336.

eCollection
2019.
Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances.
Tuli HS(1), Tuorkey MJ(2), Thakral F(1), Sak K(3), Kumar M(4), Sharma AK(1),
Sharma U(5), Jain A(5), Aggarwal V(6), Bishayee A(7).
Author information:
(1)Department of Biotechnology, Maharishi Markandeshwar (Deemed to be
University), Mullana-Ambala, India.
(2)Division of Physiology, Zoology Department, Faculty of Science, Damanhour
University, Damanhour, Egypt.
(3)NGO Praeventio, Tartu, Estonia.
(4)Department of Chemistry, Maharishi Markandeshwar University, Sadopur, India.
(5)Department of Animal Sciences, Central University of Punjab, Bathinda, India.
(6)Department of Histopathology, Post Graduate Institute of Medical Education
and Research, Chandigarh, India.
(7)Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States.
Background: Genistein is one among the several other known isoflavones that is
found in different soybeans and soy products. The chemical name of genistein is
4',5,7-trihydroxyisoflavone. Genistein has drawn attention of scientific
community because of its potential beneficial effects on human grave diseases,
such as cancer. Mechanistic insight of genistein reveals its potential for
apoptotic induction, cell cycle arrest, as well as antiangiogenic,
antimetastatic, and anti-inflammatory effects. Objective: The purpose of this
review is to unravel and analyze various molecular mechanisms of genistein in
diverse cancer models. Data sources: English language literature was searched
using various databases, such as PubMed, ScienceDirect, EBOSCOhost, Scopus, Web
of Science, and Cochrane Library. Key words used in various combinations
included genistein, cancer, anticancer, molecular mechanisms prevention,
treatment, in vivo, in vitro, and clinical studies. Study selection: Study
selection was carried out strictly in accordance with the statement of Preferred
Reporting Items for Systematic Reviews and Meta-analyses. Data extraction: Four
authors independently carried out the extraction of articles. Data synthesis:
One hundred one papers were found suitable for use in this review. Conclusion:
This review covers various molecular interactions of genistein with various
cellular targets in cancer models. It will help the scientific community
understand genistein and cancer biology and will provoke them to design novel
therapeutic strategies.
Copyright © 2019 Tuli, Tuorkey, Thakral, Sak, Kumar, Sharma, Sharma, Jain,
Aggarwal and Bishayee.
DOI: 10.3389/fphar.2019.01336
PMCID: PMC6910185
PMID: 31866857
205. Eur J Epidemiol. 2020 Jun;35(6):567-578. doi: 10.1007/s10654-019-00585-4. Epub
2019 Nov 21.
Soy intake and breast cancer risk: a prospective study of 300,000 Chinese women
and a dose-response meta-analysis.
Wei Y(1), Lv J(1)(2)(3), Guo Y(4), Bian Z(4), Gao M(1), Du H(5)(6), Yang
L(5)(6), Chen Y(5)(6), Zhang X(7), Wang T(7), Chen J(8), Chen Z(6), Yu C(9), Huo
D(10), Li L(1); China Kadoorie Biobank Collaborative Group.
Collaborators: Chen J, Chen Pi Z, Clarke R, Collins R, Guo Y, Li Pi L, Lv J,

Peto R, Walters R, Avery D, Boxall R, Bennett D, Chang Y, Chen Y, Chen Z, Clarke
R, Du H, Gilbert S, Hacker A, Hill M, Holmes M, Iona A, Kartsonaki C, Kerosi R,
Kong L, Kurmi O, Lancaster G, Lewington S, Lin K, McDonnell J, Millwood I, Nie
Q, Radhakrishnan J, Ryder P, Sansome S, Schmidt D, Sherliker P, Sohoni R,
Stevens B, Turnbull I, Walters R, Wang J, Wang L, Wright N, Yang L, Yang X, Bian
Z, Guo Y, Han X, Hou C, Lv J, Pei P, Liu C, Tan Y, Yu C, Pang Z, Gao R, Li S,
Wang S, Liu Y, Du R, Zang Y, Cheng L, Tian X, Zhang H, Zhai Y, Ning F, Sun X, Li
F, Lv S, Wang J, Hou W, Zeng M, Jiang G, Zhou X, Yang L, He H, Yu B, Li Y, Xu Q,
Kang Q, Guo Z, Wang D, Hu X, Chen J, Fu Y, Fu Z, Wang X, Weng M, Guo Z, Wu S, Li
Y, Li H, Fu Z, Wu M, Zhou Y, Zhou J, Tao R, Yang J, Su J, Liu F, Zhang J, Hu Y,
Lu Y, Ma L, Tang A, Zhang S, Jin J, Liu J, Tang Z, Chen N, Huang Y, Li M, Meng
J, Pan R, Jiang Q, Lan J, Liu Y, Wei L, Zhou L, Chen N, Wang P, Meng F, Qin Y,
Wang S, Wu X, Zhang N, Chen X, Zhou W, Luo G, Li J, Chen X, Zhong X, Liu J, Sun
Q, Ge P, Ren X, Dong C, Zhang H, Mao E, Wang X, Wang T, Zhang X, Zhang D, Zhou
G, Feng S, Chang L, Fan L, Gao Y, He T, Sun H, He P, Hu C, Zhang X, Wu H, He P,
Yu M, Hu R, Wang H, Qian Y, Wang C, Xie K, Chen L, Zhang Y, Pan D, Gu Q, Huang
Y, Chen B, Yin L, Liu H, Fu Z, Xu Q, Xu X, Zhang H, Long H, Li X, Zhang L, Qiu
Z.
Author information:
(1)Department of Epidemiology and Biostatistics, School of Public Health, Peking
University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
(2)Key Laboratory of Molecular Cardiovascular Sciences (Peking University),
Ministry of Education, Beijing, China.
(3)Peking University Institute of Environmental Medicine, Beijing, China.
(4)Chinese Academy of Medical Sciences, Beijing, China.
(5)Medical Research Council Population Health Research Unit, University of
Oxford, Oxford, UK.
(6)Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield
Department of Population Health, University of Oxford, Oxford, UK.
(7)NCDs Prevention and Control Department, Maiji CDC, Tianshui, Gansu, China.
(8)China National Center for Food Safety Risk Assessment, Beijing, China.
(9)Department of Epidemiology and Biostatistics, School of Public Health, Peking
University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
yucanqing@pku.edu.cn.
(10)Department of Public Health Sciences, The University of Chicago, 5841 S.
Maryland Ave., MC2000, Chicago, IL, 60637, USA. dhuo@health.bsd.uchicago.edu.
Epidemiological evidence on the association of soy intake with breast cancer

risk is still inconsistent due to different soy intake levels across previous
studies and small number of breast cancer cases. We aimed to investigate this
issue by analyzing data from the China Kadoorie Biobank (CKB) study and
conducting a dose-response meta-analysis to integrate existing evidence. The CKB
study included over 300,000 women aged 30-79 from 10 regions across China
enrolled between 2004 and 2008, and followed-up for breast cancer events until
31 December 2016. Information on soy intake was collected from baseline, two
resurveys and twelve 24-h dietary recalls. We also searched for relevant
prospective cohort studies to do a dose-response meta-analysis. The mean (SD)
soy intake was 9.4 (5.4) mg/day soy isoflavones among CKB women. During 10 years
of follow-up, 2289 women developed breast cancers. The multivariable-adjusted
relative risk was 1.00 (95% confidence interval [CI] 0.81-1.22) for the fourth
(19.1 mg/day) versus the first (4.5 mg/day) soy isoflavone intake quartile.
Meta-analysis of prospective studies found that each 10 mg/day increment in soy
isoflavone intake was associated with a 3% (95% CI 1-5%) reduced risk of breast
cancer. The CKB study demonstrated that moderate soy intake was not associated
with breast cancer risk among Chinese women. Higher amount of soy intake might
provide reasonable benefits for the prevention of breast cancer.
DOI: 10.1007/s10654-019-00585-4
PMCID: PMC7320952
Conflict of interest statement: We declare that we have no conflicts of

interest.
206. Eur J Cancer Prev. 2020 Nov;29(6):493-500. doi: 10.1097/CEJ.0000000000000561.
Association between flavonoids, flavonoid subclasses intake and breast cancer

risk: a case-control study in China.
Feng XL(1)(2), Ho SC(3), Mo XF(4), Lin FY(5), Zhang NQ(1)(2), Luo H(1), Zhang
X(1), Zhang CX(1)(2).
Author information:
(1)Department of Epidemiology, School of Public Health, Sun Yat-sen University.
(2)Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of
Public Health, Sun Yat-sen University, Guangzhou.
Care, The Chinese University of Hong Kong, Hong Kong SAR.
(4)Department of Thyroid and Breast Surgery, the First Affiliated Hospital of
Sun Yat-sen University.
(5)Nursing Department, the First Affiliated Hospital of Sun Yat-sen University,
Guangzhou, People's Republic of China.
Anti-tumor effect of dietary flavonoids has been sustained by laboratory

experiments, but epidemiological studies with breast cancer risk remained
inconsistent and insufficient. This study aimed to investigate the associations
between total and subclasses of flavonoid and breast cancer risk among Chinese
population. This case-control study recruited 1522 eligible breast cancer cases
and 1547 frequency-matched control subjects from June 2007 to July 2018 in
Guangdong, China. Dietary intake was obtained by face-to-face interview using a
validated food frequency questionnaire. Odds ratios and 95% confidence intervals
were calculated by multivariable logistic regression models. After adjusting for
potential confounders, inverse associations were observed between total
flavonoids, anthocyanidins, proanthocyanidins, flavanones, flavones, flavonols
and isoflavones and overall breast cancer risk. Comparing the highest versus the
lowest quartile, odds ratio (95% confidence interval) was 0.66 (0.54-0.82) for
total flavonoids, 0.61 (0.49-0.75) for anthocyanidins, 0.67 (0.54-0.83) for
proanthocyanidins, 0.71 (0.57-0.88) for flavanones, 0.48 (0.39-0.60) for
flavones, 0.51 (0.41-0.63) for flavonols and 0.67 (0.54-0.83) for isoflavones,
respectively. No significant association was found between flavanols,
flavan-3-ol monomers, theaflavins and breast cancer risk. Stratified analysis by
menopausal status and estrogen receptor/progesterone receptor status showed that
the associations of total flavonoids, most flavonoid subclasses with breast
cancer risk were generally not modified by menopausal or estrogen
receptor/progesterone receptor status. This study indicates that total
flavonoids and most flavonoid subclasses intakes were inversely associated with
breast cancer risk.
DOI: 10.1097/CEJ.0000000000000561
207. Arch Pharm Res. 2019 Dec;42(12):1081-1091. doi: 10.1007/s12272-019-01191-4.

Epub
2019 Nov 8.
Protective effects of 6,7,4'-trihydroxyisoflavone, a major metabolite of

daidzein, on 6-hydroxydopamine-induced neuronal cell death in SH-SY5Y human
neuroblastoma cells.
Ko YH(1), Kwon SH(1), Kim SK(1), Lee BR(1), Hur KH(1), Kim YJ(1), Kim SE(1), Lee
SY(1), Jang CG(2).
Author information:
(1)Department of Pharmacology, School of Pharmacy, Sungkyunkwan University,
Suwon, 16419, Republic of Korea.
(2)Department of Pharmacology, School of Pharmacy, Sungkyunkwan University,
Suwon, 16419, Republic of Korea. jang@skku.edu.
Daidzein, one of the important isoflavones, is extensively metabolized in the

human body following consumption. In particular, 6,7,4'-trihydroxyisoflavone
(THIF), a major metabolite of daidzein, has been the focus of recent
investigations due to its various health benefits, such as anti-cancer and
anti-obesity effects. However, the protective effects of 6,7,4'-THIF have not
yet been studied in models of Parkinson's disease (PD). Therefore, the present
study aimed to investigate the protective activity of 6,7,4'-THIF on
6-hydroxydopamine (OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma
cells. Pretreatment of SH-SY5Y cells with 6,7,4'-THIF significantly inhibited
6-OHDA-induced neuronal cell death, lactate dehydrogenase release, and reactive
oxygen species production. In addition, 6,7,4'-THIF significantly attenuated
reductions in 6-OHDA-induced superoxide dismutase activity and glutathione
content. Moreover, 6,7,4'-THIF attenuated alterations in Bax and Bcl-2
expression and caspase-3 activity in 6-OHDA-induced SH-SY5Y cells. Furthermore,
6,7,4'-THIF significantly reduced 6-OHDA-induced phosphorylation of c-Jun
N-terminal kinase, p38 mitogen-activated protein kinase, and extracellular
signal-regulated kinase 1/2. Additionally, 6,7,4'-THIF effectively prevented
6-OHDA-induced loss of tyrosine hydroxylase. Taken together, these results
suggest that 6,7,4'-THIF, a major metabolite of daidzein, may be an attractive
option for treating and/or preventing neurodegenerative disorders such as PD.
DOI: 10.1007/s12272-019-01191-4
208. Molecules. 2019 Nov 4;24(21):3982. doi: 10.3390/molecules24213982.
The Polyphenols as Potential Agents in Prevention and Therapy of Prostate

Diseases.
Pejčić T(1)(2), Tosti T(3), Džamić Z(4)(5), Gašić U(6), Vuksanović A(7)(8),
Dolićanin Z(9), Tešić Ž(10).
Author information:
(1)Clinic of Urology, Clinical Centre of Serbia, 11060 Belgrade, Serbia.
tomislav.pejcic@gmail.com.
(2)Faculty of Medicine, University of Belgrade; Bulevar Despota Stefana 142,
11060 Belgrade, Serbia. tomislav.pejcic@gmail.com.
(3)Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, P.O. Box
51, 11158 Belgrade, Serbia. tosti@chem.bg.ac.rs.
dzamiczoran960@gmail.com.
11060 Belgrade, Serbia. dzamiczoran960@gmail.com.
(6)Institute for Biological Research "Siniša Stanković", University of Belgrade,
Bulevar despota Stefana 142, 11060 Belgrade, Serbia. urosgasic@gmail.com.
avuksano@mts.rs.
11060 Belgrade, Serbia. avuksano@mts.rs.
(9)Department for Biomedical Sciences, State University at Novi Pazar, 36300
Novi Pazar, Serbia. zdolicanin@np.ac.rs.
(10)Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, P.O. Box
51, 11158 Belgrade, Serbia. ztesic@chem.bg.ac.rs.
In recent years, the progress of science and medicine greatly has influenced
human life span and health. However, lifestyle habits, like physical activity,
smoking cessation, moderate alcohol consumption, diet, and maintaining a normal
body weight represent measures that greatly reduce the risk of various diseases.
The type of diet is very important for disease development. Numerous
epidemiological clinical data confirm that longevity is linked to predominantly
plant-based diets and it is related to a long life; whereas the western diet,
rich in red meat and fats, increases the risk of oxidative stress and thus the
risk of developing various diseases and pre-aging. This review is focused on the
bioavailability of polyphenols and the use of polyphenols for the prevention of
prostate diseases. Special focus in this paper is placed on the isoflavonoids
and flavan-3-ols, subgroups of polyphenols, and their protective effects against
the development of prostate diseases.
PMCID: PMC6864651
209. Molecules. 2019 Oct 29;24(21):3892. doi: 10.3390/molecules24213892.
Genistein as Potential Therapeutic Candidate for Menopausal Symptoms and Other

Related Diseases.
Thangavel P(1), Puga-Olguín A(2), Rodríguez-Landa JF(3), Zepeda RC(4).
Author information:
(1)Programa de Posgrado en Neuroetología, Instituto de Neuroetología,
Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n, Col. Industrial
Ánimas, Xalapa C.P. 91190, Veracruz, Mexico. prakashjacob47@gmail.com.
(2)Laboratorio de Neurofarmacología, Instituto de Neuroetología, Universidad
Veracruzana, Av. Dr. Luis Castelazo Ayala s/n, Col. Industrial Ánimas, Xalapa
C.P. 91190, Veracruz, Mexico. abra_puga@hotmail.com.
(3)Laboratorio de Neurofarmacología, Instituto de Neuroetología, Universidad
Veracruzana, Av. Dr. Luis Castelazo Ayala s/n, Col. Industrial Ánimas, Xalapa
C.P. 91190, Veracruz, Mexico. juarodriguez@uv.mx.
(4)Centro de Investigaciones Biomédicas, Universidad Veracruzana, Av. Dr. Luis
Castelazo Ayala s/n, Col. Industrial Ánimas, Xalapa C.P. 91190, Veracruz,
Mexico. rzepeda@uv.mx.
Plant-derived compounds have recently attracted greater interest in the field of

new therapeutic agent development. These compounds have been widely screened for
their pharmacological effects. Polyphenols, such as soy-derived isoflavones,
also called phytoestrogens, have been extensively studied due to their ability
to inhibit carcinogenesis. These compounds are chemically similar to
17β-estradiol, and mimic the binding of estrogens to its receptors, exerting
estrogenic effects in target organs. Genistein is an isoflavone derived from
soy-rich products and accounts for about 60% of total isoflavones found in
soybeans. Genistein has been reported to exhibit several biological effects,
such as anti-tumor activity (inhibition of cell proliferation, regulation of the
cell cycle, induction of apoptosis), improvement of glucose metabolism,
impairment of angiogenesis in both hormone-related and hormone-unrelated cancer
cells, reduction of peri-menopausal and postmenopausal hot flashes, and
modulation of antioxidant effects. Additionally, epidemiological and clinical
studies have reported health benefits of genistein in many chronic diseases,
such as cardiovascular disease, diabetes, and osteoporosis, and aid in the
amelioration of typical menopausal symptoms, such as anxiety and depression.
Although the biological effects are promising, certain limitations, such as low
bioavailability, biological estrogenic activity, and effects on target organs,
have limited the clinical applications of genistein to some extent. Moreover,
studies report that modification of its molecular structure may eliminate the
biological estrogenic activity and its effects on target organs. In this review,
we summarize the potential benefits of genistein on menopause symptoms and
menopause-related diseases like cardiovascular, osteoporosis, obesity, diabetes,
anxiety, depression, and breast cancer.
PMCID: PMC6864469
210. J Nutr Sci Vitaminol (Tokyo). 2019;65(5):375-382. doi: 10.3177/jnsv.65.375.
Vegetable-Fruit-Soybean Dietary Pattern and Breast Cancer: A Meta-Analysis of

Observational Studies.
Zhang L(1), Huang S(1), Cao L(1), Ge M(1), Li Y(1), Shao J(1).
Author information:
(1)Xuzhou Medical University.
Breast cancer is one of the most common cancers among women worldwide, and
several studies have investigated the association of dietary patterns and breast
cancer. However, findings of studies are inconclusive. Therefore, we aimed to
conduct a meta-analysis to summarize the available data regarding the
association of vegetable-fruit-soybean dietary pattern and breast cancer. A
systematic literature search was conducted via PubMed, Web of Science and EMBASE
to identify eligible cohort studies before February 2019. A total of 12 cohort
studies were included in the meta-analysis. The summary relative risks (RR) with
95% CI were calculated with a fixed-effects model. The overall RR of breast
cancer for the highest versus lowest intake of vegetable-fruit-soybean dietary
pattern was 0.87 (95% CI, 0.82-0.91), with little heterogeneity (p=0.73, I2=0%).
There was no obvious publication bias according to funnel plot and Begg's and
Egger's test. In summary, the evidence from this meta-analysis indicates that
vegetable-fruit-soybean dietary pattern was inversely associated with breast
cancer. However, well-designed randomized controlled trials are needed to elicit
the clear effect of vegetable-fruit-soybean dietary pattern and breast cancer.
Women can reduce the risks of breast cancer by eating more fruits and vegetables
and soybeans, which is a constructive suggestion.
DOI: 10.3177/jnsv.65.375
211. Int J Radiat Biol. 2020 Feb;96(2):245-256. doi: 10.1080/09553002.2020.1683642.

Epub 2019 Nov 4.
Isoflavone-mediated radioprotection involves regulation of early endothelial

cell death and inflammatory signaling in Radiation-Induced lung injury.
Fountain MD(1)(2), McLellan LA(1), Smith NL(1), Loughery BF(2), Rakowski JT(2),
Tse HY(1), Hillman GG(1)(2).
Author information:
(1)Department of Biochemistry, Microbiology & Immunology, Wayne State University
School of Medicine, Detroit, MI, USA.
(2)Department of Oncology, Division of Radiation Oncology, Wayne State
University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA.
Purpose: Vascular damage and inflammation are limiting toxic effects of lung
cancer radiotherapy, which lead to pneumonitis and pulmonary fibrosis. We have
demonstrated that soy isoflavones (SIF) mitigate these toxic effects at late
time points after radiation. However, the process by which SIF impacts the onset
of radiation-induced inflammation remains to be elucidated. We have now
investigated early events of radiation-induced inflammation and identified
cellular and molecular signaling patterns by endothelial cells that could be
modified by SIF to control vascular damage and the initiation of lung
inflammation.Materials and methods: Histopathological, cellular and molecular
studies were performed on mouse lungs from C57Bl/6 mice treated with 10 Gy of
thoracic radiation (XRT) in conjunction with daily oral SIF treatment given
prior and after radiation. Parallel studies were performed in-vitro using
EA.hy926 endothelial cell line with SIF and radiation. Immunohistochemistry,
western blots analysis, and flow cytometry were performed on lung tissue or
EA.hy926 cells to analyze endothelial cells, their patterns of cell death or
survival, and signaling molecules involved in inflammatory events.Results:
Histopathological differences in inflammatory infiltrates and vascular injury in
lungs, including vascular endothelial cells, were observed with SIF treatment at
early time points post-XRT. XRT-induced expression of proinflammatory adhesion
molecule ICAM-1 cells was reduced by SIF in-vitro and in-vivo in endothelial
cells. Molecular changes in endothelial cells with SIF treatment in conjunction
with XRT included increased DNA damage, reduced cell viability and cyclin B1,
and inhibition of nuclear translocation of NF-κB. Analysis of cell death showed
that SIF treatment promoted apoptotic endothelial cell death and decreased
XRT-induced type III cell death. In-vitro molecular studies indicated that
SIF + XRT increased apoptotic caspase-9 activation and production of IFNβ while
reducing the release of inflammatory HMGB-1 and IL-1α, the cleavage of
pyroptotic gasdermin D, and the release of active IL-1β, which are all events
associated with type III cell death.Conclusions: SIF + XRT caused changes in
patterns of endothelial cell death and survival, proinflammatory molecule
release, and adhesion molecule expression at early time points post-XRT
associated with early reduction of immune cell recruitment. These findings
suggest that SIF could mediate its radioprotective effects in irradiated lungs
by limiting excessive immune cell homing via vascular endothelium into damaged
lung tissue and curtailing the overall inflammatory response to radiation.
DOI: 10.1080/09553002.2020.1683642
PMCID: PMC6995443
Conflict of interest statement: Disclosure of interest: The authors report no

conflict of interest
212. Chem Res Toxicol. 2019 Nov 18;32(11):2353-2364. doi:

10.1021/acs.chemrestox.9b00352. Epub 2019 Oct 29.
Isoflavones as Ah Receptor Agonists in Colon-Derived Cell Lines:

Structure-Activity Relationships.
Park H(1), Jin UH(1), Orr AA(2), Echegaray SP(2), Davidson LA(3), Allred CD(3),
Chapkin RS(3), Jayaraman A(2), Lee K(4), Tamamis P(2), Safe S(1).
Author information:
(1)Department of Veterinary Physiology and Pharmacology , Texas A&M University ,
College Station , Texas 77843 , United States.
(2)Artie McFerrin Department of Chemical Engineering , Texas A&M University ,
College Station , Texas 77840 , United States.
(3)Department of Nutrition and Food Science , Texas A&M University , College
Station , Texas 77843 , United States.
(4)Department of Chemical and Biological Engineering , Tufts University ,
Medford , Massachusetts 02155 , United States.
Many of the protective responses observed for flavonoids in the gastrointestinal

track resemble aryl hydrocarbon receptor (AhR)-mediated effects. Therefore, we
examined the structure-activity relationships of isoflavones and isomeric
flavone and flavanones as AhR ligands on the basis of their induction of CYP1A1,
CYP1B1, and UGT1A1 gene expression in colon cancer Caco2 cells and young adult
mouse colonocyte (YAMC) cells. Caco2 cells were significantly more Ah-responsive
than YAMC cells, and this was due, in part, to flavonoid-induced cytotoxicity in
the latter cell lines. The structure-activity relationships for the flavonoids
were complex and both response and cell context specific; however, there was
significant variability in the AhR activities of the isomeric substituted
isoflavones and flavones. For example, 4',5,7-trihydroxyisoflavone (genistein)
was AhR-inactive whereas 4',5,7-trihydroxyflavone (apigenin) induced CYP1A1,
CYP1B1, and UGT1A1 in Caco2 cells. In contrast, both 5,7-dihydroxy-4-methoxy
substituted isoflavone (biochanin A) and flavone (acacetin) induced all three
AhR-responsive genes; 4',5,7-trimethoxyisoflavone was a potent AhR agonist, and
the isomeric flavone was AhR-inactive. These results coupled with simulation
studies modeling flavonoid interaction within the AhR binding pocket demonstrate
that the orientation of the substituted phenyl ring at C-2 (flavones) or C-3
(isoflavones) on the common 4-H-chromen-4-one ring strongly influences the
activities of isoflavones and flavones as AhR agonists.
DOI: 10.1021/acs.chemrestox.9b00352
PMCID: PMC6938648

interest.
213. Int J Mol Sci. 2019 Oct 9;20(20):4981. doi: 10.3390/ijms20204981.
Role of Phytochemicals in Cancer Prevention.
Ranjan A(1), Ramachandran S(2)(3), Gupta N(4), Kaushik I(5)(6), Wright S(7)(8),
Srivastava S(9), Das H(10), Srivastava S(11), Prasad S(12), Srivastava
SK(13)(14).
Author information:
(1)Department of Biomedical Sciences, Texas Tech University Health Sciences
Center, Amarillo, TX 79106, USA. alok.ranjan@nih.gov.
Center, Amarillo, TX 79106, USA. sharvan.ramachandran@ttuhsc.edu.
(3)Department of Immunotherapeutics and Biotechnology, and Center for Tumor
Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences
Center, Abilene, TX 79601, USA. sharvan.ramachandran@ttuhsc.edu.
Center, Amarillo, TX 79106, USA. nehal.gupta@ttuhsc.edu.
Center, Amarillo, TX 79106, USA. i.kaushik@ttuhsc.edu.
Center, Abilene, TX 79601, USA. i.kaushik@ttuhsc.edu.
Center, Amarillo, TX 79106, USA. stephen.wright@ttuhsc.edu.
(8)Department of Internal Medicine, Texas Tech University Health Sciences
Center, Amarillo, TX 79106, USA. stephen.wright@ttuhsc.edu.
Center, Amarillo, TX 79106, USA. suyash.srivastava17@gmail.com.
Center, Amarillo, TX 79106, USA. hiranmoy.das@ttuhsc.edu.
(11)Department of Chemistry, Lucknow University, Mahatma Gandhi Road, Lucknow,
UP 226007, India. sangeetas.lu@gmail.com.
Center, Abilene, TX 79601, USA. sahdeo.prasad@ttuhsc.edu.
Center, Amarillo, TX 79106, USA. sanjay.srivastava@ttuhsc.edu.
Center, Abilene, TX 79601, USA. sanjay.srivastava@ttuhsc.edu.
The use of synthetic, natural, or biological agents to minimize the occurrence

of cancer in healthy individuals is defined as cancer chemoprevention.
Chemopreventive agents inhibit the development of cancer either by impeding DNA
damage, which leads to malignancy or by reversing or blocking the division of
premalignant cells with DNA damage. The benefit of this approach has been
demonstrated in clinical trials of breast, prostate, and colon cancer. The
continuous increase in cancer cases, failure of conventional chemotherapies to
control cancer, and excessive toxicity of chemotherapies clearly demand an
alternative approach. The first trial to show benefit of chemoprevention was
undertaken in breast cancer patients with the use of tamoxifen, which
demonstrated a significant decrease in invasive breast cancer. The success of
using chemopreventive agents for protecting the high risk populations from
cancer indicates that the strategy is rational and promising. Dietary components
such as capsaicin, cucurbitacin B, isoflavones, catechins, lycopenes, benzyl
isothiocyanate, phenethyl isothiocyanate, and piperlongumine have demonstrated
inhibitory effects on cancer cells indicating that they may serve as
chemopreventive agents. In this review, we have addressed the mechanism of
chemopreventive and anticancer effects of several natural agents.
DOI: 10.3390/ijms20204981
PMCID: PMC6834187
214. Mol Nutr Food Res. 2020 Feb;64(4):e1900751. doi: 10.1002/mnfr.201900751. Epub
2019 Oct 14.
Soy and Isoflavone Consumption and Multiple Health Outcomes: Umbrella Review of
Systematic Reviews and Meta-Analyses of Observational Studies and Randomized
Trials in Humans.
Li N(1), Wu X(2), Zhuang W(2), Xia L(2), Chen Y(2), Zhao R(2), Yi M(2), Wan
Q(2), Du L(3), Zhou Y(2).
Author information:
(1)Department of Ophthalmology, West China Hospital, Sichuan University,
Chengdu, 610041, China.
(2)Department of Gastrointestinal Surgery, West China Hospital, Sichuan
University, Chengdu, 610041, China.
(3)Chinese Evidence-based Medicine/Cochrane Center, Chengdu, 610041, China.
SCOPE: To assess the existing evidence of associations between consumption of

soy and isoflavone and multiple health outcomes.
METHODS AND RESULTS: This is an umbrella review of meta-analyses and systematic
reviews of randomized trials and observational studies in humans. 114
Meta-analyses and systematic reviews are identified with 43 unique outcomes. Soy
and isoflavone consumption seems more beneficial than harmful for a series of
health outcomes. Beneficial associations are identified for cancers,
cardiovascular disease, gynecological, metabolic, musculoskeletal, endocrine,
neurological, and renal outcomes, particularly in perimenopausal women. Harmful
association is only found for gastric cancer (RR: 1.17, 95% CI: 1.02-1.36) for
high intake of miso soup (1-5 cups per day) in male.
CONCLUSION: Generally, soy and isoflavone consumption is more beneficial than
harmful. The results herein support promoting soy intake as part of a healthy
diet. Randomized controlled trials are necessary to confirm this finding.
© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/mnfr.201900751
Equol: A Bacterial Metabolite from The Daidzein Isoflavone and Its Presumed
Beneficial Health Effects.
Mayo B(1)(2), Vázquez L(3)(4), Flórez AB(5)(6).
Author information:
(1)Departamento de Microbiología y Bioquímica, Instituto de Productos Lácteos de
Asturias (IPLA), Consejo Superior de Investigaciones Científicas (CSIC), Paseo
Río Linares s/n, 33300 Villaviciosa, Spain. baltasar.mayo@ipla.csic.es.
(2)Instituto de Investigación Sanitaria del Principado de Asturias (ISPA),
Avenida de Roma s/n, 33011 Oviedo, Spain. baltasar.mayo@ipla.csic.es.
Río Linares s/n, 33300 Villaviciosa, Spain. lucia.vazquez@ipla.csic.es.
Avenida de Roma s/n, 33011 Oviedo, Spain. lucia.vazquez@ipla.csic.es.
Río Linares s/n, 33300 Villaviciosa, Spain. abflorez@ipla.csic.es.
Avenida de Roma s/n, 33011 Oviedo, Spain. abflorez@ipla.csic.es.
Epidemiological data suggest that regular intake of isoflavones from soy reduces
the incidence of estrogen-dependent and aging-associated disorders, such as
menopause symptoms in women, osteoporosis, cardiovascular diseases and cancer.
Equol, produced from daidzein, is the isoflavone-derived metabolite with the
greatest estrogenic and antioxidant activity. Consequently, equol has been
endorsed as having many beneficial effects on human health. The conversion of
daidzein into equol takes place in the intestine via the action of reductase
enzymes belonging to incompletely characterized members of the gut microbiota.
While all animal species analyzed so far produce equol, only between one third
and one half of human subjects (depending on the community) are able to do so,
ostensibly those that harbor equol-producing microbes. Conceivably, these
subjects might be the only ones who can fully benefit from soy or isoflavone
consumption. This review summarizes current knowledge on the microorganisms
involved in, the genetic background to, and the biochemical pathways of, equol
biosynthesis. It also outlines the results of recent clinical trials and
meta-analyses on the effects of equol on different areas of human health and
discusses briefly its presumptive mode of action.
DOI: 10.3390/nu11092231
PMCID: PMC6770660
216. Biomed Res Int. 2019 Jul 28;2019:5854315. doi: 10.1155/2019/5854315.

eCollection
2019.
Potential Anticancer Properties and Mechanisms of Action of Formononetin.
Jiang D(1), Rasul A(1)(2), Batool R(2), Sarfraz I(2), Hussain G(3), Mateen Tahir
M(2), Qin T(1), Selamoglu Z(4), Ali M(5), Li J(6), Li X(1).
Author information:
(1)The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and
Cytology, Northeast Normal University, Changchun 130024, China.
(2)Department of Zoology, Faculty of Life Sciences, Government College
University Faisalabad (GCUF), 38000, Pakistan.
(3)Department of Physiology, Faculty of Life Sciences, Government College
University Faisalabad (GCUF), 38000, Pakistan.
(4)Department of Medical Biology, Faculty of Medicine, Nigde Ömer Halisdemir
University, Nigde, Campus 51240, Turkey.
(5)Quaid-e-Azam University, Islamabad 45320, Pakistan.
(6)Dental Hospital, Jilin University, Changchun 130021, China.
Nature, a vast reservoir of pharmacologically active molecules, has been most
promising source of drug leads for the cure of various pathological conditions.
Formononetin is one of the bioactive isoflavones isolated from different plants
mainly from Trifolium pratense, Glycine max, Sophora flavescens, Pycnanthus
angolensis, and Astragalus membranaceus. Formononetin has been well-documented
for its anti-inflammatory, anticancer, and antioxidant properties. Recently
anticancer activity of formononetin is widely studied. This review aims to
highlight the pharmacological potential of formononetin, thus providing an
insight of its status in cancer therapeutics. Formononetin fights progression of
cancer via inducing apoptosis, arresting cell cycle, and halting metastasis via
targeting various pathways which are generally modulated in several cancers.
Although reported data acclaims various biological properties of formononetin,
further experimentation on mechanism of its action, medicinal chemistry studies,
and preclinical investigations are surely needed to figure out full array of its
pharmacological and biological potential.
DOI: 10.1155/2019/5854315
PMCID: PMC6699357
Conflict of interest statement: Authors declare that there are no conflicts of

interest.
217. Medicina (Kaunas). 2019 Aug 28;55(9):544. doi: 10.3390/medicina55090544.
A Nutraceutical Approach to Menopausal Complaints.
De Franciscis P(1), Colacurci N(1), Riemma G(1), Conte A(1), Pittana E(1), Guida
M(2), Schiattarella A(3).
Author information:
(1)Department of Women, Child and General and Specialized Surgery, University of
Campania "Luigi Vanvitelli", 80138 Naples, Italy.
(2)Department of Neuroscience, Reproductive Sciences and Dentistry, School of
Medicine, University of Naples "Federico II", 80138 Naples, Italy.
(3)Department of Women, Child and General and Specialized Surgery, University of
Campania "Luigi Vanvitelli", 80138 Naples, Italy. aschiattarella@gmail.com.
The menopausal transition, or perimenopause, is characterized by menstrual

irregularities, vasomotor symptoms, sleep disturbances, mood symptoms, and
urogenital tract atrophy. These changes can also affect the quality of life and
one's self-esteem. Hormone replacement therapy (HRT) is considered the best
option to achieve therapeutic relief of different menopausal symptoms but is
usually restricted to moderate or severe symptoms. Moreover, many women refuse
HRT for a variety of reasons concerning the fear of cancer and other adverse
effects. According to these considerations, new topics are emerging:
Dissatisfaction with drug costs and conventional healthcare, desire for
personalized medicines, and the public perception that "natural is good". In
this context, nonhormonal therapies are mostly evolving, and it is not unusual
that women often request a "natural" approach for their symptoms. The aim of
this study is to investigate nonhormonal therapies that have been identified to
reduce the menopausal symptoms.
DOI: 10.3390/medicina55090544
PMCID: PMC6780855
Conflict of interest statement: Authors declare no conflict of interests,

commercial or financial in writing this article.
218. Clin Chim Acta. 2021 Jan;512:100-105. doi: 10.1016/j.cca.2019.08.023. Epub

2019
Aug 26.
Genistein upregulates cyclin D1 and CDK4 expression and promotes the

proliferation of ovarian cancer OVCAR-5 cells.
Wang Y(1), Li W(2), Wang Z(2), Ren H(2), Li Y(2), Zhang Y(2), Yang P(2), Pan
S(2).
Author information:
(1)Department Radiation Oncology of The Second Affiliated Hospital of Xi'an
Jiaotong University, Xi'an 710004, China. Electronic address:
yaliwang72@163.com.
(2)Department Radiation Oncology of The Second Affiliated Hospital of Xi'an
Jiaotong University, Xi'an 710004, China.
BACKGROUND: Ovarian epithelial cancer is the leading cause of deaths associated

with gynecologic malignancies. Genistein represents a major type of
phytoestrogens widely found in foods and herbal medicines. Although multiple
epidemiological studies indicated that the consumption of genistein or other
isoflavones is associated with a decreased ovarian cancer risk, the cellular
effects and underlying mechanisms are not fully understood. This study focuses
on the effect of genistein on the proliferation and cell cycle regulation of
ovarian cancer cells.
METHODS: Ovarian cancer OVCAR-5 cells were treated with genistein in an
estrogen-free condition. Cell counting and MTS assays were performed to
determine the cell proliferation alterations. Real-time PCR and Western blotting
were conducted to examine the expression changes in key cell cycle regulators.
RESULTS: Genistein significantly promoted the proliferation and the viability of
OVCAR-5 cells. Upon genistein treatment, cellular mRNA and protein expression
levels of PCNA, Cyclin D1 and CDK4 were increased, but those of p21 and p27 were
decreased.
CONCLUSION: In contrary to results of many previous studies, we observed that
genistein was able to upregulate the proliferation and G1-S transition of
ovarian cancer OVCAR-5 cells. The discrepancy could be caused by diverged
experimental conditions and/or different ER expression patterns of cell lines.
The findings may provide basic information for in-depth analysis on the role(s)
and mechanisms by which genistein confers its effect on ovarian cancer
progression.
DOI: 10.1016/j.cca.2019.08.023
219. Cancers (Basel). 2019 Aug 12;11(8):1153. doi: 10.3390/cancers11081153.
Main Inflammatory Cells and Potentials of Anti-Inflammatory Agents in Prostate

Cancer.
Hayashi T(1), Fujita K(2), Matsushita M(1), Nonomura N(1).
Author information:
(1)Department of Urology, Osaka University Graduate School of Medicine, Suita,
Osaka 565-0871, Japan.
(2)Department of Urology, Osaka University Graduate School of Medicine, Suita,
Osaka 565-0871, Japan. fujita@uro.med.osaka-u.ac.jp.
Prostate cancer is the most common type of cancer and the leading cause of
cancer deaths among men in many countries. Preventing progression is a major
concern for prostate cancer patients on active surveillance, patients with
recurrence after radical therapies, and patients who acquired resistance to
systemic therapies. Inflammation, which is induced by various factors such as
infection, microbiome, obesity, and a high-fat diet, is the major etiology in
the development of prostate cancer. Inflammatory cells play important roles in
tumor progression. Various immune cells including tumor-associated neutrophils,
tumor-infiltrating macrophages, myeloid-derived suppressor cells, and mast cells
promote prostate cancer via various intercellular signaling. Further basic
studies examining the relationship between the inflammatory process and prostate
cancer progression are warranted. Interventions by medications and diets to
control systemic and/or local inflammation might be effective therapies for
prostate cancer progression. Epidemiological investigations and basic research
using human immune cells or mouse models have revealed that non-steroidal
anti-inflammatory drugs, metformin, statins, soy isoflavones, and other diets
are potential interventions for preventing progression of prostate cancer by
suppressing inflammation. It is essential to evaluate appropriate indications
and doses of each drug and diet.
DOI: 10.3390/cancers11081153
PMCID: PMC6721573
PMID: 31408948

interpretation of data; in the writing of the manuscript, or in the decision to
220. Complement Ther Clin Pract. 2019 Aug;36:181-194. doi:

10.1016/j.ctcp.2019.07.007. Epub 2019 Jul 19.
Complementary and alternative medicine for natural and treatment-induced

vasomotor symptoms: An overview of systematic reviews and meta-analyses.
Guo PP(1), Li P(2), Zhang XH(3), Liu N(4), Wang J(5), Chen DD(6), Sun WJ(7),
Zhang W(8).
Author information:
(1)Nursing school, Jilin University, Changchun, Jilin province, 130021, China.
Electronic address: 694532381@qq.com.
(2)Department of Developmental Pediatrics, the Second Hospital of Jilin
University, Changchun, Jilin province, 130041, China. Electronic address:
l-ping@jlu.edu.cn.
Electronic address: hlzhangw99@163.com.
BACKGROUND AND PURPOSE: Vasomotor symptoms (VMS) are very common in menopausal
populations and cancer patients and can cause physical and mental discomfort. We
aim to summarize the findings of systematic reviews and meta-analyses (SRs/MAs)
that assessed the effectiveness of complementary and alternative
medicines(CAMs)on VMS to provide solid evidence for future practice.
METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched
from inception to May 2019 to identify relevant SRs/MAs. The methodological
quality of SRs/MAs and evidence levels of the outcomes were assessed.
RESULTS: A total of 29 SRs/MAs were reviewed. Evidence has shown that
acupuncture, hypnosis, paced respiration, cognitive behavioural therapy,
genistein, soy isoflavones, S-equol, combined preparations of black cohosh, and
omega-3 supplements could significantly reduce VMS. The methodological quality
of the SRs/MAs was moderate or high.
CONCLUSION: CAMs might be beneficial for reducing VMS, but the evidence levels
were not high. Several priorities for future practice were identified.
DOI: 10.1016/j.ctcp.2019.07.007
221. Phytother Res. 2019 Sep;33(9):2221-2243. doi: 10.1002/ptr.6419. Epub 2019 Jul
29.
Polyphenols: A concise overview on the chemistry, occurrence, and human health.
Durazzo A(1), Lucarini M(1), Souto EB(2)(3), Cicala C(4), Caiazzo E(4), Izzo
AA(4), Novellino E(4), Santini A(4).
Author information:
(1)CREA - Research Centre for Food and Nutrition, Rome, Italy.
(2)Faculty of Pharmacy of University of Coimbra Azinhaga de Santa Comba,
Coimbra, Portugal.
(3)CEB-Centre of Biological Engineering, University of Minho, Braga, Portugal.
(4)Department of Pharmacy, University of Napoli Federico II, Napoli, Italy.
This review gives an updated picture of each class of phenolic compounds and
their properties. The most common classification implies the subdivision of
phenolics in two main groups: flavonoids (e.g., anthocyanins, flavanols,
flavanones, flavonols, flavonones, and isoflavones) and non-flavonoids (e.g.,
phenolic acids, xanthones, stilbens, lignans, and tannins) polyphenols. The
great interest in polyphenols is associated with their high potential
application for food preservation and for therapeutic beneficial use. The
relationship between polyphenol intake and human health has been exploited with
special reference to cardiovascular diseases, hypertension, diabetes, metabolic
syndrome, obesity, and cancer. The use of current existing databases of
bioactive compounds including polyphenols is described as key tools for human
health research.
© 2019 John Wiley & Sons, Ltd.
DOI: 10.1002/ptr.6419
222. Genes (Basel). 2019 Jul 26;10(8):566. doi: 10.3390/genes10080566.
Rodent Models Assessing Mammary Tumor Prevention by Soy or Soy Isoflavones.
Moorehead RA(1).
Author information:
(1)Department of Biomedical Sciences, Ontario Veterinary College, University of
Guelph, Guelph, ON N1G2W1, Canada. rmoorehe@uoguelph.ca.
While epidemiological studies performed in Asian countries generally show that

high levels of dietary soy are associated with reduced breast cancer risk,
studies in Western countries have typically failed to show this correlation. In
an attempt to model the preventative actions of soy on mammary tumor
development, rodent models have been employed. Thirty-four studies were
identified that evaluated the impact of soy products or purified soy isoflavones
on mammary tumor initiation (studies evaluating established mammary tumors or
mammary tumor cell lines were not included) and these studies were separated
into mammary tumors induced by chemical carcinogens or transgenic expression of
oncogenes based on the timing of soy administration. Regardless of when
soy-based diets or purified isoflavones were administered, no consistent
protective effects were observed in either carcinogen-induced or
oncogene-induced mammary tumors. While some studies demonstrated that soy or
purified isoflavones could reduce mammary tumor incidence, other studies showed
either no effect or tumor promoting effects of soy products or isoflavones. Most
importantly, only five studies found a decrease in mammary tumor incidence and
six studies observed a decrease in tumor multiplicity, two relevant measures of
the tumor preventative effects of soy or isoflavones. The variable outcomes of
the studies examined were not completely surprising given that few studies
employed the same experimental design. Future studies should be carefully
designed to more accurately emulate soy consumption observed in Asian cultures
including lifetime exposure to less refined soy products and potentially the
incorporation of multigenerational feeding studies.
DOI: 10.3390/genes10080566
PMCID: PMC6722900
223. J Adv Res. 2019 Jun 21;20:117-127. doi: 10.1016/j.jare.2019.06.002.

eCollection
2019 Nov.
Flavonoids from the stems of Millettia pachyloba Drake mediate cytotoxic

activity through apoptosis and autophagy in cancer cells.
Yan W(1), Yang J(1), Tang H(1), Xue L(1), Chen K(2), Wang L(2), Zhao M(1), Tang
M(1), Peng A(1), Long C(3), Chen X(3), Ye H(1), Chen L(1).
Author information:
(1)Lab of Natural Product Drugs and Cancer Biotherapy, West China Hospital, West
China Medical School, Sichuan University, Chengdu 610041, People's Republic of
China.
(2)School of Chemical Engineering, Sichuan University, Chengdu 610041, People's
Republic of China.
(3)Guangdong Zhongsheng Pharmaceutical Co Ltd., Dongguan 440100, People's
Republic of China.
In this study, systematic separation and subsequent pharmacological activity
studies were carried out to identify cytotoxic natural products from the dried
stems of Millettia pachyloba Drake. Five previously undescribed isoflavones,
pachyvones A-E; one previously undescribed xanthone, pachythone A; and
twenty-two known compounds were obtained. The structures of these compounds were
assigned on the basis of 1D/2D NMR data and high-resolution electrospray
ionization mass spectroscopy analysis. Preliminary activity screening with HeLa
and MCF-7 cells showed that ten compounds (3-5, 9, 12, 17-19, 24, and 25) had
potential cytotoxicity. Further in-depth activity studies with five cancer cell
lines (HeLa, HepG2, MCF-7, Hct116, and MDA-MB-231) and one normal cell line
(HUVEC) revealed that these ten compounds showed specific cytotoxicity in cancer
cells, with IC50 values ranging from 5 to 40 μM, while they had no effect on
normal cell lines. To investigate whether the cytotoxicity of these ten
compounds was associated with autophagy, their autophagic effects were evaluated
in GFP-LC3-HeLa cells. The results demonstrated that compound 9 (durmillone)
significantly induced autophagy in a concentration-dependent manner and had the
best activity as an autophagy inducer among all of the compounds. Therefore,
compound 9 was selected for further study. The PI/Annexin V double staining
assay and Western blotting results revealed that compound 9 also induced obvious
apoptosis in HeLa and MCF-7 cells, which suggests that it mediates cytotoxic
activity through activation of both apoptosis and autophagy. Taken together,
this study identified ten natural cytotoxic products from the dried stems of
Millettia pachyloba Drake, of which compound 9 induced apoptosis and autophagy
and could be an anticancer drug candidate.
DOI: 10.1016/j.jare.2019.06.002
PMCID: PMC6626068
PMID: 31338224
224. Nutrients. 2019 Jul 20;11(7):1660. doi: 10.3390/nu11071660.
Biological Effect of Soy Isoflavones in the Prevention of Civilization Diseases.
Pabich M(1), Materska M(2).
Author information:
(1)Department of Chemistry, Faculty of Food Science and Biotechnology,
University of Life Sciences in Lublin, Akademicka 15 Street, 20-950 Lublin,
Poland. marzena.pabich@up.lublin.pl.
(2)Department of Chemistry, Faculty of Food Science and Biotechnology,
University of Life Sciences in Lublin, Akademicka 15 Street, 20-950 Lublin,
Poland.
Scientific advancements in recent years have shed new light on the relationship
between diet and human health. Nutrients play an important role in the
prevention of many civilization diseases, such as osteoporosis, type II
diabetes, hypercholesterolemia, and cardiovascular diseases. The biological
activity of natural plant components allows their use in the treatment of
various diseases, especially civilization diseases, to be speculated. Special
attention is paid to phenolic compounds that have numerous health-promoting
properties. Isoflavones, phenolic compounds, are commonly found in legumes,
especially in soybeans. Their structural similarity to 17-β-estradiol (E2), the
main female sex hormone, allows them to induce estrogenic and antiestrogenic
effects by binding to estrogen receptors, and their consumption has been
associated with a decreased risk of hormone-related cancers. In addition,
numerous epidemiological studies and related meta-analyses suggest that soy
consumption may be associated with a lower incidence of certain diseases.
However, there are some doubts about the potential effects on health, such as
the effectiveness of cardiovascular risk reduction or breast cancer-promoting
properties. The purpose of this review is to present the current knowledge on
the potential effects of soy isoflavone consumption with regard to civilization
diseases.
DOI: 10.3390/nu11071660
PMCID: PMC6683102
225. J Acad Nutr Diet. 2019 Sep;119(9):1483-1500.e17. doi:

10.1016/j.jand.2019.04.011. Epub 2019 Jul 2.
Soy, Soy Isoflavones, and Protein Intake in Relation to Mortality from All
Causes, Cancers, and Cardiovascular Diseases: A Systematic Review and
Dose-Response Meta-Analysis of Prospective Cohort Studies.
Nachvak SM, Moradi S, Anjom-Shoae J, Rahmani J, Nasiri M, Maleki V, Sadeghi O.
OBJECTIVE: We conducted a systematic review and dose-response meta-analysis of

prospective studies to summarize findings on the associations between intakes of
soy, soy isoflavones, and soy protein and risk of mortality from all causes,
cancers, and cardiovascular diseases.
METHODS: Online databases were systematically searched to identify relevant
articles published earlier than May 2018. We applied restricted cubic splines
using random-effects analysis to assess dose-response associations.
Between-study heterogeneity was assessed by I2 value and Cochrane Q test.
Potential publication bias was assessed by visual inspection of funnel plots and
Begg regression test.
RESULTS: In total, 23 prospective studies with an overall sample size of 330,826
participants were included in the current systematic review and the
meta-analysis. Soy/soy products consumption was inversely associated with deaths
from cancers (pooled relative risk 0.88, 95% CI 0.79 to 0.99; P=0.03; I2=47.1%,
95% CI 0.0% to 75.4%) and cardiovascular diseases (pooled effect size: 0.85, 95%
CI 0.72 to 0.99; P=0.04; I2=50.0%, 95% CI 0.0% to 77.6%). Such significant
associations were also observed for all-cause mortality in some subgroups of the
included studies, particularly those with higher quality. In addition, higher
intake of soy was associated with decreased risk of mortality from gastric,
colorectal, and lung cancers as well as ischemic cardiovascular diseases.
Participants in the highest category of dietary soy isoflavones intake had a 10%
lower risk of all-cause mortality compared with those in the lowest category. We
also found that a 10-mg/day increase in intake of soy isoflavones was associated
with 7% and 9% decreased risk of mortality from all cancers and also breast
cancer respectively. Furthermore, a 12% reduction in breast cancer death was
indicated for each 5-g/day increase in consumption of soy protein. However,
intake of soy protein was not significantly associated with all-cause and
cardiovascular diseases mortality.
CONCLUSIONS: Soy and its isoflavones may favorably influence risk of mortality.
In addition, soy protein intake was associated with a decreased risk in the
mortality of breast cancer. Our findings may support the current recommendations
to increase intake of soy for greater longevity.
Copyright © 2019 Academy of Nutrition and Dietetics. Published by Elsevier Inc.

All rights reserved.
DOI: 10.1016/j.jand.2019.04.011
226. Cancer Chemother Pharmacol. 2019 Sep;84(3):591-598. doi:

10.1007/s00280-019-03886-3. Epub 2019 Jun 15.
Genistein combined with FOLFOX or FOLFOX-Bevacizumab for the treatment of

metastatic colorectal cancer: phase I/II pilot study.
Pintova S(1)(2), Dharmupari S(3), Moshier E(4), Zubizarreta N(4), Ang C(3),
Holcombe RF(3)(5).
Author information:
(1)Division of Hematology and Medical Oncology, Department of Medicine, Icahn
School of Medicine At Mount Sinai, New York, NY, USA.
sofya.pintova@mountsinai.org.
(2)Mount Sinai Hospital, One Gustave L Levy Place, Box 1128, New York, NY,
10029, USA. sofya.pintova@mountsinai.org.
(3)Division of Hematology and Medical Oncology, Department of Medicine, Icahn
School of Medicine At Mount Sinai, New York, NY, USA.
(4)Department of Population Health Science and Policy, Institute for Healthcare
Delivery Science, Icahn School of Medicine At Mount Sinai, New York, NY, USA.
(5)University of Hawai'I Cancer Center, Honolulu, HI, USA.
BACKGROUND: Epidemiologic and preclinical data suggest isoflavones have

anticancer activity in colorectal malignancy prevention and treatment. This is
the first clinical trial assessing safety and tolerability of Genistein in
combination with chemotherapy in metastatic colorectal cancer.
METHODS: Patients who had histologically confirmed metastatic colorectal cancer
and had not received previous treatment were eligible to enroll. Subjects were
treated with FOLFOX or FOLFOX-Bevacizumab as per the investigator choice.
Genistein was administered orally for 7 days every 2 weeks, beginning 4 days
prior to chemotherapy and continuing through days 1-3 of infusional
chemotherapy. Primary endpoint was safety and secondary endpoints included cycle
6 response rate, best overall response rate (BOR), and median progression-free
survival (PFS).
RESULTS: Thirteen patients received chemotherapy with Genistein in this trial.
The most common adverse events related to Genistein alone were mild and included
headaches, nausea, and hot flashes. One subject was observed to have grade 3
hypertension. No increase in chemotherapy-related adverse events was observed
when Genistein was added. BOR and median PFS were 61.5% and 11.5 months,
respectively.
CONCLUSION: We observed that adding Genistein to FOLFOX or FOLFOX-Bevacizumab
was safe and tolerable. Efficacy results are notable and warrant verification in
larger clinical trials.
CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov
Identifier: NCT01985763.
DOI: 10.1007/s00280-019-03886-3

10.1080/10408398.2019.1622505. Epub 2019 Jun 4.
Bacterial metabolism as responsible of beneficial effects of phytoestrogens on

human health.
Peirotén Á(1), Bravo D(1), Landete JM(1).

Author information:
(1)Departamento de Tecnología de Alimentos, Instituto Nacional de Investigación
y Tecnología Agraria y Alimentaria (INIA), Madrid, Spain.
Phytoestrogens (PE) are compounds found in plants such as soy (isoflavones),

flax seeds and cereals (lignans) and pomegranates (ellagitannins). PE have shown
estrogenic/antiestrogenic, antioxidant, anti-inflammatory, antineoplastic and
apoptotic activities. The human studies are showing promising although
inconsistent results about the beneficial effects of PE on ameliorating the
menopausal symptoms or reducing the risk of certain cancers, cardiovascular
disease or diabetes. The effects of PE on the organism are mediated by the
intestinal microbiota, which transforms them into bioactive PE such as
genistein, equol, enterolignans and certain urolithins. In this work, we review
the most recent findings about the bacteria able to metabolize PE, together with
the latest studies on the effects of PE on health. In addition, we describe the
possible factors hindering the demonstration of the beneficial effect of PE on
health, evincing the importance of measuring the actual circulating PE in order
to encompass the variability of PE metabolism due to the intestinal microbiota.
With this in mind, we also explore an approach to ensure the access to bioactive
PE.
DOI: 10.1080/10408398.2019.1622505
228. Cancer Causes Control. 2019 Aug;30(8):847-857. doi: 10.1007/s10552-019-01173-

3.
Epub 2019 Jun 1.
Soy and tea intake on cervical cancer risk: the Singapore Chinese Health Study.
Paul P(1), Koh WP(2)(3), Jin A(2), Michel A(4), Waterboer T(4), Pawlita M(4),
Wang R(5), Yuan JM(6)(5), Butler LM(6)(5).
Author information:
(1)Department of Epidemiology, Graduate School of Public Health, University of
Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA. prp25@pitt.edu.
(2)Health Services and Systems Research, Duke-NUS Medical School, Singapore,
Singapore.
(3)Saw Swee Hock School of Public Health, National University of Singapore,
Singapore, Singapore.
(4)Division of Molecular Diagnostics of Oncogenic Infections, German Cancer
Research Center (DKFZ), Heidelberg, Germany.
(5)Cancer Control and Population Sciences, University of Pittsburgh Cancer
Institute, Pittsburgh, PA, USA.
(6)Department of Epidemiology, Graduate School of Public Health, University of
Pittsburgh, 130 De Soto St, Pittsburgh, PA, 15261, USA.
PURPOSE: Soy isoflavones and tea catechins have immunomodulating and

chemopreventive properties relevant for cervical carcinogenesis; however, there
are limited epidemiologic data on the relationship of soy and tea consumption
with cervical cancer risk. The aim of our study was to examine effects of soy
and tea intake on cervical cancer risk among Singapore Chinese women.
METHODS: The association between intake of soy and tea drinking and cervical
cancer risk was investigated in a prospective, population-based cohort of 30,744
Chinese women in Singapore with an average 16.7 years of follow-up and 312
incident cervical cancer cases. Multivariable proportional hazard models were
used to estimate hazard ratio (HR) and 95% confidence interval (CI) of cervical
cancer associated with intake levels of soy and tea.
RESULTS: High intake of soy alone was associated with a statistically borderline
significant 20% reduced risk of cervical cancer (HR 0.80, 95% CI 0.61, 1.05)
while green tea alone was not (HR 0.97, 95% CI: 0.76, 1.22). In stratified
analysis, high intake of soy was associated with a statistically significant
decrease in cervical cancer risk among green tea drinkers (HR 0.43; 95% CI 0.28,
0.69) but not among non-drinkers of green tea. The difference in the
soy-cervical cancer risk association between green tea drinkers and non-drinkers
was statistically significant (p for interaction = 0.004). This inverse
association between soy intake and cervical cancer risk remained after further
adjustment for human papillomavirus serostatus. Black tea consumption was not
associated with cervical cancer risk.
CONCLUSIONS: These findings suggest that a protective effect of soy against
cervical cancer development may depend on green tea constituents.
DOI: 10.1007/s10552-019-01173-3
Is Chickpea a Potential Substitute for Soybean? Phenolic Bioactives and

Potential Health Benefits.
de Camargo AC(1), Favero BT(2), Morzelle MC(3), Franchin M(4), Alvarez-Parrilla

E(5), de la Rosa LA(6), Geraldi MV(7), Maróstica Júnior MR(8), Shahidi F(9),
Schwember AR(10).
Author information:
(1)Departamento de Ciencias Vegetales, Facultad de Agronomía e Ingeniería
Forestal, Pontificia Universidad Católica de Chile, Casilla 306-22, Santiago,
Chile. adrianoesalq@gmail.com.
(2)University of Copenhagen, Department of Plant and Environmental Sciences,
2630 Taastrup, Denmark. btf@plen.ku.dk.
(3)Department of Food and Nutrition, Faculty of Nutrition, Federal University of
Mato Grosso, Fernando Correa Avenue, P.O. box 2367, Cuiabá, MT 78060-900,
Brazil. maressamorzelle@hotmail.com.
(4)Department of Physiological Sciences, Piracicaba Dental School, University of
Campinas, Piracicaba, SP 13414-903, Brazil. marcelo.franchin@yahoo.com.br.
(5)Department of Chemical Biological Sciences, Universidad Autónoma de Ciudad
Juárez, Anillo Envolvente del Pronaf y Estocolmo, s/n, Cd, Juárez, Chihuahua
32310, México. ealvarez@uacj.mx.
(6)Department of Chemical Biological Sciences, Universidad Autónoma de Ciudad
Juárez, Anillo Envolvente del Pronaf y Estocolmo, s/n, Cd, Juárez, Chihuahua
32310, México. ldelaros@uacj.mx.
(7)Department of Food and Nutrition, University of Campinas-UNICAMP, Campinas,
SP 13083-862, Brazil. marinavilar35@gmail.com.
(8)Department of Food and Nutrition, University of Campinas-UNICAMP, Campinas,
SP 13083-862, Brazil. mmarosti@unicamp.br.
(9)Department of Biochemistry, Memorial University of Newfoundland, St. John's,
NL A1B 3X9, Canada. fshahidi@mun.ca.
(10)Departamento de Ciencias Vegetales, Facultad de Agronomía e Ingeniería
Forestal, Pontificia Universidad Católica de Chile, Casilla 306-22, Santiago,
Chile. aschwember@uc.cl.
Legume seeds are rich sources of protein, fiber, and minerals. In addition,
their phenolic compounds as secondary metabolites render health benefits beyond
basic nutrition. Lowering apolipoprotein B secretion from HepG2 cells and
decreasing the level of low-density lipoprotein (LDL)-cholesterol oxidation are
mechanisms related to the prevention of cardiovascular diseases (CVD). Likewise,
low-level chronic inflammation and related disorders of the immune system are
clinical predictors of cardiovascular pathology. Furthermore, DNA-damage
signaling and repair are crucial pathways to the etiology of human cancers.
Along CVD and cancer, the prevalence of obesity and diabetes is constantly
increasing. Screening the ability of polyphenols in inactivating digestive
enzymes is a good option in pre-clinical studies. In addition, in vivo studies
support the role of polyphenols in the prevention and/or management of diabetes
and obesity. Soybean, a well-recognized source of phenolic isoflavones, exerts
health benefits by decreasing oxidative stress and inflammation related to the
above-mentioned chronic ailments. Similar to soybeans, chickpeas are good
sources of nutrients and phenolic compounds, especially isoflavones. This review
summarizes the potential of chickpea as a substitute for soybean in terms of
health beneficial outcomes. Therefore, this contribution may guide the industry
in manufacturing functional foods and/or ingredients by using an undervalued
feedstock.
DOI: 10.3390/ijms20112644
PMCID: PMC6600242
230. Int J Cancer. 2019 Sep 1;145(5):1238-1244. doi: 10.1002/ijc.32431. Epub 2019
Jun
11.
Circulating sex hormone levels and colorectal cancer risk in Japanese

postmenopausal women: The JPHC nested case-control study.
Mori N(1), Sawada N(1), Iwasaki M(1), Yamaji T(1), Goto A(1), Shimazu T(1),
Inoue M(1), Murphy N(2), Gunter MJ(2), Tsugane S(1).
Author information:
(2)Section of Nutrition and Metabolism, International Agency for Research on
Cancer, Lyon, France.
Previous epidemiological studies evaluated endogenous sex hormone levels and

colorectal cancer (CRC) risk have yielded inconsistent results. Also, it is
unknown if consumption of dietary isoflavones may influence the endogenous sex
hormones and CRC relationships. We conducted a nested case-control study within
the JPHC Study Cohort II wherein 11,644 women provided blood samples at the
5-year follow-up survey. We selected two matched controls for each case from the
cohort (185 CRC cases and 361 controls). Multivariable conditional logistic
regression was used to estimate odds ratios (ORs), 95% confidence intervals
(CIs) for the association between circulating sex hormone levels and CRC risk.
Comparing extreme tertiles, circulating testosterone levels were positively
associated with CRC risk (OR = 2.10, 95% CI = 1.11-3.99, p for trend = 0.03).
Levels of estradiol, SHBG, and progesterone were not associated with CRC risk.
In a subgroup analysis by dietary isoflavone intake, SHBG levels were positively
associated with CRC risk among those with low total isoflavone intake (p for
trend = 0.03), with a statistically nonsignificant inverse association among
those with high total isoflavone intake (p for trend = 0.22; p for
interaction = 0.002). Endogenous levels of testosterone were positively
associated with CRC among postmenopausal women. The association of endogenous
SHBG with CRC development may be altered by the level of dietary isoflavone
intake.
© 2019 UICC.
DOI: 10.1002/ijc.32431
231. Ecancermedicalscience. 2019 Mar 11;13:909. doi: 10.3332/ecancer.2019.909.

eCollection 2019.
Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an

update.
Biglia N(1), Bounous VE(1), De Seta F(2), Lello S(3), Nappi RE(4), Paoletti
AM(5).
Author information:
(1)Division of Gynecology and Obstetrics, Department of Surgical Sciences,
School of Medicine, University of Torino, Largo Turati 62, 10128 Torino, Italy.
(2)Institute for Maternal and Child Health-IRCCS 'Burlo Garofolo', University of
Trieste, via dell'Istria 65/1, 34137 Trieste, Italy.
(3)Department of Woman and Child Health, Policlinico Gemelli Foundation, Largo
Gemelli 1, 00168 Rome, Italy.
(4)Research Center for Reproductive Medicine, Gynecological Endocrinology and
Menopause, IRCCS S Matteo Foundation, Department of Clinical, Surgical,
Diagnostic and Paediatric Sciences, University of Pavia, Viale Camillo Golgi 19,
27100 Pavia, Italy.
(5)Department of Obstetrics and Gynecology, Department of Surgical Sciences,
University of Cagliari, University Hospital of Cagliari, SS 554 km 4,500, 09042
Monserrato, Italy.
Vasomotor symptoms, particularly hot flushes (HFs), are the most frequently
reported symptom by menopausal women. In particular, for young women diagnosed
with breast cancer, who experience premature ovarian failure due to cancer
treatments, severe HFs are an unsolved problem that strongly impacts on quality
of life. The optimal management of HFs requires a personalised approach to
identify the treatment with the best benefit/risk profile for each woman.
Hormonal replacement therapy (HRT) is effective in managing HFs but it is
contraindicated in women with previous hormone-dependent cancer. Moreover, many
healthy women are reluctant to take HRT and prefer to manage symptoms with
non-hormonal strategies. In this narrative review, we provide an update on the
current available non-oestrogenic strategies for HFs management for women who
cannot, or do not wish to, take oestrogens. Since isoflavones have oestrogenic
properties and it is not known if they can be safely consumed by women with
previous hormone-dependent cancer, they were excluded. Selective serotonin
reuptake inhibitors/selective serotonin-norepinephrine reuptake inhibitors, as
well as other neuroactive agents, some herbal remedies and behavioural
strategies are considered.
DOI: 10.3332/ecancer.2019.909
PMCID: PMC6445536
PMID: 31123492
Conflict of interest statement: Anna Maria Paoletti, Francesco De Seta and

Stefano Lello declare no conflict of interests. Nicoletta Biglia had a financial
relationship (lecturer, member of advisory boards and/or consultant) with Gedeon
Richter, Shionogi Limited and Italfarmaco. Rossella E Nappi has a financial
relationship (lecturer, member of advisory boards and/or consultant) with Bayer
HealthCare, Endoceutics, Gedeon Richter, HRA Pharma, MSD, Novo Nordisk, Pfizer,
Shionogi and Teva. Valentina E Bounous had a financial relationship with
Italfarmaco S.p.A. (medical writing) and has a financial relationship with
Shionogi (medical writing, tables preparation).
232. EXCLI J. 2019 Feb 19;18:106-126. eCollection 2019.
Prostate cancer metastasis and soy isoflavones: a dogfight over a bone.
Ajdžanovic V(1), Filipovic B(1), Miljic D(2), Mijatovic S(3), Maksimovic-Ivanic

D(3), Miler M(1), Živanovic J(1), Miloševic V(1).
Author information:
(1)Department of Cytology, Institute for Biological Research "Siniša Stankovic",
University of Belgrade, Belgrade, Serbia.
(2)Clinic for Endocrinology, Diabetes and Diseases of Metabolism, Clinical
Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
(3)Department of Immunology, Institute for Biological Research "Siniša
Stankovic", University of Belgrade, Belgrade, Serbia.
Prostate cancer is a complex, progressive, bone-tropic disease, which is usually

associated with skeletal issues, poor mobility and a fatal outcome when it
reaches the metastatic phase. Soy isoflavones, steroid-like compounds from
soy-based food/dietary supplements, have been found to decrease the risk of
prostate cancer in frequent consumers. Herein, we present a systematization of
the data on soy isoflavone effects at different stages of metastatic prostate
cancer progression, with a particular interest in the context of bone-related
molecular events. Specifically, soy isoflavones have been determined to
downregulate the prostate cancer cell androgen receptors, reverse the epithelial
to mesenchymal transition of these cells, decrease the expressions of
prostate-specific antigen, matrix metalloproteinase and serine proteinase, and
reduce the superficial membrane fluidity in prostate cancer cells. In addition,
soy isoflavones suppress the angiogenesis that follows prostate cancer growth,
obstruct prostate cancer cells adhesion to the vascular endothelium and their
extravasation in the area of future bone lesions, improve the general bone
morphofunctional status, have a beneficial effect on prostate cancer
metastasis-caused osteolytic/osteoblastic lesions and possibly affect the
pre-metastatic niche formation. The observed, multilevel antimetastatic
properties of soy isoflavones imply that they should be considered as promising
components of combined therapeutic approaches to advanced prostate cancer.
PMCID: PMC6449674
PMID: 30956643
233. Bioorg Chem. 2019 Jun;87:474-483. doi: 10.1016/j.bioorg.2019.03.034. Epub 2019

Mar 15.
Semi-synthetic isoflavones as BACE-1 inhibitors against Alzheimer's disease.
Ribaudo G(1), Coghi P(2), Zanforlin E(1), Law BYK(2), Wu YYJ(2), Han Y(2), Qiu
AC(2), Qu YQ(2), Zagotto G(3), Wong VKW(4).
Author information:
Padova, Via Marzolo 5, 35131 Padova, Italy.
University of Science and Technology, Avenida Wai Long, Taipa, Macau.
Padova, Via Marzolo 5, 35131 Padova, Italy. Electronic address:
giuseppe.zagotto@unipd.it.
University of Science and Technology, Avenida Wai Long, Taipa, Macau. Electronic
address: bowaiong@gmail.com.
BACE-1 is considered to be one of the targets for prevention and treatment of

Alzheimer's disease (AD). We here report a novel class of semi-synthetic
derivatives of prenylated isoflavones, obtained from the derivatization of
natural flavonoids from Maclura pomifera. In vitro anti-AD effect of the
synthesized compounds were evaluated via human recombinant BACE-1 inhibition
assay. Compound 7, 8 and 13 were found to be the most active candidates which
demonstrates good correlation between the computational docking and
pharmacokinetic predictions. Moreover, cytotoxic studies demonstrated that the
compounds are not toxic against normal and cancer cell lines. Among these three
compounds, compound 7 enhance the activity of P-glycoprotein (P-gp) on A549
cancer cells and increases the activity of P-gp ATPase with a possible role on
the efflux of amyloid-β across the blood- brain barrier. In conclusion, the
present findings may pave the way for the discovery of a novel class of
compounds to prevent and/or treat AD.
DOI: 10.1016/j.bioorg.2019.03.034
234. Cancer Causes Control. 2019 May;30(5):527-535. doi: 10.1007/s10552-019-01158-

2.
Epub 2019 Mar 22.
Flavonoids and bladder cancer risk.
Rossi M(1), Strikoudi P(2), Spei ME(3), Parpinel M(4), Serraino D(5), Montella
M(6), Libra M(7), La Vecchia C(1), Rosato V(8).
Author information:
(1)Department of Clinical Sciences and Community Health, Università degli Studi
di Milano, Via A. Vanzetti 5, 20133, Milan, Italy.
(2)Department of Nutrition and Dietetics, Faculty of Agriculture Technology,
Food Technology and Nutrition, Alexander Technological Educational Institution
of Thessaloniki, P.C. 57400, Sindos, Thessaloniki, Greece.
(3)Department of Hygiene, Epidemiology, and Medical Statistics, School of
Medicine, National and Kapodistrian University of Athens, 75 M. Asias Street,
115 27, Goudi, Athens, Greece.
(4)Department of Medicine, Università degli Studi di Udine, Via Colugna 50,
33100, Udine, Italy.
(5)Cancer Epidemiology Unit, Istituto di Ricovero e Cura a Carattere Scientifico
(IRCCS) Centro di Riferimento Oncologico, Via F. Gallini 2, 33081, Aviano (PN),
Italy.
(6)Unit of Epidemiology, Istituto Nazionale Tumori Fondazione G. Pascale, Via M.
Semmola 1, 80131, Napoli, Italy.
(7)Section of Oncologic, Clinic and General Pathology, Department of Biomedical
& Biotechnological Sciences, Università degli Studi di Catania, Via Santa Sofia
97, 95123, Catania, Italy.
(8)Unit of Medical Statistics and Biometry, Fondazione IRCCS Istituto Nazionale
dei Tumori di Milano, Via G. Venezian 1, 20133, Milano, Italy.
Valentina.Rosato@istitutotumori.mi.it.
PURPOSE: Flavonoids have drawn attention because of their antioxidant capacity
and anti-carcinogenic effect in various types of cancer. A limited number of
studies has investigated their potential effect on the risk of bladder cancer,
with inconsistent results.
METHODS: We analyzed data from an Italian case-control study including 690
incident bladder cancer cases and 665 controls admitted to the same network of
hospitals for acute, non-neoplastic, non tobacco-related diseases. Subjects were
interviewed using a reproducible and validated food-frequency questionnaire. We
applied data on food and beverage composition to estimate the intake of
isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones and flavonols.
We estimated odds ratios (ORs) through multiple logistic regression models,
including terms for potential confounding factors, including tobacco smoking and
total energy intake.
RESULTS: We found an inverse association between isoflavones (OR for the highest
compared to the lowest quintile of intake = 0.56, 95% CI 0.37-0.84) and flavones
(OR = 0.64, 95% CI 0.44-0.95) and bladder cancer. Non-significant inverse
association was found for flavan-3-ols (OR = 0.70), flavonols (OR = 0.85) and
total flavonoids (OR = 0.76). The results were consistent for
non-muscle-invasive and muscle-invasive bladder cancers.
CONCLUSIONS: Our data indicate an inverse association between isoflavones and
flavones with respect to bladder cancer risk.
DOI: 10.1007/s10552-019-01158-2
235. Integr Cancer Ther. 2019 Jan-Dec;18:1534735419835310. doi:

10.1177/1534735419835310.
Soy Isoflavones in Integrative Oncology: Increased Efficacy and Decreased

Toxicity of Cancer Therapy.
Sahin I(1), Bilir B(2)(3), Ali S(4), Sahin K(5), Kucuk O(2)(3).
Author information:
(1)1 The Warren Alpert Medical School of Brown University, Providence, RI, USA.
(2)2 Emory University School of Medicine, Atlanta, GA, USA.
(3)3 Emory University, Atlanta, GA, USA.
(4)4 Jamia Hamdard, New Delhi, India.
(5)5 Firat University, Elazig, Turkey.
Soy consumption in human diet has been linked to decreased incidence of a

variety of cancers, suggesting a potential role of soy products in cancer
prevention and control. Furthermore, a substantial body of evidence in the
literature suggests that soy supplementation may improve the efficacy and
prevent the adverse effects of cancer chemotherapy and radiation therapy.
Isoflavones constitute the predominant anticancer bioactive compounds in soy.
Genistein, which is the most abundant and active isoflavone in soy, has a
multitude of effects on cancer cells, including inhibition of NF-κB activation
and DNA methylation, enhancement of histone acetylation, inhibition of cell
growth and metastasis, and antiangiogenic, anti-inflammatory, and anti-oxidant
effects. Isoflavones are orally bioavailable, easily metabolized, and usually
considered safe. In this article, we review in vitro and in vivo evidence as
well as the results of clinical and epidemiological studies on the effects of
soy isoflavones, with a focus on sensitization of cancer cells to chemotherapy
and radiation while at the same time protecting normal cells from the harmful
effects of these treatments.
DOI: 10.1177/1534735419835310
PMCID: PMC6431760
Conflict of interest statement: Declaration of Conflicting Interests: The

author(s) declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this article.
Isoflavones.
Křížová L(1), Dadáková K(2), Kašparovská J(3), Kašparovský T(4).
Author information:
(1)Department of Biochemistry, Faculty of Science, Masaryk University, Kotlarska
2, 61137 Brno, Czech Republic. Ludmila.S@seznam.cz.
2, 61137 Brno, Czech Republic. 147047@mail.muni.cz.
2, 61137 Brno, Czech Republic. 20829@muni.cz.
2, 61137 Brno, Czech Republic. tkasp@sci.muni.cz.
Phytoestrogens are naturally occurring nonsteroidal phenolic plant compounds

that, due to their molecular structure and size, resemble vertebrate steroids
estrogens. This review is focused on plant flavonoids isoflavones, which are
ranked among the most estrogenic compounds. The main dietary sources of
isoflavones for humans are soybean and soybean products, which contain mainly
daidzein and genistein. When they are consumed, they exert estrogenic and/or
antiestrogenic effects. Isoflavones are considered chemoprotective and can be
used as an alternative therapy for a wide range of hormonal disorders, including
several cancer types, namely breast cancer and prostate cancer, cardiovascular
diseases, osteoporosis, or menopausal symptoms. On the other hand, isoflavones
may also be considered endocrine disruptors with possible negative influences on
the state of health in a certain part of the population or on the environment.
This review deals with isoflavone classification, structure, and occurrence,
with their metabolism, biological, and health effects in humans and animals, and
with their utilization and potential risks.
PMCID: PMC6470817
237. Adv Cancer Res. 2019;142:187-207. doi: 10.1016/bs.acr.2019.01.005. Epub 2019

Mar
6.
Pharmacology of ME-344, a novel cytotoxic isoflavone.
Zhang L(1), Zhang J(1), Ye Z(1), Townsend DM(2), Tew KD(3).
Author information:
(1)Department of Cell and Molecular Pharmacology and Experimental Therapeutics,
Medical University of South Carolina, Charleston, SC, United States.
(2)Drug Discovery and Biomedical Sciences, Medical University of South Carolina,
Charleston, SC, United States.
(3)Department of Cell and Molecular Pharmacology and Experimental Therapeutics,
Medical University of South Carolina, Charleston, SC, United States. Electronic
address: tewk@musc.edu.
Isoflavones isolated from members of the Fabaceae (primarily Leguminosae) family

have been characterized for their phytoestrogenic properties, but certain
derivatives have also shown potential as possible cancer therapeutic agents.
ME-344, related to phenoxodiol (Fig. 1), is a second generation isoflavone with
a recent history of both preclinical and early clinical testing. The drug has
unusual cytotoxicity profiles, where cancer cell lines can be categorized as
either intrinsically sensitive or resistant to the drug. Evolving studies show
that the cytotoxic properties of the drug are enacted through targeting
mitochondrial bioenergetics. While the drug has undergone early Phase I/II
trials in solid tumors with confined dose limiting effects and some evidence of
disease response, there is a continuing need to define specific cellular targets
that determine sensitivity, with the long-term goal of applying such information
to individualized therapy. This review article details some of the existing and
ongoing studies that are assisting in the continued drug development processes
that may lead to new drug application (NDA) status.
© 2019 Elsevier Inc. All rights reserved.
DOI: 10.1016/bs.acr.2019.01.005
PMCID: PMC7432957
Conflict of interest statement: Conflict of Interest KDT has been the recipient
of research support from MEI Pharma.
238. Phytomedicine. 2019 May;58:152853. doi: 10.1016/j.phymed.2019.152853. Epub

2019
Jan 30.
Cytotoxicity of isoflavones and biflavonoids from Ormocarpum kirkii towards

multi-factorial drug resistant cancer.
Adem FA(1), Mbaveng AT(2), Kuete V(3), Heydenreich M(4), Ndakala A(5), Irungu
B(6), Yenesew A(7), Efferth T(8).
Author information:
(1)Department of Chemistry, University of Nairobi, P.O. Box 30197-00100,
Nairobi, Kenya; Department of Pharmaceutical Biology, Institute of Pharmacy and
Biochemistry, Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz,
Germany. Electronic address: fozuti@yahoo.com.
(2)Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry,
Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany;
Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon.
Electronic address: armbatsa@yahoo.fr.
Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany;
Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon.
Electronic address: kuetevictor@yahoo.fr.
(4)Institute of Chemistry, University of Potsdam, P.O. Box 60 15 53, D-14415
Potsdam, Germany. Electronic address: mheydenr@uni-potsdam.de.
Nairobi, Kenya. Electronic address: andakala@uonbi.ac.ke.
(6)Centre for Traditional Medicine and Drug Research, Kenya Medical Research
Institute, P.O. Box 54840-00200, Nairobi, Kenya. Electronic address:
birungu18@gmail.com.
Nairobi, Kenya. Electronic address: ayenesew@uonbi.ac.ke.
Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany.
Electronic address: efferth@uni-mainz.de.
BACKGROUND: While incidences of cancer are continuously increasing, drug

resistance of malignant cells is observed towards almost all pharmaceuticals.
Several isoflavonoids and flavonoids are known for their cytotoxicity towards
various cancer cells.
PURPOSE: The aim of this study was to determine the cytotoxicity of isoflavones:
osajin (1), 5,7-dihydroxy-4'-methoxy-6,8-diprenylisoflavone (2) and
biflavonoids: chamaejasmin (3), 7,7″-di-O-methylchamaejasmin (4) and
campylospermone A (5), a dimeric chromene [diphysin(6)] and an ester of ferullic
acid with long alkyl chain [erythrinasinate (7)] isolated from the stem bark and
roots of the Kenyan medicinal plant, Ormocarpum kirkii. The mode of action of
compounds 2 and 4 was further investigated.
METHODS: The cytotoxicity of compounds was determined based on the resazurin
reduction assay. Caspases activation was evaluated using the caspase-Glo assay.
Flow cytometry was used to analyze the cell cycle (propodium iodide (PI)
staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential
(MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). CCRF-CEM leukemia
cells were used as model cells for mechanistic studies.
RESULTS: Compounds 1, 2 and 4 displayed IC50 values below 20 µM towards CCRF-CEM
and CEM/ADR5000 leukemia cells, and were further tested towards a panel of 7
carcinoma cells. The IC50 values of the compounds against carcinoma cells varied
from 16.90 µM (in resistant U87MG.ΔEGFR glioblastoma cells) to 48.67 µM (against
HepG2 hepatocarcinoma cells) for 1, from 7.85 µM (in U87MG.ΔEGFR cells) to
14.44 µM (in resistant MDA-MB231/BCRP breast adenocarcinoma cells) for 2, from
4.96 µM (towards U87MG.ΔEGFRcells) to 7.76 µM (against MDA-MB231/BCRP cells) for
4, and from 0.07 µM (against MDA-MB231 cells) to 2.15 µM (against HepG2 cells)
for doxorubicin. Compounds 2 and 4 induced apoptosis in CCRF-CEM cells mediated
by MMP alteration and increased ROS production.
CONCLUSION: The present report indicates that isoflavones and biflavonoids from
Ormocarpum kirkii are cytotoxic compounds with the potential of being exploited
in cancer chemotherapy. Compounds 2 and 4 deserve further studies to develop new
anticancer drugs to fight sensitive and resistant cancer cell lines.
Copyright © 2019 Elsevier GmbH. All rights reserved.
DOI: 10.1016/j.phymed.2019.152853
239. Am J Clin Nutr. 2019 Mar 1;109(3):597-605. doi: 10.1093/ajcn/nqy313.
Use of dietary supplements containing soy isoflavones and breast cancer risk
among women aged >50 y: a prospective study.
Touillaud M(1)(2), Gelot A(3)(4)(5), Mesrine S(3)(4)(5), Bennetau-Pelissero

C(6), Clavel-Chapelon F(3)(4)(5), Arveux P(3)(4)(5)(7), Bonnet F(3)(4)(5)(8),
Gunter M(9), Boutron-Ruault MC(3)(4)(5), Fournier A(3)(4)(5).
Author information:
(1)Léon Bérard Cancer Center, UNICANCER, Lyon, France.
(2)Cancer Research Centre of Lyon, French Institute of Health and Medical
Research (INSERM) 1052, French National Centre for Scientific Research (CNRS)
5286, Lyon, France.
(3)Center for Research in Epidemiology and Population Health (CESP), "Health
across Generations" team, INSERM U1018, Villejuif, France.
(4)CESP, University of Paris-Saclay, Villejuif, France.
(5)Gustave Roussy, Villejuif, France, Neurocentre Magendie, Bordeaux, France.
(6)University of Bordeaux, Physiopathologie de la plasticité neuronale, INSERM
U1215, Neurocentre Magendie, Bordeaux, France.
(7)Breast and Gynaecologic Cancer Registry of Cote d'Or, Georges-Francois
Leclerc Cancer Centre, UNICANCER, Dijon, France.
(8)Centre Hospitalier Universitaire (CHU) de Rennes, University of Rennes 1,
Department of Endocrinology, Diabetology and Nutrition, Rennes, France.
(9)International Agency for Research on Cancer, Section of Nutrition and
Metabolism, Lyon, France.
BACKGROUND: Soy-based dietary supplements have been promoted as natural

alternatives to menopausal hormone therapy, but their potential effect on breast
cancer development is controversial.
OBJECTIVES: We examined the relation between the consumption of soy supplements
and the risk of breast cancer, overall and by tumor hormone receptor status,
among women aged >50 y.
METHODS: In total, 76,442 women from the Etude Epidemiologique aupres de Femmes
de la Mutuelle Generale de l'Education Nationale (E3N) cohort, born between 1925
and 1950, were followed from 2000 to 2011 (11.2 y on average, starting at a mean
age of 59.5 y; 3608 incident breast cancers), with soy supplement use assessed
every 2-3 y. HRs of breast cancer were estimated with the use of multivariable
Cox models.
RESULTS: Compared with never using soy supplements, the HRs associated with
current use of soy supplements were 0.92 (95% CI: 0.76, 1.11) for all, 0.78 (95%
CI: 0.60, 0.99) for estrogen receptor (ER)-positive, and 2.01 (95% CI: 1.41,
2.86) for ER-negative breast cancers. There was no association between past use
of soy supplements and breast cancer. HRs for current use were 1.36 (95% CI:
0.95, 1.93) and 0.82 (95% CI: 0.65, 1.02) among women with and without a family
history of breast cancer, respectively (P-interaction = 0.03) and 1.06 (95% CI:
0.87, 1.30) ≥5 y after menopause compared with 0.50 (95% CI: 0.31, 0.81) in
premenopause or ≤5 y postmenopause (P-interaction = 0.04).
CONCLUSIONS: In this cohort of women aged >50 y, we report opposing associations
of soy supplements with ER-positive and ER-negative breast cancer risk. Our
results also caution against the use of these supplements in women with a family
history of breast cancer. Whether the risk profile of soy supplements could be
more favorable among premenopausal or recently postmenopausal women deserves
further investigation.
© 2019 American Society for Nutrition.
DOI: 10.1093/ajcn/nqy313
240. Curr Pharm Des. 2018;24(46):5555-5579. doi: 10.2174/1381612825666190222142537.
Potent Cytotoxic Natural Flavonoids: The Limits of Perspective.
Taleghani A(1), Tayarani-Najaran Z(2)(3).
Author information:
(1)Department of Chemistry, Faculty of Science, Gonbad Kavous University,
Golestan Province, Gonbad Kavus, P.O. Box 163, Iran.
(2)Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad
(3)Medical Toxicology Research Center, Mashhad University of Medical Sciences,
Mashhad, Iran.
BACKGROUND: Besides the numerous biologic and pharmacologic functions in the

human body that act as potent antioxidants, flavonoids (flavones, flavanones,
flavonols, flavanols and isoflavones) are noted as cancer preventive or
therapeutic agents.
METHODS: This review summarizes the published data using PubMed, Science Direct,
and Scopus.
RESULTS: In this context, recognition and introduction of the most active
cytotoxic flavonoids as promising agents for cancer therapy gives insight for
further evaluations. However, there are some critical points that may affect the
entering of flavonoids as active cytotoxic phytochemicals in the clinical phase.
Issues such as the abundance of active species in nature, the methods of
extraction and purification, solubility, pharmacokinetic profile, presence of
the chiral moieties, method of synthesis, and structure modification may limit
the entry of a selected compound for use in humans. Although plenty of basic
evidence exists for cytotoxic/antitumor activity of the versatility of
flavonoids for entry into clinical trials, the above-mentioned concerns must be
considered.
CONCLUSION: This review is an effort to introduce cytotoxic natural flavonoids
(IC50< 10 µM) that may have the potential to be used against various tumor
cells. Also, active constituents, molecular mechanisms, and related clinical
trials have been discussed as well as the limitations and challenges of using
flavonoids in clinic.

DOI: 10.2174/1381612825666190222142537
241. J BUON. 2018 Dec;23(7):53-59.
Influence of soy isoflavones in breast cancer angiogenesis: a multiplex glass

ELISA approach.
Uifalean A(1), Rath H, Hammer E, Ionescu C, Iuga CA, Lalk M.
Author information:
University of Medicine and Pharmacy, Cluj-Napoca, Romania.
PURPOSE: The aim of this study was to evaluate the anti-angiogenic properties of
soy isoflavones using two breast cancer cell lines, by measuring the
concentration of 30 cytokines involved in angiogenesis using a multiplex glass
slide ELISA-based array.
METHODS: Estrogen-dependent MCF-7 cells and estrogen-independent MDA-MB-231
cells were exposed to genistein (Gen), daidzein (Dai) and a soy seed extract
(Ext) for 72 hrs, at selected concentration levels. The conditioned medium was
analyzed using a glass slide, multiplex sandwich ELISA-based platform with
fluorescent detection which allowed the identification and the quantification of
30 angiogenesis-related cytokines.
RESULTS: In MCF-7 cells, low, stimulatory concentrations of test compounds
determined the increase of CXCL16 and VEGF-A level. Gen induced the greatest
effect, with 1.5-fold change compared to control. When MDA-MB-231 cells were
exposed to inhibitory concentrations, all test compounds determined a reduction
of CXCL16 and VEGF-A level with approximately 30%.
CONCLUSIONS: Soluble CXCL16 and VEGF-A are two promoters of angiogenesis and
metastasis in breast cancer. The stimulation of these two angiogenesis-related
cytokines could represent one of the mechanisms explaining the proliferative
effects of low isoflavone doses in estrogen-dependent cells. In
estrogen-independent cells, soy isoflavones inhibited their secretion,
demonstrating promising anti-angiogenic properties.
242. Mol Clin Oncol. 2019 Feb;10(2):191-204. doi: 10.3892/mco.2018.1792. Epub 2018
Dec 11.
Androgen receptor and soy isoflavones in prostate cancer.
Sivoňová MK(1), Kaplán P(1)(2), Tatarková Z(1), Lichardusová L(2), Dušenka R(3),
Jurečeková J(2).
Author information:
(1)Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin,
Comenius University in Bratislava, 03601 Martin, Slovakia.
(2)Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius
University in Bratislava, 03601 Martin, Slovakia.
(3)Department of Urology, Jessenius Faculty of Medicine and UHM in Martin,
Comenius University in Bratislava, 03601 Martin, Slovakia.
Androgens and androgen receptor (AR) play a critical role not only in normal
prostate development, but also in prostate cancer. For that reason, androgen
deprivation therapy (ADT) is the primary treatment for prostate cancer. However,
the majority of patients develop castration-resistant prostate cancer, which
eventually leads to mortality. Novel therapeutic approaches, including dietary
changes, have been explored. Soy isoflavones have become a focus of interest
because of their positive health benefits on numerous diseases, particularly
hormone-related cancers, including prostate and breast cancers. An important
strategy for the prevention and/or treatment of prostate cancer might thus be
the action of soy isoflavones on the AR signaling pathway. The current review
article provides a detailed overview of the anticancer potential of soy
isoflavones (genistein, daidzein and glycitein), as mediated by their effect on
AR.
DOI: 10.3892/mco.2018.1792
PMCID: PMC6327222
PMID: 30680195
243. Front Oncol. 2018 Dec 21;8:644. doi: 10.3389/fonc.2018.00644. eCollection

2018.
Cancer Chemoprevention: Classic and Epigenetic Mechanisms Inhibiting

Tumorigenesis. What Have We Learned So Far?
de Melo FHM(1), Oliveira JS(1), Sartorelli VOB(1), Montor WR(1).
Author information:
(1)Department of Physiological Sciences, Santa Casa de São Paulo School of
Medical Sciences (FCMSCSP), São Paulo, Brazil.
Cancers derive from step by step processes which are differentiated by the
progressively accumulated mutations. For some tumors there is a clear
progressive advancement from benign lesions to malignancy and for these,
preventive screening programs exist. In such cases having those benign lesions
are a clear indicator of predisposition while for some other cases, familial
patterns of cancer incidence and the identification of mutations are the main
indicators of higher risk for having the disease. For patients identified as
having predisposition, chemoprevention is a goal and in some cases a
possibility. Chemoprevention is the use of any compound, either natural or
synthetic that abrogates carcinogenesis or tumor progression, through different
mechanisms, some of which have already been described. For example, the classic
mechanisms may involve activation of free radical scavenging enzymes, control of
chronic inflammation, and downregulation of specific signaling pathways. More
recently, epigenetics allowed further understanding of the chemopreventive
potential of several agents, such as sulforaphane, green tea derived compounds,
resveratrol, isoflavones, and others which we exploit in this review article.
Throughout the text we discuss the properties compounds should have in order to
be classified as chemopreventive ones and the challenges in translational
research in this area, as lots of the success achieved in vitro cannot be
translated into the clinical settings, due to several different drawbacks, which
include toxicity, cost, dose definition, patient adherence, and regimen of use.
DOI: 10.3389/fonc.2018.00644
PMCID: PMC6309127
PMID: 30627525

10.1080/10408398.2018.1541866.
Epub 2018 Dec 22.
Bioactive compounds from Cudrania tricuspidata: A natural anticancer source.
Li X(1), Yao Z(1), Jiang X(1), Sun J(2), Ran G(1), Yang X(1), Zhao Y(1), Yan
Y(1), Chen Z(3), Tian L(1), Bai W(1).
Author information:
(1)Department of Food Science and Engineering, Institute of Food Safety and
Nutrition, Guangdong Engineering Technology Center of Food Safety Molecular
Rapid Detection, Jinan University, Guangzhou, PR China.
(2)>Department of Food Science and Engineering, Faculty of Chemical Engineering
and Light Industry, Guangdong University of Technology, Guangzhou, PR China.
(3)Department of Respiratory Medicine, The Sixth Affiliated Hospital of
Guangzhou Medical University, Qingyuan, PR China.
The tumor is becoming a critical threat to our lives in these years. Searching
for antitumor substances from natural products is a great interest of
scientists. Cudrania tricuspidata (C. tricuspidata) is a regional plant
containing 158 flavonoids and 99 xanthones, and others ingredients with
favorable bioactivity. This review comprehensively analyzes the antitumor
compounds from C. tricuspidata against different tumors, and 78 flavonoids plus
xanthones are considered as underlying antineoplastic. Importantly, the
structure of preylation groups is the primary source of antitumor activity among
45 flavonoids plus xanthones, which could be a direction of structural
modification for a better antitumor ability. Additionally, the fruits are also
preferable sources of antitumor compounds compared to the roots and barks due to
the abundant isoflavones and sustainability. However, many studies only focused
on the cells viability inhibition of the compounds, the underlying molecular
mechanisms, and the intracellular targets remain ambiguous. In conclusion, C.
tricuspidata has a great potential for anti-tumor prevention or therapy, but
more attention should be paid to deeper research in vitro and in vivo models.
DOI: 10.1080/10408398.2018.1541866
245. Nat Prod Res. 2020 Aug;34(16):2295-2300. doi: 10.1080/14786419.2018.1536132.

Epub 2018 Dec 23.
Prenylated isoflavones with potential antiproliferative activities from

Mappianthus iodoides.
Liu YP(1)(2), Sun LL(1)(2), Zhang XL(1)(2), Niu HY(1)(2), Pan ZH(3), Fu
YH(1)(2)(3).
Author information:
(1)Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of
Education, Hainan Normal University, Haikou, P. R. China.
(2)Key Laboratory of Southern Medicinal Plants Resources of Haikou City, Hainan
Normal University, Haikou, P. R. China.
(3)Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization,
Guangxi Institute of Botany, Guangxi Zhuang Autonomous Region and Chinese
Academy of Sciences, Guilin, P. R. China.
A phytochemical investigation on the stems of Mappianthus iodoides led to the

isolation of a new naturally occurring prenylated isoflavone, mappianthone A
(1), together with seven known analogues (2-8). The structure of 1 was
elucidated by extensive spectroscopic methods and the known compounds were
identified by comparison with data reported in the literature. All isolated
compounds were evaluated for their antiproliferative activities against five
human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro.
Compounds 1-8 showed significant antiproliferative effects against several human
cancer cell lines with IC50 values ranging from 0.16 to 12.68 μM. [Formula: see
text].
DOI: 10.1080/14786419.2018.1536132
246. Onco Targets Ther. 2018 Dec 10;11:8901-8908. doi: 10.2147/OTT.S183302.

eCollection 2018.
Drug-target-disease network analysis of gene-phenotype connectivity for

genistein in ovarian cancer.
Zhang C(1), Yang F(2), Ni S(1), Teng W(1), Ning Y(3).
Author information:
(1)Department of Clinical Pharmacy, Guangzhou First People's Hospital, Guangzhou
(2)Department of Health Examination, The First Affiliated Hospital of Guangzhou
(3)Department of Gynaecology and Obstetrics, The First Affiliated Hospital of
Guangzhou Medical University, Guangzhou 510120, China, ningyingxia@163.com.
PURPOSE: Genistein belongs to the group of isoflavones, which include powerful

anticancer agents. Its antitumor properties have been intensively described in
many cancers, but related studies assessing ovarian cancer are scarce. The aim
of this study was to develop a new method of the underlying mechanisms of
genistein's effects and broaden the perspective of targeted therapies in ovarian
carcinoma.
MATERIALS AND METHODS: Genistein targets were searched in the DrugBank database.
Prediction of drug interactions with targets (including secondary targets) was
performed with STRING database. Interaction pairs with overall score above 0.9
were recorded for protein-protein interaction (PPI) network generation based on
the Cytoscape software. Genes with intense interconnections were grouped into a
module. Then, PPI network modules with significance were assessed using
Molecular Complex Detection (MCODE) analysis tool. The Kyoto Encyclopedia of
Genes and Genomes (KEGG) pathway enrichment analysis was performed for the
critical genes. Furthermore, disease targets were searched in Comparative
Toxicogenomics Database (CTD). The overlapping targets were studied using a
Kaplan-Meier analysis to evaluate ovarian carcinoma survival.
RESULTS: A total of 13 direct targets and 372 secondary targets were identified
for genistein and further analyzed with the MCODE analysis tool to identify
critical genes. The top 72 genes were further assessed with KEGG. Then, the term
"ovarian cancer" was searched in CTD, and 123 genes associated only with the
marker "T" or "M" were recorded. Next, seven overlapping genes (CDKN1B, PTEN,
EGFR, MAPK1, MAPK3, PIK3C, and AKT1) resulting from the intersection of three
pathways and 123 genes were obtained from CTD. Elevated CDKN1B amounts showed
correlation with overall survival (log-rank P=0.021) according to Kaplan-Meier
analysis.
CONCLUSION: The current findings indicated that drug-target-disease network
analysis represents a useful tool in gene-phenotype connectivity for genistein
in ovarian cancer. Our result also showed that CDKN1B is worthy of further
research.
DOI: 10.2147/OTT.S183302
PMCID: PMC6292408
PMID: 30573976
Conflict of interest statement: Disclosure The authors report no conflicts of

interest in this work.
247. Semin Radiat Oncol. 2019 Jan;29(1):62-71. doi:

10.1016/j.semradonc.2018.10.002.
Soy Isoflavones Protect Normal Tissues While Enhancing Radiation Responses.
Hillman GG(1).
Author information:
(1)Department of Oncology, Radiation Oncology Division, and Department of
Biochemistry, Microbiology and Immunology, Barbara Ann Karmanos Cancer
Institute, Wayne State University School of Medicine, Detroit, MI. Electronic
address: hillmang@karmanos.org.
Soy isoflavones have demonstrated chemopreventive and anticancer properties in

epidemiology and biological studies, in addition to their function as
antioxidants in prevention of cardiovascular disease. We have explored the
potential of soy isoflavones, as a safe biological approach, to enhance the
efficacy of radiotherapy for local tumor control and limit normal tissue damage
in solid tumors. This review presents studies investigating the interaction
between soy isoflavones and radiation in different malignancies, including
prostate cancer, renal cell carcinoma, and nonsmall cell lung cancer. Soy
isoflavones were found to be potent sensitizers of cancer cells to radiation
causing increased cell killing in vitro in human tumor cell lines and greater
tumor inhibition in vivo in preclinical orthotopic murine tumor models. In the
course of these studies, radioprotection of normal tissues and organs in the
field of radiation was observed both in a clinical trial for prostate cancer and
in preclinical models. The mechanisms of radiosensitization and radioprotection
mediated by soy isoflavones are discussed and emphasize the role of soy
isoflavones in increasing radiation effect on tumor and mitigating inflammatory
responses induced by radiation in normal tissues. Soy isoflavones could be used
as a safe, nontoxic complementary strategy that simultaneously increases
radiation effectiveness on the malignancy while reducing damage in normal
tissues in the field of radiation.
DOI: 10.1016/j.semradonc.2018.10.002
248. Mol Nutr Food Res. 2019 Jan;63(2):e1800635. doi: 10.1002/mnfr.201800635. Epub
2018 Dec 10.
Impact of Oxidative Metabolism on the Cytotoxic and Genotoxic Potential of

Genistein in Human Colon Cancer Cells.
Schroeter A(1), Aichinger G(1), Stornig K(1), Marko D(1).
Author information:
(1)Department of Food Chemistry and Toxicology, University of Vienna, Vienna,
Austria.
SCOPE: Genistein (GEN) is known to be genotoxic via targeting topoisomerase-II

(TOPII). Oxidative metabolism of GEN is shown to generate hydroxylated
metabolites with catecholic structures. The present study focuses on the impact
of oxidative metabolism of GEN, exemplified for 3'-hydroxygenistein (3'-OH-GEN)
and 6-hydroxygenistein (6-OH-GEN), on topoisomerase interference and the
resulting genotoxic potential in HT-29 human colon carcinoma cells.
METHODS AND RESULTS: In a cell-free decatenation assay, 3'-OH-GEN slightly
exceeds the TOPII-inhibiting potential of GEN. In HT-29 cells, its inhibitory
action on TOPII does not differ from GEN, but it has greater activity with
respect to causing DNA damage (measured by the comet assay), p53 activation
(Western blot), apoptosis induction (ELISA), and cytotoxicity (WST-1 assay).
This may to some extent be related to a stronger pro-oxidative potential of
3'-OH-GEN in comparison to GEN, as observed for the highest concentrations (DCF
assay). 6-OH-GEN exerts much weaker toxic effects than GEN in cell-based assays,
including TOPII poisoning, DNA strand-breaking potential, and ROS generation.
This might in part arise from decreased cellular uptake of the metabolite, as
measured by HPLC-DAD.
CONCLUSION: Oxidative metabolism alters the toxicological potential of GEN.
Depending on the site of oxidation, the toxicity of the parent compound is
exceeded (3'-OH-GEN) or attenuated (6-OH-GEN).
DOI: 10.1002/mnfr.201800635
249. J Nutr. 2019 Jan 1;149(1):26-35. doi: 10.1093/jn/nxy232.
A Novel Tomato-Soy Juice Induces a Dose-Response Increase in Urinary and Plasma

Phytochemical Biomarkers in Men with Prostate Cancer.
Grainger EM(1), Moran NE(1)(2), Francis DM(3), Schwartz SJ(4), Wan L(1),
Thomas-Ahner J(1), Kopec RE(4), Riedl KM(1)(4), Young GS(1)(5), Abaza R(6),
Bahnson RR(6), Clinton SK(1)(7).
Author information:
(1)The Ohio State University Comprehensive Cancer Center College of Medicine,
The Ohio State University, Columbus, OH 43210.
(2)USDA/Agricultural Research Service Children's Nutrition Research Center,
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
(3)Department of Horticulture and Crop Science, The Ohio State University, Ohio
Agricultural Research and Development Center, Wooster, OH 44691.
(4)Department of Food Science and Technology, College of Food, Agriculture, and
Environmental Sciences, The Ohio State University, Columbus, OH 43210.
(5)Center for Biostatistics College of Medicine, The Ohio State University,
Columbus, OH 43210.
(6)Department of Urology College of Medicine, The Ohio State University,
Columbus, OH 43210.
(7)Division of Medical Oncology, College of Medicine The Ohio State University,
Columbus, OH 43210.
BACKGROUND: Tomato and soy intake is associated with reduced prostate cancer
risk or severity in epidemiologic and experimental studies.
OBJECTIVE: On the basis of the principle that multiple bioactives in tomato and
soy may act on diverse anticancer pathways, we developed and characterized a
tomato-soy juice for clinical trials. In this phase 2 dose-escalating study, we
examined plasma, prostate, and urine biomarkers of carotenoid and isoflavone
exposure.
METHODS: Men scheduled for prostatectomy were recruited to consume 0, 1, or 2
cans of tomato-soy juice/d before surgery (mean ± SD duration: 24 ± 4.6 d). The
juice provided 20.6 mg lycopene and 66 mg isoflavone aglycone equivalents/177-mL
can. Plasma carotenoids and urinary isoflavone metabolites were quantified by
HPLC-photometric diode array and prostate carotenoids and isoflavones by
HPLC-tandem mass spectrometry.
RESULTS: We documented significant dose-response increases (P < 0.05) in plasma
concentrations of tomato carotenoids. Plasma concentrations were 1.86-, 1.69-,
1.73-, and 1.69-fold higher for lycopene, β-carotene, phytoene, and phytofluene,
respectively, for the 1-can/d group and 2.34-, 3.43-, 2.54-, and 2.29-fold
higher, respectively, for the 2-cans/d group compared with 0 cans/d. Urinary
isoflavones daidzein, genistein, and glycitein increased in a dose-dependent
manner. Prostate carotenoid and isoflavone concentrations were not
dose-dependent in this short intervention; yet, correlations between plasma
carotenoid and urinary isoflavones with respective prostate concentrations were
documented (R2 = 0.78 for lycopene, P < 0.001; R2 = 0.59 for dihydrodaidzein,
P < 0.001). Secondary clustering analyses showed urinary isoflavone metabolite
phenotypes. To our knowledge, this is the first demonstration of the phytoene
and phytofluene in prostate tissue after a dietary intervention. Secondary
analysis showed that the 2-cans/d group experienced a nonsignificant decrease in
prostate-specific antigen slope compared with 0 cans/d (P = 0.078).
CONCLUSION: These findings provide the foundation for evaluating a
well-characterized tomato-soy juice in human clinical trials to define the
impact on human prostate carcinogenesis. This trial is registered at
clinicaltrials.gov as NCT01009736.
DOI: 10.1093/jn/nxy232
PMCID: PMC6351139
250. Carcinogenesis. 2019 Mar 12;40(1):93-101. doi: 10.1093/carcin/bgy158.
Urolithin A gains in antiproliferative capacity by reducing the glycolytic

potential via the p53/TIGAR axis in colon cancer cells.
Norden E(1), Heiss EH(1).
Author information:
(1)Department of Pharmacognosy, University of Vienna, Vienna, Austria.
Polyphenols have shown promising bioactivity in experimental in vitro and in

vivo models for cancer chemoprevention. However, consumed orally, they are often
transformed by gut microbes into new active principles with so far incompletely
deciphered molecular mechanisms. Here, enterolacton, S-equol and urolithin A as
representatives of metabolites of lignans, isoflavones and ellagitannins,
respectively, were examined for their impact on HCT116 colon cancer cell growth,
cooperativity with oxaliplatin and p53 dependency in vitro. Whereas enterolacton
and S-equol (≤60 µM) did not elicit growth inhibition or positive cooperativity
with oxaliplatin, urolithin A showed an IC50 value of 19 µM (72 h) and synergism
with oxaliplatin. Urolithin A induced p53 stabilization and p53 target gene
expression, and absence of p53 significantly dampened the antiproliferative
effect of urolithin A (IC50(p53-/-) = 38 µM). P53 was dispensable for the G2/M
arrest in HCT116 cells but required for induction of a senescence-like phenotype
upon long-term exposure and for the observed synergism with oxaliplatin.
Moreover, extracellular flux analyses and knockdown approaches uncovered a
reduced glycolytic potential via the p53/TIGAR axis which was linked to the
higher susceptibility of wildtype cells to urolithin A. Overall, the p53 status
turned out to be an important determinant for the potential benefit of dietary
ellagitannins in cancer chemoprevention or use in adjuvant therapy.
DOI: 10.1093/carcin/bgy158
PMCID: PMC6412115
251. Biochem Biophys Res Commun. 2018 Dec 2;506(4):773-779. doi:

10.1016/j.bbrc.2018.10.184. Epub 2018 Oct 31.
Morin suppresses cachexia-induced muscle wasting by binding to ribosomal protein

S10 in carcinoma cells.
Yoshimura T(1), Saitoh K(1), Sun L(1), Wang Y(1), Taniyama S(1), Yamaguchi K(1),
Uchida T(2), Ohkubo T(3), Higashitani A(4), Nikawa T(2), Tachibana K(1),
Hirasaka K(5).
Author information:
(1)Graduate School of Fisheries and Environmental Sciences, and Nagasaki
University, Nagasaki, 8528521, Japan.
(2)Department of Nutritional Physiology, Institute of Medical Nutrition,
Tokushima University Medical School, Tokushima, 7708503, Japan.
(3)Nutritional Foods Division, Taiyo Kagaku Co., Ltd, Mie, 5121111, Japan.
(4)Graduate School of Life Sciences, Tohoku University, Sendai, 9808577, Japan.
(5)Graduate School of Fisheries and Environmental Sciences, and Nagasaki
University, Nagasaki, 8528521, Japan; Organization for Marine Science and
Technology, Nagasaki University, Nagasaki, 8528521, Japan. Electronic address:
hirasaka@nagasaki-u.ac.jp.
Cachexia, observed in most cancer patients, is a syndrome that includes wasting
of bodily energy reserves and is characterized by muscle atrophy and fat loss.
We have previously demonstrated that isoflavones, such as genistein and
daidzein, prevent muscle wasting in tumor-bearing mice. In this study, we
examined the effect of morin, a flavonoid, on cachexia. The wet weight and
myofiber size of muscles in Lewis lung carcinoma (LLC) cell-bearing mice fed a
normal diet were decreased, compared with those in control mice fed a normal
diet. In contrast, intake of morin prevented the reduction of muscle wet weight
and myofiber size. Moreover, the tumor weight in mice fed the morin diet was
lower than that in mice fed the normal diet. Both cell viability and protein
synthetic ability of LLC cells were reduced by treatment with morin, but C2C12
myotubes were not affected. Binding assay using morin-conjugated magnetic beads
identified ribosomal protein S10 (RPS10) as a target protein of morin.
Consistent with the result of morin treatment, knockdown of RPS10 suppressed LLC
cell viability. These results suggest that morin indirectly prevents muscle
wasting induced by cancer cachexia by suppressing cancer growth via binding to
RPS10.
DOI: 10.1016/j.bbrc.2018.10.184
252. Eur J Nutr. 2019 Dec;58(8):3079-3090. doi: 10.1007/s00394-018-1853-4. Epub

2018
Oct 31.
Soy and isoflavones consumption and breast cancer survival and recurrence: a
systematic review and meta-analysis.
Qiu S(1), Jiang C(2).
Author information:
(1)School of Sport Economics and Management, Central University of Finance and
Economics, 39 South College Road, Haidian District, Beijing, 100081, People's
Republic of China. qiusm0066@126.com.
(2)Youth Sports Research Center, China Institute of Sport Science, Beijing,
BACKGROUND: Some studies have investigated the association between soy and
isoflavones consumption and breast cancer survival, but the results are far from
conclusive. Accordingly, we performed a systematic review and meta-analysis to
explore this issue.
METHODS: We performed a comprehensive search of Web of Science, PubMed, and
Embase from inception to January 2018. The summary hazard ratios (HRs) and 95%
confidence intervals (CIs) were estimated using a random effects model.
RESULTS: A total of 12 articles were included, which reported overall survival
(OS), breast cancer specific survival (BCSS), and recurrence in 5770, 2386, and
1500 cases, respectively, among 37,275 women with breast cancer. The summary HR
(95% CI) for the association (highest vs. lowest) of pre-diagnosis soy and
isoflavones consumption with OS and BCSS was 0.84 (0.71-0.98) and 0.89
(0.74-1.07), respectively. Stratified analyses suggested that the reduced OS was
more easily detected in studies that focused on post-menopausal patients. No
significant association was found between post-diagnosis soy and isoflavones
consumption with OS and BCSS, with summary HRs (95% CIs) of 0.80 (0.62-1.04) and
0.83 (0.64-1.07), respectively. Pre- and post-diagnosis soy isoflavones
consumption were associated with reduced risk of recurrence.
CONCLUSION: This study provides limited evidence that pre-diagnosis soy and
isoflavones intake is associated with a small reduction in post-menopausal
breast cancer OS.
DOI: 10.1007/s00394-018-1853-4
253. Ann N Y Acad Sci. 2019 May;1443(1):3-19. doi: 10.1111/nyas.13980. Epub 2018
Nov
1.
Effects of phytochemicals on thyroid function and their possible role in thyroid

disease.
Pistollato F(1), Masias M(1)(2), Agudo P(1), Giampieri F(3), Battino M(3).
Author information:
(1)Center for Nutrition & Health, CITICAN, Universidad Europea del Atlántico,
Parque Científico y Tecnológico de Cantabria, Santander, Spain.
(2)Área de Nutrición y Salud, Universidad Internacional Iberoamericana (UNINI),
Campeche, Mexico.
(3)Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche, Sez,
Biochimica, Università Politecnica delle Marche, Ancona, Italy.
About 1 of 10 women, particularly those older than 60 years of age, shows some
degree of thyroid hormone deficiency. Thyroid diseases are generally
characterized by perturbations of thyroid signaling homeostasis. The most common
examples of thyroid diseases include hypothyroidism, hyperthyroidism, and
several types of thyroid cancers. Phytochemicals have been shown to have either
beneficial or detrimental effects on thyroid function. Some flavonoids have been
reported to affect the expression and the activity of several thyroid-related
enzymes and proteins, and for this reason some concerns have been raised about
the possible thyroid-disruptive properties of foods enriched in these
substances. On the other hand, the beneficial effects of some plant-derived
compounds, such as myricetin, quercetin, apigenin, rutin, genistein, and
curcumin, and their possible role as adjuvants for the treatment of thyroid
cancers have been described. Here, the role of phytochemicals in thyroid
signaling modulation and their possible beneficial or detrimental effects on
thyroid disease risk are discussed.
© 2018 New York Academy of Sciences.
DOI: 10.1111/nyas.13980
254. Curr Dev Nutr. 2017 Dec 19;2(3):nzx009. doi: 10.3945/cdn.117.002063.

eCollection
2018 Mar.
Postdiagnosis Isoflavone and Lignan Intake in Newly Diagnosed Breast Cancer

Patients: Cross-Sectional Survey Shows Considerable Intake from Previously
Unassessed High-Lignan Foods.
Boucher BA(1)(2), Wanigaratne S(3), Harris SA(1)(4), Cotterchio M(1)(4).
Author information:
(1)Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
(2)Department of Nutritional Sciences, Faculty of Medicine, University of
Toronto, Toronto, ON, Canada.
(3)Centre for Urban Health Solutions, St Michael's Hospital, Toronto, ON,
Canada.
(4)Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
Canada.
BACKGROUND: Isoflavones and lignans (phytoestrogens) are dietary components with

potential anticarcinogenic effects. Although the intake of isoflavones and
lignans may affect breast cancer treatment and prognosis-and associations may
differ by menopausal status-postdiagnosis intake data are limited.
OBJECTIVE: We aimed to describe postdiagnosis isoflavone and lignan intake in
newly diagnosed breast cancer patients, examine differences by menopausal status
and phytoestrogen type, and inform the assessment of diet and survival in future
prognostic studies.
METHODS: Our cross-sectional study included 278 women aged 25-74 y, diagnosed
with pathologically confirmed breast cancer in April-May 2010 and identified
using the Ontario Cancer Registry. Intake in the previous 2 mo was assessed
using questionnaires listing 17 soy and 3 high-lignan foods (flaxseed, flaxseed
bread, sesame seeds), completed 71 d after breast cancer diagnosis, on average.
Food consumption by menopausal status was examined. Geometric mean and median
phytoestrogen intakes were estimated among all patients and in consumers only;
differences by menopausal status and phytoestrogen type were assessed.
RESULTS: Among all patients, foods were similarly consumed by menopausal status
and isoflavone intakes were low (median: 56 µg/d). Consumers (n = 219) had
higher intakes (median isoflavones: 1808 µg/d); 7% of isoflavone and 21% of
lignan consumers had intakes ≥10 mg/d. Intakes were higher in premenopausal than
in postmenopausal consumers, particularly for lignans, but were not
significantly different (median lignans: 4375 compared with 1863 µg/d;
P = 0.07). Lignans were significantly higher than isoflavones among most
consumers (postmenopausal means: 746 compared with 100 µg/d; P < 0.0001).
CONCLUSIONS: Postdiagnosis lignan intakes from 3 high-content foods may be
considerable among newly diagnosed breast cancer patients, yet they have been
unassessed in previous prognostic studies. The inclusion of these foods in
dietary assessment methods may improve future intake estimates and the
distributions on which breast cancer survival analyses are based.
DOI: 10.3945/cdn.117.002063
PMCID: PMC6201681
PMID: 30377679
255. Bioorg Chem. 2019 Mar;83:135-144. doi: 10.1016/j.bioorg.2018.10.017. Epub 2018

Oct 10.
Dual effects of isoflavonoids from Pueraria lobata roots on estrogenic activity

and anti-proliferation of MCF-7 human breast carcinoma cells.
Ahn SY(1), Jo MS(2), Lee D(2), Baek SE(1), Baek J(2), Yu JS(2), Jo J(3), Yun
H(3), Kang KS(4), Yoo JE(5), Kim KH(6).
Author information:
(1)Department of Obstetrics and Gynecology, College of Korean Medicine, Daejeon
University, Daejeon 35235, Republic of Korea.
(2)School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
(3)College of Pharmacy, Pusan National University, Busan 46241, Republic of
Korea.
(4)College of Korean Medicine, Gachon University, Seongnam 13120, Republic of
Korea.
(5)Department of Obstetrics and Gynecology, College of Korean Medicine, Daejeon
University, Daejeon 35235, Republic of Korea. Electronic address:
jeyoo@dju.ac.kr.
(6)School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Electronic address: khkim83@skku.edu.
Pueraria lobata root (PLR), well known as Kudzu root, has recently become
commercially available in Western dietary supplements for menopausal symptoms.
The scientific basis for its action has been attributed to the action of
phytoestrogens. This study aimed to investigate the estrogen-like activity of
isoflavonoids isolated from P. lobata root and their safety with respect to
their effect on breast cancer cell proliferation. In an E-screen assay, crude
MeOH extract of PLR significantly increased the proliferation of MCF-7 cells in
a concentration-dependent manner. Among the four fractions obtained by solvent
fractionation of MeOH extract, the n-BuOH fraction had significant estrogen-like
activities at all concentrations tested. Phytochemical analysis of the n-BuOH
fraction led to the isolation of 10 isoflavones (1-10), among which genistein
(10) had significant estrogen-like activities at all concentrations tested.
These activities were significantly enhanced by treatment with genistein and
17β-estradiol compared with 17β-estradiol alone, and this effect was mediated by
decreased expression of estrogen receptor (ER)α and phospho-ERα in MCF-7 cells.
In a cell cytotoxicity assay, genistein (10) exhibited significant cytotoxicity
in both ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells. This
cytotoxicity was characterized by the induction of apoptotic cells stained with
annexin V conjugated with Alexa Fluor 488 and involved activation of
mitochondria-independent and -dependent apoptosis pathways in MCF-7 cells. Our
results demonstrated that genistein (10) has estrogen-like effects dependent on
ER pathway activation and anti-proliferative effects mediated by the apoptosis
pathway rather than the ER pathway in MCF-7 breast cancer cells.
DOI: 10.1016/j.bioorg.2018.10.017
256. Prostate. 2019 Feb;79(2):223-233. doi: 10.1002/pros.23727. Epub 2018 Oct 21.
Lack of combination effects of soy isoflavones and taxane chemotherapy of

castration-resistant prostate cancer.
Eskra JN(1), Schlicht MJ(1), Bosland MC(1).
Author information:
Chicago, Chicago, Illinois.
BACKGROUND: Patients with cancer, including prostate cancer, often use dietary
supplements, such as soy or isoflavones, before, during, or after therapy. There
is little information about possible interactions between supplements and cancer
chemotherapy. There are some reports suggesting enhancement by genistein of
taxane chemotherapy for castrate-resistant prostate cancer (CRPC).
METHODS: We investigated whether physiologically attainable concentrations of
soy isoflavones (≤10 μM) interact with taxanes on growth inhibition of CRPC
cells in vitro and in vivo in nude mice exposed via the diet, on microtubule
disassembly in vitro, and on P-glycoprotein-mediated drug efflux in 22Rv1 cells
and CYP3A4 activity in microsomes.
RESULTS: Genistein, daidzein, and equol did not affect growth of VCaP, 22Rv1,
C4-2, and PC-3 CRPC cells or growth inhibition of these cells by docetaxel and
cabazitaxel. These isoflavones did not inhibit microtubule disassembly in vitro
or inhibit the microtubule effects of taxanes and genistein did not bind
substantially to microtubules. Genistein considerably inhibited
P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in
microsomes. However, dietary supplementation with genistein at 250 and 500 ppm
did not affect the tumor growth inhibiting effect of docetaxel on 22Rv1 cells
xenografted in nude mice.
CONCLUSIONS: Our results with relevant cell models and clinically achievable
concentrations of soy isoflavones do not support the notion that genistein or
other soy isoflavones can enhance the effects of taxane chemotherapy in CRPC
cell and xenograft models. Yet, the inhibitory effects of genistein on drug
efflux in 22Rv1 cells and on microsomal CYP3A4 activity raise the possibility
that genistein can affect taxane effects on CRPC cells in other circumstances
than those we studied, which merits further research.
© 2018 Wiley Periodicals, Inc.
DOI: 10.1002/pros.23727
257. Cancer Res. 2018 Oct 15;78(20):6028. doi: 10.1158/0008-5472.CAN-18-2386.
Retraction: Down-regulation of Apurinic/Apyrimidinic Endonuclease 1/Redox

Factor-1 Expression by Soy Isoflavones Enhances Prostate Cancer Radiotherapy In
vitro and In vivo.
[No authors listed]
Retraction of
Cancer Res. 2007 Mar 1;67(5):2141-9.
DOI: 10.1158/0008-5472.CAN-18-2386
PMID: 30322962
258. Molecules. 2018 Sep 26;23(10):2471. doi: 10.3390/molecules23102471.
Binding of Red Clover Isoflavones to Actin as A Potential Mechanism of

Anti-Metastatic Activity Restricting the Migration of Cancer Cells.
Budryn G(1), Grzelczyk J(2), Pérez-Sánchez H(3).
Author information:
Sciences, Lodz University of Technology, 90-924 Lodz, Poland.
grazyna.budryn@p.lodz.pl.
Sciences, Lodz University of Technology, 90-924 Lodz, Poland.
joanna.grzelczyk@edu.p.lodz.pl.
(3)Bioinformatics and High-Performance Computing Research Group (BIO-HPC),
Computer Engineering Department, Universidad Católica de Murcia (UCAM),
Guadalupe, 30107 Murcia, Spain. hperez@ucam.edu.
Actin functions are crucial for the ability of the cell to execute dynamic
cytoskeleton reorganization and movement. Nutraceuticals that form complexes
with actin and reduce its polymerization can be used in cancer therapy to
prevent cell migration and metastasis of tumors. The aim of this study was to
evaluate the ability of isoflavones to form complexes with actin. Docking
simulation and isothermal titration calorimetry were used for this purpose. The
formation of complexes by hydrogen bonds, hydrophobic and π-π interactions was
demonstrated. Interactions occurred at the ATP binding site, which may limit the
rotation of the actin molecule observed during polymerization and also at the
site responsible for contacts during polymerization, reducing the ability of the
molecule to form filaments. The greatest therapeutic potential was demonstrated
by isoflavones occurring in red clover sprouts, i.e., biochanin A and
formononetin, being methoxy derivatives of genistein and daidzein.
PMCID: PMC6222305
259. Biomed Pharmacother. 2018 Nov;107:1648-1666. doi:

10.1016/j.biopha.2018.08.100.
Epub 2018 Sep 8.
Phytoestrogens and breast cancer: In vitro anticancer activities of isoflavones,

lignans, coumestans, stilbenes and their analogs and derivatives.
Basu P(1), Maier C(2).
Author information:
(1)Department of Biology, Texas Woman's University, Denton, TX, 76204-5799, USA.
(2)Department of Biology, Texas Woman's University, Denton, TX, 76204-5799, USA.
Electronic address: cmaier@mail.twu.edu.
Breast cancer is one of the leading causes of cancer-related morbidity and

mortality among women worldwide. Phytoestrogens, plant-derived polyphenols that
structurally and functionally mimic 17β-estradiol, the mammalian estrogen
hormone, are known to modulate multiple molecular targets in breast cancer
cells. The structural and chemical similarities to estradiol enable
phytoestrogens to exert estrogenic or antiestrogenic activities by binding to
the estrogen receptors. Although phytoestrogens have low affinity for estrogen
receptors, they are able to compete with 17β-estradiol for the ligand-binding
domain of the receptors. Phytoestrogens trigger epigenomic effects that could be
beneficial in breast cancer prevention and/or treatment. Few studies have
focused on the cytotoxic and structure-activity relationships of phytoestrogen
analogs and derivatives with more effective anticancer properties than their
corresponding parent compounds. Phytoestrogens and their analogs and derivatives
bind to estrogen receptors, with a preferential affinity for ERβ, and inhibit
the growth promoting activity of ERα. These bioactive compounds also exert
growth inhibitory effects through various cell signaling pathways. At the level
of cell cycle, they inhibit the expression of oncogenic cyclin D1, increase the
expression of cyclin-dependent kinase inhibitors (p21, p27, and p57) and tumor
suppressor genes (APC, ATM, PTEN, SERPINB5). Phytoestrogens and their analogs
and derivatives mediate their effects on breast cancer by inhibiting estrogen
synthesis and metabolism, as well as exerting antiangiogenic, antimetastatic,
and epigenetic effects. Furthermore, these bioactive compounds reverse
multi-drug resistance. This review offers a comprehensive summary of current
literature and future perspectives on the in vitro molecular mechanisms of the
anticancer activities of phytoestrogens and their analogs and derivatives on
breast cancer.
DOI: 10.1016/j.biopha.2018.08.100
260. Biomed Pharmacother. 2018 Nov;107:1119-1127. doi:

10.1016/j.biopha.2018.08.073.
Epub 2018 Aug 27.
Biochanin A improves insulin sensitivity and controls hyperglycemia in type 2

diabetes.
Oza MJ(1), Kulkarni YA(2).
Author information:
(1)Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management,
SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India; SVKM's Dr.
Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, India.
(2)Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management,
SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, India. Electronic
address: yogeshkulkarni101@yahoo.com.
Biochanin A (5,7-Dihydroxy-4'-methoxyisoflavone) is an O-methylated isoflavone

known for its anti-inflammatory, lipid lowering and anti-cancer activity. The
current study was designed to find out antidiabetic efficacy of Biochanin A in
type 2 diabetes in rats. Induction of type 2 diabetes mellitus in experimental
animals was carried out by manipulation of diet using high fat diet for fourteen
days and then administration of streptozotocin at low dose of 35 mg/kg, i.p. The
diabetic animals were treated with 10, 20 and 40 mg/kg of Biochanin A for 28
days. The effect of Biochanin A treatment in diabetic animals was evaluated by
measuring changes in body weight, biochemical parameters, insulin sensitivity
index, Homeostatic model assessment-Insulin resistance (HOMA-IR), oral glucose
tolerance test, glycohaemoglobin and hepatic glycogen level. Changes in
histopathological characteristics of pancreatic tissue were also evaluated after
treatment with Biochanin A. Immunohistochemical analysis of pancreatic tissue
was carried out for the expression of SIRT1. The results showed that the
selected doses of (10, 20 and 40 mg/kg) Biochanin A significantly decreased
blood glucose (p < 0.001). The higher dose (40 mg/kg) of Biochanin A
significantly reduced glucose tolerance (p < 0.001) in diabetic animals.
Biochanin A treatment significantly reduced insulin resistance (p < 0.001) and
improved inulin sensitivity (p < 0.01 for 10 mg/kg, 20 mg/kg, p < 0.001 for
40 mg/kg) at all selected dose levels. It also improved lipid profile
significantly (p < 0.001) at lower, middle and higher dose level.
Glycohaemoglobin formation was significantly decreased in diabetic animals
(p < 0.001) after treatment with Biochanin A at all three dose levels. Liver
glycogen level was also improved significantly after treatment with Biochanin A
in diabetic animals at 20 mg/kg and 40 mg/kg dose level. Biochanin A at dose of
40 mg/kg increased SIRT1 expression in pancreatic tissue. In conclusion,
Biochanin A has significant effect in type 2 diabetes mellitus which might be
linked to its effects on SIRT1.
DOI: 10.1016/j.biopha.2018.08.073
261. Med Res Rev. 2019 Jul;39(4):1274-1293. doi: 10.1002/med.21536. Epub 2018 Sep
1.
Polyphenolic natural products and natural product-inspired steroidal mimics as

aromatase inhibitors.
Nielsen AJ(1), McNulty J(1).
Author information:
(1)Department of Chemistry & Chemical Biology, McMaster University, Hamilton,
Ontario, Canada.
The discovery of biologically active polyphenolic natural products, including

chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven
to be a subject of considerable importance in medicine. Some of these natural
compounds have been shown to modulate key human metabolic processes via
steroidal hormone receptors, or to inhibit crucial enzymes involved in the
biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as
genistein are well known for this "phytoestrogenic" biological activity. This
review focuses on the ability of select polyphenolics and their synthetic
derivatives to function as steroidal mimics in the inhibition of the enzyme
aromatase, thereby lowering production of endogenous estrogen growth hormones.
The discovery of potent, natural product-based aromatase inhibitors (AIs) as hit
compounds has led to the introduction of steroidal-based irreversible
inhibitors, such as exemestane and reversible AIs such as anastrozole and
letrozole, now standard therapy in the treatment of estrogen receptor-positive
breast cancer and other hormone related indications. Pursuit of this strategy
over the last few decades has been largely successful although complications and
challenges remain. This review highlights the aromatase activity of natural
stilbenes, chalcones, and flavanones and synthetically inspired versions thereof
and draws attention to new and under-investigated areas within each class worthy
of pursuit.
DOI: 10.1002/med.21536
262. Front Pharmacol. 2018 Aug 15;9:918. doi: 10.3389/fphar.2018.00918. eCollection

2018.
Exploring the Mechanism of Flavonoids Through Systematic Bioinformatics

Analysis.
Qiu T(1), Wu D(2), Yang L(3), Ye H(4)(5), Wang Q(2), Cao Z(2), Tang K(2).
Author information:
(1)Institute of Biomedical Sciences, Fudan University, Shanghai, China.
(2)School of Life Sciences and Technology, Tongji University, Shanghai, China.
(3)Hebei Key Laboratory of Metabolic Diseases and Clinical Medicine Research
Center, Hebei General Hospital, Hebei, China.
(4)Sinotech Genomics Ltd., Shanghai, China.
(5)East China University of Science and Technology, Shanghai, China.
Flavonoids are the largest class of plant polyphenols, with common structure of
diphenylpropanes, consisting of two aromatic rings linked through three carbons
and are abundant in both daily diets and medicinal plants. Fueled by the
recognition of consuming flavonoids to get better health, researchers became
interested in deciphering how flavonoids alter the functions of human body.
Here, systematic studies were performed on 679 flavonoid compounds and 481
corresponding targets through bioinformatics analysis. Multiple human diseases
related pathways including cancers, neuro-disease, diabetes, and infectious
diseases were significantly regulated by flavonoids. Specific functions of each
flavonoid subclass were further analyzed in both target and pathway level.
Flavones and isoflavones were significantly enriched in multi-cancer related
pathways, flavan-3-ols were found focusing on cellular processing and lymphocyte
regulation, flavones preferred to act on cardiovascular related activities and
isoflavones were closely related with cell multisystem disorders. Relationship
between chemical constitution fragment and biological effects indicated that
different side chain could significantly affect the biological functions of
flavonoids subclasses. Results will highlight the common and preference
functions of flavonoids and their subclasses, which concerning their
pharmacological and biological properties.
DOI: 10.3389/fphar.2018.00918
PMCID: PMC6104453
PMID: 30158870
263. Ceska Slov Farm. 2018 Summer;67(1):3-13.
Genistein: a promising molecule modulating tumour growth and wound healing?
[Article in English]
Mitrengová P, Mučaji P, Peržeľová V, Dosedla E, Gál P.
Although it has been shown that oestrogen replacement therapy is able to improve
wound healing, several side effects of this replacement therapy have precluded
its common use in clinical practice. On the other hand, the phytoestrogen
genistein (the selective oestrogen receptor modulator belonging to the group of
isoflavones) has been introduced into several clinical trials to improve cancer
treatment efficiency and experiments suggest its positive effect on wound
healing. The main mechanisms of action, which have been elucidated so far,
include induction of apoptosis, cell cycle arrest, inhibition of angiogenesis
and tyrosine kinase activity as well as cancer chemoprevention and reduction of
climacteric symptoms. Unfortunately, all underlying mechanism in the modulation
of biological processes involved in wound healing and tumour growth are not yet
fully understood. Therefore, the present review summarizes the effects of
genistein on biological processes in different wound healing models and selected
tumours. Key words: genistein • tissue repair and regeneration • carcinoma •
skin.
264. Arch Toxicol. 2018 Sep;92(9):2703-2748. doi: 10.1007/s00204-018-2279-8. Epub

2018 Aug 21.
Effects of isoflavones on breast tissue and the thyroid hormone system in

humans: a comprehensive safety evaluation.
Hüser S(1), Guth S(1), Joost HG(2), Soukup ST(3), Köhrle J(4), Kreienbrock L(5),
Diel P(6), Lachenmeier DW(7), Eisenbrand G(8), Vollmer G(9), Nöthlings U(10),
Marko D(11), Mally A(12), Grune T(13), Lehmann L(14), Steinberg P(15)(16),
Kulling SE(17).
Author information:
(1)Institute for Food Toxicology, Senate Commission on Food Safety, University
of Veterinary Medicine Hannover, Hannover, Germany.
(2)Department of Experimental Diabetology, German Institute of Human Nutrition
(DIfE), Nuthetal, Germany.
(3)Department of Safety and Quality of Fruit and Vegetables, Max
Rubner-Institut, Federal Research Institute of Nutrition and Food,
Haid-und-Neu-Str. 9, 76131, Karlsruhe, Germany.
(4)Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin
Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu
Berlin, Berlin Institute of Health, CVK, Berlin, Germany.
(5)Department of Biometry, Epidemiology and Information Processing, University
of Veterinary Medicine Hannover, Hannover, Germany.
(6)Department of Molecular and Cellular Sports Medicine, Institute of
Cardiovascular Research and Sports Medicine, German Sport University Cologne,
Cologne, Germany.
(7)Chemisches und Veterinäruntersuchungsamt Karlsruhe, Karlsruhe, Germany.
(8)Division of Food Chemistry and Toxicology, Molecular Nutrition, Department of
Chemistry, Technische Universität Kaiserslautern, Kaiserslautern, Germany.
(9)Department of Biology, Molecular Cell Physiology and Endocrinology,
Technische Universität Dresden, Dresden, Germany.
(10)Department of Nutrition and Food Sciences, Nutritional Epidemiology,
Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany.
(11)Department of Food Chemistry and Toxicology, Faculty of Chemistry,
University of Vienna, Vienna, Austria.
(12)Department of Toxicology, University of Würzburg, Würzburg, Germany.
(13)Department of Molecular Toxicology, German Institute of Human Nutrition
(DIfE), Nuthetal, Germany.
(14)Department of Food Chemistry, Institute for Pharmacy and Food Chemistry,
University of Würzburg, Würzburg, Germany.
(15)Institute for Food Toxicology, University of Veterinary Medicine Hannover,
Hannover, Germany.
(16)Max Rubner-Institut, Federal Research Institute of Nutrition and Food,
Haid-und-Neu-Str. 9, 76131, Karlsruhe, Germany.
Rubner-Institut, Federal Research Institute of Nutrition and Food,
Haid-und-Neu-Str. 9, 76131, Karlsruhe, Germany. sabine.kulling@mri.bund.de.
Isoflavones are secondary plant constituents of certain foods and feeds such as
soy, linseeds, and red clover. Furthermore, isoflavone-containing preparations
are marketed as food supplements and so-called dietary food for special medical
purposes to alleviate health complaints of peri- and postmenopausal women. Based
on the bioactivity of isoflavones, especially their hormonal properties, there
is an ongoing discussion regarding their potential adverse effects on human
health. This review evaluates and summarises the evidence from interventional
and observational studies addressing potential unintended effects of isoflavones
on the female breast in healthy women as well as in breast cancer patients and
on the thyroid hormone system. In addition, evidence from animal and in vitro
studies considered relevant in this context was taken into account along with
their strengths and limitations. Key factors influencing the biological effects
of isoflavones, e.g., bioavailability, plasma and tissue concentrations,
metabolism, temporality (pre- vs. postmenopausal women), and duration of
isoflavone exposure, were also addressed. Final conclusions on the safety of
isoflavones are guided by the aim of precautionary consumer protection.
DOI: 10.1007/s00204-018-2279-8
PMCID: PMC6132702
Conflict of interest statement: The authors declare that they have no conflict
of interest.
265. Cancer Epidemiol Biomarkers Prev. 2018 Nov;27(11):1371-1375. doi:
10.1158/1055-9965.EPI-18-0283. Epub 2018 Aug 21.
Soy Isoflavone Intake and Bladder Cancer Risk in Japan: From the Takayama Study.
Wada K(1), Tsuji M(2)(3), Tamura T(2)(4), Konishi K(2), Goto Y(2), Mizuta F(2),
Koda S(2), Uji T(2), Hori A(5), Tanabashi S(6), Matsushita S(7), Tokimitsu N(6),
Nagata C(2).
Author information:
(1)Department of Epidemiology and Preventive Medicine, Gifu University Graduate
School of Medicine, Gifu, Japan. dr_keiko@gifu-u.ac.jp.
(2)Department of Epidemiology and Preventive Medicine, Gifu University Graduate
School of Medicine, Gifu, Japan.
(3)Department of Food Science and Nutrition, Nagoya Women's University, Nagoya,
Japan.
(4)Department of Preventive Medicine, Nagoya University Graduate School of
Medicine, Nagoya, Japan.
(5)Directer, Kumiai Kosei Hospital, Gifu, Japan.
(6)Department of Internal Medicine, Takayama Red Cross Hospital, Gifu, Japan.
(7)Department of Radiology, Takayama Red Cross Hospital, Gifu, Japan.
Background: There is growing evidence suggesting that soy isoflavones play a

protective role in the development of cancer. However, few epidemiological
studies have investigated the association between soy isoflavone intake and
bladder cancer.Methods: We evaluated the associations of soy and isoflavone
intakes with bladder cancer incidence in a population-based prospective study in
Japan. Subjects were 14,233 men and 16,584 women age 35 years or older in
September 1992. Soy and isoflavone intakes were assessed via a validated
food-frequency questionnaire, while controlling for total energy intake. Cancer
incidence was mainly confirmed through regional population-based cancer
registries. Bladder cancer was defined as code C67 according to the
International Classification of Diseases and Health Related Problems, 10th
Revision.Results: During mean follow-up of 13.6 years, 120 men and 41 women had
developed bladder cancer. After adjustments for multiple confounders, compared
with the lowest quartile of soy food intake, the estimated hazard ratios for the
second, third, and highest quartiles of soy food intake were 0.74, 0.52, and
0.55, respectively, in men (P-trend: 0.023). The corresponding values were 0.60,
0.75, and 0.64, respectively, in women (P-trend: 0.43). Similar inverse
associations were observed between isoflavone intake and bladder cancer
risk.Conclusions: A significant decreased risk of bladder cancer was observed
among men who had higher intakes of total soy and isoflavones.Impact: Our
finding on the potential benefit of consuming soy foods against bladder cancer
is promising and warrants further studies. Cancer Epidemiol Biomarkers Prev;
27(11); 1371-5. ©2018 AACR.
DOI: 10.1158/1055-9965.EPI-18-0283
266. Pharmaceuticals (Basel). 2018 Aug 14;11(3):78. doi: 10.3390/ph11030078.
Isolation and Structural Characterization of Bioactive Molecules on Prostate

Cancer from Mayan Traditional Medicinal Plants.
Fort RS(1), Trinidad Barnech JM(2)(3), Dourron J(4), Colazzo M(5),

Aguirre-Crespo FJ(6), Duhagon MA(7)(8), Álvarez G(9).
Author information:
(1)Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad
de la República, Montevideo, C.P. 11400, Uruguay. rfort@fcien.edu.uy.
de la República, Montevideo, C.P. 11400, Uruguay.
juan.manuel.trinidad13@gmail.com.
(3)Laboratorio de Moléculas Bioactivas, CENUR Litoral Norte, Universidad de la
República, Ruta 3 (km 363), Paysandú, C.P. 60000, Uruguay.
juan.manuel.trinidad13@gmail.com.
juli.dourron@gmail.com.
(5)Departamento de Química del Litoral, CENUR Litoral Norte, Universidad de la
República, Paysandú, C.P. 60000, Uruguay. mcolazzo@gmail.com.
(6)Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Campeche,
Campeche, C.P. 24039, Mexico. fjaguirr@uacam.mx.
de la República, Montevideo, C.P. 11400, Uruguay. mduhagon@fmed.edu.uy.
(8)Departamento de Genética, Facultad de Medicina, Universidad de la República,
Montevideo, C.P. 11800, Uruguay. mduhagon@fmed.edu.uy.
guzmanalvarezlqo@gmail.com.
Prostate cancer is the most common cancer in men around the world. It is a
complex and heterogeneous disease in which androgens and their receptors play a
crucial role in the progression and development. The current treatment for
prostate cancer is a combination of surgery, hormone therapy, radiation and
chemotherapy. Therapeutic agents commonly used in the clinic include steroidal
and non-steroidal anti-androgens, such as cyproterone acetate, bicalutamide and
enzalutamide. These few agents have multiple adverse effects and are not 100%
effective. Several plant compounds and mixtures, including grape seed polyphenol
extracts, lycopene and tomato preparations, soy isoflavones, and green tea
extracts, have been shown to be effective against prostate cancer cell growth.
In vivo activity of some isolated compounds like capsaicin and curcumin was
reported in prostate cancer murine models. We prepared a library of plant
extracts from traditional Mayan medicine. These plants were selected for their
use in the contemporaneous Mayan communities for the treatment of different
diseases. The extracts were assessed in a phenotypic screening using LNCaP
prostate cancer androgen sensitive cell line, with a fixed dose of 25 μg/mL. MTT
assay identified seven out of ten plants with interesting anti-neoplastic
activity. Extracts from these plants were subjected to a bioguided fractionation
to study their major components. We identified three compounds with
anti-neoplastic effects against LNCaP cells, one of which shows selectivity for
neoplastic compared to benign cells.
DOI: 10.3390/ph11030078
PMCID: PMC6160984
PMID: 30110911
267. Eur J Med Chem. 2018 Aug 5;156:554-562. doi: 10.1016/j.ejmech.2018.07.017.

Epub
2018 Jul 9.
Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli
antagonists bearing the isoflavone scaffold.
Berardozzi S(1), Bernardi F(2), Infante P(3), Ingallina C(4), Toscano S(4), De
Paolis E(1), Alfonsi R(2), Caimano M(2), Botta B(4), Mori M(5), Di Marcotullio
L(6), Ghirga F(3).
Author information:
(1)Department of Chemistry and Technology of Drugs, Sapienza University of Rome,
Piazzale Aldo Moro 5, 00185 Rome, Italy; Center for Life Nano Science@Sapienza,
Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.
(2)Department of Molecular Medicine, Sapienza University of Rome, Viale Regina
Elena 291, 00161 Rome, Italy.
(3)Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale
Regina Elena 291, 00161 Rome, Italy.
(4)Department of Chemistry and Technology of Drugs, Sapienza University of Rome,
Piazzale Aldo Moro 5, 00185 Rome, Italy.
(5)Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale
Regina Elena 291, 00161 Rome, Italy. Electronic address: mattia.mori@iit.it.
(6)Department of Molecular Medicine, Sapienza University of Rome, Viale Regina
Elena 291, 00161 Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti,
Sapienza University of Rome, 00161 Rome, Italy. Electronic address:
lucia.dimarcotullio@uniroma1.it.
Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset
and progression of several malignancies. Small molecules able to block the
pathway at the upstream receptor Smoothened (Smo) or the downstream effector
Gli1 have thus emerged recently as valuable anticancer agents. Here, we have
designed, synthesized, and tested new Hh inhibitors taking advantage by the
highly versatile and privileged isoflavone scaffold. The introduction of
specific substitutions on the isoflavone's ring B allowed the identification of
molecules targeting preferentially Smo or Gli1. Biological assays coupled with
molecular modeling corroborated the design strategy, and provided new insights
into the mechanism of action of these molecules. The combined administration of
two different isoflavones behaving as Smo and Gli antagonists, respectively, in
primary medulloblastoma (MB) cells highlighted the synergistic effects of these
agents, thus paving the way to further and innovative strategies for the
pharmacological inhibition of Hh signaling.
DOI: 10.1016/j.ejmech.2018.07.017
268. Drug Metab Rev. 2018 Aug;50(3):343-356. doi: 10.1080/03602532.2018.1485691.

Epub
2018 Jul 16.
Insights into the intestinal bacterial metabolism of flavonoids and the

bioactivities of their microbe-derived ring cleavage metabolites.
Feng X(1), Li Y(1)(2), Brobbey Oppong M(1)(2), Qiu F(1)(2).
Author information:
(1)a School of Traditional Chinese Medicine , Tianjin University of Traditional
Chinese Medicine , Tianjin , China.
(2)b Tianjin State Key Laboratory of Modern Chinese Medicine , Tianjin
University of Traditional Chinese Medicine , Tianjin , China.
Flavonoids are a group of phytochemicals widely distributed in plants, fruits,
and vegetables that possess numerous bioactivities. After oral administration,
flavonoids can be metabolized by the intestinal bacteria into a wide range of
low-molecular-weight phenolic acids. In this review, the intestinal bacterial
metabolic pathways of different flavonoids (flavones, isoflavones, flavonols,
flavanones, and chalcones) and the bioactivities of their microbe-derived ring
cleavage metabolites are summarized. Flavonoids undergo different intestinal
bacterial metabolic reactions, depending on the characteristics of their
structure. Free hydroxyl groups, especially 5 and 4' free hydroxyl groups play
significant roles in fission metabolism. Microbe-derived ring cleavage
metabolites such as 3,4-dihydroxyphenylacetic acid (3,4-DHPAA) and
3,4-dihydroxytoluene (3,4-DHT) possess various bioactivities including
antioxidant, anti-inflammatory, antidiabetic, neuroprotective, and anti-colon
cancer effects. Also, the intestinal bacteria associated with the bacterial
metabolism of flavonoids are covered in this review.
DOI: 10.1080/03602532.2018.1485691
269. Drug Metab Lett. 2018;12(2):138-144. doi: 10.2174/1872312812666180709150440.
Genistein Affects Expression of Cytochrome P450 (CYP450) Genes in Hepatocellular

Carcinoma (HEPG2/C3A) Cell Line.
Lepri SR(1), Sartori D(2), Semprebon SC(1), Baranoski A(1), Coatti GC(3),
Mantovani MS(1).
Author information:
(1)Departamento de Biologia Geral, Universidade Estadual de Londrina (UEL),
Londrina, Parana, Brazil.
(2)Departamento de Bioquimica, Universidade Estadual de Londrina (UEL),
Londrina, Parana, Brazil.
(3)Instituto de Biociencias. Centro de Pesquisas sobre o Genoma Humano e
Celulas-Tronco, Universidade de Sao Paulo (USP), Sao Paulo, Brazil.
BACKGROUND: Genistein (5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one)

is the most abundant isoflavone in soybean, which has been associated with a
lower risk of development of cancer and cardiovascular diseases. Of particular
interest regarding cancer preventive properties of flavonoids is their
interaction with cytochrome P450 enzymes (CYPs). However, contradictory data
report the effect of genistein on expression of СYPs enzymes.
OBJECTIVE: The aim of this study was to investigate the effects of genistein on
cytochrome P450 (CYP) gene expression levels in human hepatocellular carcinoma
(HepG2/C3A) and colon adenocarcinoma (HT29) cells.
METHODS: Real-time RT-PCR was used to examine the expression of genes families
involved in xenobiotic metabolism, such as CYP1 (CYP1A1, CYP1B1), CYP2 (CYP2E1,
CYP2D6), CYP3 (CYP3A4); and of a family involved in the catabolism of the
all-trans-retinoic acid (ATRA), CYP26 (CYP26A1, CYP26B1).
RESULTS: RT-qPCR data analysis showed that after 12 h of exposure of HepG2/C3A
cells to genistein (5 and 50 µM) there was an upregulation of CYP1A1 and CYP1B1
and downregulation of CYP2D6, CYP26A1 and CYP26B1 mRNA levels. There was no
change in the mRNA levels of CYP P450 genes in HT29 cells.
CONCLUSION: Our results suggest that treatment with genistein in non-toxic
concentrations may impact the expression level of CYPs involved in the
biotransformation of xenobiotics and drug metabolizing enzymes. Moreover, the
downregulation of ATRA metabolism-related genes opens a new research path for
the study of genistein as retinoic acid metabolism blocking agent for treating
cancer and other pathologies.
epub@benthamscience.org.
DOI: 10.2174/1872312812666180709150440
PMCID: PMC6350198
270. Int J Cancer. 2018 Dec 1;143(11):2677-2686. doi: 10.1002/ijc.31640. Epub 2018
Sep 29.
Circulating isoflavone and lignan concentrations and prostate cancer risk: a

meta-analysis of individual participant data from seven prospective studies
including 2,828 cases and 5,593 controls.
Perez-Cornago A(1), Appleby PN(1), Boeing H(2), Gil L(3)(4), Kyrø C(5), Ricceri
F(6)(7), Murphy N(8), Trichopoulou A(9), Tsilidis KK(10)(11), Khaw KT(12), Luben
RN(12), Gislefoss RE(13), Langseth H(13), Drake I(14), Sonestedt E(14),
Wallström P(14)(15), Stattin P(16), Johansson A(17), Landberg R(18)(19), Nilsson
LM(19)(20), Ozasa K(21), Tamakoshi A(22), Mikami K(23), Kubo T(24), Sawada
N(25), Tsugane S(25), Key TJ(1), Allen NE(26)(27), Travis RC(1).
Author information:
(1)Cancer Epidemiology Unit, Nuffield Department of Population Health,
University of Oxford, Oxford, United Kingdom.
(2)Department of Epidemiology, German Institute of Human Nutrition
Potsdam-Rehbrücke, Nuthetal, Germany.
(3)Public Health Division of Gipuzkoa-BIODONOSTIA, Basque Regional Health
Department, San Sebastian, Spain.
(4)CIBER of Epidemiology and Public Health, Madrid, Spain.
(5)Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen,
Denmark.
(6)Department of Clinical and Biological Sciences, University of Turin, Turin,
Italy.
(7)Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Italy.
(8)Section of Nutrition and Metabolism, International Agency for Research on
Cancer, Lyon, France.
(9)Hellenic Health Foundation, Athens, Greece.
(10)Department of Epidemiology and Biostatistics, School of Public Health,
Imperial College London, London, United Kingdom.
(11)Department of Hygiene and Epidemiology, University of Ioannina School of
Medicine, Ioannina, Greece.
(12)Department of Public Health and Primary Care, University of Cambridge,
Cambridge, United Kingdom.
(13)Department of Research, Cancer Registry of Norway, Oslo, Norway.
(14)Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden.
(15)Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
(16)Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
(17)Nutritional Research and Molecular Periodontology, Umeå University, Umeö,
Sweden.
(18)Department of Biology and Biological Engineering, Food and Nutrition
Science, Chalmers University of Technology, Gothenburg, Sweden.
(19)Department of Public Health and Clinical Medicine, Nutritional Research,
Umeå University, Umeå, Sweden.
(20)Arctic Research Centre, Umeå University, Umeå, Sweden.
(21)Department of Epidemiology, Radiation Effects Research Foundation,
Minami-ku, Hiroshima, Japan.
(22)Department of Public Health, Hokkaido University Graduate School of
Medicine, Kita-ku, Sapporo, Japan.
(23)Department of Urology, Kyoto Prefectural University of Medicine Graduate
School of Medical Science, Kamikgyo-ku, Kyoto, Japan.
(24)Department of Preventive Medicine and Community Health, University of
Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan.
(26)Clinical Trial Service Unit, Nuffield Department of Population Health, Big
Data Institute, University of Oxford, Oxford, United Kingdom.
(27)Epidemiological Studies Unit, Nuffield Department of Population Health, Big
Data Institute, University of Oxford, Oxford, United Kingdom.
Phytoestrogens may influence prostate cancer development. This study aimed to

examine the association between prediagnostic circulating concentrations of
isoflavones (genistein, daidzein, equol) and lignans (enterolactone and
enterodiol) and the risk of prostate cancer. Individual participant data were
available from seven prospective studies (two studies from Japan with 241 cases
and 503 controls and five studies from Europe with 2,828 cases and 5,593
controls). Because of the large difference in circulating isoflavone
concentrations between Japan and Europe, analyses of the associations of
isoflavone concentrations and prostate cancer risk were evaluated separately.
Prostate cancer risk by study-specific fourths of circulating concentrations of
each phytoestrogen was estimated using multivariable-adjusted conditional
logistic regression. In men from Japan, those with high compared to low
circulating equol concentrations had a lower risk of prostate cancer
(multivariable-adjusted OR for upper quartile [Q4] vs. Q1 = 0.61, 95% confidence
interval [CI] = 0.39-0.97), although there was no significant trend (OR per 75
percentile increase = 0.69, 95 CI = 0.46-1.05, ptrend = 0.085); Genistein and
daidzein concentrations were not significantly associated with risk (ORs for Q4
vs. Q1 = 0.70, 0.45-1.10 and 0.71, 0.45-1.12, respectively). In men from Europe,
circulating concentrations of genistein, daidzein and equol were not associated
with risk. Circulating lignan concentrations were not associated with the risk
of prostate cancer, overall or by disease aggressiveness or time to diagnosis.
There was no strong evidence that prediagnostic circulating concentrations of
isoflavones or lignans are associated with prostate cancer risk, although
further research is warranted in populations where isoflavone intakes are high.
© 2018 The Authors. International Journal of Cancer published by John Wiley &
Sons Ltd on behalf of UICC.
DOI: 10.1002/ijc.31640
PMCID: PMC6283047
271. Nutrients. 2018 Jun 30;10(7):853. doi: 10.3390/nu10070853.
Neuroprotective Effects of Soy Isoflavones on Scopolamine-Induced Amnesia in

Mice.
Lu C(1)(2), Wang Y(3), Wang D(4), Zhang L(5), Lv J(6), Jiang N(7), Fan B(8), Liu
X(9), Wang F(10).
Author information:
Sciences (CAAS), Beijing 100193, China. lucong198912@126.com.
(2)Research Center for Pharmacology & Toxicology, Institute of Medicinal Plant
Development (IMPLAD), Chinese Academy of Medical Sciences (CAMS) and Peking
Union Medical College (PUMC), Beijing 100193, China. lucong198912@126.com.
Sciences (CAAS), Beijing 100193, China. wy198565@163.com.
Sciences (CAAS), Beijing 100193, China. wangdonghui01@caas.cn.
Sciences (CAAS), Beijing 100193, China. zhanglijingg@126.com.
Union Medical College (PUMC), Beijing 100193, China. jwlv000@163.com.
Union Medical College (PUMC), Beijing 100193, China. jiangning0603@163.com.
Sciences (CAAS), Beijing 100193, China. fanbei517@163.com.
Union Medical College (PUMC), Beijing 100193, China. xmliu@implad.ac.cn.
Sciences (CAAS), Beijing 100193, China. wangfengzhong@sina.com.
In the recent years, interest in soybean as a neuroprotective nutrient in the

management of Alzheimer’s disease (AD) has increased and soy isoflavones
(SI), as kinds of soybean phytochemicals, are thought to be biologically active
components that confer this beneficial effect against neurodegenerative
diseases. However, the neuroprotective effect of SI is not well understood.
Therefore, the present study (30 days) was conducted to investigate the
neuroprotective effects of soy isoflavones (SI) on scopolamine (SCOP)-induced
memory impairments in Institute of Cancer Research (ICR) mice (aged 4 weeks) and
to elucidate its underlying mechanisms of action. SI (40 mg/kg) administration
improved the cognitive performance of SCOP-treated mice in an object location
recognition task and the Morris water maze test. SI (40 mg/kg) administration
significantly enhanced cholinergic system function and suppressed oxidative
stress levels in the hippocampus of SCOP-treated mice. Furthermore, SI (40
mg/kg) treatment markedly upregulated the phosphorylation levels of
extracellular signal-regulated kinase (ERK), cAMP response element-binding
protein (CREB) and brain-derived neurotrophic factor (BDNF) expression levels in
the hippocampus. Taken together, these results demonstrated that soy isoflavones
exerted a significant neuroprotective effect on cognitive dysfunctions induced
by scopolamine, suggesting that soy isoflavones could be a good candidate for
possible treatment of neurodegenerative diseases, such as Alzheimer’s
disease (AD).
DOI: 10.3390/nu10070853
PMCID: PMC6073222
272. Front Microbiol. 2018 Jun 4;9:1182. doi: 10.3389/fmicb.2018.01182. eCollection

2018.
To Construct an Engineered (S)-Equol Resistant E. coli for in Vitro (S)-Equol

Production.
Li H(1)(2)(3), Mao S(3), Chen H(1)(2), Zhu L(2), Liu W(2), Wang X(2), Yin
Y(1)(2).
Author information:
(1)Key Laboratory of Comprehensive Utilization of Advantage Plants Resources in
Hunan South, College of Chemistry and Bioengineering, Hunan University of
Science and Engineering, Yongzhou, China.
(2)State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and Disease
Control, Institute of Plant Protection and Microbiology, Zhejiang Academy of
Agricultural Sciences, Hangzhou, China.
(3)Hunan Provincial Key Laboratory for Forestry Biotechnology, College of Life
Science and Technology, Central South University of Forestry and Technology,
Changsha, China.
(S)-equol is one of the major metabolites of daidzein that is produced by human

and animal gut bacteria. Most of the physiological functions of soybean
isoflavones, such as anti-oxidative activity, anti-cancer activity, and
cardiovascular protection have been ascribed to (S)-equol. However, only 30-50%
people contain this kind of equol-producing bacteria, and therefore are able to
convert daidzein to (S)-equol. Administration of (S)-equol may be more
beneficial than soybean isoflavones. The aim of this study was to construct an
engineered (S)-equol resistant Escherichia coli to enhance (S)-equol production
in vitro. First, transposon mutagenesis libraries were constructed and screened
to isolate the (S)-equol resistant mutant E. coli strain BL21 (ydiS) in order to
overcome the inhibitory effects of (S)-equol on bacterial growth. Bacterial full
genome scan sequencing and in vitro overexpression results revealed that the
ydiS gene was responsible for this resistance. Second, the (S)-equol-producing
genes L-dznr, L-ddrc, L-dhdr, and L-thdr of Lactococcus strain 20-92 were
synthesized and cloned into compatible vectors, pETDuet-1 and pCDFDuet-1. These
plasmids were subsequently transformed into BL21 (DE3) and its mutant BL21
(ydiS). Both engineered BL21 (DE3) and BL21 (ydiS) could use daidzein as
substrate to produce (S)-equol under both anaerobic and aerobic conditions. As
expected, engineered BL21 (ydiS) had faster growth rates than BL21 (DE3) when
supplemented with high concentrations of (S)-equol. The yield and the daidzein
utilization ratio were higher for engineered BL21 (ydiS). Interestingly,
engineered BL21 (ydiS) was able to convert daidzein to (S)-equol efficiently
under aerobic conditions, providing a convenient method for (S)-equol production
in vitro. In addition, a two-step method was developed to produce (S)-equol
using daidzin as substrate.
DOI: 10.3389/fmicb.2018.01182
PMCID: PMC5994542
PMID: 29915570
273. Food Nutr Res. 2018 May 11;62. doi: 10.29219/fnr.v62.1384. eCollection 2018.
Genistein and daidzein induce apoptosis of colon cancer cells by inhibiting the
accumulation of lipid droplets.
Liang YS(1)(2), Qi WT(1), Guo W(1), Wang CL(2), Hu ZB(3), Li AK(1).
Author information:
(1)1Cereals & Oils Nutrition Research Group, Academy of State Administration of
Grain (ASAG), Beijing, The People's Republic of China.
(2)2Key Laboratory of Food Safety and Sanitation, Ministry of Education, College
of Food Engineering and Biotechnology, Tianjin University of Science and
Technology, Tianjin, The People's Republic of China.
(3)3Institute for In Vitro Diagnostic Reagents Control, The National Institutes
for Food and Drug Control (NIFDC), Beijing, The People's Republic of China.
AIM: The purpose of this study was to investigate the possible mechanisms of
genistein (GEN) and daidzein (DAI) in inducing apoptosis of colon cancer cells
by inhibition of lipid droplets (LDs) accumulation.
METHODS: HT-29 cells were used and treated by GEN or DAI in this paper. LDs
accumulation was induced and inhibited by oleic acid (OA) and C75, respectively.
The expression changes of LDs-related markers were confirmed by semiquantitative
real time-PCR (RT-PCR), Western blotting, and immunofluorescence staining.
RESULTS: GEN and DAI effectively reduced the LDs accumulation and downregulated
the expression of Perilipin-1, ADRP and Tip-47 family proteins and vimentin
levels. GEN and DAI significantly induced the mRNA expression of PPAR-γ, Fas,
FABP, glycerol-3-phosphate acyltransferase (GPAT3), and microsomal TG transfer
protein (MTTP), and reduced the mRNA expression of UCP2. Furthermore, the
results showed a decrease of PI3K expression by GEN and DAI when compared with
OA treatment, and both GEN and DAI can increase the expression of FOXO3a and
caspase-8 significantly when these proteins were decreased by OA treatment. GEN
is more effective than DAI in inducing cell apoptosis.
CONCLUSION: Our results demonstrated that GEN and DAI inhibit the accumulation
of LDs by regulating LDs-related factors and lead to a final apoptosis of colon
cancer cells. These results may provide important new insights into the possible
molecular mechanisms of isoflavones in anti-obesity and anti-tumor functions.
DOI: 10.29219/fnr.v62.1384
PMCID: PMC5965345
PMID: 29849534
Conflict of interest statement: The authors have not received any funding or
benefits from industry or elsewhere to conduct this study.
274. J Parasit Dis. 2018 Jun;42(2):151-161. doi: 10.1007/s12639-018-0984-0. Epub

2018
Mar 5.
Genistein: is the multifarious botanical a natural anthelmintic too?
Tandon V(1), Das B(2).
Author information:
(1)Biotech Park, Jankipuram Sector G, Kursi Road, Lucknow, 226021 India.
(2)2Department of Zoology, North-Eastern Hill University, Shillong, Meghalaya
793022 India.
Genistein (4',5,7-trihydroxyisoflavone) is naturally present in plants of the

soy family and is known to have various pharmacological activities, such as
anti-cancer, anti-diabetic, anti-oxidant, etc. The phytoestrogen is one of the
major isoflavones found in some medicinal plants having anthelmintic properties.
This review describes the putative role of genistein as an anthelmintic, which
has been tested on some helminth parasites in vitro. Genistein has been shown to
cause paralysis and alterations in the tegument and tegumental enzymes (acid
phosphatase, alkaline phosphatase, adenosine triphosphatase, and
5'-nucleotidase) of helminth parasites. Alterations in the activities of several
enzymes associated with the coordination system (specifically non-specific
esterases, acetylcholine esterase, and nitric oxide synthase), and changes in
the concentration of nitric oxide, cGMP, free amino acid pool, and tissue
ammonia are observed in helminth parasites treated with genistein. The
phytoestrogen also affects the carbohydrate metabolism by altering the
activities of key enzymes involved in glycogen- and glucose-metabolism of a
cestode parasite. Considering the significance of phosphoenolpyruvate
carboxykinase (PEPCK) in glycolysis of the cestode parasite, Ki of the
phytoestrogen for PEPCK in the parasite has been determined, and molecular
docking of genistein into the active site of the enzyme has also been described.
The potential beneficial role of genistein as a natural alternative in
management of helminth parasites needs to be further explored, particularly
considering its in vivo efficacy and pharmacokinetics.
DOI: 10.1007/s12639-018-0984-0
PMCID: PMC5962493
PMID: 29844617
Conflict of interest statement: Compliance with ethical standardsThe authors

declare that they have no conflicts of interest.
275. Curr Drug Metab. 2019;20(1):46-53. doi: 10.2174/1389200219666180427170213.
Soy Isoflavones and their Effects on Xenobiotic Metabolism.
Zhou T(1), Meng C(1), He P(1).
Author information:
(1)State Key Laboratory of Animal Nutrition, College of Animal Science and
Technology, China Agricultural University, Beijing, China.
BACKGROUND: Soy isoflavones, such as genistein and daidzein, are bioflavonoids

found in soy products that are able to interact with various hormones such as
estrogen. Epidemiological studies reveal a proper level of isoflavones in diet
can prevent many diseases like cancers or diabetes. Therefore, it is important
to study the biotransformation and xenobiotic metabolism of soy isoflavones.
METHODS: A systematic review of published studies was carried out to investigate
the characterization of isoflavones and their metabolites, sample pretreatment
and quantitative analysis of isoflavones, and the influence of soy isoflavones
on drug and xenobiotic metabolism.
RESULTS: Aglycones with weak estrogen-like activities are the biologically
active forms of the soy isoflavones in mammals. The most recent advances
including extraction, purification and detection of isoflavones in soybean and
soy products are discussed. The effects of soy isoflavones on drug and
xenobiotic metabolism involve in regulation of phase I cytochrome P450 (CYPs)
enzyme and phase I detoxifying enzymes expression and activity. At the molecular
level, soy isoflavones have proved capable of estrogenic/antiestrogenic with
tissue-selective, anti-cancer, antiobesity, anti-oxidation, and tyrosine kinase
inhibition activities.
CONCLUSION: This review summarized different aspects of soy isoflavones and
their molecular mechanisms of pharmacological action on xenobiotic, which
demonstrated that soy isoflavones can decrease the incidence of many diseases
and benefit for human health. However, since the lack of clinical research for
evaluation of the proper dosage of intake of soy isoflavones in diet or
adjunctive therapy, there is a need for further studies on the selection of
doses, biomedical applications and adverse effects of isoflavones for human
health.

DOI: 10.2174/1389200219666180427170213
276. BMC Public Health. 2018 Apr 17;18(1):510. doi: 10.1186/s12889-018-5424-7.
The association between dietary isoflavones intake and gastric cancer risk: a
meta-analysis of epidemiological studies.
You J(1), Sun Y(1), Bo Y(1), Zhu Y(1), Duan D(1), Cui H(1), Lu Q(2).
Author information:
(1)Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou
University, Zhengzhou, 450001, Henan, China.
(2)Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou
University, Zhengzhou, 450001, Henan, China. lqjnutr@zzu.edu.cn.
BACKGROUND: Isoflavones, a class of phytoestrogenic compounds, are abundant in

soybeans. A number of epidemiological studies have investigated the association
between dietary isoflavones intake and the risk of gastric cancer. However, the
results are inconclusive. Therefore, the meta-analysis was conducted to evaluate
the effect of dietary isoflavones intake on the risk of gastric cancer.
METHODS: Relevant studies from May 1992 to May 2017 were identified through
searching PubMed and Web of Science. Additional articles were identified from
the reference lists of relevant review articles. Pooled risk ratios (RRs) or
odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a
fixed-effects model. Funnel plot and Egger's test were used to evaluate
publication bias.
RESULTS: Seven articles reporting 12 studies were included in the current
meta-analysis. We found no significant association between dietary isoflavones
intake and gastric cancer risk with the highest versus the lowest categories of
dietary isoflavones intake (OR = 0.97, 95% CI = 0.87-1.09, I2 = 27.5%). Subgroup
analyses generally yield similar results.
CONCLUSIONS: Higher dietary isoflavones intake is not associated with a decline
in the risk of gastric cancer.
DOI: 10.1186/s12889-018-5424-7
PMCID: PMC5905165
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not

applicable. COMPETING INTERESTS: The authors declare that they have no competing
interests. PUBLISHER’S NOTE: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
277. Nat Prod Res. 2019 Sep;33(18):2609-2617. doi: 10.1080/14786419.2018.1462179.

Epub 2018 Apr 16.
Cytotoxic flavonoids from two Lonchocarpus species.
Adem FA(1)(2), Kuete V(2)(3), Mbaveng AT(2)(3), Heydenreich M(4), Koch A(4),
Ndakala A(1), Irungu B(5), Yenesew A(1), Efferth T(2).
Author information:
(1)a Department of Chemistry , University of Nairobi , Nairobi , Kenya.
(2)b Department of Pharmaceutical Biology, Institute of Pharmacy and
Biochemistry , Johannes Gutenberg University , Mainz , Germany.
(3)c Faculty of Science, Department of Biochemistry , University of Dschang ,
Dschang , Cameroon.
(4)d Institute of Chemistry , University of Potsdam , Potsdam , Germany.
(5)e Centre for Traditional Medicine and Drug Research , Kenya Medical Research
Institute , Nairobi , Kenya.
A new isoflavone, 4'-prenyloxyvigvexin A (1) and a new pterocarpan,

(6aR,11aR)-3,8-dimethoxybitucarpin B (2) were isolated from the leaves of
Lonchocarpus bussei and the stem bark of Lonchocarpus eriocalyx, respectively.
The extract of L. bussei also gave four known isoflavones, maximaisoflavone H,
7,2'-dimethoxy-3',4'-methylenedioxyisoflavone,
6,7,3'-trimethoxy-4',5'-methylenedioxyisoflavone, durmillone; a chalcone,
4-hydroxylonchocarpin; a geranylated phenylpropanol, colenemol; and two known
pterocarpans, (6aR,11aR)-maackiain and (6aR,11aR)-edunol. (6aR,11aR)-Edunol was
also isolated from the stem bark of L. eriocalyx. The structures of the isolated
compounds were elucidated by spectroscopy. The cytotoxicity of the compounds was
tested by resazurin assay using drug-sensitive and multidrug-resistant cancer
cell lines. Significant antiproliferative effects with IC50 values below 10 μM
were observed for the isoflavones
6,7,3'-trimethoxy-4',5'-methylenedioxyisoflavone and durmillone against leukemia
CCRF-CEM cells; for the chalcone, 4-hydroxylonchocarpin and durmillone against
its resistant counterpart CEM/ADR5000 cells; as well as for durmillone against
the resistant breast adenocarcinoma MDA-MB231/BCRP cells and resistant
gliobastoma U87MG.ΔEGFR cells.
DOI: 10.1080/14786419.2018.1462179
Identification by Molecular Docking ofHomoisoflavones from Leopoldia comosa as

Ligands of Estrogen Receptors.
Grande F(1), Rizzuti B(2), Occhiuzzi MA(3), Ioele G(4), Casacchia T(5), Gelmini
F(6), Guzzi R(7)(8), Garofalo A(9), Statti G(10).
Author information:
(1)Department of Pharmacy, Health and Nutritional Sciences, University of
Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Rende (CS), Italy.
fedora.grande@unical.it.
(2)CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics,
University of Calabria, Via P. Bucci, 87036 Rende (CS), Italy.
bruno.rizzuti@cnr.it.
mariaantonietta.occhiuzzi@unical.it.
giuseppina.ioele@unical.it.
teresa.casacchia@unical.it.
(6)Department of Environmental Science and Policy-ESP, University of Milan, Via
Celoria 2, 20133 Milan, Italy. fabrizio.gelmini@unimi.it.
(7)CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics,
University of Calabria, Via P. Bucci, 87036 Rende (CS), Italy.
rita.guzzi@fis.unical.it.
(8)Department of Physics, University of Calabria, Via P. Bucci, 87036 Rende
(CS), Italy. rita.guzzi@fis.unical.it.
antonio.garofalo@unical.it.
giancarlo.statti@unical.it.
The physiological responses to estrogen hormones are mediated within specific
tissues by at least two distinct receptors, ER and ER. Several natural and
synthetic molecules show activity by interacting with these proteins. In
particular, a number of vegetal compounds known as phytoestrogens shows
estrogenic or anti-estrogenic activity. The majority of these compounds belongs
to the isoflavones family and the most representative one, genistein, shows
anti-proliferative effects on various hormone-sensitive cancer cells, including
breast, ovarian and prostate cancer. In this work we describe the identification
of structurally related homoisoflavones isolated from Leopoldia comosa (L.)
Parl. (L. comosa), a perennial bulbous plant, potentially useful as hormonal
substitutes or complements in cancer treatments. Two of these compounds have
been selected as potential ligands of estrogen receptors (ERs) and the
interaction with both isoforms of estrogen receptors have been investigated
through molecular docking on their crystallographic structures. The results
provide evidence of the binding of these compounds to the target receptors and
their interactions with key residues of the active sites of the two proteins,
and thus they could represent suitable leads for the development of novel tools
for the dissection of ER signaling and the development of new pharmacological
treatments in hormone-sensitive cancers.
PMCID: PMC6017050
279. Am J Transl Res. 2018 Mar 15;10(3):784-795. eCollection 2018.
Novasoy and genistein inhibit endometrial cancer cell proliferation through

disruption of the AKT/mTOR and MAPK signaling pathways.
Malloy KM(1)(2), Wang J(3), Clark LH(2)(4), Fang Z(2)(3), Sun W(2), Yin Y(2),
Kong W(3), Zhou C(2)(4), Bae-Jump VL(2)(4).
Author information:
(1)Virginia Tech/Carilion Clinic, Department of Obstetrics and
GynecologyBlacksburg, VA.
(2)Division of Gynecologic Oncology, University of North Carolina at Chapel
HillChapel Hill, NC. USA.
(3)Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology
Hospital, Capital Medical UniversityBeijing, P. R. China.
(4)Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel HillChapel Hill, NC. USA.
OBJECTIVES: Excess estrogen states, such as those generated by obesity, have

long been associated with the development of type I endometrial cancers.
Epidemiological studies have linked consumption of isoflavones with a decreased
incidence of endometrial malignancy. Thus, our goal was to assess the effect of
the isoflavones, novasoy and genistein, on cell proliferation, cell cycle,
apoptosis, progesterone receptor (PR) and estrogen receptor-alpha (ERα)
expression and the AKT/mTOR and MAPK pathways in endometrial cancer cells.
METHODS: The endometrial cancer cell lines ECC-1 and RL-95-2 were used. Cell
proliferation was assessed with MTT assay after exposure to novasoy and
genistein at varying concentrations. Cell cycle progression was analyzed by flow
cytometry. Apoptosis was assessed by flow cytometery for annexin V expression
and ELISA for caspase-3 activity. Expression of ERα, PR and hTERT mRNA were
evaluated using real time RT-PCR. Western immunoblotting was performed to
evaluate the effects of novasoy and genistein on the AKT/mTOR and MAPK signaling
pathways.
RESULTS: Novasoy and genistein inhibited cell growth in a dose-dependent manner
in both cell lines through induction of cell cycle G2 arrest and apoptosis.
Treatment with novasoy and genistein decreased hTERT expression in a
dose-dependent manner. Genistein decreased ERα mRNA expression while increasing
PR expression. Genistein induced phosphorylation of p42/44 in a dose dependent
manner in both cell lines but reduced phosphorylation of S6 in only the RL-95-2
cells.
CONCLUSIONS: Novasoy and genistein inhibited cell proliferation through varying
pathways in different cell lines but included decreased ERα expression and
subsequent alteration in the expression of proteins upstream and downstream of
the AKT/mTOR and MAPK pathways. Thus, isoflavones may be a promising therapeutic
agent in the treatment and prevention of endometrial cancer.
PMCID: PMC5883119
PMID: 29636868
Conflict of interest statement: None.
280. J Biomol Struct Dyn. 2019 Apr;37(6):1511-1519. doi:

10.1080/07391102.2018.1461687. Epub 2018 May 4.
Docking, steered molecular dynamics, and QSAR studies as strategies for studying
isoflavonoids as 5-, 12-, and 15-lipoxygenase inhibitors.
Cabezas F(1), Mascayano C(1).
Author information:
(1)a Laboratorio de Simulación Molecular y Diseño Racional de Fármacos, Facultad
de Química y Biología, Departamento de Ciencias del Ambiente , Universidad de
Santiago de Chile , Santiago , Chile .
Lipoxygenases (LOX) are enzymes that catalyze polyunsaturated fatty acid

peroxidation and have a non-heme iron atom located in their active site. They
are implicated in the arachidonic acid pathway and involved in inflammation,
fever, pain production, and in the origins of several diseases such as cancer,
asthma, and psoriasis. The search for inhibitors of these enzymes has emerged in
the last years, and isoflavonoids have a broad spectrum of biological activity
with low cytotoxicity. Our previous results have shown that isoflavonoids
inhibited different LOX isoforms in vitro. For this reason, we studied the most
important interactions that govern the potency and selectivity of some
isoflavones and isoflavans toward different LOX isoforms using computational
methods. The docking results have shown that all the molecules can be located in
different zones in the LOX active site. Steered molecular dynamics indicated
that selectivity was present at the cavity entry, but not at its exit. We also
observed the correlation between the potential mean force and the best (HIR-303)
and worst inhibitors (IR-213) in 5-LOX. Finally, structure-activity relationship
(QSAR) studies showed a good correlation between theoretical IC50 values and
experimental data for 5-LOX and 12-LOX with 96 and 95%, respectively, and a
lower correlation for 15-LOX (79%). Conclusively, pharmacophore analysis showed
that our proposed molecules should possess a donor-acceptor and aromatic centers
to encourage interactions in the active site.
DOI: 10.1080/07391102.2018.1461687
281. Arch Biochem Biophys. 2018 May 15;646:107-112. doi: 10.1016/j.abb.2018.03.022.

Epub 2018 Mar 23.
Research trends in flavonoids and health.
Perez-Vizcaino F(1), Fraga CG(2).
Author information:
(1)Departamento de Farmacología, Facultad de Medicina, Universidad Complutense
de Madrid, 28040 Madrid, Spain; Ciber Enfermedades Respiratorias (Ciberes),
Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IISGM).
Madrid, Spain. Electronic address: fperez@med.ucm.es.
(2)Fisicoquimica, Facultad de Farmacia y Bioquímica, Universidad de Buenos
Aires, Buenos Aires, Argentina; Instituto de Bioquímica y Medicina Molecular
(IBIMOL), Universidad de Buenos Aires-Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Department of
Nutrition, University of California, Davis, CA, 95616, USA.
Herein we describe, based on some bibliometric data, how the field of research
on flavonoids has evolved over the last 25 years. The number of papers on
flavonoids has risen in an exponential manner over these years, much faster than
other fields on food constituents. This increase appears to be related to the
contemporary explosion of interest in healthy foods, supplements and
nutraceuticals. It was also probably triggered by large epidemiological studies
on fruits and vegetables, and particularly on flavonoids, consumption and
incidence of cancer, stroke and coronary heart disease. The widely distributed
flavonols constitute the flavonoid subgroup upon which the greatest interest has
been focused, followed by flavanols and more recently by anthocyanidins and
other related polyphenols such as resveratrol. Research on isoflavones rapidly
emerged in the 1990s but plateaued in the 2000s. In the 1990s flavonoids were
mainly considered as the active components of medicinal plants, while from 2000
onward, they switched to be mainly regarded as bioactive food ingredients. We
envision a continuation in the growth of research for the coming decade focused
on clearly demonstrating the importance of flavonoids for human health.
DOI: 10.1016/j.abb.2018.03.022
282. Int J Prev Med. 2018 Feb 8;9:12. doi: 10.4103/ijpvm.IJPVM_249_16. eCollection
2018.
Effect of Genistein on Apoptosis and Proliferation of Hepatocellular Carcinoma

Hepa1-6 Cell Line.
Sanaei M(1), Kavoosi F(1), Valiani A(2), Ghobadifar MA(3).
Author information:
(1)Research Center for Noncommunicable Diseases, Jahrom University of Medical
Sciences, Jahrom, Iran.
(2)Department of Anatomical Sciences and Molecular Biology, Medical School,
Isfahan University of Medical Sciences, Isfahan, Isfahan Province, Iran.
(3)Department of Student Research Committee, Jahrom University of Medical
Sciences, Jahrom, Iran.
BACKGROUND: One of the main causes of mortality is hepatocellular carcinoma

(HCC) which accounts for the third leading cause of deaths and one in forty
deaths worldwide. The flavonoids, natural antioxidant compounds, account for a
major group of polyphenolic compounds. One of the major isoflavones in soybean
is genistein (GE) which can inhibit proliferation and induce apoptosis.
Isoflavones, major type of phenolic materials, derived from dietary plants and
medicinal herbs play a significant role in cancer prevention and treatment.
Correlation between dietary habits and cancer risk including breast, prostate,
and colon cancer has been reported. Various bioactivities of these compounds
such as anticarcinogenic and antioxidant are responsible for their
chemopreventive activities by which induce migration, proliferation, cell cycle
arrest, and apoptosis. GE, one of the major isoflavones, is considered as a
potent chemopreventive agent against cancer. The aim of this study was to
investigate the inhibitory and apoptotic effects of GE on HCC Hepa1-6 cell line.
METHODS: Cell viability assay and cell cycle analysis with flow cytometry were
used to evaluate proliferative and apoptotic effect GE.
RESULTS: GE inhibited the growth of Hepa1-6 cells and induced apoptosis with a
concentration and time-dependent fashion. During GE treatment for 24, the half
maximal inhibitory concentration (IC50) was 20 μM, and the maximum inhibition of
cell growth was 52% (P < 0.01). The percentage of apoptotic cells with a
concentration of 20 μM of GE after 24, 48, and 72 h was 35, 42, and 65%,
respectively (P < 0.01).
CONCLUSIONS: Our finding clearly indicated that GE can significantly inhibit
proliferation of hepatocellular carcinoma Hepa 1-6 cell line and induce
apoptosis in this cell line.
DOI: 10.4103/ijpvm.IJPVM_249_16
PMCID: PMC5843956
PMID: 29541427
Conflict of interest statement: There are no conflicts of interest.
283. BMC Complement Altern Med. 2018 Mar 9;18(1):83. doi: 10.1186/s12906-018-2148-
2.
Extract from Astragalus membranaceus inhibit breast cancer cells proliferation

via PI3K/AKT/mTOR signaling pathway.
Zhou R(1), Chen H(1), Chen J(1), Chen X(2), Wen Y(2), Xu L(3).
Author information:
(1)Department of Chest and Breast Surgery, Xiamen Hospital of Traditional
Chinese Medicine, Fujian University of Traditional Chinese Medicine, 1739
Xianyue Road, Xiamen, 361009, People's Republic of China.
(2)Department of Pharmacy, Xiamen Hospital of Traditional Chinese Medicine,
Fujian University of Traditional Chinese Medicine, 1739 Xianyue Road, Xiamen,
361009, People's Republic of China.
(3)Department of Science and Education, Xiamen Hospital of Traditional Chinese
Medicine, Fujian University of Traditional Chinese Medicine, 1739 Xianyue Road,
Xiamen, 361009, People's Republic of China. xuleqin@163.com.
BACKGROUND: Astragalus membranaceus (AM) is a commonly used herb in traditional

Chinese medicine (TCM), which has been used as an essential tonic to treat
various diseases for more than 2000 years. In this study, we aimed to
investigate the biological effects of extract from AM on breast cancer cell and
its mechanism.
METHODS: To prepare the extract, dried AM were ground and extracted with water
extraction-ethanol supernatant method. Then the main isoflavones in the extract
was detect by HPLC analysis. Furthermore, the anti-proliferative activity of AM
extract was examined by MTT assay and morphological observation. Cell apoptosis
was evaluated with flow cytometric analysis. The expressions of total and
phosphorylated PI3K, GS3Kβ, Akt and mTOR were determined by western blot
analysis.
RESULTS: HPLC analysis demonstrated that AM extract contained with four kinds of
isoflavones, campanulin, ononin, calycosin and formononetin. The MTT test and
morphological observation indicated that cells proliferation of MCF-7, SK-BR-3
and MDA-MB-231were inhibited by AM extract in a dose dependent manner.
Furthermore, flow cytometric analysis displayed that after treated with 25 μg/ml
and 50 μg/ml AM extract, apoptosis of breast cancer cells was significantly
increased as compared with DMSO and blank control group (all p < 0.05). Western
blot analysis found that the level of p-PI3K, p-GS3Kβ, p-Akt, and p-mTOR were
significantly decreased, but the level of total-mTOR was observably increased as
compared with DMSO control group.
CONCLUSIONS: Taken together, the inhibited cell proliferation and induced cell
apoptosis effect of AM extract via PI3K/AKT/mTOR pathway confirmed the
anti-tumor potential of AM. Therefore, our findings provide a new insight into
anti-cancer effect of AM extract as a promising agent in breast cancer
treatment.
DOI: 10.1186/s12906-018-2148-2
PMCID: PMC5845298
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not

applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
284. Exp Oncol. 2017 Jul;39(2):98-105.
Current epidemiological knowledge about the role of flavonoids in prostate

carcinogenesis.
Sak K(1).
Author information:
(1)NGO Praeventio, Näituse 22-3, Tartu 50407, Estonia.
Numerous experimental studies have demonstrated anticancer action of

polyphenolic plant metabolites. However, data about associations between dietary
intake of plant-derived flavonoids and prostate cancer risk are still sparse and
inconsistent. This minireview compiles the epidemiological findings published to
date on the role of flavonoids in prostate tumorigenesis, discusses the reasons
of inconsistencies and elicits the promising results for chemoprevention of this
malignancy. Long-term consumption of high doses of soy isoflavones can be the
reason of markedly lower clinically detectable prostate cancer incidence among
Asian men compared to their counterparts in the Western world. The ability to
metabolize daidzein to equol, the most biologically active isoflavone, by the
certain intestinal bacteria also seems to contribute to this important health
benefit. The increasing incidence rate of prostate cancer related to adoption of
westernized lifestyle and dietary habits makes the issue of chemoprevention ever
more important and directs the eyes to specific food components in the Eastern
diet. If further large-scale epidemiological studies will confirm the protective
effects of isoflavones against prostate cancer, this could provide an important
way for prostate cancer prevention, as diet is a potentially modifiable factor
in our behavioral pattern.

285. Nat Prod Res. 2019 Jan;33(2):212-218. doi: 10.1080/14786419.2018.1443096. Epub
2018 Feb 22.
Two new prenylated isoflavones from Maclura cochinchinensis collected in Hoa

Binh province Vietnam.
Chien TV(1), Anh NT(1), Thanh NT(1), Thao TTP(1), Loc TV(1), Sung TV(1).
Author information:
(1)a Institute of Chemistry , Academy of Science and Technology (VAST) , Hanoi ,
Vietnam.
Two new prenylisoflavones,

3',4',5-trihydroxy-8-prenyl-dihydrofuran[2″,3″:7,6]isoflavone (1) and
4',5-dihydroxy-8-prenyl-dihydrofuran[2″,3″:7,6]isoflavone (2), along with five
known prenylisoflavones (3-7), benzylalcohol-4-O-β-d-glucoside (8) and two
cinnamic acid esters (9, 10) were isolated from the leaves of Maclura
cochinchinensis (Cudrania cochinchinensis). Their structures were elucidated by
analysis of NMR (1H-, 13C-NMR, HSQC, HMBC), MS spectra and comparison with the
published data. Compounds 4-10 were the first time isolated from this species.
Prenylisoflavones 1-4 and 6-7 were evaluated for their in vitro cytotoxic
activity on KB and HepG2 cancer cell lines. Compound 4 showed cytotoxic activity
against both cancer cell lines with IC50 values of 26.99 and 19.95 μM,
respectively. The other compounds were considered as inactive.
DOI: 10.1080/14786419.2018.1443096
286. Curr Pharmacol Rep. 2017 Dec;3(6):423-446. doi: 10.1007/s40495-017-0113-2.

Epub
2017 Oct 14.
Plant flavone apigenin: An emerging anticancer agent.
Shankar E(1)(2), Goel A(3), Gupta K(1)(2), Gupta S(1)(2)(4)(5)(6).
Author information:
(1)Department of Urology, The James and Eilleen Dicke Laboratory, Case Western
Reserve University, Cleveland, OH 44106, USA.
(2)Department of Urology, The Urology Institute, University Hospitals Cleveland
Medical Center, Cleveland, OH 44106, USA.
(3)Department of Biology, School of Undergraduate Studies, Case Western Reserve
University, Cleveland, OH 44106, USA.
(4)Department of Nutrition, Case Western Reserve University, Cleveland, OH
44106, USA.
(5)Division of General Medical Sciences, Case Comprehensive Cancer Center,
Cleveland, OH 44106, USA.
(6)Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical
Center, Cleveland, OH 44106, USA.
Research in cancer chemoprevention provides convincing evidence that increased

intake of vegetables and fruits may reduce the risk of several human
malignancies. Phytochemicals present therein provide beneficial
anti-inflammatory and antioxidant properties that serve to improve the cellular
microenvironment. Compounds known as flavonoids categorized anthocyanidins,
flavonols, flavanones, flavonols, flavones, and isoflavones have shown
considerable promise as chemopreventive agents. Apigenin (4', 5,
7-trihydroxyflavone), a major plant flavone, possessing antioxidant,
anti-inflammatory, and anticancer properties affecting several molecular and
cellular targets used to treat various human diseases. Epidemiologic and
case-control studies have suggested apigenin reduces the risk of certain
cancers. Studies demonstrate that apigenin retain potent therapeutic properties
alone and/or increases the efficacy of several chemotherapeutic drugs in
combination on a variety of human cancers. Apigenin's anticancer effects could
also be due to its differential effects in causing minimal toxicity to normal
cells with delayed plasma clearance and slow decomposition in liver increasing
the systemic bioavailability in pharmacokinetic studies. Here we discuss the
anticancer role of apigenin highlighting its potential activity as a
chemopreventive and therapeutic agent. We also highlight the current caveats
that preclude apigenin for its use in the human trials.
DOI: 10.1007/s40495-017-0113-2
PMCID: PMC5791748
PMID: 29399439
Conflict of interest statement: Conflict of Interest The authors have no

competing interest.
287. Chin J Nat Med. 2017 Nov;15(11):871-880. doi: 10.1016/S1875-5364(18)30022-0.
Synthesis and cytotoxicity evaluation of 3-amino-2-hydroxypropoxygenistein

derivatives.
Geng XT(1), Tang JJ(2), Cheng KP(1), Fu YT(1), Hu R(3), Lu JR(4).
Author information:
(1)Department of Organic Chemistry, China Pharmaceutical University, Nanjing
210009, China.
(2)State Key Laboratory of Natrual Medicines, Department of Physiology, China
Pharmaceutical University, Nanjing 210009, China.
(3)State Key Laboratory of Natrual Medicines, Department of Physiology, China
Pharmaceutical University, Nanjing 210009, China. Electronic address:
ronghu@cpu.edu.cn.
(4)Department of Organic Chemistry, China Pharmaceutical University, Nanjing
210009, China. Electronic address: L_John81@sina.com.
Soy isoflavones exhibit various biological activities, such as antioxidant,

anti-tumor, anti-inflammatory, and cardiovascular protective effects. The
present study was designed to investigate the effects of sixteen synthesized
3-amino-2-hydroxypropoxy genistein derivatives on cell proliferation and
activation of Nrf2 (Nuclear factor erythroid 2-related factor 2)/ARE
(antioxidant response elements) pathway in human cancer cell lines. Most of the
tested compounds exerted greater cytotoxic activity than genistein, as measured
by MTT assay. Moreover, compound 8c showed the highest ARE-luciferase reporter
activity among the test compounds. It strongly promoted Nrf2 nuclear
translocation and up-regulated the expression of total Nrf2 and downstream
targets NQO-1 and HO-1 at protein level. The present study may provide a basis
for the application of isoflavone derivatives as Nrf2/ARE pathway inducers for
cancer therapy and cancer prevention.
Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All

rights reserved.
DOI: 10.1016/S1875-5364(18)30022-0
Soy, Soy Foods and Their Role in Vegetarian Diets.
Rizzo G(1), Baroni L(2).
Author information:
(1)Via Venezuela 66, 98121 Messina, Italy. gianlucarizzo@email.it.
(2)Primary Care Unit, Northern District, Local Health Unit 2, 31100 Treviso,
Italy. luciana_baroni@yahoo.it.
Soy is a basic food ingredient of traditional Asian cuisine used for thousands
of years. In Western countries, soybeans have been introduced about a hundred
years ago and recently they are mainly used for surrogate foods production. Soy
and soy foods are common nutritional solutions for vegetarians, due to their
high protein content and versatility in the production of meat analogues and
milk substitutes. However, there are some doubts about the potential effects on
health, such as the effectiveness on cardiovascular risk reduction or,
conversely, on the possible disruption of thyroid function and sexual hormones.
The soy components that have stimulated the most research interest are
isoflavones, which are polyphenols with estrogenic properties highly contained
in soybeans. In this review, we discuss the characteristics of soy and soy
foods, focusing on their nutrient content, including phytoestrogens and other
bioactive substances that are noteworthy for vegetarians, the largest soy
consumers in the Western countries. The safety of use will also be discussed,
given the growing trend in adoption of vegetarian styles and the new soy-based
foods availability.
DOI: 10.3390/nu10010043
PMCID: PMC5793271
Soy Consumption and the Risk of Prostate Cancer: An Updated Systematic Review
and Meta-Analysis.
Applegate CC(1), Rowles JL(2), Ranard KM(3), Jeon S(4), Erdman JW(5)(6).
Author information:
(1)Division of Nutritional Sciences, University of Illinois at Urbana-Champaign,
Urbana, IL 61801, USA. cca2@illinois.edu.
Urbana, IL 61801, USA. jrowles2@illinois.edu.
Urbana, IL 61801, USA. ranard2@illinois.edu.
Urbana, IL 61801, USA. sjeon17@illinois.edu.
Urbana, IL 61801, USA. jwerdman@illinois.edu.
(6)Department of Food Science and Human Nutrition, University of Illinois at
Urbana-Champaign, Urbana, IL 61801, USA. jwerdman@illinois.edu.
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men,
accounting for 15% of all cancers in men worldwide. Asian populations consume
soy foods as part of a regular diet, which may contribute to the lower PCa
incidence observed in these countries. This meta-analysis provides a
comprehensive updated analysis that builds on previously published
meta-analyses, demonstrating that soy foods and their isoflavones (genistein and
daidzein) are associated with a lower risk of prostate carcinogenesis. Thirty
articles were included for analysis of the potential impacts of soy food intake,
isoflavone intake, and circulating isoflavone levels, on both primary and
advanced PCa. Total soy food (p < 0.001), genistein (p = 0.008), daidzein (p =
0.018), and unfermented soy food (p < 0.001) intakes were significantly
associated with a reduced risk of PCa. Fermented soy food intake, total
isoflavone intake, and circulating isoflavones were not associated with PCa
risk. Neither soy food intake nor circulating isoflavones were associated with
advanced PCa risk, although very few studies currently exist to examine
potential associations. Combined, this evidence from observational studies shows
a statistically significant association between soy consumption and decreased
PCa risk. Further studies are required to support soy consumption as a
prophylactic dietary approach to reduce PCa carcinogenesis.
DOI: 10.3390/nu10010040
PMCID: PMC5793268
290. Clin Nutr. 2019 Feb;38(1):136-145. doi: 10.1016/j.clnu.2017.12.006. Epub 2017

Dec 15.
Dietary isoflavones or isoflavone-rich food intake and breast cancer risk: A

meta-analysis of prospective cohort studies.
Zhao TT(1), Jin F(1), Li JG(1), Xu YY(1), Dong HT(1), Liu Q(1), Xing P(1), Zhu
GL(2), Xu H(3), Miao ZF(4).
Author information:
(1)Department of Breast Surgery, First Hospital of China Medical University,
Shenyang, Liaoning Province, China.
(2)Department of Breast Surgery, Fifth People's Hospital of Shenyang, Shenyang,
Liaoning Province, China.
(3)Department of Medical Oncology, Shengjing Hospital of China Medical
University, Shenyang, Liaoning Province, China.
(4)Department of Surgical Oncology, First Hospital of China Medical University,
Shenyang, Liaoning Province, China. Electronic address: zfmiao@cmu.edu.cn.
BACKGROUND & AIMS: Previous studies implied that dietary isoflavone intake may
reduce the risk of developing breast cancer, but some have shown ambiguous
results. This study aimed to systematically evaluate and summarize available
evidence on the effect dietary isoflavone intake has on the risk of developing
breast cancer.
METHODS: PubMed, Embase, and the Cochrane Library were searched for prospective
cohort studies published through April 2017 that evaluated the effect of dietary
isoflavone intake on the development of breast cancer.
RESULTS: Sixteen prospective cohort studies, involving 11,169 breast cancer
cases and 648,913 participants, were identified and included in our data
analysis. The pooled relative risk (RR) of breast cancer was 0.99 for high
versus low intake of isoflavones (95% confidence interval [CI], 0.91-1.09;
P = 0.876) and 0.99 for moderate versus low intake of isoflavones (95%CI,
0.92-1.05; P = 0.653), with insignificant heterogeneity (P = 0.187 for high
versus low, and P = 0.192 for moderate versus low). While a moderate consumption
of soy-based foods did not significantly affect breast cancer risk, a high
intake of soy-based foods associated with a lower risk of developing breast
cancer. Considering specific foods, an increased the risk of developing breast
cancer was seen with a moderate intake of formononetin, but no significant
associations were found between breast cancer risk and other isoflavone-rich
diets.
CONCLUSIONS: The present meta-analysis indicates that women with a high dietary
intake of soy foods may experience a statistically significant reduction in
breast cancer risk. However, moderate formononetin consumption may increase the
risk of developing breast cancer.
Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and
Metabolism. All rights reserved.
DOI: 10.1016/j.clnu.2017.12.006
291. J Clin Diagn Res. 2017 Sep;11(9):FC13-FC16. doi:

10.7860/JCDR/2017/26034.10654.
Epub 2017 Sep 1.
The Effect of Soy Isoflavones on the Menopause Rating Scale Scoring in

Perimenopausal and Postmenopausal Women: A Pilot Study.
Ahsan M(1), Mallick AK(2).
Author information:
(1)Assistant Professor, Department of Pharmacology, Rohilkhand Medical College,
Bareilly, Uttar Pradesh, India.
(2)Associate Professor, Department of Biochemistry, Rohilkhand Medical College,
Bareilly, Uttar Pradesh, India.
INTRODUCTION: Menopause is associated with many unpleasant symptoms which vary

in different phases of menopausal transition. Although, Hormone Replacement
Therapy (HRT) is considered the most effective mode of treatment for these
symptoms, its use is associated with increased risk of breast cancer,
endometrial cancer and thromboembolic events. Soy isoflavones are being widely
used as a safer alternative to HRT, even though scientific evidence of their
efficacy is poor or lacking.
AIM: To study the effect of soy isoflavone supplementation on the menopausal
symptoms in perimenopausal and postmenopausal women.
MATERIALS AND METHODS: An observational pilot study was done involving 29
perimenopausal and 21 postmenopausal women prescribed 100 mg soy isoflavones for
12 weeks. Menopause Rating Scale (MRS) questionnaire was administered to the
patients before starting soy isoflavone therapy and at the end of treatment.
Responses were analysed using Statistical Package for Social Sciences (SPSS)
software 23.0.
RESULTS: Total score of both the groups were comparable at baseline. Among
perimenopausal women highest score was given to symptoms of psychological
domain. Urogenital symptoms were the worst among postmenopausal women. After 12
weeks of treatment, total scores improved significantly by 19.55% and 12.62% in
the perimenopausal and postmenopausal women respectively. The greatest
improvement was seen in scores of hot flashes for both the groups and the least
improvement was shown by symptoms of urogenital subscale.
CONCLUSION: Soy isoflavone improves the MRS score among both the perimenopausal
and postmenopausal women. As they are most effective for somatic and
psychological symptoms, their use could be beneficial during perimenopause.
DOI: 10.7860/JCDR/2017/26034.10654
PMCID: PMC5713750
PMID: 29207728
292. J Zhejiang Univ Sci B. 2017 Dec.;18(12):1101-1112. doi: 10.1631/jzus.B1700189.
Apoptosis induction of colorectal cancer cells HTL-9 in vitro by the transformed

products of soybean isoflavones by Ganoderma lucidum.
Cui ML(1), Yang HY(2)(3), He GQ(2)(3).
Author information:
(1)College of Food Science, Shanxi Normal University, Linfen 041004, China.
(2)College of Biosystems Engineering and Food Science, Zhejiang University,
Hangzhou 310058, China.
(3)Zhejiang Provincial Key Laboratory of Food Microbiology, Zhejiang University,
Hangzhou 310058, China.
Soybean isoflavones have been one of the potential preventive candidates for
antitumor research in recent years. In this paper, we first studied the
transformation of soybean isoflavones with the homogenized slurry of Ganoderma
lucidum. The resultant transformed products (TSI) contained (703.21±4.35) mg/g
of genistein, with transformed rates of 96.63% and 87.82% of daidzein and
genistein, respectively, and TSI also could enrich the bioactive metabolites of
G. lucidum. The antitumor effects of TSI on human colorectal cancer cell line
HTL-9, human breast cancer cell line MCF-7, and human immortalized gastric
epithelial cell line GES-1 were also studied. The
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay
showed that TSI could dramatically reduce the viability rates of HTL-9 cells and
MCF-7 cells without detectable cytotoxicity on GES-1 normal cells when the TSI
concentration was lower than 100 μg/ml. With 100 μg/ml of TSI, HTL-9 cells were
arrested in the G1 phase, and late-apoptosis was primarily induced, accompanied
with partial early-apoptosis. TSI could induce primarily early-apoptosis by
arresting cells in the G1 phase of MCF-7 cells. For HTL-9 cells, Western-blot
and reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed
that TSI (100 μg/ml) can up-regulate the expression of Bax, Caspase-3,
Caspase-8, and cytochrome c (Cyto-c), indicating that TSI could induce cell
apoptosis mainly through the mitochondrial pathway. In addition, the expression
of p53 was up-regulated, while the expression of Survivin and nuclear factor κB
(NF-κB) was down-regulated. All these results showed that TSI could induce
apoptosis of HTL-9 cells by the regulation of multiple apoptosis-related genes.
DOI: 10.1631/jzus.B1700189
PMCID: PMC5742293
Conflict of interest statement: Compliance with ethics guidelines: Mei-lin CUI,

Huan-yi YANG, and Guo-qing HE declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects
performed by any of the authors.
293. J Ethnopharmacol. 2018 Mar 25;214:37-46. doi: 10.1016/j.jep.2017.11.016. Epub

2017 Nov 29.
Potential cancer chemopreventive and anticancer constituents from the fruits of

Ficus hispida L.f. (Moraceae).
Zhang J(1), Zhu WF(2), Xu J(2), Kitdamrongtham W(3), Manosroi A(3), Manosroi
J(3), Tokuda H(4), Abe M(5), Akihisa T(6), Feng F(7).
Author information:
(1)Department of Natural Medicine Chemistry, China Pharmaceutical University, 24
Tongjiaxiang, Nanjing 210009, PR China; Key Laboratory of Biomedical Functional
Materials, China Pharmaceutical University, Nanjing 211198, PR China.
Tongjiaxiang, Nanjing 210009, PR China.
(3)Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.
(4)Division of Food Science and Biotechnology, Graduate School of Agriculture,
Kyoto University, Kyoto 606-8502, Japan.
(5)Research Institute for Science and Technology, Tokyo University of Science,
2641 Yamazaki, Noda, Chiba 278-8510, Japan.
(6)Research Institute for Science and Technology, Tokyo University of Science,
2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address:
akihisa_toshihiro@yahoo.co.jp.
Tongjiaxiang, Nanjing 210009, PR China; Key Laboratory of Biomedical Functional
Materials, China Pharmaceutical University, Nanjing 211198, PR China; Jiangsu
Food and Pharmaceutical Science College, Huaian, Jiangsu 223003, China.
Electronic address: fengfeng@cpu.edu.cn.
ETHNOPHARMACOLOGICAL RELEVANCE: Ficus hispida L.f. (Moraceae) has been used as

alternative for traditional medicine in the treatment of various ailments
including cancer-cure. The aim of this study was to evaluate the cancer
chemopreventive and anticancer activities of crude extracts of F. hispida, with
the objective to screen the inhibition of Epstein-Barr virus early antigen, and
cytotoxic active components, and provide foundation for potential applications
of this promising medical plant.
MATERIALS AND METHODS: Compounds were isolated from the MeOH extract of F.
hispida fruits, and their structure elucidation was performed on the basis of
extensive spectroscopic analysis. The isolated compounds were evaluated for
their inhibitory activities against the Epstein-Barr virus early antigen
(EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in
Raji cells, and cytotoxic activities against human cancer cell lines (HL60,
A549, SKBR3, KB, Hela, HT29, and HepG2) and a normal cell (LO2) using MTT
method. For the compound with potent cytotoxic activity, its apoptosis inducing
activity was evaluated by the observation of ROS generation level expression,
and membrane phospholipid exposure and DNA fragmentation in flow cytometry. The
mechanisms of the apoptosis induction were analyzed by Western blotting.
RESULTS: Nineteen compounds, 1-19, including two new isoflavones,
3'-formyl-5,7-dihydroxy-4'-methoxyisoflavone (2) and
5,7-dihydroxy-4'-methoxy-3'- (3-methyl-2-hydroxybuten-3-yl)isoflavone (3), were
isolated from the MeOH extract of F. hispida fruits. Five compounds,
isowigtheone hydrate (1), 2, 3, 9, and 19, showed potent inhibitory effects on
EBV-EA induction with IC50 values in the range of 271-340 molar ratio 32 pmol-1
TPA. In addition, five phenolic compounds, 1-3, 10, and 13, exhibited cytotoxic
activity against two or more cell lines (IC50 2.5-95.8μM), as well as compounds
1 and 3 were also displayed high selectivity for LO2/HepG2 (SI 23.5 and 11.8,
respectively), while the compound 1-induced ROS generation leads to activated
caspases-3, -8, and -9 apoptotic process in HL60 cells.
CONCLUSION: This study has established that the MeOH extract of F. hispida
fruits contains isoflavones, coumarins, caffeoylquinic acids, along with other
compounds including phenolics and steroid glucoside as active principles, and
has demonstrated that the chemical constituents of F. hispida may be valuable as
potential chemopreventive and anticancer agents.
DOI: 10.1016/j.jep.2017.11.016
294. Phytother Res. 2018 Mar;32(3):384-394. doi: 10.1002/ptr.5966. Epub 2017 Nov
29.
Comprehensive evaluation of the role of soy and isoflavone supplementation in

humans and animals over the past two decades.
Xiao Y(1), Zhang S(1), Tong H(1), Shi S(1)(2).
Author information:
(1)Poultry Institute, Chinese Academy of Agriculture Science, 58 Cangjie Road,
Yangzhou, 225125, Jiangsu, China.
(2)Jiangsu Co-innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, 225125, Jiangsu, China.
Soy and soy-based foods are considered healthy, particularly in many

Asia-Pacific countries, where soy products have long been consumed. Soy and
soy-related products have been found to help prevent the occurrence of
cardiovascular diseases and certain types of cancer, such as breast and prostate
cancer. These products can also have antioxidative effects that alleviate hot
flashes during menopause and bone loss. These biological and therapeutic
functions are primarily due to the isoflavones derived from soy, whose structure
is similar to the structure of 17-β-oestradiol. Despite the many health benefits
for humans and animals, the application of isoflavones remains controversial
because of their anti-oestrogenic properties. We focused on general information
regarding isoflavones, as well as their structure, function, and application. We
summarized evidence showing that dietary or supplemental isoflavones exert
protective effects on the health of humans and animals. Based on the literature,
we conclude that soy foods and isoflavones may be effective and safe; however,
more high-quality trials are needed to fully substantiate their potential use.
Copyright © 2017 John Wiley & Sons, Ltd.
DOI: 10.1002/ptr.5966
295. Int J Cancer. 2018 Feb 15;142(4):719-728. doi: 10.1002/ijc.31095. Epub 2017
Nov
8.
Dietary intake of isoflavones and coumestrol and the risk of prostate cancer in
the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.
Reger MK(1)(2), Zollinger TW(1), Liu Z(3), Jones JF(4), Zhang J(1)(5).
Author information:
(1)Department of Epidemiology, Indiana University Richard M. Fairbanks School of
Public Health, Indianapolis, IN.
(2)College of Health Professions, Ferris State University, Big Rapids, MI.
(3)Department of Biostatistics, Indiana University Richard M. Fairbanks School
of Public Health and School of Medicine, Indianapolis, IN.
(4)Department of Health Informatics, School of Informatics and Computing,
Indiana University-Purdue University Indianapolis, Indianapolis, IN.
(5)Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN.
Experimental studies have revealed that phytoestrogens may modulate the risk of
certain sites of cancer due to their structural similarity to 17β-estradiol. The
present study investigates whether intake of these compounds may influence
prostate cancer risk in human populations. During a median follow up of 11.5
years, 2,598 cases of prostate cancer (including 287 advanced cases) have been
identified among 27,004 men in the intervention arm of the Prostate, Lung,
Colorectal and Ovarian Cancer Screening Trial. Dietary intake of phytoestrogens
(excluding lignans) was assessed with a food frequency questionnaire. Cox
proportional hazards regression analysis was performed to estimate hazard ratios
(HRs) and 95% confidence intervals (CI) for dietary isoflavones and coumestrol
in relation to prostate cancer risk. After adjustment for confounders, an
increased risk of advanced prostate cancer [HR (95% CI) for quintile (Q) 5 vs.
Q1] was found for the dietary intake of total isoflavones [1.91 (1.25-2.92)],
genistein [1.51 (1.02-2.22), daidzein [1.80 (1.18-2.75) and glycitein [1.67
(1.15-2.43)] (p-trend for all associations ≤0.05). For example, HR (95% CI) for
comparing the Q2, Q3, Q4 and Q5 with Q1 of daidzein intake was 1.45 (0.93-2.25),
1.65 (1.07-2.54), 1.73 (1.13-2.66) and 1.80 (1.18-2.75), respectively (p-trend:
0.013). No statistically significant associations were observed between the
intake of total isoflavones and individual phytoestrogens and non-advanced and
total prostate cancer after adjustment for confounders. This study revealed that
dietary intake of isoflavones was associated with an elevated risk of advanced
prostate cancer.
© 2017 UICC.
DOI: 10.1002/ijc.31095
296. Nutr Cancer. 2017 Nov-Dec;69(8):1300-1307. doi: 10.1080/01635581.2017.1367945.

Epub 2017 Nov 2.
Equol Enhances Apoptosis-inducing Activity of Genistein by Increasing Bax/Bcl-xL

Expression Ratio in MCF-7 Human Breast Cancer Cells.
Ono M(1), Ejima K(1), Higuchi T(1), Takeshima M(1), Wakimoto R(1), Nakano S(1).
Author information:
(1)a Graduate School of Health and Nutritional Sciences, Nakamura Gakuen
University , Fukuoka , Fukuoka , Japan.
Anticancer activities of soy isoflavones, such as genistein and equol, a

bioactive metabolite of daidzein, have been extensively studied because of
possible involvement in the prevention of breast cancer. However, their
interactions still remain unclear. We investigated here whether cytotoxic
activity of genistein was enhanced by equol, using estrogen receptor positive
MCF-7, HER2-positive SK-BR-3, and triple-negative MDA-MB-468 cell lines.
Although cytotoxicity of genistein did not significantly differ between three
subtypes of breast cancer cells, cytotoxic activities of genistein were
significantly enhanced in combination with 50 μM equol in MCF-7 cells, but not
in SK-BR-3 and MDA-MB-468 cells. In fluorescence activated cell sorting (FACS)
analyses, MCF-7 cells were arrested at the G2/M by genistein but at G1/S by
equol. Combination treatment arrested cells at G2/M but abolished equol-induced
G1 block, indicating an antagonistic activity of genistein against equol in
cell-cycle progression. Although apoptosis was not so evident with genistein
alone, the combination made a drastic induction of apoptosis, accompanied by the
increase of Bax/Bcl-xL expression ratio, without affecting the activities of Akt
and mTOR. Taken together, these data suggest that enhancement of genistein
activity by equol would be mainly mediated by augmented induction of apoptosis
rather than arrest or delay of the cell cycle.
DOI: 10.1080/01635581.2017.1367945
297. Front Pharmacol. 2017 Oct 5;8:699. doi: 10.3389/fphar.2017.00699. eCollection

2017.
The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast

Cancer Cells: A Targeted Metabolomics Approach.
Poschner S(1), Maier-Salamon A(1), Zehl M(2), Wackerlig J(3), Dobusch D(3),
Pachmann B(1), Sterlini KL(1), Jäger W(1)(4).
Author information:
(1)Division of Clinical Pharmacy and Diagnostics, Department of Pharmaceutical
Chemistry, University of Vienna, Vienna, Austria.
(2)Department of Analytical Chemistry, Faculty of Chemistry, University of
Vienna, Vienna, Austria.
(3)Division of Drug Design and Medicinal Chemistry, Department of Pharmaceutical
Chemistry, University of Vienna, Vienna, Austria.
(4)Vienna Metabolomics Center (VIME), University of Vienna, Vienna, Austria.
The beneficial effect of dietary soy food intake, especially for women diagnosed
with breast cancer, is controversial, as in vitro data has shown that the soy
isoflavones genistein and daidzein may even stimulate the proliferation of
estrogen-receptor alpha positive (ERα+) breast cancer cells at low
concentrations. As genistein and daidzein are known to inhibit key enzymes in
the steroid metabolism pathway, and thus may influence levels of active
estrogens, we investigated the impacts of genistein and daidzein on the
formation of estrogen metabolites, namely 17β-estradiol (E2),
17β-estradiol-3-(β-D-glucuronide) (E2-G), 17β-estradiol-3-sulfate (E2-S) and
estrone-3-sulfate (E1-S) in estrogen-dependent ERα+ MCF-7 cells. We found that
both isoflavones were potent inhibitors of E1 and E2 sulfation (85-95%
inhibition at 10 μM), but impeded E2 glucuronidation to a lesser extent (55-60%
inhibition at 10 μM). The stronger inhibition of E1 and E2 sulfation compared
with E2 glucuronidation was more evident for genistein, as indicated by
significantly lower inhibition constants for genistein [Kis: E2-S (0.32 μM) <
E1-S (0.76 μM) < E2-G (6.01 μM)] when compared with those for daidzein [Kis:
E2-S (0.48 μM) < E1-S (1.64 μM) < E2-G (7.31 μM)]. Concomitant with the
suppression of E1 and E2 conjugation, we observed a minor but statistically
significant increase in E2 concentration of approximately 20%. As the content of
genistein and daidzein in soy food is relatively low, an increased risk of
breast cancer development and progression in women may only be observed
following consumption of high-dose isoflavone supplements. Further long-term
human studies monitoring free estrogens and their conjugates are therefore
highly warranted to evaluate the potential side effects of high-dose genistein
and daidzein, especially in patients diagnosed with ERα+ breast cancer.
DOI: 10.3389/fphar.2017.00699
PMCID: PMC5633874
PMID: 29051735
298. BMC Public Health. 2017 Oct 10;17(1):800. doi: 10.1186/s12889-017-4819-1.

Is vegetarian diet associated with a lower risk of breast cancer in Taiwanese
women?
Chang YJ(1)(2), Hou YC(3), Chen LJ(4)(5), Wu JH(3), Wu CC(1)(2), Chang YJ(6)(7),
Chung KP(4).
Author information:
(1)School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan.
(2)Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical
Foundation, New Taipei City, Taiwan.
(3)Division of Nutrition, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical
Foundation, New Taipei City, Taiwan.
(4)Graduate Institute of Health Policy and Management, College of Public Health,
National Taiwan University, Taipei, Taiwan.
(5)Department of Ophthalmology, Heping Branch, Taipei City Hospital, Taipei,
Taiwan.
(6)Department of General Surgery, Zhongxing Branch, Taipei City Hospital,
No.145, Zhengzhou Rd., Datong District, Taipei, Taiwan.
yunjauchang2003@yahoo.com.tw.
(7)Department of General Surgery, National Taiwan University Hospital, Taipei,
Taiwan. yunjauchang2003@yahoo.com.tw.
BACKGROUND: Studies on the relationship between vegetarian diet and breast

cancer in Asian populations are limited. This study aimed to investigate the
relationship between vegetarian diet, dietary patterns, and breast cancer in
Taiwanese women.
METHODS: This case-control study compared the dietary patterns of 233 breast
cancer patients and 236 age-matched controls. A questionnaire about vegetarian
diets and 28 frequently-consumed food items was administered to these 469
patients in the surgical department of Taipei Tzu Chi Hospital. Serum
biochemical status was also examined.
RESULTS: There were no significant differences between the two groups for age,
education, family history, oral contraceptive usage, or regular exercise.
However, the cancer group presented with both a higher body mass index and an
older age of primiparity (P < 0.05). Two food items (shellfish and seafood) were
highly correlated (correlation coefficient = 0.77), so shellfish was excluded to
avoid multicollinearity. A factor analysis of 27 food items produced five
dietary patterns: meat, processed meat, fruit/vegetable/soybean, dessert/sugar,
and fermented food. Multivariate logistic regression showed that meat/fat and
processed meat dietary patterns were associated with breast cancer risk (odds
ratio (OR): 2.22, 95% CI 1.67-2.94, P < 0.001; OR: 1.49, 95% CI 1.09-2.04,
P = 0.013, respectively). Vegetarian diet, high isoflavone intake, and high
albumin levels were inversely associated with breast cancer risk (P < 0.05).
Vegetarians had a higher daily soy isoflavone intake than non-vegetarians
(25.9 ± 25.6 mg vs. 18.1 ± 15.6 mg, P < 0.001).
CONCLUSIONS: Vegetarian diets show as protective role against breast cancer
risk, while meat and processed meat dietary patterns are associated with a
higher breast cancer risk.
DOI: 10.1186/s12889-017-4819-1
PMCID: PMC5635543
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The

institutional review board of Taipei Tzu Chi Hospital approved this survey and
signed consent sheets were obtained from all participants (01-XD22–047). All
procedures performed in this study involving human participants were conducted
in accordance with the ethical standards of the institutional review board of
Taipei Tzu Chi Hospital and the tenets of the Declaration of Helsinki. CONSENT
FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that
they have no competing interests. PUBLISHER’S NOTE: Springer Nature remains
neutral with regard to jurisdictional claims in published maps and institutional
affiliations.
299. Chem Res Toxicol. 2017 Nov 20;30(11):2084-2092. doi:

10.1021/acs.chemrestox.7b00237. Epub 2017 Oct 19.
Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists
Enhance Genotoxic Estrogen Metabolism.
Dunlap TL(1), Howell CE(1), Mukand N(1), Chen SN(1), Pauli GF(1), Dietz BM(1),
Bolton JL(1).
Author information:
(1)UIC/NIH Center for Botanical Dietary Supplements Research, Department of
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of
Illinois at Chicago , 833 S. Wood Street, Chicago, Illinois 60612-7231, United
States.
Many women consider botanical dietary supplements (BDSs) as safe alternatives to

hormone therapy for menopausal symptoms. However, the effect of BDSs on breast
cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway,
P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized
to genotoxic quinones that initiate and promote breast cancer. In contrast, P450
1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current
study evaluated the effects of red clover, a popular BDS used for women's
health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein
(GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen
metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS, and CYP1A1 and CYP1B1
gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial
cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from
normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract
(RCE, 10 μg/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A
cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression
and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments
with the isoflavones showed that the AhR agonists (BA, FN) preferentially
induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN,
DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism.
Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced
XRE-luciferase reporter activity and reversed GN and DZ induced downregulation
of CYP1A1 expression. Overall, these studies show that red clover and its
isoflavones have differential effects on estrogen metabolism in "normal" vs
breast cancer cells. In breast cancer cells, the AhR agonists stimulate
genotoxic metabolism, and the ER agonists downregulate the detoxification
pathway. These data may suggest that especially breast cancer patients should
avoid red clover and isoflavone based BDSs when making choices for menopausal
symptom relief.
DOI: 10.1021/acs.chemrestox.7b00237
PMCID: PMC5698877

interest.
300. Nutr Rev. 2017 Aug 1;75(8):616-641. doi: 10.1093/nutrit/nux021.
Association of isoflavone biomarkers with risk of chronic disease and mortality:

a systematic review and meta-analysis of observational studies.
Rienks J(1), Barbaresko J(1), Nöthlings U(1).
Author information:
(1)Department of Nutrition and Food Sciences, Group of Nutritional Epidemiology,
University of Bonn, Bonn, North Rhine-Westphalia, Germany.
CONTEXT: Isoflavones have been suggested to play a role in disease prevention.

The accuracy of assessing exposure to isoflavones might be improved by using
them as biomarkers.
OBJECTIVE: A systematic review of observational studies on the association of
isoflavone biomarkers with the risk of chronic disease and mortality was
conducted. Meta-analyses of specific biomarker and disease combinations were
performed.
DATA SOURCES: PubMed and Web of Science databases were searched.
DATA EXTRACTION: Two authors screened the titles and abstracts of candidate
publications. The third author was consulted to resolve discrepancies. Forty
studies were included and their quality assessed. PRISMA-P guidelines were
followed.
DATA ANALYSIS: Eight different isoflavone biomarkers were investigated in
association with cancer (26 studies), mortality (2 studies), cardiovascular
disease (3 studies), metabolic syndrome risk factors (7 studies), and other
outcomes (2 studies). Meta-analyses of studies on individual isoflavonic
compounds were conducted for breast and prostate cancer and type 2 diabetes.
Higher daidzein and genistein concentrations were associated with lower risk of
breast cancer and diabetes. Only daidzein concentrations were inversely
associated with risk of prostate cancer. For the remaining endpoints, evidence
for associations was inconsistent and scarce, perhaps owing to heterogeneity in
study exposures and outcomes.
CONCLUSIONS: Further research using biomarker information is warranted.

International Life Sciences Institute. All rights reserved. For Permissions,
DOI: 10.1093/nutrit/nux021
Phytoestrogen Concentrations in Human Urine as Biomarkers for Dietary

Phytoestrogen Intake in Mexican Women.
Chávez-Suárez KM(1), Ortega-Vélez MI(2), Valenzuela-Quintanar AI(3),

Galván-Portillo M(4), López-Carrillo L(5), Esparza-Romero J(6), Saucedo-Tamayo
MS(7), Robles-Burgueño MR(8), Palma-Durán SA(9), Gutiérrez-Coronado ML(10),
Campa-Siqueiros MM(11), Grajeda-Cota P(12), Caire-Juvera G(13).
Author information:
(1)Department of Nutrition, Section of Public Nutrition and Health, Centro de
Investigación en Alimentación y Desarrollo, A.C. (CIAD), Carretera a La Victoria
km 0.6, 83304 Hermosillo, Sonora, Mexico. kamachasu@gmail.com.
km 0.6, 83304 Hermosillo, Sonora, Mexico. iortega@ciad.mx.
(3)Department of Food Sciences, Centro de Investigación en Alimentación y
Desarrollo, A.C. (CIAD), Carretera a La Victoria km 0.6, 83304 Hermosillo,
Sonora, Mexico. aquintanar@ciad.mx.
(4)Center for Population Health Research, Instituto Nacional de Salud Pública,
Universidad No. 655, Colonia Santa María Ahuacatitlán, Cerrada Los Pinos y
Caminera, 62100 Cuernavaca, Morelos, Mexico. mgalvan@insp.mx.
(5)Center for Population Health Research, Instituto Nacional de Salud Pública,
Universidad No. 655, Colonia Santa María Ahuacatitlán, Cerrada Los Pinos y
Caminera, 62100 Cuernavaca, Morelos, Mexico. lizbeth@insp.mx.
km 0.6, 83304 Hermosillo, Sonora, Mexico. julian@ciad.mx.
km 0.6, 83304 Hermosillo, Sonora, Mexico. coco@ciad.mx.
Sonora, Mexico. cuquis@ciad.mx.
Sonora, Mexico. sussypalmaa@gmail.com.
Sonora, Mexico. lulu@ciad.mx.
km 0.6, 83304 Hermosillo, Sonora, Mexico. melita379@hotmail.com.
Sonora, Mexico. grajeda@ciad.mx.
km 0.6, 83304 Hermosillo, Sonora, Mexico. gcaire@ciad.mx.
There has been substantial interest in phytoestrogens, because of their

potential effect in reducing cancer and heart disease risk. Measuring
concentrations of phytoestrogens in urine is an alternative method for
conducting epidemiological studies. Our objective was to evaluate the urinary
excretion of phytoestrogens as biomarkers for dietary phytoestrogen intake in
Mexican women. Participants were 100 healthy women from 25 to 80 years of age. A
food frequency questionnaire (FFQ) and a 24 h recall were used to estimate
habitual and recent intakes of isoflavones, lignans, flavonols, coumestrol,
resveratrol, naringenin, and luteolin. Urinary concentrations were measured by
liquid chromatography (HPLC) coupled to mass spectrometry (MS) using the
electrospray ionization interface (ESI) and diode array detector (DAD)
(HPLC-DAD-ESI-MS). Spearman correlation coefficients were used to evaluate
associations between dietary intake and urine concentrations. The habitual
consumption (FFQ) of total phytoestrogens was 37.56 mg/day. In urine, the higher
compounds were naringenin (60.1 µg/L) and enterolactone (41.7 µg/L). Recent
intakes (24 h recall) of isoflavones (r = 0.460, p < 0.001), lignans (r = 0.550,
p < 0.0001), flavonoids (r = 0.240, p < 0.05), and total phytoestrogens (r =
0.410, p < 0.001) were correlated to their urinary levels. Total phytoestrogen
intakes estimated by the FFQ showed higher correlations to urinary levels (r =
0.730, p < 0.0001). Urinary phytoestrogens may be useful as biomarkers of
phytoestrogen intake, and as a tool for evaluating the relationship of intake
and disease risk in Mexican women.
DOI: 10.3390/nu9101078
PMCID: PMC5691695
302. Asian Pac J Cancer Prev. 2017 Sep 27;18(9):2309-2328. doi:

10.22034/APJCP.2017.18.9.2309.
Epidemiological Evidences on Dietary Flavonoids and Breast Cancer Risk: A

Narrative Review.
Sak K(1).
Author information:
(1)NGO Praeventio, Näituse 22-3, Tartu 50407, Estonia. Email:
katrin.sak.001@mail.ee
Epidemiological studies on associations between intake of flavonoids and breast

cancer risk are highly needed to assess the actual effects of flavonoids in
humans. Experimental investigations in vitro conditions cannot detect and model
the real action of these phytochemicals due to the limitations to consider
absorption and metabolic biotransformation as well as several complex
interactions. Therefore, the data about association findings between intake of
flavonoids and breast cancer risk are compiled and analyzed in the current
review by evaluating both the results obtained using food composition databases
as well as different biomarkers. Although several case-control studies
demonstrate some reduction in breast cancer risk related to high consumption of
flavones and flavonols, large-scale prospective cohort studies with follow-up
times of many years do not confirm these findings. Intake of isoflavones can be
associated with a decrease in breast tumorigenesis only in Asian countries where
the consumption of soy foods is high but not among Western women with
significantly lower ingestion amounts, suggesting the presence of so-called
threshold level of effect. Besides doses, the timing of exposure to isoflavones
seems also to be a significant factor as childhood and prepubertal age can be
critical periods. Although women may need to consume high amounts of isoflavones
typical to Asian diets to gain beneficial effects and protection against mammary
carcinogenesis, it is still too early to give any specific recommendations to
prevent breast tumors by diet rich in certain flavonoids.
Creative Commons Attribution License
DOI: 10.22034/APJCP.2017.18.9.2309
PMCID: PMC5720631
PMID: 28950673
303. Medicines (Basel). 2017 Apr 7;4(2):18. doi: 10.3390/medicines4020018.
Dietary Isoflavones and Breast Cancer Risk.
Ziaei S(1), Halaby R(2).
Author information:
(1)Department of Biology, Montclair State University, 1 Normal Avenue,
Montclair, NJ 07043, USA. ziaeis@montclair.edu.
(2)Department of Biology, Montclair State University, 1 Normal Avenue,
Montclair, NJ 07043, USA. halabyr@montclair.edu.
Breast cancer is the deadliest neoplasm in women globally, resulting in a
significant health burden. In many cases, breast cancer becomes resistant to
chemotherapy, radiation, and hormonal therapies. It is believed that genetics is
not the major cause of breast cancer. Other contributing risk factors include
age at first childbirth, age at menarche, age at menopause, use of oral
contraceptives, race and ethnicity, and diet. Diet has been shown to influence
breast cancer incidence, recurrence, and prognosis. Soy isoflavones have long
been a staple in Asian diets, and there appears to be an increase, albeit
modest, compared to Asian populations, in soy consumption among Americans.
Isoflavones are phytoestrogens that have antiestrogenic as well as estrogenic
effects on breast cancer cells in culture, in animal models, and in clinical
trials. This study will investigate anticancer and tumor promoting properties of
dietary isoflavones and evaluate their effects on breast cancer development.
Furthermore, this work seeks to elucidate the putative molecular pathways by
which these phytochemicals modulate breast cancer risk by synergizing or
antagonizing the estrogen receptor (ER) and in ER-independent signaling
mechanisms.
DOI: 10.3390/medicines4020018
PMCID: PMC5590054
PMID: 28930233
304. Curr Opin Clin Nutr Metab Care. 2017 Nov;20(6):512-521. doi:
10.1097/MCO.0000000000000424.
Polyphenols: dietary assessment and role in the prevention of cancers.
Rothwell JA(1), Knaze V, Zamora-Ros R.
Author information:
(1)aNutrition and Metabolism Section, Biomarkers Group, International Agency for
Research on Cancer (IARC), Lyon, France bUnit of Nutrition and Cancer, Cancer
Epidemiology Research Programme, Catalan Institute of Oncology, Bellvitge
Biomedical Research Institute (IDIBELL), Barcelona, Spain.
PURPOSE OF REVIEW: Polyphenols are a large and diverse family of phytochemicals

widely consumed by humans. Here we summarize the latest epidemiological evidence
for associations between cancer risk and polyphenol intake, taking into account
difficulties in the accurate estimation of exposure.
RECENT FINDINGS: Flavonoids are the most studied subgroup of polyphenols with
regard to cancer risk. In recent epidemiological studies, total flavonoid intake
has rarely been associated with a reduction in cancer risk. However,
isoflavones, whose main dietary source is soy foods, plausibly reduce the risk
of colorectal, breast, and prostate cancers, especially in Asian countries.
Findings depend heavily upon the assessment of polyphenol intake, which is
usually measured by food frequency questionnaires coupled to databases of food
polyphenol composition. To a lesser extent, nutritional biomarkers have been
used whenever estimating associations of polyphenol intake with cancer.
SUMMARY: Polyphenol intake may mitigate cancer risk but this depends on cancer
site, the subgroup of compounds under study, and accurate assessment of dietary
exposure. Further work must better characterize the effects of intake of
different flavonoid subclasses and begin to investigate the role of phenolic
acids and other minor polyphenol classes.
DOI: 10.1097/MCO.0000000000000424
305. J Radiat Oncol. 2017 Sep;6(3):307-315. doi: 10.1007/s13566-017-0301-z. Epub
2017
Mar 22.
Radiation injury to cardiac arteries and myocardium is reduced by soy

isoflavones.
Dominello MM(#)(1), Fountain MD(#)(1)(2), Rothstein SE(1), Cannon AC(1),

Abernathy LM(1)(2)(3), Hoogstra D(1), Chen W(1), Joiner MC(1), Hillman GG(1)(2).
Author information:
(1)Department of Oncology, Division of Radiation Oncology, Karmanos Cancer
Institute, Wayne State University School of Medicine, Research Center, room 515,
4100 John R, Detroit, MI 48201, USA.
(2)Department of Immunology & Microbiology, Karmanos Cancer Institute, Wayne
State University School of Medicine, Detroit, MI 48201, USA.
(3)Department of Microbiology and Immunology, Indiana University School of
Medicine at Notre Dame, South Bend, IN 46617, USA.
(#)Contributed equally
OBJECTIVE: The negative effects of incidental radiation on the heart and its
vessels, particularly in the treatment of locally advanced non-small cell lung
cancer, esophageal cancer, left-sided breast cancer, and lymphoma, are known.
Late cardiac events induced by radiotherapy including coronary artery disease,
ischemia, congestive heart failure, and myocardial infarction can manifest
months to years after radiotherapy. We have previously demonstrated that soy
isoflavones mitigate inflammatory responses induced in lungs by thoracic
irradiation resulting in decreased vascular damage, inflammation, and fibrosis.
In the current study, we investigate the use of soy isoflavones to protect
cardiac vessels and myocardium from radiation injury.
METHODS: Mice received a single dose of 10-Gy thoracic irradiation and daily
oral treatment with soy isoflavones. At different time points, hearts were
processed for histopathology studies to evaluate the effect of soy isoflavones
on radiation-induced damage to cardiac vessels and myocardium.
RESULTS: Radiation damage to arteries and myocardium was detected by 16 weeks
after radiation. Soy isoflavones given in conjunction with thoracic irradiation
were found to reduce damage to the artery walls and radiation-induced fibrosis
in the myocardium.
CONCLUSION: Our histopathological findings suggest a radioprotective role of soy
isoflavones to prevent cardiac injury. This approach could translate to the use
of soy isoflavones as a safe complement to thoracic radiotherapy with the goal
of improving the overall survival in patients whose cancer has been successfully
controlled by the radiotherapy but who otherwise succumb to heart toxicity.
DOI: 10.1007/s13566-017-0301-z
PMCID: PMC6903690
PMID: 31824587
Conflict of interest statement: Conflict of interest The authors declare that

306. Nutr Rev. 2017 Jul 1;75(7):500-515. doi: 10.1093/nutrit/nux016.
Health impact of childhood and adolescent soy consumption.
Messina M(1), Rogero MM(2), Fisberg M(3), Waitzberg D(4).

Author information:
(1)Nutrition Matters, Inc., Pittsfield, Massachusets, United States.
(2)Department of Nutrition, School of Public Health, University of São Paulo,
São Paulo, Brazil.
(3)Nutrition and Feeding Difficulty Center, Pensi Institute, José Luiz Setubal
Foundation, Sabará Children's Hospital, São Paulo, Brazil.
(4)University of Sao Paulo Medical School and Ganep Humana Nutrition, São Paulo,
Brazil.
Soyfoods have been intensely researched, primarily because they provide such
abundant amounts of isoflavones. Isoflavones are classified as both plant
estrogens and selective estrogen receptor modulators. Evidence suggests that
these soybean constituents are protective against a number of chronic diseases,
but they are not without controversy. In fact, because soyfoods contain such
large amounts of isoflavones, concerns have arisen that these foods may cause
untoward effects in some individuals. There is particular interest in
understanding the effects of isoflavones in young people. Relatively few studies
involving children have been conducted, and many of those that have are small in
size. While the data are limited, evidence suggests that soy does not exert
adverse hormonal effects in children or affect pubertal development. On the
other hand, there is intriguing evidence indicating that when soy is consumed
during childhood and/or adolescence, risk of developing breast cancer is
markedly reduced. Relatively few children are allergic to soy protein, and most
of those who initially are outgrow their soy allergy by 10 years of age. The
totality of the available evidence indicates that soyfoods can be healthful
additions to the diets of children, but more research is required to allow
definitive conclusions to be made.

International Life Sciences Institute. All rights reserved. For Permissions,
DOI: 10.1093/nutrit/nux016
307. Aging Male. 2018 Mar;21(1):48-54. doi: 10.1080/13685538.2017.1365834. Epub

2017
Aug 17.
Association between dietary phytoestrogens intakes and prostate cancer risk in

Sicily.
Russo GI(1), Di Mauro M(1), Regis F(1), Reale G(1), Campisi D(1), Marranzano
M(2), Lo Giudice A(1), Solinas T(3), Madonia M(3), Cimino S(1), Morgia G(1).
Author information:
(1)a Urology Section , University of Catania , Catania , Italy.
(2)b Department of Medical and Surgical Sciences and Advanced Technologies "G.F.
Ingrassia", Section of Hygiene and Preventive Medicine , University of Catania ,
Catania , Italy.
(3)c Urology Section , University of Sassari , Sassari , Italy.
OBJECTIVE: In this study we aimed to investigate the association between dietary

phytoestrogen consumption and prostate cancer in a sample of southern Italian
individuals.
METHODS: A population-based case-control study on the association between
prostate cancer and dietary factors was conducted from January 2015 to December
2016 in a single institution of the municipality of Catania, southern Italy
(Registration number: 41/2015). A total of 118 histopathological-verified
prostate cancer (PCa) cases and a total of 222 controls were collected. Dietary
data was collected by using two food frequency questionnaires.
RESULTS: Patients with PCa consumed significantly higher levels of
phytoestrogens. Multivariate logistic regression showed that lignans
(Q[quartile]4 vs. Q1, OR [odds ratio] = 4.72; p < .05) and specifically,
lariciresinol (Q4 vs. Q1, OR = 4.60; p < .05), pinoresinol (Q4 vs. Q1,
OR = 5.62; p < .05), matairesinol (Q4 vs. Q1, OR = 3.63; p < .05),
secoisolariciresinol (Q4 vs. Q1, OR = 4.10; p < .05) were associated with
increased risk of PCa. Furthermore, we found that isoflavones (Q3 vs. Q1,
OR = 0.28; p < .05) and specifically, genistein (Q4 vs. Q1, OR = 0.40; p < .05)
were associated with reduced risk of PCa.
CONCLUSION: We found of an inverse association between dietary isoflavone intake
and PCa, while a positive association was found with lignans intake.
DOI: 10.1080/13685538.2017.1365834
308. Clin Nutr. 2018 Oct;37(5):1675-1682. doi: 10.1016/j.clnu.2017.07.014. Epub

2017
Jul 18.
Plasma phytoestrogens concentration and risk of colorectal cancer in two

different Asian populations.
Ko KP(1), Yeo Y(2), Yoon JH(1), Kim CS(3), Tokudome S(4), Ngoan LT(5), Koriyama
C(6), Lim YK(7), Chang SH(8), Shin HR(9), Kang D(2), Park SK(10), Kang CH(11),
Yoo KY(12).
Author information:
(1)Department of Preventive Medicine, Gachon University College of Medicine, 191
Hambakmoeiro, Yeonsu-Gu, Incheon, South Korea.
Medicine, 103 Daehangno, Chongno-gu, Seoul, South Korea.
(3)Division of Medical Science Knowledge Management, Center for Genome Science,
Korea Centers for Disease Control and Prevention, 187 Osongsaengmyeong 2-ro,
Osong-eup, Cheonju, South Korea.
(4)National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku, Tokyo,
Japan.
(5)Department of Occupational Health, Hanoi Medical University, 1A Duc Thang
Road, North Tu Liem District, Hanoi, Viet Nam; International University of
Health and Welfare, 4-3 Kozunomori, Narita, Japan.
(6)Department of Epidemiology and Preventive Medicine, Kagoshima University
Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima,
Japan.
(7)Department of Radiology, Gachon University, 191 Hambakmoeiro Yeonsu-Gu,
Incheon, South Korea.
(8)Department of Preventive Medicine, Konkuk University, 268 Chungwon-daero,
Chungju, South Korea.
(9)Noncommunicable Diseases and Health Promotion, World Health Organization
Western Pacific Regional Office, United Nations Ave Ermita, Brgy 669 Zone 72,
Manila, Philippines.
Medicine, 103 Daehangno, Chongno-gu, Seoul, South Korea; Seoul National
University Cancer Research Institute, 103 Daehangno, Chongno-gu, Seoul, South
Korea; Department of Biomedical Science, Seoul National University Graduate
School, 103 Daehangno, Chongno-gu, Seoul, South Korea.
(11)Clinical Preventive Medicine Center, Seoul National University Bundang
Hospital, 82 Gumi-ro, Bundang-gu, Gyeonggi-do, South Korea.
Medicine, 103 Daehangno, Chongno-gu, Seoul, South Korea; Korean Armed Forces
Capital Hospital, Yul-dong, Seongnam, South Korea. Electronic address:
kyyoo@snu.ac.kr.
BACKGROUND & AIMS: To evaluate the relationship between phytoestrogen and colon
cancer risk, we quantified plasma isoflavones (Genistein and Daidzein) and
lignan (enterolactone) in a Korean nested case-control study and conducted
replication study in a Vietnamese case-control study.
METHODS: Study populations of 101 cases and 391 controls were selected from the
Korean Multicenter Cancer Cohort which was constructed from 1993 to 2004. For
replication study, Vietnamese hospital-based case-control subjects of 222 cases
and 206 controls were selected from 2003 to 2007. The concentrations of plasma
genistein, daidzein, and enterolactone were quantified by liquid
chromatography-mass spectrometry. Logistic regression models were used to
compute odds ratios (ORs) and 95% confidence intervals (CIs), and meta-analysis
was conducted to estimate combined ORs (CORs) and 95% Cis of Korean and
Vietnamese population in 2014.
RESULTS: Genistein showed a continual decrease in colorectal cancer risk
according to level up of the concentration categories in Korean and Vietnamese
population (P for trend = 0.032, and 0.001, respectively) and a significantly
decreased risk was found at the highest concentration of genistein and daidzein
(for the highest category compared to the lowest: COR (95% CI) = 0.46
(0.30-0.69), and COR (95% CI) = 0.54 (0.36-0.82)). When the study population was
stratified, the beneficial relationship of genistein with colorectal cancer was
observed regardless of sex and anatomical subtype. However, enterolacton level
was not associated with colorectal cancer risk.
CONCLUSIONS: High plasma levels of isoflavones had relationship with a decreased
risk of colorectal cancer, regardless of different ethnic background.
Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and
Metabolism. All rights reserved.
DOI: 10.1016/j.clnu.2017.07.014
309. Nutrients. 2017 Aug 4;9(8):834. doi: 10.3390/nu9080834.
Soymilk Improves Muscle Weakness in Young Ovariectomized Female Mice.
Kitajima Y(1), Ogawa S(2), Egusa S(3), Ono Y(4).
Author information:
(1)Musculoskeletal Molecular Biology Research Group, Basic and Translational
Research Center for Hard Tissue Disease, Nagasaki University Graduate School of
Biomedical Sciences, Nagasaki 852-8588, Japan. mysha.kita@gmail.com.
(2)Research and Development Division, Marusanai Co., Ltd., Aichi 444-2193,
Japan. shizuka.ogawa@marusanai.co.jp.
(3)Research and Development Division, Marusanai Co., Ltd., Aichi 444-2193,
Japan. shintaro.egusa@marusanai.co.jp.
(4)Musculoskeletal Molecular Biology Research Group, Basic and Translational
Research Center for Hard Tissue Disease, Nagasaki University Graduate School of
Biomedical Sciences, Nagasaki 852-8588, Japan. yusuke-ono@nagasaki-u.ac.jp.
Estrogens play a key role in an extensive range of physiological functions in

various types of tissues throughout the body in females. We previously showed
that estrogen insufficiency caused muscle weakness that could be rescued by
estrogen administration in a young female ovariectomized (OVX) mouse model.
However, long-term estrogen replacement therapy increases risks of breast cancer
and cardiovascular diseases. Soymilk contains plant-based protein and
isoflavones that exert estrogen-like activity. Here we examined the effects of
prolonged soymilk intake on muscle and its resident stem cells, called satellite
cells, in the estrogen-insufficient model. Six-week-old C57BL/6 OVX female mice
were fed with a dried soymilk-containing diet. We found that prolonged soymilk
intake upregulated grip strength in OVX mice. Correspondingly, cross-sectional
area of tibialis anterior muscle was significantly increased in OVX mice fed
with soymilk. Furthermore, soymilk diet mitigated dysfunction of satellite cells
isolated from OVX mice. Thus, these results indicated that prolonged soymilk
intake is beneficial for improving muscle weakness in an estrogen-insufficient
state in females.
DOI: 10.3390/nu9080834
PMCID: PMC5579627

authors S.O. and S.E. are employees of Marusanai Co., Ltd.
310. Am J Clin Nutr. 2017 Sep;106(3):909-920. doi: 10.3945/ajcn.117.153353. Epub

2017
Aug 2.
Combined bioavailable isoflavones and probiotics improve bone status and

estrogen metabolism in postmenopausal osteopenic women: a randomized controlled
trial.
Lambert MNT(1), Thybo CB(1), Lykkeboe S(2), Rasmussen LM(3), Frette X(4),
Christensen LP(4), Jeppesen PB(5).
Author information:
(1)Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
(2)Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg,
Denmark.
(3)Department of Clinical Biochemistry and Pharmacology, Odense University
Hospital, Odense, Denmark; and.
(4)Department of Chemical Engineering, Biotechnology and Environmental
Technology, University of Southern Denmark, Odense, Denmark.
(5)Department of Clinical Medicine, Aarhus University, Aarhus, Denmark;
per.bendix.jeppesen@clin.au.dk.
Background: Female age-related estrogen deficiency increases the risk of

osteoporosis, which can be effectively treated with the use of hormone
replacement therapy. However, hormone replacement therapy is demonstrated to
increase cancer risk. Bioavailable isoflavones with selective estrogen receptor
affinity show potential to prevent and treat osteoporosis while minimizing or
eliminating carcinogenic side effects.Objective: In this study, we sought to
determine the beneficial effects of a bioavailable isoflavone and probiotic
treatment against postmenopausal osteopenia.Design: We used a novel red clover
extract (RCE) rich in isoflavone aglycones and probiotics to concomitantly
promote uptake and a favorable intestinal bacterial profile to enhance
isoflavone bioavailability. This was a 12-mo, double-blind, parallel design,
placebo-controlled, randomized controlled trial of 78 postmenopausal osteopenic
women supplemented with calcium (1200 mg/d), magnesium (550 mg/d), and
calcitriol (25 μg/d) given either RCE (60 mg isoflavone aglycones/d and
probiotics) or a masked placebo [control (CON)].Results: RCE significantly
attenuated bone mineral density (BMD) loss at the L2-L4 lumbar spine vertebra (P
< 0.05), femoral neck (P < 0.01), and trochanter (P < 0.01) compared with CON
(-0.99% and -2.2%; -1.04% and -3.05%; and -0.67% and -2.79, respectively).
Plasma concentrations of collagen type 1 cross-linked C-telopeptide was
significantly decreased in the RCE group (P < 0.05) compared with CON (-9.40%
and -6.76%, respectively). RCE significantly elevated the plasma isoflavone
concentration (P < 0.05), the urinary 2-hydroxyestrone (2-OH) to
16α-hydroxyestrone (16α-OH) ratio (P < 0.05), and equol-producer status (P <
0.05) compared with CON. RCE had no significant effect on other bone turnover
biomarkers. Self-reported diet and physical activity were consistent and
differences were nonsignificant between groups throughout the study. RCE was
well tolerated with no adverse events.Conclusions: Twice daily RCE intake over 1
y potently attenuated BMD loss caused by estrogen deficiency, improved bone
turnover, promoted a favorable estrogen metabolite profile (2-OH:16α-OH), and
stimulated equol production in postmenopausal women with osteopenia. RCE intake
combined with supplementation (calcium, magnesium, and calcitriol) was more
effective than supplementation alone. This trial was registered at
clinicaltrials.gov as NCT02174666.
DOI: 10.3945/ajcn.117.153353
311. Mol Nutr Food Res. 2017 Nov;61(11). doi: 10.1002/mnfr.201700449. Epub 2017 Sep
1.
Genistein and enterolactone in relation to Ki-67 expression and HER2 status in

postmenopausal breast cancer patients.
Jaskulski S(1), Jung AY(1), Rudolph A(1), Johnson T(1), Thöne K(2), Herpel E(3),
Sinn P(3), Chang-Claude J(1)(4).
Author information:
(1)German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg,
Germany.
(2)University Medical Center Hamburg-Eppendorf, Department of Cancer
Epidemiology/ Clinical Cancer Registry, University Cancer Center Hamburg,
Hamburg, Germany.
(3)Heidelberg University Hospital, Department of Pathology, Heidelberg, Germany.
(4)University Medical Center Hamburg-Eppendorf, University Cancer Center
Hamburg, Genetic Tumour Epidemiology Group, Hamburg, Germany.
SCOPE: Phytoestrogens (PE) may improve breast cancer prognosis by modifying

tumor prognostic markers, such as cell proliferation marker Ki-67 and human
epidermal growth factor receptor 2 (HER2). Epidemiological evidence linking
lignans and isoflavones to Ki-67 and HER2 is limited. We examined associations
between the major metabolites of lignans and isoflavones - enterolactone (ENL)
and genistein (GEN) - respectively, and Ki-67 expression and HER2 in tumor
tissue of breast cancer patients.
METHODS AND RESULTS: Data from 1060 invasive breast cancer patients from the
population-based MARIE study were used. Multivariate-adjusted linear (Ki-67
log-transformed) and quantile regression, and logistic regression analyses
(HER2, Ki-67 dichotomized) were performed to calculate β estimates and ORs,
respectively. Median post-diagnostic ENL and GEN concentrations were 19.5 and
4.8 nmol/L, respectively. Median Ki-67 was 12.0%, and 21.2% of the tumors were
HER2+. After adjustment, there was an inverse association between GEN and Ki-67
at high expression levels (OR for Ki-67 ≥20% versus <20% of 0.93 (95%CI
[0.87;0.99]) per 10 nmol/L GEN increment).
CONCLUSION: Our findings indicate an inverse association between GEN and Ki-67
at high levels of Ki-67 expression. Additional investigations are recommended to
confirm our findings and to further elucidate mechanisms linking PE metabolites
to breast cancer survival.
DOI: 10.1002/mnfr.201700449
312. J Nutr. 2017 Sep;147(9):1729-1738. doi: 10.3945/jn.117.251579. Epub 2017 Jul

19.
Dietary Flavonoid Intake Reduces the Risk of Head and Neck but Not Esophageal or
Gastric Cancer in US Men and Women.
Sun L(1)(2), Subar AF(3), Bosire C(2), Dawsey SM(2), Kahle LL(4), Zimmerman
TP(5), Abnet CC(2), Heller R(2)(6), Graubard BI(2), Cook MB(2), Petrick JL(7).
Author information:
(1)Department of Epidemiology, Harvard T.H. Chan School of Public Health,
Boston, MA.
(2)Divisions of Cancer Epidemiology and Genetics and.
(3)Cancer Control and Population Sciences, National Cancer Institute, Bethesda,
MD.
(4)Information Management Services, Rockville, MD.
(5)Westat, Rockville, MD; and.
(6)Department of Statistics and Operations Research, Tel Aviv University, Tel
Aviv-Yafo, Israel.
(7)Divisions of Cancer Epidemiology and Genetics and jessica.petrick@nih.gov.
Background: Flavonoids are bioactive polyphenolic compounds found in fruits,

vegetables, and beverages of plant origin. Previous studies have shown that
flavonoid intake reduces the risk of certain cancers; however, few studies to
date have examined associations of flavonoids with upper gastrointestinal
cancers or used prospective cohorts.Objective: Our study examined the
association between intake of flavonoids (anthocyanidins, flavan-3-ols,
flavanones, flavones, flavonols, and isoflavones) and risk of head and neck,
esophageal, and gastric cancers.Methods: The NIH-AARP Diet and Health Study is a
prospective cohort study that consists of 469,008 participants. Over a mean 12-y
follow-up, 2453 head and neck (including 1078 oral cavity, 424 pharyngeal, and
817 laryngeal), 1165 esophageal (890 adenocarcinoma and 275 squamous cell
carcinoma), and 1297 gastric (625 cardia and 672 noncardia) cancer cases were
identified. We used Cox proportional hazards regression models to estimate HRs
and CIs for the associations between flavonoid intake assessed at study baseline
and cancer outcomes. For 56 hypotheses examined, P-trend values were adjusted
using the Benjamini-Hochberg (BH) procedure for false discovery rate
control.Results: The highest quintile of total flavonoid intake was associated
with a 24% lower risk of head and neck cancer (HR: 0.76; 95% CI: 0.66, 0.86;
BH-adjusted 95% CI: 0.63, 0.91; P-trend = 0.02) compared with the lowest
quintile. Notably, anthocyanidins were associated with a 28% lower risk of head
and neck cancer (HR: 0.72; 95% CI: 0.62, 0.82; BH-adjusted 95% CI: 0.59, 0.87;
P-trend = 0.0005), and flavanones were associated with a 22% lower risk of head
and neck cancer (HR: 0.78; 95% CI: 0.68, 0.89; BH-adjusted 95% CI: 0.64, 0.94;
P-trend: 0.02). No associations between flavonoid intake and risk of esophageal
or gastric cancers were found.Conclusions: Our results indicate that flavonoid
intake is associated with lower head and neck cancer risk. These associations
suggest a protective effect of dietary flavonoids on head and neck cancer risk,
and thus potential as a risk reduction strategy.
DOI: 10.3945/jn.117.251579
PMCID: PMC5572494
Conflict of interest statement: Author disclosures: LS, AFS, CB, SMD, LLK, TPZ,
CCA, RH, BIG, MBC, and JLP, no conflicts of interest. The funding source had no
role in the design or conduct of the study.
313. Cell Commun Signal. 2017 Jun 30;15(1):26. doi: 10.1186/s12964-017-0182-1.
Glyceollins trigger anti-proliferative effects through estradiol-dependent and

independent pathways in breast cancer cells.
Lecomte S(1)(2), Chalmel F(1)(3), Ferriere F(1)(2), Percevault F(1)(2), Plu

N(4), Saligaut C(1)(2), Surel C(4), Lelong M(1)(2), Efstathiou T(4), Pakdel
F(5)(6).
Author information:
(1)Institut de Recherche en Santé-Environnement-Travail (IRSET), University of
Rennes 1, 9 Avenue du Pr Léon Bernard, 35000, Rennes, France.
(2)Inserm U1085, Team Transcription, Environment and Cancer, 9 Avenue du Pr Léon
Bernard, 35000, Rennes, France.
(3)Inserm U1085, Team Viral and Chemical Environment & Reproduction, 9 Avenue du
Pr Léon Bernard, 35000, Rennes, France.
(4)Laboratoire Nutrinov, Technopole Atalante Champeaux, 8 rue Jules Maillard de
la Gournerie, 35012, Rennes Cedex, France.
(5)Institut de Recherche en Santé-Environnement-Travail (IRSET), University of
Rennes 1, 9 Avenue du Pr Léon Bernard, 35000, Rennes, France.
farzad.pakdel@univ-rennes1.fr.
(6)Inserm U1085, Team Transcription, Environment and Cancer, 9 Avenue du Pr Léon
Bernard, 35000, Rennes, France. farzad.pakdel@univ-rennes1.fr.
BACKGROUND: Estrogen receptors (ER) α and β are found in both women and men in
many tissues, where they have different functions, including having roles in
cell proliferation and differentiation of the reproductive tract. In addition to
estradiol (E2), a natural hormone, numerous compounds are able to bind ERs and
modulate their activities. Among these compounds, phytoestrogens such as
isoflavones, which are found in plants, are promising therapeutics for several
pathologies. Glyceollins are second metabolites of isoflavones that are mainly
produced in soybean in response to an elicitor. They have potentially
therapeutic actions in breast cancer by reducing the proliferation of cancer
cells. However, the molecular mechanisms driving these effects remain elusive.
METHODS: First, to determine the proliferative or anti-proliferative effects of
glyceollins, in vivo and in vitro approaches were used. The length of epithelial
duct in mammary gland as well as uterotrophy after treatment by E2 and
glyceollins and their effect on proliferation of different breast cell line were
assessed. Secondly, the ability of glyceollin to activate ER was assessed by
luciferase assay. Finally, to unravel molecular mechanisms involved by
glyceollins, transcriptomic analysis was performed on MCF-7 breast cancer cells.
RESULTS: In this study, we show that synthetic versions of glyceollin I and II
exert anti-proliferative effects in vivo in mouse mammary glands and in vitro in
different ER-positive and ER-negative breast cell lines. Using transcriptomic
analysis, we produce for the first time an integrated view of gene regulation in
response to glyceollins and reveal that these phytochemicals act through at
least two major pathways. One pathway involving FOXM1 and ERα is directly linked
to proliferation. The other involves the HIF family and reveals that stress is a
potential factor in the anti-proliferative effects of glyceollins due to its
role in increasing the expression of REDD1, an mTORC1 inhibitor.
CONCLUSION: Overall, our study clearly shows that glyceollins exert
anti-proliferative effects by reducing the expression of genes encoding cell
cycle and mitosis-associated factors and biomarkers overexpressed in cancers and
by increasing the expression of growth arrest-related genes. These results
reinforce the therapeutic potential of glyceollins for breast cancer.
DOI: 10.1186/s12964-017-0182-1
PMCID: PMC5493871
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All

animal procedures were performed according to the guidelines for animal models
in research defined by the Ethics Committee and approved by the Ministry of
France (reference project number, 2015061812074056_V2). All experiments were
conducted by FF and FPe, who are qualified in laboratory animal care and use
procedures. CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: The
authors declare that they have no conflicts of interest.
314. J Nat Prod. 2017 Jul 28;80(7):2060-2066. doi: 10.1021/acs.jnatprod.7b00255.

Epub
2017 Jun 30.
Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp. teitensis.
Deyou T(1)(2), Marco M(1), Heydenreich M(3), Pan F(4)(5), Gruhonjic A(2)(6),
Fitzpatrick PA(6), Koch A(3), Derese S(1), Pelletier J(7), Rissanen K(4),
Yenesew A(1), Erdélyi M(2)(8).
Author information:
(1)Department of Chemistry, University of Nairobi , P.O. Box 30197-00100,
Nairobi, Kenya.
(2)Department of Chemistry and Molecular Biology, University of Gothenburg ,
SE-412 96 Gothenburg, Sweden.
(3)Institut für Chemie, Universität Potsdam , Karl-Liebknecht-Straße 24-25,
D-14476, Potsdam, Germany.
(4)Department of Chemistry, Nanoscience Center, University of Jyvaskyla , P.O.
Box 35, FI-40014, Jyvaskyla, Finland.
(5)College of Chemistry, Central China Normal University , Wuhan, 430079,
(6)Sahlgrenska Cancer Centre, University of Gothenburg , SE-405 30 Gothenburg,
Sweden.
(7)Department of Biochemistry, McGill University , Montreal, QC H3G 1Y6, Canada.
(8)Swedish NMR Center, University of Gothenburg , P.O. Box 465, SE-405 30,
Gothenburg, Sweden.
A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids

A-D (2-5), along with nine known compounds (6-14), were isolated from the
CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by
chromatographic separation. The purified compounds were identified by NMR
spectroscopic and mass spectrometric analyses, whereas the absolute
configurations of the rotenoids were established on the basis of chiroptical
data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone
J (11) and oblarotenoid C (4) showed weak activity against the human breast
cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 μM, respectively.
DOI: 10.1021/acs.jnatprod.7b00255
315. J Cell Biochem. 2018 Jan;119(1):185-196. doi: 10.1002/jcb.26244. Epub 2017 Oct
4.
Diet and cancer prevention: Dietary compounds, dietary MicroRNAs, and dietary
exosomes.
Banikazemi Z(1), Haji HA(2), Mohammadi M(3), Taheripak G(4), Iranifar E(5),
Poursadeghiyan M(6), Moridikia A(7), Rashidi B(8), Taghizadeh M(9), Mirzaei
H(10).
Author information:
(1)Biochemistry of Nutrition Research Center, School of Medicine, Mashhad
University of Medical Science, Mashhad, Iran.
(2)School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
(3)Faculty of Pharmacy, Razi Herbal Medicines Research Center and Department of
Pharmaceutical Biotechnology, Lorestan University of Medical Sciences,
Khorramabad, Iran.
(4)Faculty of Medicine, Department of Biochemistry, Iran University of Medical
(5)Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.
(6)Research Center in Emergency and Disaster Health, University of Social
Welfare and Rehabilitation Sciences, Tehran, Iran.
(7)Chemical Injuries Research Center, Baqiyatallah University of Medical
(8)Department of Anatomical Sciences and Molecular Biology, School of Medicine,
Isfahan University of Medical Sciences, Isfahan, Iran.
(9)Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan
University of Medical Sciences, Kashan, I.R. Iran.
(10)Department of Medical Biotechnology, School of Medicine, Mashhad University
of Medical Sciences, Mashhad, Iran.
Cancer is one of main health public problems worldwide. Several factors are
involved in beginning and development of cancer. Genetic and internal/external
environmental factors can be as important agents that effect on emerging and
development of several cancers. Diet and nutrition may be as one of important
factors in prevention or treatment of various cancers. A large number studies
indicated that suitable dietary patterns may help to cancer prevention or could
inhibit development of tumor in cancer patients. Moreover, a large numbers
studies indicated that a variety of dietary compounds such as curcumin, green
tea, folat, selenium, and soy isoflavones show a wide range anti-cancer
properties. It has been showed that these compounds via targeting a sequence of
cellular and molecular pathways could be used as suitable options for cancer
chemoprevention and cancer therapy. Recently, dietary microRNAs and exosomes
have been emerged as attractive players in cancer prevention and cancer therapy.
These molecules could change behavior of cancer cells via targeting various
cellular and molecular pathways involved in cancer pathogenesis. Hence, the
utilization of dietary compounds which are associated with powerful molecules
such as microRNAs and exosomes and put them in dietary patterns could contribute
to prevention or treatment of various cancers. Here, we summarized various
studies that assessed effect of dietary patterns on cancer prevention shortly.
Moreover, we highlighted the utilization of dietary compounds, dietary
microRNAs, and dietary exosomes and their cellular and molecular pathways in
cancer chemoprevention.
DOI: 10.1002/jcb.26244
316. Food Funct. 2017 Sep 20;8(9):3064-3074. doi: 10.1039/c7fo00205j.
The role of soybean extracts and isoflavones in hormone-dependent breast cancer:

aromatase activity and biological effects.
Amaral C(1), Toloi MRT, Vasconcelos LD, Fonseca MJV, Correia-da-Silva G,

Teixeira N.
Author information:
(1)UCIBIO.REQUIMTE, Laboratory of Biochemistry, Department of Biological
Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
natercia@ff.up.pt.
Estrogen receptor-positive (ER+) breast cancer is the most common cause of

cancer death in women worldwide. Nowadays, the relationship between soya diet
and breast cancer is controversial due to the unknown role of its isoflavones,
genistein (G) and daidzein (D). In this work, we investigated not only the
anti-tumor properties of a soybean extract (NBSE) but also whether the
biotransformation of extract (BSE) by the fungus Aspergillus awamori increased
its effectiveness. The BSE showed a stronger anti-aromatase activity and
anti-proliferative efficacy in ER+ aromatase-overexpressing breast cancer cells.
D and G were weak aromatase inhibitors, but inhibited cancer cell growth, being
G the isoflavone that contributed to the BSE-induced effects. This work
demonstrated that the biotransformation increased the anti-aromatase activity
and the anti-tumoral efficacy of soybean extract in breast cancer cells.
Moreover, it elucidated the potential use of soya in the prevention and/or
treatment of ER+ breast cancer.
DOI: 10.1039/c7fo00205j
317. Anal Chim Acta. 2017 Aug 1;979:1-23. doi: 10.1016/j.aca.2017.05.012. Epub 2017
May 26.
New horizons in the extraction of bioactive compounds using deep eutectic

solvents: A review.
Zainal-Abidin MH(1), Hayyan M(2), Hayyan A(3), Jayakumar NS(1).
Author information:
(1)University of Malaya Centre for Ionic Liquids (UMCiL), Department of Chemical
Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia; Institute of
Halal Research University of Malaya (IHRUM), Academy of Islamic Studies,
University of Malaya, Kuala Lumpur 50603, Malaysia. Electronic address:
maan_hayyan@yahoo.com.
Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia; Institute of
Halal Research University of Malaya (IHRUM), Academy of Islamic Studies,
University of Malaya, Kuala Lumpur 50603, Malaysia.
With the rapid development of ionic liquid analogues, termed 'deep eutectic
solvents' (DESs), and their application in a wide range of chemical and
biochemical processes in the past decade, the extraction of bioactive compounds
has attracted significant interest. Recently, numerous studies have explored the
extraction of bioactive compounds using DESs from diverse groups of natural
sources, including animal and plant sources. This review summarizes
the-state-of-the-art effort dedicated to the application of DESs in the
extraction of bioactive compounds. The aim of this review also was to introduce
conventional and recently-developed extraction techniques, with emphasis on the
use of DESs as potential extractants for various bioactive compounds, such as
phenolic acid, flavonoids, tanshinone, keratin, tocols, terpenoids,
carrageenans, xanthones, isoflavones, α-mangostin, genistin, apigenin, and
others. In the near future, DESs are expected to be used extensively for the
extraction of bioactive compounds from various sources.
DOI: 10.1016/j.aca.2017.05.012
318. Curr Med Chem. 2018;25(36):4671-4692. doi: 10.2174/0929867324666170609080357.
Anticancer Polyphenols from Cultured Plant Cells: Production and New

Bioengineering Strategies.
Bulgakov VP(1)(2), Vereshchagina YV(1), Veremeichik GN(1).
Author information:
(1)Institute of Biology and Soil Science, Far Eastern Branch of the Russian
Academy of Sciences, 159 Stoletija Str., Vladivostok, 690022, Russian
Federation.
(2)Far Eastern Federal University, Vladivostok, 690950, Russian Federation.
BACKGROUND: For many years, anticancer polyphenols have attracted significant

attention as substances that prevent tumor growth and progression. These
compounds are simple phenolic acids, complex phenolic acids, such as
caffeoylquinic acids, rosmarinic acid and its derivatives, stilbenes, flavones,
isoflavones, and anthocyanins. Some compounds, such as tea and coffee
polyphenols, can be produced in large quantities by traditional methods, while
many others cannot.
METHODS: We reviewed the available literature regarding the biotechnological
aspects of polyphenol production by cultured plant cells and described
approaches that have been used to obtain high levels of anticancer polyphenols
(resveratrol, podophyllotoxin, genistein, lithospermic acid B, and others).
Additionally, we provide our view on bioengineering strategies that could be
important for the further improvement of cell biosynthetic characteristics.
RESULTS: The main trend in the field is the activation of entire biosynthetic
pathways based on a comprehensive knowledge of protein-protein interaction
networks involved in the regulation of polyphenol biosynthesis. As an example,
we consider the jasmonate subnetwork, which will be increasingly used by plant
biotechnologists. The next-generation technologies to sustained polyphenol
production involve manipulations with microRNAs and reproduction of rol-gene
effects.
CONCLUSION: Plant polyphenols play an important role in maintaining human
health, and their role in the prevention of cancer will continue to grow.
Targeting mechanisms involved in uncontrolled cancer cell proliferation will
increasingly become the standard for cancer patients. Plant biotechnological
studies aiming at producing anticancer compounds will be developed in parallel
with these studies to provide a wider range of metabolites for each particular
case.

DOI: 10.2174/0929867324666170609080357
319. PLoS One. 2017 Jun 7;12(6):e0176590. doi: 10.1371/journal.pone.0176590.

eCollection 2017.
Combined Red Clover isoflavones and probiotics potently reduce menopausal

vasomotor symptoms.
Lambert MNT(1), Thorup AC(1), Hansen ESS(2), Jeppesen PB(1).
Author information:
(1)Department of Endocrinology and Internal Medicine, Aarhus University
Hospital, Aarhus, Denmark.
(2)MR Research Centre, Aarhus University Hospital, Skejby, Denmark.
BACKGROUND: Natural estrogen decline leads to vasomotor symptoms (VMS). Hormone

therapy alleviates symptoms but increases cancer risk. Effective treatments
against VMS with minimal cancer risks are needed. We investigate the effects of
a highly bioavailable aglycone rich Red Clover isoflavone treatment to alleviate
existing menopausal VMS, assessed for the first time by 24hour ambulatory skin
conductance (SC).
METHODS AND RESULTS: We conducted a parallel, double blind, randomised control
trial of 62 peri-menopausal women aged 40-65, reporting ≥ 5 hot flushes/day and
follicle stimulating hormone ≥35 IU/L. Participants received either twice daily
treatment with bioavailable RC extract (RCE), providing 34 mg/d isoflavones and
probiotics, or masked placebo formulation for 12 weeks. The primary outcome was
change in daily hot flush frequency (HFF) from baseline to 12 weeks using 24hr
SC. Secondary outcomes were change in SC determined hot flush intensity (HFI),
self-reported HFF (rHFF) and hot flush severity (rHFS), blood pressure and
plasma lipids. A significant decrease in 24hr HFF (P < 0.01) and HFI (P<0.05)
was found when comparing change from baseline to 12 months of the RCE (-4.3
HF/24hr, CI -6.8 to -2.3; -12956 μS s-1, CI -20175 to -5737) with placebo (0.79
HF/24hr, CI -1.56 to 3.15; 515 μS s-1, CI -5465 to 6496). rHFF was also
significantly reduced (P <0.05)in the RCE (-2.97 HFs/d, CI -4.77 to -1.17) group
compared to placebo (0.036 HFs/d, CI -2.42 to 2.49). Other parameters were
non-significant. RCE was well tolerated.
CONCLUSION: Results suggest that moderate doses of RCE were more effective and
superior to placebo in reducing physiological and self-reported VMS. Findings
support that objective physiological symptom assessment methods should be used
together with self-report measures in future studies on menopausal VMS.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02028702.
DOI: 10.1371/journal.pone.0176590
PMCID: PMC5462345
Conflict of interest statement: Competing Interests: ML, AT and PBJ are

co-inventors on the patent application “PCT/DK2013/050428” for the production of
the Red Clover extract used in the present trial as required by US patent
authorities. All rights have been assigned to the company Herrens Mark without
any kind of compensation, where ML, AT and PBJ have forgone their rights as
stipulated by terms and conditions of Aarhus University. Hence, the authors
declare no financial or other interests. This does not alter our adherence to
all the PLOS ONE policies on sharing data and materials.
320. Eur J Nutr. 2018 Mar;57(2):423-432. doi: 10.1007/s00394-017-1459-2. Epub 2017

Apr 22.
Does soy protein affect circulating levels of unbound IGF-1?
Messina M(1)(2), Magee P(3).
Author information:
(1)Soy Nutrition Institute, St.Louis, USA. markjohnmessina@gmail.com.
(2), 26 Spadina Parkway, Pittsfield, MA, 01201, USA. markjohnmessina@gmail.com.
(3)Human Nutrition, Northern Ireland Centre for Food and Health (NICHE),
University of Ulster, Coleraine, BT52 1SA, UK.
INTRODUCTION: Despite the enormous amount of research that has been conducted on
the role of soyfoods in the prevention and treatment of chronic disease, the
mechanisms by which soy exerts its physiological effects are not fully
understood. The clinical data show that neither soyfoods nor soy protein nor
isoflavones affect circulating levels of reproductive hormones in men or women.
However, some research suggests that soy protein, but not isoflavones, affects
insulin-like growth factor I (IGF-1).
METHODS: Since IGF-1 may have wide-ranging physiological effects, we sought to
determine the effect of soy protein on IGF-1 and its major binding protein
insulin-like growth factor-binding protein (IGFBP-3). Six clinical studies were
identified that compared soy protein with a control protein, albeit only two
studies measured IGFBP-3 in addition to IGF-1.
RESULTS: Although the data are difficult to interpret because of the different
experimental designs employed, there is some evidence that large amounts of soy
protein (>25 g/day) modestly increase IGF-1 levels above levels observed with
the control protein.
CONCLUSION: The clinical data suggest that a decision to incorporate soy into
the diet should not be based on its possible effects on IGF-1.
DOI: 10.1007/s00394-017-1459-2
321. Anticancer Res. 2017 Apr;37(4):1647-1653. doi: 10.21873/anticanres.11495.
ME-143 Is Superior to Genistein in Suppression of WNT Signaling in Colon Cancer

Cells.
Pintova S(1), Planutis K(2), Planutiene M(2), Holcombe RF(2).
Author information:
(1)Department of Medicine, Division of Hematology and Medical Oncology, Mount
Sinai Medical Center, Tisch Cancer Institute, New York, NY, U.S.A.
sofya.pintova@mssm.edu.
(2)Department of Medicine, Division of Hematology and Medical Oncology, Mount
Sinai Medical Center, Tisch Cancer Institute, New York, NY, U.S.A.
BACKGROUND: This study tested the effect of the soy isoflavones genistein and
ME-143, and two chemotherapeutic agents, 5-fluorouracil (5FU) and oxaliplatin,
on WNT signaling.
MATERIALS AND METHODS: Colon cancer cell lines RKO (hereditary nonpolyposis
colorectal cancer type) and DLD1 (most common colorectal cancer type driven by a
mutation in WNT pathway) were utilized. WNT throughput was measured using a
β-catenin-responsive SuperTopFlash luciferase assay. A stabilized β-catenin
construct was employed to test β-catenin involvement in the mechanism of drug
activity.
RESULTS: ME-143 was a more than 10-fold potent inhibitor of DLD1 proliferation
than genistein at 3.125 μM. Genistein alone did not inhibit WNT signaling in
either cell line. In RKO cells, oxaliplatin and its combination with 5FU
significantly inhibited WNT throughput. Neither 5FU, oxaliplatin nor their
combination inhibited WNT signaling in DLD1 cells. In both the RKO and DLD1 cell
lines, ME-143 significantly reduced WNT throughput by 65-75%. The introduction
of stabilized β-catenin attenuated the ME-143-dependent inhibition of the
WNT/β-catenin pathway.
CONCLUSION: ME-143 alone and in combination with 5FU and oxaliplatin effectively
inhibits the WNT/β-catenin pathway in colorectal cancer cells of diverse genetic
background. β-Catenin is directly involved in the mechanism of inhibition, and
clinical studies are warranted.
Copyright© 2017, International Institute of Anticancer Research (Dr. George J.

322. Cancer Prev Res (Phila). 2017 May;10(5):308-318. doi:

10.1158/1940-6207.CAPR-16-0318. Epub 2017 Mar 21.
The Prolyl Isomerase Pin1 Is a Novel Target of 6,7,4'-Trihydroxyisoflavone for

Suppressing Esophageal Cancer Growth.
Lim TG(1), Lee SY(2), Duan Z(3), Lee MH(3), Chen H(2), Liu F(3), Liu K(3), Jung
SK(1), Kim DJ(3), Bode AM(2), Lee KW(4)(5), Dong Z(6).
Author information:
(1)Korea Food Research Institute, Gyeonggi, Korea.
(2)The Hormel Institute, University of Minnesota, Austin, Minnesota.
(3)China-US (Henan) Hormel Cancer Institute, Jinshui District, Zhengzhou, Henan,
China.
(4)Major in Biomodulation, Department of Agricultural Biotechnology and Research
Institute of Agriculture and Life Sciences, Seoul National University, Seoul,
Republic of Korea. zgdong@hi.umn.edu kiwon@snu.ac.kr.
(5)Wellness Emergence Center, Advanced Institutes of Convergence Technology,
Seoul National University, Suwon, Republic of Korea.
(6)The Hormel Institute, University of Minnesota, Austin, Minnesota.
zgdong@hi.umn.edu kiwon@snu.ac.kr.
Intake of soy isoflavones is inversely associated with the risk of esophageal

cancer. Numerous experimental results have supported the anticancer activity of
soy isoflavones. This study aimed to determine the anti-esophageal cancer
activity of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), a major metabolite of
daidzein, which is readily metabolized in the human body. Notably, 6,7,4'-THIF
inhibited proliferation and increased apoptosis of esophageal cancer cells. On
the basis of a virtual screening analysis, Pin1 was identified as a target
protein of 6,7,4'-THIF. Pull-down assay results using 6,7,4'-THIF Sepharose 4B
beads showed a direct interaction between 6,7,4'-THIF and the Pin1 protein. Pin1
is a critical therapeutic and preventive target in esophageal cancer because of
its positive regulation of β-catenin and cyclin D1. The 6,7,4'-THIF compound
simultaneously reduced Pin1 isomerase activity and the downstream activation
targets of Pin1. The specific inhibitory activity of 6,7,4'-THIF was analyzed
using Neu/Pin1 wild-type (WT) and Neu/Pin1 knockout (KO) MEFs. 6,7,4'-THIF
effected Neu/Pin1 WT MEFs, but not Neu/Pin1 KO MEFs. Furthermore, the results of
a xenograft assay using Neu/Pin1 WT and KO MEFs were similar to those obtained
from the in vitro assay. Overall, we found that 6,7,4'-THIF specifically reduced
Pin1 activity in esophageal cancer models. Importantly, 6,7,4'-THIF directly
bound to Pin1 but not FKBP or cyclophilin A, the same family of proteins.
Because Pin1 acts like an oncogene by modulating various carcinogenesis-related
proteins, this study might at least partially explain the underlying
mechanism(s) of the anti-esophageal cancer effects of soy isoflavones. Cancer
Prev Res; 10(5); 308-18. ©2017 AACR.
DOI: 10.1158/1940-6207.CAPR-16-0318
323. Res Vet Sci. 2017 Oct;114:59-63. doi: 10.1016/j.rvsc.2017.02.027. Epub 2017
Mar
8.
Genistein affects proliferation and migration of bovine oviductal epithelial

cells.
García DC(1), Valdecantos PA(1), Miceli DC(1), Roldán-Olarte M(2).
Author information:
(1)Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT, and
Instituto de Biología "Dr. Francisco D. Barbieri", Facultad de Bioquímica,
Química y Farmacia, UNT. Chacabuco 461, T4000ILI San Miguel de Tucumán,
Argentina.
(2)Instituto Superior de Investigaciones Biológicas (INSIBIO), CONICET-UNT, and
Instituto de Biología "Dr. Francisco D. Barbieri", Facultad de Bioquímica,
Química y Farmacia, UNT. Chacabuco 461, T4000ILI San Miguel de Tucumán,
Argentina. Electronic address: emroldanolarte@fbqf.unt.edu.ar.
Genistein is one of the most abundant isoflavones in soybean. This molecule

induces cell cycle arrest and apoptosis in different normal and cancer cells.
Genistein has been of considerable interest due to its adverse effects on bovine
reproduction, altering estrous cycle, implantation and fetal development and
producing subfertility or infertility. The objective of this work was to study
the effects of genistein on the expression of selected genes involved in the
regulation of cell cycle and apoptosis. Primary cultures of bovine oviductal
epithelial cells (BOEC) were treated with different genistein concentrations
(0.2, 2 and 10μM) to analyze CYCLIN B1, BCL-2 and BAX gene expression by
Real-time RT-PCR. Results showed that genistein down-regulated CYCLIN B1
expression, affecting cell cycle progression, and caused a decrease in the
BCL-2/BAX ratio starting at 2μM of genistein. In addition, in order to determine
if genistein affects BOEC migration, in vitro wound healing assays were
performed. A significant reduction in cell migration after 12h of culture was
observed at both 0.2 and 10μM genistein concentrations. Also, in the presence of
genistein the percentage of mitotic cells decreased, although apoptotic cells
percentages were not affected. These findings indicate that genistein has an
inhibitory effect on BOEC proliferation and migration, suggesting that it could
influence the normal physiology of the oviductal epithelium.
DOI: 10.1016/j.rvsc.2017.02.027
324. Curr Pharm Des. 2017;23(19):2731-2741. doi: 10.2174/1381612823666170317122913.
A Critical Review of Bioactive Food Components, and of their Functional

Mechanisms, Biological Effects and Health Outcomes.
Perez-Gregorio R(1), Simal-Gandara J(2).
Author information:
(1)LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da
Universidade do Porto, Rua do Campo Alegre 687, Porto, Portugal.
(2)Nutrition and Bromatology Group, Department of Analytical and Food Chemistry,
Faculty of Food Science and Technology, University of Vigo - Ourense Campus,
E-32004 Ourense, Spain.
BACKGROUND: Eating behaviours are closely related to some medical conditions

potentially leading to death such as cancer, cardiovascular disease and
diabetes. Healthy eating practices, maintaining a normal weight, and regular
physical activity could prevent up to 80% of coronary heart disease, 90% of
type-2 diabetes and onethird of all cancers [1].
METHOD: Over the last two decades, the food industry has invested much effort in
research and development of healthier, more nutritious foods. These foods are
frequently designated "functional" when they contain nutritional components
required for healthy living or "nutraceuticals" when intended to treat or
prevent disease or disorders through a variety of bioactive (e.g., antioxidant,
antimicrobial, immunomodulatory, hypocholesterolaemic) functions that are
performed by functional enzymes, probiotics, prebiotics, fibres, phytosterols,
peptides, proteins, isoflavones, saponins or phytic acid, among other
substances.
RESULTS: Some agricultural and industrial residues have proven to be excellent
choices as raw materials for producing bioactive compounds and have been
proposed as potentially safe natural sources of antimicrobials and/or
antioxidants for the food industry. Functional food ingredients containing
bioactive compounds could be used as plant extracts by pharmaceutical and food
industries.
CONCLUSION: Bioactive food components influence health outcomes.

DOI: 10.2174/1381612823666170317122913
325. Biomed Res Int. 2017;2017:9758982. doi: 10.1155/2017/9758982. Epub 2017 Feb
15.
Functional Effects of Prebiotic Fructans in Colon Cancer and Calcium Metabolism

in Animal Models.
Rivera-Huerta M(1), Lizárraga-Grimes VL(1), Castro-Torres IG(2), Tinoco-Méndez

M(1), Macías-Rosales L(1), Sánchez-Bartéz F(1), Tapia-Pérez GG(3), Romero-Romero
L(4), Gracia-Mora MI(1).
Author information:
(1)Unidad de Investigación Preclínica (UNIPREC), Facultad de Química,
Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
(2)Colegio de Ciencias y Humanidades, Plantel Sur, Universidad Nacional Autónoma
de México, Ciudad de México, Mexico.
(3)Departamento de Genética y Bioestadística, Facultad de Medicina Veterinaria y
Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
(4)Departamento de Patología, Facultad de Medicina Veterinaria y Zootecnia,
Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
Inulin-type fructans are polymers of fructose molecules and are known for their
capacity to enhance absorption of calcium and magnesium, to modulate gut
microbiota and energy metabolism, and to improve glycemia. We evaluated and
compared the effects of Chicory inulin "Synergy 1®" and inulin from Mexican
agave "Metlin®" in two experimental models of colon cancer and bone calcium
metabolism in mice and rats. Inulins inhibited the development of dextran
sulfate sodium-induced colitis and colon cancer in mice; these fructans reduced
the concentration of tumor necrosis factor alpha and prevented the formation of
intestinal polyps, villous atrophy, and lymphoid hyperplasia. On the other hand,
inulin treatments significantly increased bone densitometry (femur and vertebra)
in ovariectomized rats without altering the concentration of many serum
biochemical parameters and urinary parameters. Histopathology results were
compared between different experimental groups. There were no apparent
histological changes in rats treated with inulins and a mixture of
inulins-isoflavones. Our results showed that inulin-type fructans have
health-promoting properties related to enhanced calcium absorption, potential
anticancer properties, and anti-inflammatory effects. The use of inulin as a
prebiotic can improve health and prevent development of chronic diseases such as
cancer and osteoporosis.
DOI: 10.1155/2017/9758982
PMCID: PMC5331302
Conflict of interest statement: The authors disclose no conflict of interests.
326. Sci Rep. 2017 Mar 9;7(1):128. doi: 10.1038/s41598-017-00117-8.
Dietary Flavonoids, CYP1A1 Genetic Variants, and the Risk of Colorectal Cancer
in a Korean population.
Cho YA(1), Lee J(1), Oh JH(2), Chang HJ(2), Sohn DK(2), Shin A(3)(4), Kim J(5).
Author information:
(1)Molecular Epidemiology Branch, National Cancer Center, Goyang, South Korea.
(2)Center for Colorectal Cancer, National Cancer Center Hospital, National
Cancer Center, Goyang, South Korea.
shinaesun@snu.ac.kr.
Medicine, Seoul, South Korea. shinaesun@snu.ac.kr.
jskim@ncc.re.kr.
The role of dietary flavonoid intake in colorectal carcinogenesis might differ

according to flavonoid subclasses and individual genetic variants related to
carcinogen metabolism. Therefore, we examined whether greater dietary intake of
flavonoid subclasses was associated with a lower risk of colorectal cancer and
whether CYP1A1 genetic variants altered this association. A semi-quantitative
food frequency questionnaire was used to assess the dietary intake of six
flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols,
anthocyanidins, and isoflavones) in 923 patients with colorectal cancer and
1,846 controls; furthermore, CYP1A1 genetic variants (rs4646903 and rs1048943)
were genotyped. Among the subclasses of flavonoids, higher intake of flavonols
and flavan-3-ols showed a stronger association with a reduced risk of colorectal
cancer after adjusting for potential confounding factors. Carriers of the CYP1A1
rs4646903 CC homozygous variant showed a reduced risk of rectal cancer compared
with that in TT carriers. The inverse association between dietary flavonol
intake and colorectal cancer risk was stronger among carriers of the CC
homozygous variant than among T allele carriers (P for interaction = 0.02),
particularly for rectal cancer (P for interaction = 0.005). In conclusion, the
effect of dietary flavonoid intake on colorectal cancer risk differs according
to flavonoid subclasses and CYP1A1 genetic variants.
DOI: 10.1038/s41598-017-00117-8
PMCID: PMC5427897
Conflict of interest statement: The authors declare that they have no competing
interests.
327. Food Sci Nutr. 2016 May 26;5(2):197-204. doi: 10.1002/fsn3.382. eCollection
2017
Mar.
Genistein suppresses the proliferation of telomerase-negative cells.
Lin CC(1), Hsieh MH(2), Teng SC(2).
Author information:
(1)Department of Food Science China University of Science and Technology Taipei
115 Taiwan.
(2)Department of Microbiology College of Medicine National Taiwan University
Taipei 100 Taiwan.
In both tumor and yeast cells that lack telomerase, telomeres are maintained via
an alternative recombination mechanism. In this study, we tested genistein, a
potential TOP2 inhibitor required for telomere-telomere recombination, on the
repression of telomere-telomere recombination. Genistein on the repression of
type II recombination on a tlc1 yeast strain was examined by the telomeric DNA
structures using Southern blot analysis. Telomere patterns of freshly dissected
tlc1 spores containing an empty plasmid (pYES2) or a yeast TOP2 (yTOP2) plasmid
were analyzed. The results indicated that the reintroduction of TOP2 recovered
the type II pattern, implying genistein in the blockage of type II survivors in
the tlc1 strain. The effects of genistein on both tlc1 and tlc1 rad 51 strains
in liquid and solid mediums were also examined. Finally, treatment of 10 μmol/L
of genistein showed inhibitory effect on the growth of telomerase-negative U2OS
alternative lengthening of telomere (ALT) cells, but not in telomerase-positive
HCT116 cells. These results provide evidences that the inhibitory effects of
genistein on telomerase-negative cells depend on type II recombination pathway
in yeast and the ALT pathway in human tumors.
DOI: 10.1002/fsn3.382
PMCID: PMC5332266
PMID: 28265354
328. Nutrients. 2017 Feb 27;9(3):201. doi: 10.3390/nu9030201.
Proteins in Soy Might Have a Higher Role in Cancer Prevention than Previously
Expected: Soybean Protein Fractions Are More Effective MMP-9 Inhibitors Than
Non-Protein Fractions, Even in Cooked Seeds.
Lima A(1), Oliveira J(2), Saúde F(3), Mota J(4), Ferreira RB(5).
Author information:
(1)Disease & Stress Biology Group, LEAF (Linking Landscape, Environment,
Agriculture and Food), Instituto Superior de Agronomia, Universidade de Lisboa,
1349-017 Lisbon, Portugal. agusmaolima@gmail.com.
1349-017 Lisbon, Portugal. jenniferoliveira@live.com.pt.
1349-017 Lisbon, Portugal. fccsaude@gmail.com.
1349-017 Lisbon, Portugal. joana.mota.p@gmail.com.
1349-017 Lisbon, Portugal. rbferreira@isa.ulisboa.pt.
The search for anticancer MMP-9 inhibitors (MMPIs) in food products has become a
major goal for research. MMPIs in soy have been related only to saponins and
isoflavones, but recently, low specific protein fractions in soybeans were shown
to reduce MMP-9 activity as well. The present work aimed at comparing the MMPI
potential of protein fractions (P) and non-protein fractions (NP) isolated from
soybean seeds, before and after soaking and cooking, mimicking dietary
exposures. Reverse and substrate zymography, as well as a fluoregenic DQ gelatin
assay were used to evaluate MMP-9 activities. Colon cancer cell migration and
proliferation was also tested in HT29 cells. Regarding MMP-9 inhibition,
proteins in soy presented IC50 values 100 times lower than non-protein extracts,
and remained active after cooking, suggesting that proteins may be more
effective MMP-9 inhibitors than non-protein compounds. Using the determined IC50
concentrations, NP fractions were able to induce higher inhibitions of HT29 cell
migration and proliferation, but not through MMP-9 inhibition, whilst protein
fractions were shown to specifically inhibit MMP-9 activity. Overall, our
results show that protein fractions in soybeans might have a higher role in
soy-related cancer prevention as MMPIs than previously expected. Being nontoxic
and active at lower concentrations, the discovery of these heat-resistant
specific MMPI proteins in soy can be of significant importance for cancer
preventive diets, particularly considering the increasing use of soy proteins in
food products and the controversy around isoflavones amongst consumers.
DOI: 10.3390/nu9030201
PMCID: PMC5372864
Conflict of interest statement: The authors declare no potential conflict of

interest.
329. Cancer. 2017 Jun 1;123(11):1901-1903. doi: 10.1002/cncr.30614. Epub 2017 Mar
6.
Soy foods, isoflavones, and breast cancer.
Kucuk O(1).
Author information:
(1)Department of Hematology and Medical Oncology and Winship Cancer Institute,
Emory University, Atlanta, Georgia.
Comment on
Cancer. 2017 Jun 1;123(11):2070-2079.
DOI: 10.1002/cncr.30614
330. J Nutr Biochem. 2017 Aug;46:1-12. doi: 10.1016/j.jnutbio.2017.01.006. Epub

2017
Jan 24.
Dietary flavonoids and modulation of natural killer cells: implications in

malignant and viral diseases.
Burkard M(1), Leischner C(2), Lauer UM(3), Busch C(4), Venturelli S(5), Frank
J(6).
Author information:
(1)Institute of Physiology, Department of Physiology I, Medical University
Hospital, Tuebingen, Germany. Electronic address:
markus.burkard@uni-tuebingen.de.
Hospital, Tuebingen, Germany. Electronic address: chlei@gmx.de.
(3)Department of Internal Medicine VIII, Medical University Hospital, Tuebingen,
Germany. Electronic address: ulrich.lauer@med.uni-tuebingen.de.
(4)Division of Dermatologic Oncology, Department of Dermatology and Allergology,
Medical University Hospital, Tuebingen, Germany. Electronic address:
christian.busch@med.uni-tuebingen.de.
Hospital, Tuebingen, Germany. Electronic address:
sascha.venturelli@med.uni-tuebingen.de.
(6)Institute of Biological Chemistry and Nutrition, University of Hohenheim,
Stuttgart, Germany. Electronic address: jan.frank@nutres.de.
Flavonoids are a large group of secondary plant metabolites present in the diet
with numerous potentially health-beneficial biological activities. In addition
to antioxidant, anti-inflammatory, cholesterol-lowering, and many other
biological functions reported in the literature, flavonoids appear to inhibit
cancer cell proliferation and stimulate immune function. Although the
immunomodulatory potential of flavonoids has been intensively investigated, only
little is known about their impact on natural killer (NK) cells. Enhancing NK
cell activity, however, would have strong implications for a possible clinical
use of flavonoids, especially in the treatment and prevention of diseases like
cancer and viral infections. Therefore, the purpose of this review is to
summarize the currently available information on NK cell modulation by
flavonoids. Many of the structurally diverse flavonoids stimulate NK cell
activity and have thus great potential as diet-derived immune-modulatory
chemopreventive agents and may even serve as therapeutic compounds or lead
structures for the development of novel drugs for the treatment of both
malignant and viral diseases.
DOI: 10.1016/j.jnutbio.2017.01.006
331. Front Oncol. 2017 Jan 23;7:7. doi: 10.3389/fonc.2017.00007. eCollection 2017.
Innate Immune Pathways Associated with Lung Radioprotection by Soy Isoflavones.
Abernathy LM(1), Fountain MD(2), Joiner MC(3), Hillman GG(2).
Author information:
University School of Medicine, Detroit, MI, USA; Department of Immunology and
Microbiology, Wayne State University School of Medicine, Detroit, MI, USA;
Department of Microbiology and Immunology, Indiana University School of Medicine
at Notre Dame, South Bend, IN, USA.
University School of Medicine, Detroit, MI, USA; Department of Immunology and
Microbiology, Wayne State University School of Medicine, Detroit, MI, USA.
University School of Medicine , Detroit, MI , USA.
INTRODUCTION: Radiation therapy for lung cancer causes pneumonitis and fibrosis.
Soy isoflavones protect against radiation-induced lung injury, but the mediators
of radioprotection remain unclear. We investigated the effect of radiation on
myeloid-derived suppressor cells (MDSCs) in the lung and their modulation by soy
isoflavones for a potential role in protection from radiation-induced lung
injury.
METHODS: BALB/c mice (5-6 weeks old) received a single 10 Gy dose of thoracic
irradiation and soy isoflavones were orally administrated daily before and after
radiation at 1 mg/day. Arginase-1 (Arg-1) and nuclear factor κB (NF-κB) p65 were
detected in lung tissue by western blot analysis and immunohistochemistry. Lung
MDSC subsets and their Arg-1 expression were analyzed by flow cytometry.
Cytokine levels in the lungs were measured by ELISA.
RESULTS: At 1 week after radiation, CD11b+ cells expressing Arg-1 were decreased
by radiation in lung tissue yet maintained in the lungs treated with radiation
and soy isoflavones. Arg-1 was predominantly expressed by CD11b+Ly6ClowLy6G+
granulocytic MDSCs (gr-MDSCs). Arg-1 expression in gr-MDSCs was reduced by
radiation and preserved by supplementation with soy isoflavones. A persistent
increase in Arg-1+ cells was observed in lung tissue treated with combined
radiation and soy isoflavones at early and late time points, compared to
radiation alone. The increase in Arg-1 expression mediated by soy isoflavones
could be associated with the inhibition of radiation-induced activation of NF-κB
and the control of pro-inflammatory cytokine production demonstrated in this
study.
CONCLUSION: A radioprotective mechanism of soy isoflavones may involve the
promotion of Arg-1-expressing gr-MDSCs that could play a role in downregulation
of inflammation and lung radioprotection.
DOI: 10.3389/fonc.2017.00007
PMCID: PMC5253714
PMID: 28168165
332. Genes Environ. 2017 Feb 1;39:10. doi: 10.1186/s41021-016-0071-7. eCollection

2017.
Estrogen- and stress-induced DNA damage in breast cancer and chemoprevention
with dietary flavonoid.
Yasuda MT(1), Sakakibara H(2), Shimoi K(1).
Author information:
(1)School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada,
Suruga-ku, Shizuoka, 422-8526 Japan.
(2)Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-kibanadai-nishi,
Miyazaki, 889-2192 Japan.
Breast cancer is one of the most commonly diagnosed female cancers and a leading
cause of cancer-related death in women. Multiple factors are responsible for
breast cancer and heritable factors have received much attention. DNA damage in
breast cancer is induced by prolonged exposure to estrogens, such as
17β-estradiol, daily social/psychological stressors, and environmental chemicals
such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs).
DNA damage induced by estrogen and stress is an important factor in the
pathogenesis and development of breast cancer and is now recognized as a
critical provision for chemoprevention of breast cancer. In this review, we
summarize the relationships between estrogen- and stress-induced DNA damage with
regard to the pathogenesis and development of breast cancer. We also discuss
recent investigations into chemoprevention using dietary flavonoids such as
quercetin and isoflavones.
DOI: 10.1186/s41021-016-0071-7
PMCID: PMC5286800
PMID: 28163803
333. J Epidemiol. 2017 Jan;27(1):2-7. doi: 10.1016/j.je.2016.09.001. Epub 2016 Nov

15.
Risk and preventive factors for prostate cancer in Japan: The Japan Public
Health Center-based prospective (JPHC) study.
Sawada N(1).
Author information:
(1)Epidemiology Division, Center for Public Health Sciences, National Cancer
Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address:
nsawada@ncc.go.jp.
The incidence of prostate cancer is much lower in Asian than in Western

populations. Lifestyle and dietary habits may play a major role in the etiology
of this cancer. Given the possibility that risk factors for prostate cancer
differ by disease aggressiveness, and the fact that 5-year relative survival
rate of localized prostate cancer is 100%, identifying preventive factors
against advanced prostate cancer is an important goal. Using data from the Japan
Public Health Center-based Prospective Study, the author elucidates various
lifestyle risk factors for prostate cancer among Japanese men. The results show
that abstinence from alcohol and tobacco might be important factors in the
prevention of advanced prostate cancer. Moreover, the isoflavones and green tea
intake in the typical Japanese diet may decrease the risk of localized and
advanced prostate cancers, respectively.
Copyright © 2016 The Author. Production and hosting by Elsevier B.V. All rights
reserved.
DOI: 10.1016/j.je.2016.09.001
PMCID: PMC5328733
334. J Nat Prod. 2017 Feb 24;80(2):377-383. doi: 10.1021/acs.jnatprod.6b00839. Epub

2017 Jan 23.
Flavonoids from Erythrina schliebenii.
Nyandoro SS(1)(2), Munissi JJ(1)(2), Kombo M(1), Mgina CA(1), Pan F(3),
Gruhonjic A(4), Fitzpatrick P(4), Lu Y(5), Wang B(5), Rissanen K(3), Erdélyi
M(2)(6).
Author information:
(1)Chemistry Department, College of Natural and Applied Sciences, University of
Dar es Salaam , P.O. Box 35061, Dar es Salaam, Tanzania.
(2)Department of Chemistry and Molecular Biology, University of Gothenburg ,
Gothenburg SE-412 96, Sweden.
(3)Department of Chemistry, Nanoscience Center, University of Jyvaskyla , P.O.
Box. 35, FI-40014 University of Jyvaskyla, Finland.
(4)Sahlgrenska Cancer Centre, University of Gothenburg , Gothenburg SE-405 30,
Sweden.
(5)Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department
of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing
Tuberculosis and Thoracic Tumour Research Institute , Beijing 101149, People's
Republic of China.
(6)Swedish NMR Centre, University of Gothenburg , Gothenburg SE-405 30, Sweden.
Prenylated and O-methylflavonoids including one new pterocarpan (1), three new
isoflavones (2-4), and nineteen known natural products (5-23) were isolated and
identified from the root, stem bark, and leaf extracts of Erythrina schliebenii.
The crude extracts and their constituents were evaluated for antitubercular
activity against Mycobacterium tuberculosis (H37Rv strain), showing MICs of
32-64 μg mL-1 and 36.9-101.8 μM, respectively. Evaluation of their toxicity
against the aggressive human breast cancer cell line MDA-MB-231 indicated EC50
values of 13.0-290.6 μM (pure compounds) and 38.3 to >100 μg mL-1 (crude
extracts).
335. Med Chem Res. 2017;26(1):64-73. doi: 10.1007/s00044-016-1725-5. Epub 2016 Oct
3.
Cytotoxic activity of genistein-8-C-glucoside form Lupinus luteus L. and

genistein against human SK-OV-3 ovarian carcinoma cell line.
Antosiak A(1), Milowska K(1), Maczynska K(1), Rozalska S(2), Gabryelak T(1).
Author information:
(1)Department of General Biophysics, Faculty of Biology and Environmental
Protection, University of Lodz, 141/143 Pomorska St., Lodz, 90-236 Poland.
(2)Department of Industrial Microbiology and Biotechnology, University of Lodz,
12/16 Banacha St., Lodz, 90-237 Poland.
Genistein belongs to isoflavones, which are a subclass of flavonoids, a large

group of polyphenolic compounds widely distributed in plants. Numerous in vitro
studies suggest that isoflavones, particularly genistein, have both
chemopreventive and chemotherapeutic potential in multiple tumor types. However,
the molecular and cellular mechanisms of genistein effects on human ovarian
cancer cells are still little known. In the present study, we investigated
anticancer activity of genistein and its natural glucoside,
genistein-8-C-glucoside isolated from flowers of Lupinus luteus L. We examined
the effects of the two isoflavones alone or in combination on cultured human
SK-OV-3 ovarian carcinoma cells. The cells were exposed to genistein and
genistein-8-C-glucoside at various concentrations (1-90 µM) for 24 and 48 h. The
cytotoxic and apoptotic properties of compounds were studied by the colorimetric
3-[4,5-2-yl]-2-5-diphenyltetrazolium bromide assay and the acridine
orange/ethidium bromide staining technique. The morphological features of
SK-OV-3 cells were examined by Nomarski differential interference contrast
combined with a confocal laser scanning microscope. The level of ROS was
evaluated with fluorescence probes: dichlorofluorescein-diacetate by flow
cytometry. Changes in mitochondrial membrane potential were determined using
5,5,6,6-tetrachloro-1,1,3,3-tetraethylbenzimidazolcarbocyanine iodide.
Genistein-treatment and genistein-8-C-glucoside-treatment resulted in the
inhibition of cell proliferation, induction of apoptotic cell death and loss of
mitochondrial membrane potential. The present data provide the first evidence in
vitro that genistein-8-C-glucoside and combination
genistein-genistein-8-C-glucoside could be a potential chemotherapeutic
candidate for ovarian cancer therapy.
DOI: 10.1007/s00044-016-1725-5
PMCID: PMC5219005
PMID: 28111515
Conflict of interest statement: The authors declare that they have no conflict
of interest.
336. Phytochemistry. 2017 Apr;136:70-80. doi: 10.1016/j.phytochem.2017.01.002. Epub

2017 Jan 18.
Isolation of isoflavones from Iris kashmiriana Baker as potential anti

proliferative agents targeting NF-kappaB.
Alam A(1), Jaiswal V(2), Akhtar S(3), Jayashree BS(4), Dhar KL(5).
Author information:
(1)Faculty of Pharmaceutical Sciences, Shoolini University, Solan, Himachal
Pradesh 173229, India. Electronic address: afrozepharma@gmail.com.
Pradesh 173229, India.
(3)LE STUDIUM(®) Loire Valley Institute for Advanced Studies, Centre-Val de
Loire Region, France; Centre de Biophysique Moléculaire, CNRS UPR4301, Orléans,
France.
(4)Manipal College of Pharmaceutical Sciences, Manipal University, Udupi,
Karnataka 576104, India.
Pradesh 173229, India. Electronic address: dharkl@yahoo.com.
Cancer is possibly one of the most devastating and complex disease and therefore
involves chemotherapy as one of the frontline strategies in its therapy.
However, expected toxicity and resistance with chemotherapeutic agents encourage
us to use the plant derived natural chemotherapeutic sources at the clinical
stage of cancer therapy. In view of this strategy, herein new glycosides and
isoflavonoids were isolated from Iris kashmiriana Baker and subjected to
structure elucidation followed by their biological evaluation. Isolated
compounds and their derivatives were purified by the column chromatography and
structural identification was made by a combination of various spectroscopic
technique vis. UV, IR, 1H NMR, 13C NMR, DEPT, 2-D NMR and mass spectrometry
coupled with chemical analysis. Furthermore, an in silico library of isolated
isoflavones and its analogues were designed. NF-kappaB (transcription factor
that facilitates angiogenesis, inflammation, invasion and metastasis) was
selected as a target to evaluate the anticancer and antioxidant activity of
isoflavones and its analogues. Designed library of isoflavones and analogues
were docked into the active site of NF-kappa B and the most active 15 analogues
were selected for synthesis. Finally, all compounds were evaluated for their
cytotoxicity against various cell lines and antioxidant activity with different
methods that demonstrate their anti-cancer and anti-oxidant potential. The cell
cycle specificity of the cytotoxicity was further analyzed by corresponding
analysis, using flow cytometer. Most of the compounds exhibit moderate activity,
whereas the 5,7,8-trihydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one,
5,7,8-trihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one,
5,7,8-triacetoxyoxy-3-(4-methoxyphenyl)-4H-chromen-4-one and
6,7-diacetoxyoxy-3-(4-methoxyphenyl)-4H-chromen-4-one showed distinct
broad-spectrum anticancer activity with IC50 values ranges between 3.8 and
5.6 μg/mL. Cell cycle analysis indicates that these compounds induced cell cycle
arrest at G2/M phase.
DOI: 10.1016/j.phytochem.2017.01.002
337. Br J Nutr. 2016 Dec;116(12):2115-2128. doi: 10.1017/S0007114516004360. Epub

2017
Jan 16.
Phyto-oestrogens and colorectal cancer risk: a systematic review and

dose-response meta-analysis of observational studies.
Jiang R(1), Botma A(1), Rudolph A(1), Hüsing A(1), Chang-Claude J(1).
Author information:
(1)1Division of Cancer Epidemiology,German Cancer Research Center (DKFZ),69120
Heidelberg,Germany.
Epidemiological studies suggest that soya consumption as a source of

phyto-oestrogens and isoflavones may be associated with a reduced risk of
colorectal cancer. However, findings have not yet been synthesised for all
groups of phyto-oestrogens. A meta-analysis was conducted to quantify the
association between phyto-oestrogens and colorectal cancer risk. Relevant
observational studies published up to June 2016 were identified by searching
MEDLINE, EMBASE and Cochrane Library databases. Study-specific relative risks
(RR) were pooled in both categorical and dose-response meta-analyses. Out of
seventeen identified studies, sixteen were included in the meta-analysis.
Comparing the highest with the lowest intake category, inverse associations for
phyto-oestrogens overall and by subgroup were observed but were statistically
significant in case-controls studies and not in cohort studies. The pooled RR in
case-control studies were 0·76 (95 % CI 0·69, 0·84), 0·77 (95 % CI 0·69, 0·85)
and 0·70 (95 % CI 0·56, 0·89) for phyto-oestrogens, isoflavones and lignans,
respectively, whereas the corresponding pooled RR were 0·95 (95 % CI 0·85,
1·06), 0·94 (95 % CI 0·84, 1·05) and 1·00 (95 % CI 0·64, 1·57) in cohort
studies. Dose-response analysis yielded an 8 % reduced risk of colorectal
neoplasms for every 20 mg/d increase in isoflavones intake in Asians (pooled RR
0·92; 95 % CI 0·86, 0·97). A non-linear inverse association with colorectal
cancer risk was found for lignans intake, but no association for circulating
enterolactone concentrations was observed. Thus, study heterogeneity precludes a
rigorous conclusion regarding an effect of high exposure to isoflavones on risk
of colorectal cancer. Current evidence for an association with lignans exposure
is limited. Further prospective studies, particularly evaluating lignans, are
warranted to clarify the association between different phyto-oestrogens and
colorectal cancer risk.
DOI: 10.1017/S0007114516004360
338. J Nutr Biochem. 2017 Jul;45:1-14. doi: 10.1016/j.jnutbio.2016.11.007. Epub

2016
Nov 28.
Plant flavonoids in cancer chemoprevention: role in genome stability.
George VC(1), Dellaire G(2), Rupasinghe HPV(3).
Author information:
(1)Department of Plant, Food, and Environmental Sciences, Faculty of
Agriculture, Dalhousie University, Truro, Nova Scotia, Canada.
(2)Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax,
Nova Scotia, Canada.
(3)Department of Plant, Food, and Environmental Sciences, Faculty of
Agriculture, Dalhousie University, Truro, Nova Scotia, Canada; Department of
Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia,
Canada. Electronic address: vrupasinghe@dal.ca.
Carcinogenesis is a multistage process that involves a series of events

comprising of genetic and epigenetic changes leading to the initiation,
promotion and progression of cancer. Chemoprevention is referred to as the use
of nontoxic natural compounds, synthetic chemicals or their combinations to
intervene in multistage carcinogenesis. Chemoprevention through diet
modification, i.e., increased consumption of plant-based food, has emerged as a
most promising and potentially cost-effective approach to reducing the risk of
cancer. Flavonoids are naturally occurring polyphenols that are ubiquitous in
plant-based food such as fruits, vegetables and teas as well as in most
medicinal plants. Over 10,000 flavonoids have been characterized over the last
few decades. Flavonoids comprise of several subclasses including flavonols,
flavan-3-ols, anthocyanins, flavanones, flavones, isoflavones and
proanthocyanidins. This review describes the most efficacious plant flavonoids,
including luteolin, epigallocatechin gallate, quercetin, apigenin and chrysin;
their hormetic effects; and the molecular basis of how these flavonoids
contribute to the chemoprevention with a focus on protection against DNA damage
caused by various carcinogenic factors. The present knowledge on the role of
flavonoids in chemoprevention can be used in developing effective dietary
strategies and natural health products targeted for cancer chemoprevention.
DOI: 10.1016/j.jnutbio.2016.11.007
339. Mol Nutr Food Res. 2017 Apr;61(4). doi: 10.1002/mnfr.201600930. Epub 2017 Feb
7.
A comprehensive meta-analysis on dietary flavonoid and lignan intake and cancer

risk: Level of evidence and limitations.
Grosso G(1)(2), Godos J(1), Lamuela-Raventos R(3)(4), Ray S(2)(5), Micek A(6),
Pajak A(6), Sciacca S(1), D'Orazio N(7), Del Rio D(2)(8), Galvano F(9).
Author information:
(1)Integrated Cancer Registry of Catania-Messina-Siracusa-Enna, Azienda
Ospedaliero-Universitaria Policlinico-Vittorio Emanuele, Catania, Italy.
(2)NNEdPro Global Centre for Nutrition and Health, St John's Innovation Centre,
Cambridge, UK.
(3)Biomedical Research Center Network on Obesity and Nutrition (CIBERobn)
Physiopathology of Obesity and Nutrition, Institute of Health Carlos III,
Madrid, Spain.
(4)Nutrition and Food Science Department-XaRTA, INSA, University of Barcelona,
Barcelona, Spain.
(5)Medical Research Council (MRC) Human Nutrition Research Unit, Cambridge, UK.
(6)Department of Epidemiology and Population Studies, Jagiellonian University
Medical College, Krakow, Poland.
(7)Department of Medical and Oral Sciences and Biotechnologies, University of
Chieti, Chieti, Italy.
(8)Department of Food Science, University of Parma, Parma, Italy.
(9)Department of Biomedical and Biotechnological Sciences, University of
Catania, Catania, Italy.
SCOPE: To summarize available evidence on the association between dietary

flavonoid as well as lignan intake and cancer risk in observational studies.
METHODS AND RESULTS: A systematic search on electronic databases of all English
language case-control and prospective studies published up to June 2016 was
performed. Risk ratios (RRs) and 95% confidence intervals were calculated by
random-effects model separately by study design. Heterogeneity and publication
bias were tested. Out of the 143 studies included, meta-analyses of prospective
studies showed isoflavones significantly associated with decreased risk of lung
and stomach cancers and nearly significant breast and colorectal cancers; total
flavonoids showed nonsignificant decreased risk of breast cancer. Meta-analyses
of case-control studies showed: total and/or individual classes of flavonoids
associated with upper aero-digestive tract, colorectal, breast, and lung
cancers; isoflavones with ovarian, breast, and colorectal cancers, endometrial
and lung cancers.
CONCLUSIONS: Most evidence reported in previous meta-analyses was driven by
case-control studies. Overall results may be promising but are inconclusive.
Further prospective cohorts assessing dietary polyphenol exposure and studies
using other methods to evaluate exposure (i.e. markers of consumption,
metabolism, excretion) are needed to confirm and determine consumption levels
required to achieve health benefits.
DOI: 10.1002/mnfr.201600930
340. Nutr Cancer. 2017 Jan;69(1):146-153. doi: 10.1080/01635581.2017.1250924. Epub

2016 Dec 5.
Soy Food Intake and Biomarkers of Breast Cancer Risk: Possible Difference in
Asian Women?
Maskarinec G(1), Ju D(1), Morimoto Y(1), Franke AA(1), Stanczyk FZ(2).
Author information:
(1)a Epidemiology Program , University of Hawaii Cancer Center , Honolulu ,
Hawaii , USA.
(2)b Keck School of Medicine , University of Southern California , Los Angeles ,
California , USA.
Soy foods may protect against breast cancer in Asian but not in Western
populations. We examined if the levels of various markers of breast cancer risk
and inflammation, as well as the effects of soy food consumption on these
markers, differ between Asian and non-Asian premenopausal women in two soy
intervention trials. One study randomized 220 women to a 2-yr intervention and
the other one randomized 96 women in a crossover design to examine the effects
of consumption of 2 daily soy servings on nipple aspirate fluid (NAF) volume;
estrogens in serum, NAF, and urine; insulin-like growth factor-1 (IGF-1),
IGF-binding protein 3, and inflammatory markers in serum; and mammographic
densities. Mixed linear models were applied to assess ethnic differences in
biomarkers and response to the soy diet. Serum C-reactive protein, serum leptin,
NAF volume, and NAF estrone sulfate were lower, while urinary isoflavones were
higher in Asian than in non-Asian women. A significant interaction (pinteraction
= 0.05) between ethnicity and soy diet was observed for IGF-1 but not for other
biomarkers. The current findings suggest possible ethnic differences in levels
of biomarkers for breast cancer risk but little evidence that Asian women
respond differently to soy foods than non-Asian women.
DOI: 10.1080/01635581.2017.1250924
PMCID: PMC5248572
341. J Acad Nutr Diet. 2018 Apr;118(4):637-651. doi: 10.1016/j.jand.2016.09.036.

Epub
2016 Dec 1.
Association between Dietary Isoflavones in Soy and Legumes and Endometrial

Cancer: A Systematic Review and Meta-Analysis.
Zhong XS, Ge J, Chen SW, Xiong YQ, Ma SJ, Chen Q.
BACKGROUND: Epidemiologic studies have reported conflicting findings between

soy- and legume-derived dietary isoflavones and risk of endometrial cancer.
OBJECTIVE: The aim of the present meta-analysis was to quantitatively
investigate the association between daily intake of soy- and legume-derived
isoflavones and risk of endometrial cancer.
DESIGN: A broad search was conducted in the following electronic databases:
PubMed, EMBASE, Google Scholar, the Cochrane Library, the China Knowledge
Resource Integrated Database, and the Chinese Biomedical Database based on
combinations of the key words endometrial cancer, isoflavone, soy, and legume
for epidemiologic studies that focused on relationships between dietary
isoflavones and endometrial cancer risk. A fixed-effect or random-effect model
was used to pool study-specific risk estimates.
RESULTS: A total of 13 epidemiologic studies were included in the present
meta-analysis, consisting of three prospective cohort studies and 10
population-based case-control studies. The final results indicated that higher
dietary isoflavone levels from soy products and legumes were associated with a
reduced risk of endometrial cancer (odds ratio [OR] 0.81, 95% CI 0.74 to 0.89).
Low heterogeneous bias was observed (I2=11.7%; P=0.327). Subgroup analyses were
conducted based on study design, source of dietary isoflavones, and study
region. When restricted to study design, dietary isoflavones from soy and
legumes played a role in prevention of endometrial cancer in case-control
studies (OR 0.81, 95% CI 0.73 to 0.90). However, there did not appear to be an
association between dietary isoflavones and endometrial cancer in cohort studies
(OR 0.81, 95% CI 0.66 to 1.00). Significant associations were found between
dietary isoflavones from soy products (OR 0.82, 95% CI 0.72 to 0.92) and legumes
(OR 0.84, 95% CI 0.74 to 0.96) and endometrial cancer. Dietary isoflavones were
associated with reduced incidence of endometrial cancer, both in Asian countries
(OR 0.78, 95% CI 0.66 to 0.93) and non-Asian countries (OR 0.82, 95% CI 0.73 to
0.92).
CONCLUSIONS: The findings suggest a weak inverse association between higher
consumption of dietary isoflavones from soy products and legumes and endometrial
cancer risk. However, there is still a need for large, prospective epidemiologic
studies that provide a higher level of evidence to verify these findings.
Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc.

All rights reserved.
DOI: 10.1016/j.jand.2016.09.036
342. Nutrients. 2016 Nov 24;8(12):754. doi: 10.3390/nu8120754.
Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature.
Messina M(1).
Author information:
(1)Nutrition Matters, Inc., 26 Spadina Parkway, Pittsfield, MA 01201, USA.
markjohnmessina@gmail.com.
Soyfoods have long been recognized as sources of high-quality protein and

healthful fat, but over the past 25 years these foods have been rigorously
investigated for their role in chronic disease prevention and treatment. There
is evidence, for example, that they reduce risk of coronary heart disease and
breast and prostate cancer. In addition, soy alleviates hot flashes and may
favorably affect renal function, alleviate depressive symptoms and improve skin
health. Much of the focus on soyfoods is because they are uniquely-rich sources
of isoflavones. Isoflavones are classified as both phytoestrogens and selective
estrogen receptor modulators. Despite the many proposed benefits, the presence
of isoflavones has led to concerns that soy may exert untoward effects in some
individuals. However, these concerns are based primarily on animal studies,
whereas the human research supports the safety and benefits of soyfoods. In
support of safety is the recent conclusion of the European Food Safety Authority
that isoflavones do not adversely affect the breast, thyroid or uterus of
postmenopausal women. This review covers each of the major research areas
involving soy focusing primarily on the clinical and epidemiologic research.
Background information on Asian soy intake, isoflavones, and nutrient content is
also provided.
DOI: 10.3390/nu8120754
PMCID: PMC5188409
Conflict of interest statement: The author is the executive director of the Soy
Nutrition Institute, an organization funded by the United Soybean Board and its
soy industry members.
343. Maturitas. 2016 Dec;94:13-19. doi: 10.1016/j.maturitas.2016.08.004. Epub 2016
Aug 18.
Cancer chemoprevention by dietary phytochemicals: Epidemiological evidence.
Baena Ruiz R(1), Salinas Hernández P(2).
Author information:
(1)Hospital La Zarzuela, Madrid, Spain. Electronic address:
raul.baena.ruiz@gmail.com.
(2)Hospital La Zarzuela, Madrid, Spain.
BACKGROUND: In recent years, natural compounds called "phytochemicals", which

are present in fruits, vegetables, and plants, have received special attention
due to their potential to interfere with tumour formation and development. Many
of these phytochemicals are being used in chemoprevention strategies. However,
the scientific evidence regarding the modification of cancer risk continues to
be debated.
OBJECTIVE: The aim of this paper is to review the current scientific evidence
and the most relevant epidemiological studies regarding the consumption or use
of phytochemicals and their effects on the incidence of cancer.
DESIGN: A search for relevant articles was conducted in EMBASE and PubMed-NCBI
through to May 2016 to identify potential interactions between the consumption
or use of phytochemicals and cancer risk.
RESULTS: The use or consumption of carotenoids, such as lycopene,
alpha-carotene, and betacarotene, leads to a reduction in the risk of cancer,
such as breast and prostate tumours. For breast cancer, beta-carotene even
reduces the risk of recurrence. The use or consumption of soybean isoflavones
has led to a reduction in the risk of lung, prostate, colon (in women only), and
breast cancers, although this has depended on menopausal and oestrogen receptor
status. The use or consumption of isothiocyanates and indole-3-carbinol also
seems to reduce the risk of cancer, such as breast, stomach, colorectal, or
prostate tumours.
CONCLUSIONS: The adoption of a diet rich in phytochemicals is associated with a
modification of cancer risk. However, the scientific data supporting its use
come mainly from in vitro and in vivo studies (especially in animal models). The
epidemiological evidence is inconclusive for many of these phytochemicals, so
further studies are needed.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.maturitas.2016.08.004
344. Nat Prod Commun. 2016 Nov;11(11):1733-1740.
Multidimensional Effects of Soy Isoflavone by Food or Supplements in Menopause

Women: a Systematic Review and Bibliometric Analysis.
Perna S, Peroni G, Miccono A, Riva A, Morazzoni P, Allegrini P, Preda S,

Baldiraghi V, Guido D, Rondanelli M.
Isoflavones can exert their action on various levels: on cardiovascular system,

bone and muscle health, on cancer, on menopausal symptoms, on obesity, on
thyroid and on cognitive function. The aim of this systematic review is to
evaluate the multidimensional effects of phytoestrogens in postmenopausal woman,
and specifically to explore the impact on scientific literature. A research
strategy was planned on PubMed and Scopus by defining the following key words::
menopause, climacteric, soy, isoflavone, phytoestrogens, cardiovascular system,
bone mineral density, muscle mass, cancer, thyroid, obesity, cognitive. A total
of 43 studies (in humans) were retrieved. The majority (12) describe the
applications of soy isoflavones on cardiovascular disease, followed by effects
on bone and muscle health (9), and studies concerning their action on menopausal
symptoms (7), on cancer (6), on obesity (4), on cognitive function (3) and on
thyroid function (2). The citation analysis revealed a growing interest for this
topic and the papers on thyroid function are the most cited. Citation trends
ofthe articles regarding the action on cardiovascular disease and on obesity are
growing in the last years. Concerning the research areas, this review has
assessed the effectiveness of various activities of isoflavones on welfare of
menopausal women. In particular, literature show that a specific dosage of
isoflavdnes reduces cardiovascular disease (from 20 to 100 mg/die), may be
protective in osteoporosis and muscular fatigue (from 20 to 80 mg/die), may be
useful for cancer prevention on endometrium, mammary glands and liver (from 50
to 100 mg/die), might improve menopausal symptoms, particularly in reducing the
frequency of hot flashes (from 50 to 120 mg/die), can reduce abdominal fat and
circulating inflammatory markers (from 80 to 160 mg/die), may ameliorate the
pdssible interaction between endogenous estrogen and thyroid function (75
mg/die) and improve visual memory (from 50 to 100 mg/die).
345. Anticancer Res. 2016 Nov;36(11):5827-5833. doi: 10.21873/anticanres.11167.
Isoflavone Extracts Enhance the Effect of Epidermal Growth Factor Receptor

Inhibitors in NSCLC Cell Lines.
Ambrosio R(1), Ombra MN(2), Gridelli C(1), Picariello G(2), DI Stasio M(2),
Volpe MG(3).
Author information:
(1)Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.
(2)Institute of Food Sciences, National Research Council, Avellino, Italy.
(3)Institute of Food Sciences, National Research Council, Avellino, Italy
mgvolpe@isa.cnr.it.
AIM: We investigated the effects of the pharmacological inhibition in vitro of

epidermal growth factor receptor (EGFR) in combination with isoflavones.
MATERIALS AND METHODS: Four anticancer drugs (erlotinib, gefitinib, afatinib and
AZD9291) were combined with soy and red clover isoflavone extracts and used in
cellular proliferation assays. The antitumor activity of inhibitors alone and in
combination with isoflavone extracts was compared on three non-small cell lung
cancer (NSCLC) cell lines with affiant EGFR genotype: A549 (EGFR wt); H1795
(EGFR T790M); HCC827 (EGFR del E746-A750).
RESULTS: Combined treatment with extracts significantly enhanced the
antiproliferative activity of all inhibitors against these cell lines. Bioactive
compounds of extracts may synergize the antitumor efficacy of the inhibitors.
CONCLUSION: To date, as far as we are aware, this is the first report of the
combined effect of isoflavone extracts and EGFR inhibitors on human NCSLC cell
growth. Sequential treatment with these drugs combined with isoflavones may
represent the basis for a new therapeutic approach.
Copyright© 2016 International Institute of Anticancer Research (Dr. John G.

Delinassios), All rights reserved.
346. J Obstet Gynaecol Res. 2016 Nov;42(11):1575-1580. doi: 10.1111/jog.13073. Epub

2016 Jun 29.
Relation between premenstrual syndrome and equol-production status.
Takeda T(1), Ueno T(2), Uchiyama S(2), Hiramatsu K(3), Shiina M(4).
Author information:
(1)Division of Women's Health, Research Institute of Traditional Asian Medicine,
Kindai University School of Medicine, Osaka, Japan. take@med.kindai.ac.jp.
(2)Saga Nutraceuticals Research Institute of Otsuka Pharmaceutical Co., Ltd,
Saga, Japan.
(3)Hiramatsu Women's Clinic, Osaka, Japan.
(4)Division of Women's Health, Research Institute of Traditional Asian Medicine,
Kindai University School of Medicine, Osaka, Japan.
AIM: Consumption of isoflavones, which are predominantly derived from soybeans,

reduces the risk of estrogen-related diseases, such as menopausal symptoms,
breast cancer, osteoporosis, and cardiovascular disease. Equol is more
bioavailable than other soy isoflavones, and equol producers are believed to
benefit to a greater extent. This study was conducted to evaluate the relation
between premenstrual syndrome (PMS) and equol-production status in Japanese
reproductive-age women.
METHODS: This was a cross-sectional, observational study. The study included 144
Japanese women aged 20-45 years. PMS patients (n = 46) were recruited at three
obstetrics and gynecology clinics. Control group women (n = 98) who were not
receiving therapy for PMS were recruited from the local area by advertisement.
The participants' equol-production status was determined using urine samples
collected after a soy challenge test.
RESULTS: The prevalence of equol producers was 41.8% in the control group and
23.9% in the patient group (P = 0.042). Using univariate analysis, significant
risk factors for equol non-producers were being a PMS patient and being younger.
In multivariate analysis with a step-wise model, being a PMS patient (odds
ratio, 2.342; 95% confidence interval, 1.021-5.698) was shown to be a
significant risk factor for being an equol non-producer.
CONCLUSION: This study showed a relation between PMS and equol-production status
in Japanese women.
© 2016 Japan Society of Obstetrics and Gynecology.
DOI: 10.1111/jog.13073
347. Trends Endocrinol Metab. 2016 Nov;27(11):752-755. doi:

10.1016/j.tem.2016.08.001. Epub 2016 Aug 20.
Estrogen and Microbiota Crosstalk: Should We Pay Attention?
Chen KL(1), Madak-Erdogan Z(2).
Author information:
(1)Division of Nutritional Sciences, University of Illinois, Urbana-Champaign,
Urbana, IL, 61801, USA.
(2)Division of Nutritional Sciences, University of Illinois, Urbana-Champaign,
Urbana, IL, 61801, USA; Department of Food Science and Human Nutrition,
University of Illinois, Urbana-Champaign, Urbana, IL, 61801, USA. Electronic
address: zmadake2@illinois.edu.
Recent advances have suggested that steroid hormones such as estrogens, and gut
microbiota might synergize to influence obesity, diabetes, and cancer. We
discuss recent knowledge of the interactions between estrogens and gut
microbiota, and new insights that might offer new approaches to influence this
crosstalk and improve metabolic outcomes.
DOI: 10.1016/j.tem.2016.08.001
348. Arch Toxicol. 2017 Apr;91(4):1649-1661. doi: 10.1007/s00204-016-1853-1. Epub

2016 Oct 14.
Influence of testosterone on phase II metabolism and availability of soy

isoflavones in male Wistar rats.
Soukup ST(1), Müller DR(2), Kurrat A(2), Diel P(2), Kulling SE(3).
Author information:
Rubner-Institut, Haid-und-Neu-Straße 9, 76131, Karlsruhe, Germany.
(2)Department of Molecular and Cellular Sports Medicine, German Sport University
Cologne, Cologne, Germany.
Rubner-Institut, Haid-und-Neu-Straße 9, 76131, Karlsruhe, Germany.
sabine.kulling@mri.bund.de.
Genistein and daidzein are the main isoflavones in soy. Their potential
beneficial or adverse effects in males like the prevention of prostate cancer or
the impact on reproductive functions are controversially discussed. Major
determinants of their bioactivity are the absorption and biotransformation of
isoflavones. In this study, we focused on the influence of testosterone on
plasma availability and phase II metabolism of isoflavones. Male Wistar rats,
receiving an isoflavones rich diet, were randomized into three groups: Two
groups were orchiectomized (ORX) at postnatal day (PND) 80 and treated for
11 days with testosterone propionate (TP) (ORX TP group) or a vehicle (ORX
group) after a 7 days lasting hormonal decline. The third group served as
control and remained intact. Rats were sacrificed at PND 98. ORX rats had
reduced isoflavones plasma levels. Differently regulated mRNA expressions of
transporters relevant for transport of phase II metabolites in liver and kidney
may be responsible for this reduction, more precisely Slc10a1 and Slc21a1 in
kidney as well as Slc22a8 in liver. While main phase II metabolites in intact
rats were disulfates and sulfoglucuronides, the amount of sulfate conjugates was
significantly diminished by ORX. In accordance with that, mRNA expression of
different sulfotransferases was reduced in liver by ORX. The observed effects
could be almost restored by TP treatment. In conclusion, testosterone, and
likely further androgens, has a huge impact on phase II metabolism and
availability of isoflavones by influencing the expression of different
sulfotransferases and transporters.
DOI: 10.1007/s00204-016-1853-1
349. Nutrients. 2016 Oct 8;8(10):616. doi: 10.3390/nu8100616.
Effects of Phytoestrogen Extracts Isolated from Elder Flower on Hormone

Production and Receptor Expression of Trophoblast Tumor Cells JEG-3 and BeWo, as
well as MCF7 Breast Cancer Cells.
Schröder L(1), Richter DU(2), Piechulla B(3), Chrobak M(4), Kuhn C(5), Schulze
S(6), Abarzua S(7), Jeschke U(8), Weissenbacher T(9).
Author information:
(1)Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University of
Munich, Munich 80337, Germany. lennard.schroeder@med.uni-muenchen.de.
(2)Department of Obstetrics and Gynaecology, University of Rostock, Rostock
18059, Germany. dagmar.richter@kliniksued-rostock.de.
(3)Department of Biological Sciences, University of Rostock, Rostock 18059,
Germany. birgit.piechulla@uni-rostock.de.
Germany. chrobak@bni-hamburg.de.
Munich, Munich 80337, Germany. Christina.kuhn@med.uni-muenchen.de.
Munich, Munich 80337, Germany. sandra.schulze@med.uni-muenchen.de.
Germany. sybille.abarzua@uni-rostock.de.
Munich, Munich 80337, Germany. udo.jeschke@med.uni-muenchen.de.
Munich, Munich 80337, Germany. tobias.weissenbacher@med.uni-muenchen.de.
Hereinwe investigated the effect of elderflower extracts (EFE) and of

enterolactone/enterodiol on hormone production and proliferation of trophoblast
tumor cell lines JEG-3 and BeWo, as well as MCF7 breast cancer cells. The EFE
was analyzed by mass spectrometry. Cells were incubated with various
concentrations of EFE. Untreated cells served as controls. Supernatants were
tested for estradiol production with an ELISA method. Furthermore, the effect of
the EFE on ER/ER/PR expression was assessed by immunocytochemistry. EFE contains
a substantial amount of lignans. Estradiol production was inhibited in all cells
in a concentration-dependent manner. EFE upregulated ER in JEG-3 cell lines. In
MCF7 cells, a significant ER downregulation and PR upregulation were observed.
The control substances enterolactone and enterodiol in contrast inhibited the
expression of both ER and of PR in MCF7 cells. In addition, the production of
estradiol was upregulated in BeWo and MCF7 cells in a concentration dependent
manner. The downregulating effect of EFE on ER expression and the upregulation
of the PR expression in MFC-7 cells are promising results. Therefore, additional
unknown substances might be responsible for ER downregulation and PR
upregulation. These findings suggest potential use of EFE in breast cancer
prevention and/or treatment and warrant further investigation.
DOI: 10.3390/nu8100616
PMCID: PMC5084004
350. Int J Food Sci Nutr. 2017 Feb;68(1):28-42. doi: 10.1080/09637486.2016.1216525.

Epub 2016 Aug 9.
Phytoestrogens and risk of prostate cancer: an updated meta-analysis of
epidemiologic studies.
Zhang Q(1), Feng H(1)(2), Qluwakemi B(1), Wang J(1), Yao S(1), Cheng G(3), Xu
H(4), Qiu H(1), Zhu L(1), Yuan M(5).
Author information:
(1)a School of Public Health, Jiamusi University , Jiamusi , China.
(2)b Department of Neurology , Zhongnan Hospital of Wuhan University , Wuhan ,
China.
(3)c College of Life Science, Jiamusi University , Jiamusi , China.
(4)d College of Basic Medicine, Jiamusi University , Jiamusi , China.
(5)e Bio-Vaccine Limited Liability Company, Harbin Pharmaceutical Group , Harbin
, China.
This updated meta-analysis was performed to clarify the relationship between

phytoestrogens and prostate cancer risk. Twenty one case-control and two cohort
studies were finally selected for this meta-analysis, totaling 11,346 cases and
140,177 controls. Analytical results showed that daidzein (OR = 0.85; 95% CI:
0.75-0.96), genistein (OR = 0.87; 95% CI: 0.78-0.98), and glycitein (OR = 0.89;
95% CI: 0.81-0.98) were associated with a reduction of prostate cancer risk, but
total isoflavones (OR = 0.93; 95% CI: 0.84-1.04), equol (OR = 0.86; 95% CI:
0.66-1.14), total lignans (OROgna.05; 95% CI: 0.54-2.04), secoisolariciresinol
(OR = 1.02; 95% CI: 0.83-1.24), matairesinol (OR = 0.91; 95% CI: 0.75-1.11),
enterolactone (OR = 0.94; 95% CI: 0.73-1.20), and coumestrol (OR = 0.89; 95% CI:
0.76-1.06) were not. Sensitivity and publication bias analyses demonstrated that
the pooled estimates were stable and reliable. The results support the notion
that some phytoestrogens may have a role in decreasing the risk of prostate
cancer. Additional large and well-designed cohort studies are needed to confirm
these relationships.
DOI: 10.1080/09637486.2016.1216525
Reducing Breast Cancer Recurrence: The Role of Dietary Polyphenolics.
Braakhuis AJ(1), Campion P(2), Bishop KS(3).
Author information:
(1)Discipline of Nutrition and Dietetics, FM & HS, University of Auckland,
Private Bag 92019, Auckland 1142, New Zealand. a.braakhuis@auckland.ac.nz.
(2)Discipline of Nutrition and Dietetics, FM & HS, University of Auckland,
Private Bag 92019, Auckland 1142, New Zealand. pcam131@aucklanduni.ac.nz.
(3)Auckland Cancer Society Research Center, FM & HS, University of Auckland,
Private Bag 92019, Auckland 1142, New Zealand. kbishop@auckland.ac.nz.
Evidence from numerous observational and clinical studies suggest that

polyphenolic phytochemicals such as phenolic acids in olive oil, flavonols in
tea, chocolate and grapes, and isoflavones in soy products reduce the risk of
breast cancer. A dietary food pattern naturally rich in polyphenols is the
Mediterranean diet and evidence suggests those of Mediterranean descent have a
lower breast cancer incidence. Whilst dietary polyphenols have been the subject
of breast cancer risk-reduction, this review will focus on the clinical effects
of polyphenols on reducing recurrence. Overall, we recommend breast cancer
patients consume a diet naturally high in flavonol polyphenols including tea,
vegetables (onion, broccoli), and fruit (apples, citrus). At least five servings
of vegetables and fruit daily appear protective. Moderate soy protein
consumption (5-10 g daily) and the Mediterranean dietary pattern show the most
promise for breast cancer patients. In this review, we present an overview of
clinical trials on supplementary polyphenols of dietary patterns rich in
polyphenols on breast cancer recurrence, mechanistic data, and novel delivery
systems currently being researched.
DOI: 10.3390/nu8090547
PMCID: PMC5037532
The Impact of Soy Isoflavones on MCF-7 and MDA-MB-231 Breast Cancer Cells Using
a Global Metabolomic Approach.
Uifălean A(1)(2), Schneider S(3), Gierok P(4), Ionescu C(5), Iuga CA(6)(7), Lalk
M(8).
Author information:
University of Medicine and Pharmacy, Louis Pasteur Street 6, Cluj-Napoca 400349,
Romania. alina.uifalean@umfcluj.ro.
(2)Institute of Biochemistry, Ernst-Moritz-Arndt-University, Felix-Hausdorff
Street 4, Greifswald 17487, Germany. alina.uifalean@umfcluj.ro.
Street 4, Greifswald 17487, Germany. schneids42@uni-greifswald.de.
Street 4, Greifswald 17487, Germany. gierokp47@uni-greifswald.de.
(5)Department of Pharmaceutical Biochemistry and Clinical Laboratory, Faculty of
Pharmacy, "Iuliu Hațieganu" University of Medicine and Pharmacy, Louis Pasteur
Street 6, Cluj-Napoca 400349, Romania. corina.ionescu@umfcluj.ro.
Romania. iugac@umfcluj.ro.
(7)MedFuture Research Center for Advanced Medicine, "Iuliu Hațieganu" University
of Medicine and Pharmacy, Louis Pasteur Street 4-6, Gh. Marinescu Street 23,
Cluj-Napoca 400349, Romania. iugac@umfcluj.ro.
Street 4, Greifswald 17487, Germany. lalk@uni-greifswald.de.
Despite substantial research, the understanding of the chemopreventive

mechanisms of soy isoflavones remains challenging. Promising tools, such as
metabolomics, can provide now a deeper insight into their biochemical
mechanisms. The purpose of this study was to offer a comprehensive assessment of
the metabolic alterations induced by genistein, daidzein and a soy seed extract
on estrogen responsive (MCF-7) and estrogen non-responsive breast cancer cells
(MDA-MB-231), using a global metabolomic approach. The
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed
that all test compounds induced a biphasic effect on MCF-7 cells and only a
dose-dependent inhibitory effect on MDA-MB-231 cells. Proton nuclear magnetic
resonance (¹H-NMR) profiling of extracellular metabolites and gas
chromatography-mass spectrometry (GC-MS) profiling of intracellular metabolites
confirmed that all test compounds shared similar metabolic mechanisms. Exposing
MCF-7 cells to stimulatory concentrations of isoflavones led to increased
intracellular levels of 6-phosphogluconate and ribose 5-phosphate, suggesting a
possible upregulation of the pentose phosphate pathway. After exposure to
inhibitory doses of isoflavones, a significant decrease in glucose uptake was
observed, especially for MCF-7 cells. In MDA-MB-231 cells, the glutamine uptake
was significantly restricted, leading to alterations in protein biosynthesis.
Understanding the metabolomic alterations of isoflavones represents a step
forward in considering soy and soy derivates as functional foods in breast
cancer chemoprevention.
DOI: 10.3390/ijms17091443
PMCID: PMC5037722
353. Chem Biodivers. 2017 Jan;14(1). doi: 10.1002/cbdv.201600193. Epub 2017 Jan 3.
Chemical Composition of Roots Flemingia philippinensis and Their Inhibitory

Kinetics on Aromatase.
Sun F(1), Li Q(2), Xu J(1).
Author information:
(1)Pharmaceutical Department, Nanjing Children's Hospital Affiliated to Nanjing
Medical University, Nanjing, 210008, P. R. China.
(2)Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou,
310013, P. R. China.
Aromatase is the key enzyme responsible for catalyzing the conversion of C19
steroids to estrogens. Its inhibitors are widely used in breast cancer therapy.
The CH2 Cl2 partition of a crude ethanolic extract from the roots of Flemingia
philippinensis showed potent inhibitory activity of aromatase. The constituents
of the extract were analyzed and identified by liquid chromatography tandem mass
spectrometry. Five purified prenylated isoflavones were evaluated for aromatase
inhibition and their IC50 values ranged between 2.98 and 58.08 μm. In kinetic
studies, all tested compounds behaved as reversible competitive inhibitors and
their Ki values were calculated by Dixon plots. The most potent inhibitor
(6,8-diprenylorobol) had a Ki value of 1.42 μm. Furthermore, using UPLC and
LC/MS, 6,8-diprenylorobol was proven to be present in the native roots in high
quantities.
© 2017 Wiley-VHCA AG, Zurich, Switzerland.
DOI: 10.1002/cbdv.201600193
354. Chin J Nat Med. 2016 Jun;14(6):462-72. doi: 10.1016/S1875-5364(16)30044-9.
Synthesis and cytotoxicity evaluation of 3-amino-2-hydroxypropoxyisoflavone

derivatives.
Tang JJ(1), Geng XT(2), Wang YJ(1), Zheng TY(2), Lu JR(3), Hu R(4).
Author information:
(1)State Key Laboratory of Natural Medicines, Department of Physiology, China
Pharmaceutical University, Jiangsu Nanjing, 210009, China.
(2)Department of Organic Chemistry, China Pharmaceutical University, Jiangsu
Nanjing 210009, China.
(3)Department of Organic Chemistry, China Pharmaceutical University, Jiangsu
Nanjing 210009, China. Electronic address: L_John81@sina.com.
(4)State Key Laboratory of Natural Medicines, Department of Physiology, China
Pharmaceutical University, Jiangsu Nanjing, 210009, China. Electronic address:
ronghu@cpu.edu.cn.
Soy isoflavones exert a wide variety of biological activities, such as

antioxidant, anti-inflammatory and anti-cancer properties. Nuclear factor
erythroid 2-related factor 2 (Nrf2), a bZip transcription factor, plays a key
role in soy isoflavones induced protection against oxidative stress and cancer.
To obtain more effective isofavones, a series of
7,4'-bis-(3-amino-2-hydroxypropoxy), 7 or 4'-(3-amino-2-hydroxypropoxy)
isoflavone derivatives have been synthesized as potential antitumor agents and
Nrf2/ARE (antioxidant response element) activators. The cytotoxicity of these
compounds in human cancer cell lines MDA-MB-231, HT-29, HCT116, HepG2 and 7402
was tested by MTT assay. In this study, the cytotoxicity of compound 3b
exhibited highest cytotoxic activity and at the safety dose range, it also
strongly up-regulated antioxidant response element (ARE)-luciferase reporter
activity. In addition, compound 3b induced Nrf2 nuclear translocation and
upregulated its downstream target genes NQO-1 and HO-1 at protein level. Taken
together, our results suggest that compound 3b could be a potential agent for
cancer themotherapy or cancer chemoprevention.
Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All

rights reserved.
DOI: 10.1016/S1875-5364(16)30044-9
355. Cytotechnology. 2016 Oct;68(5):1909-23. doi: 10.1007/s10616-016-0002-2. Epub

2016 Jul 25.
Evaluation of Ceiba pentandra (L.) Gaertner bark extracts for in vitro

cytotoxicity on cancer cells and in vivo antitumor activity in solid and liquid
tumor models.
Kumar R(1), Kumar N(1), Ramalingayya GV(1), Setty MM(1), Pai KS(2).
Author information:
Manipal University, Manipal, 576104, Karnataka, India.
Manipal University, Manipal, 576104, Karnataka, India. ksr.pai@manipal.edu.
The stem bark of Ceiba pentandra (L.) Gaertner is claimed to be useful in the
treatment of tumors in the southern part of India. This plant possesses a number
of sesquiterpenoids and isoflavones which are known for their anticancer
properties. The present study was designed to scientifically evaluate the
cytotoxic potential of bark extracts in in vitro on Ehrlich ascites carcinoma
(EAC), MCF-7 and B16F10 cells and in vivo in EAC (Liquid tumor) model and
Dalton's lymphoma ascites (DLA or solid tumor) model. The bark was powdered and
extracted successively with solvents viz., petroleum ether (PE), benzene,
chloroform, acetone (AC), and ethyl alcohol in the sequential order of polarity.
Cytotoxicity of dried extracts was screened on EAC cells by trypan blue assay.
Three potent extracts namely petroleum ether, acetone, and ethanol were screened
for their cytotoxicity on MCF-7 and B16F10 cells by MTT assay and
nucleomorphological alteration by propidium iodide staining. Safe doses of these
extracts were evaluated by acute toxicity study in mice. Extracts were found to
be safe up to 300 mg/kg in acute toxicity study. Dosage of 1/10th and 1/20th of
safe dose i.e., 15 and 30 mg/kg were selected for in vivo study. In the EAC
model, both doses of the extracts showed a significant (P < 0.05) improvement in
mean survival time and a maximum decline in tumor induced increase in body
weight (an indirect measure of tumor weight) by the PE and AC treatment at
15 mg/kg compared to control. In the DLA-model, all extracts at both tested dose
levels showed >50 % reduction in tumor weight and a significant reduction
(P < 0.05) in tumor volume on the 30th day compared to control. It can be
concluded that these extracts possess cytotoxic and antitumor activity.
DOI: 10.1007/s10616-016-0002-2
PMCID: PMC5023570
PMID: 27456242
356. Nutr Res. 2016 Aug;36(8):863-71. doi: 10.1016/j.nutres.2016.03.008. Epub 2016

Mar 30.
Plasma equol concentration is not associated with breast cancer and fibrocystic
breast conditions among women in Shanghai, China.
Atkinson C(1), Ray RM(2), Li W(2), Lin MG(2), Gao DL(3), Shannon J(4), Stalsberg
H(5), Porter PL(2), Frankenfeld CL(6), Wähälä K(7), Thomas DB(2), Lampe JW(2).
Author information:
(1)Bristol Dental School, University of Bristol, Bristol, UK; NIHR Biomedical
Research Unit in Nutrition, Diet, and Lifestyle, University Hospitals Bristol
NHS Foundation Trust and University of Bristol, Bristol, UK. Electronic address:
charlotte.atkinson@bristol.ac.uk.
(2)Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
(3)Zhong Shan Hospital Cancer Center, Shanghai, China.
(4)Oregon Health & Sciences University, Portland, OR, USA.
(5)University of Tromsø, Tromsø, Norway.
(6)George Mason University, Fairfax, USA.
(7)University of Helsinki, Helsinki, Finland.
Equol (a bacterial metabolite of the soy isoflavone daidzein) is produced by 30%

to 50% of humans and may be associated with health outcomes. We hypothesized
that plasma equol would be inversely associated with risks of fibrocystic breast
conditions (FBC) and breast cancer (BC). Plasma from women in a breast
self-examination trial in Shanghai with BC (n=269) or FBC (n=443), and
age-matched controls (n=1027) was analyzed for isoflavones. Equol was grouped
into categories (<20, 20-<45, and ≥45nmol/L) and, among women with daidzein
≥20nmol/L, the log10 equol:daidzein ratio was grouped into tertiles. Where
available, non-cancerous tissue (NCT) adjacent to the carcinomas from women with
BC were classified as non-proliferative or proliferative (n=130 and 172,
respectively). The lesions from women with FBC were similarly classified (n=99
and 92, respectively). Odds ratios (OR) and 95% confidence intervals (CI) were
calculated across equol categories and tertiles of log10 equol:daidzein ratio.
Equol categories were not associated with FBC or BC (P>.05). For log10
equol:daidzein, compared to controls there were positive associations in the mid
tertile for proliferative FBC (OR 2.06, 95% CI 1.08-3.93), BC with proliferative
NCT (OR 2.95, 95% CI 1.37-6.35), and all BC regardless of histology (OR 2.37,
95% CI 1.43-3.95). However, trends in ORs with increasing plasma equol values or
equol:daidzein ratios were not observed (P>.05). The results of this study do
not provide evidence that equol plays a role in the etiology of these breast
conditions. However, further work is needed to confirm or refute this
conclusion.
DOI: 10.1016/j.nutres.2016.03.008
PMCID: PMC4987235
Conflict of interest statement: CONFLICTS OF INTEREST: None
357. Drug Metab Rev. 2016 Aug;48(3):331-41. doi: 10.1080/03602532.2016.1206562.

Epub
2016 Jul 20.
Effects of soy containing diet and isoflavones on cytochrome P450 enzyme

expression and activity.
Ronis MJ(1).
Author information:
(1)a Department of Pharmacology & Experimental Therapeutics , Louisiana State
University Health Sciences Center , New Orleans , LA , USA.
Cytochromes P450 (CYPs) play an important role in metabolism and clearance of

most clinically utilized drugs and other xenobiotics. They are important in
metabolism of endogenous compounds including fatty acids, sterols, steroids and
lipid-soluble vitamins. Dietary factors such as phytochemicals are capable of
affecting CYP expression and activity, which may be important in diet-drug
interactions and in the development of fatty liver disease, cardiovascular
disease and cancer. One important diet-CYP interaction is with diets containing
plant proteins, particularly soy protein. Soy diets are traditionally consumed
in Asian countries and are linked to lower incidence of several cancers and of
cardiovascular disease in Asian populations. Soy is also an important protein
source in vegetarian and vegan diets and the sole protein source in soy infant
formulas. Recent studies suggest that consumption of soy can inhibit induction
of CY1 enzymes by polycyclic aromatic hydrocarbons (PAHs) which may contribute
to cancer prevention. In addition, there are data to suggest that soy components
promiscuously activate several nuclear receptors including PXR, PPAR and LXR
resulting in increased expression of CYP3As, CYP4As and CYPs involved in
metabolism of cholesterol to bile acids. Such soy-CYP interactions may alter
drug pharmacokinetics and therapeutic efficacy and are associated with improved
lipid homeostasis and reduced risk of cardiovascular disease. The current review
summarizes results from in vitro; in vivo and clinical studies of soy-CYP
interactions and examines the evidence linking the effects of soy diets on CYP
expression to isoflavone phytoestrogens, particularly, genistein and daidzein
that are associated with soy protein.
DOI: 10.1080/03602532.2016.1206562
PMCID: PMC5801744
358. Clin Nutr. 2017 Jun;36(3):672-679. doi: 10.1016/j.clnu.2016.06.014. Epub 2016

Jun 30.
Tomato-based randomized controlled trial in prostate cancer patients: Effect on

PSA.
Paur I(1), Lilleby W(2), Bøhn SK(3), Hulander E(4), Klein W(5), Vlatkovic L(6),
Axcrona K(7), Bolstad N(8), Bjøro T(9), Laake P(10), Taskén KA(11), Svindland
A(12), Eri LM(13), Brennhovd B(14), Carlsen MH(15), Fosså SD(16), Smeland
SS(17), Karlsen AS(18), Blomhoff R(19).
Author information:
(1)Department of Nutrition, Institute of Basic Medical Sciences, University of
Oslo, PO Box 1046, Blindern, 0316 Oslo, Norway. Electronic address:
ingvild.paur@medisin.uio.no.
(2)Division of Cancer Medicine, Transplantation and Surgery, Oslo University
Hospital, PO Box 4950, Nydalen, 0424 Oslo, Norway. Electronic address:
WLL@ous-hf.no.
s.k.bohn@medisin.uio.no.
erik@hulander.se.
wilkle@so-hf.no.
LVLAT@ous-hf.no.
Hospital, PO Box 4950, Nydalen, 0424 Oslo, Norway; Department of Urology,
Akershus University Hospital, 1748 Lørenskog, Norway. Electronic address:
axcrona@online.no.
(8)Department of Medical Biochemistry, Oslo University Hospital, PO Box 4950,
Nydalen, 0424 Oslo, Norway. Electronic address: nilbol@ous-hf.no.
(9)Department of Medical Biochemistry, Oslo University Hospital, PO Box 4950,
Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo,
PO Box 1171, Blindern, 0318 Oslo, Norway. Electronic address: BJC@ous-hf.no.
(10)Department of Biostatistics, Institute of Basic Medical Sciences, University
of Oslo, PO Box 1122, Blindern, 0317 Oslo, Norway. Electronic address:
petter.laake@medisin.uio.no.
Hospital, PO Box 4950, Nydalen, 0424 Oslo, Norway; Institute of Clinical
Medicine, University of Oslo, PO Box 1171, Blindern, 0318 Oslo, Norway.
Electronic address: k.a.tasken@medisin.uio.no.
aud.svindland@medisin.uio.no.
lamaer@ous-hf.no.
BJORB@ous-hf.no.
m.h.carlsen@medisin.uio.no.
s.d.fossa@medisin.uio.no.
sigbjorn.smeland@medisin.uio.no.
a.s.karlsen@medisin.uio.no.
Oslo, PO Box 1046, Blindern, 0316 Oslo, Norway; Division of Cancer Medicine,
Transplantation and Surgery, Oslo University Hospital, PO Box 4950, Nydalen,
0424 Oslo, Norway. Electronic address: rune.blomhoff@medisin.uio.no.
BACKGROUND & AIMS: The effect of lycopene-containing foods in prostate cancer

development remains undetermined. We tested whether a lycopene-rich tomato
intervention could reduce the levels of prostate specific antigen (PSA) in
prostate cancer patients.
METHODS: Prior to their curative treatment, 79 patients with prostate cancer
were randomized to a nutritional intervention with either 1) tomato products
containing 30 mg lycopene per day; 2) tomato products plus selenium, omega-3
fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea
(tomato-plus); or 3) control diet for 3 weeks.
RESULTS: The main analysis, which included patients in all risk categories, did
not reveal differences in changes of PSA-values between the intervention and
control groups. Post-hoc, exploratory analyses within intermediate risk (n = 41)
patients based on tumor classification and Gleason score post-surgery, revealed
that median PSA decreased significantly in the tomato group as compared to
controls (-2.9% and +6.5% respectively, p = 0.016). In separate post-hoc
analyses, we observed that median PSA-values decreased by 1% in patients with
the highest increases in plasma lycopene, selenium and C20:5 n-3 fatty acid,
compared to an 8.5% increase in the patients with the lowest increase in
lycopene, selenium and C20:5 n-3 fatty acid (p = 0.003). Also, PSA decreased in
patients with the highest increase in lycopene alone (p = 0.009).
CONCLUSIONS: Three week nutritional interventions with tomato-products alone or
in combination with selenium and n-3 fatty acids lower PSA in patients with
non-metastatic prostate cancer. Our observation suggests that the effect may
depend on both aggressiveness of the disease and the blood levels of lycopene,
selenium and omega-3 fatty acids.
Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.clnu.2016.06.014
359. Proc Nutr Soc. 2017 May;76(2):130-144. doi: 10.1017/S0029665116000677. Epub

2016
Jul 8.
Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual

systems and behaviours.
Patisaul HB(1).
Author information:
(1)Department of Biological Sciences,Center for Human Health and the
Environment,NC State University,Raleigh,NC 27695,USA.
A wide range of health benefits have been ascribed to soya intake including a
lowered risk of osteoporosis, heart disease, breast cancer, and menopausal
symptoms. Because it is a hormonally active diet, however, soya can also be
endocrine disrupting, suggesting that intake has the potential to cause adverse
health effects in certain circumstances, particularly when exposure occurs
during development. Consequently, the question of whether or not soya
phyto-oestrogens are beneficial or harmful to human health is neither
straightforward nor universally applicable to all groups. Possible benefits and
risks depend on age, health status, and even the presence or absence of specific
gut microflora. As global consumption increases, greater awareness and
consideration of the endocrine-disrupting properties of soya by nutrition
specialists and other health practitioners is needed. Consumption by infants and
small children is of particular concern because their hormone-sensitive organs,
including the brain and reproductive system, are still undergoing sexual
differentiation and maturation. Thus, their susceptibility to the
endocrine-disrupting activities of soya phyto-oestrogens may be especially high.
As oestrogen receptor partial agonists with molecular and cellular properties
similar to anthropogenic endocrine disruptors such as bisphenol A, the soya
phyto-oestrogens provide an interesting model for how attitudes about what is
'synthetic' v. what is 'natural,' shapes understanding and perception of what it
means for a compound to be endocrine disrupting and/or potentially harmful. This
review describes the endocrine-disrupting properties of soya phyto-oestrogens
with a focus on neuroendocrine development and behaviour.
DOI: 10.1017/S0029665116000677
PMCID: PMC5646220
Conflict of interest statement: Conflicts of Interest None.
360. Eur J Med Chem. 2016 Oct 21;122:43-54. doi: 10.1016/j.ejmech.2016.06.024. Epub
2016 Jun 16.
Scaffold-hopping of bioactive flavonoids: Discovery of aryl-pyridopyrimidinones

as potent anticancer agents that inhibit catalytic role of topoisomerase IIα.
Priyadarshani G(1), Amrutkar S(2), Nayak A(3), Banerjee UC(2), Kundu CN(3),
Guchhait SK(4).
Author information:
(1)Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062,
India.
(2)Department of Pharmaceutical Technology (Biotechnology), National Institute
of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali,
Punjab 160062, India.
(3)School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar,
Orissa 751024, India.
(4)Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062,
India. Electronic address: skguchhait@niper.ac.in.
A strategy of scaffold-hopping of bioactive natural products, flavones and

isoflavones, leading to target-based discovery of potent anticancer agents has
been reported for the first time. Scaffold-hopped flavones,
2-aryl-4H-pyrido[1,2-a]pyrimidin-4-ones and the scaffold-hopped isoflavones,
3-aryl-pyrido[1,2-a]pyrimidin-4-ones were synthesized via Pd-catalyzed
activation-arylation methods. Most of the compounds were found to exhibit
pronounced human topoisomerase IIα (hTopoIIα) inhibitory activities and several
compounds were found to be more potent than etoposide (a hTopoIIα-inhibiting
anticancer drug). These classes of compounds were found to be hTopoIIα-selective
catalytic inhibitors while not interfering with topoisomerase I and interacted
with DNA plausibly in groove domain. Cytotoxicities against various cancer
cells, low toxicity in normal cells, and apoptotic effects were observed.
Interestingly, compared to parent flavones/isoflavones, their scaffold-hopped
analogs bearing alike functionalities showed significant/enhanced
hTopoIIα-inhibitory and cytotoxic properties, indicating the importance of a
natural product-based scaffold-hopping strategy in the drug discovery.
DOI: 10.1016/j.ejmech.2016.06.024
361. Planta Med. 2017 Mar;83(5):426-433. doi: 10.1055/s-0042-110179. Epub 2016 Jun
24.
Nanospray Drying as a Novel Tool to Improve Technological Properties of Soy

Isoflavone Extracts.
Del Gaudio P(1), Sansone F(1), Mencherini T(1), De Cicco F(1), Russo P(1),
Aquino RP(1).
Author information:
(1)Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
Pharmacological evidences have correlated a low incidence of osteoporosis,

breast cancer, cardiovascular disease, and colon cancer in Asian populations,
high consumers of soya, to the properties of soy isoflavones, more specifically
to daidzein and genistein. However, in spite of the potent biological activity,
their poor water solubility has a strong negative effect on bioavailability. In
this study, an innovative technique, nano spray drying, was used to obtain
nanoparticles loaded with a soybean dry extract while carboxymethyl cellulose
was used as the excipient. The optimization of the process conditions allowed
for the manufacturing of stable nanoparticles with a mean size of around 650 nm,
a narrow size distribution, and a high encapsulation efficiency (between 78 %
and 89 %). The presence of carboxymethyl cellulose was able to stabilize the
isoflavone extract and enhance its affinity with aqueous media, strongly
increasing its permeation through biological membranes up to 4.5-fold higher
than pure soy isoflavone extract raw material and twice its homologous
minispray-dried formulation. These results are very useful for the
administration of the extract, either topically or orally, suggesting that the
isoflanones extract nanoparticulate powder obtained by nano spray drying has
great potential to enhance extract bioavailability and could be used as an
ingredient to be enclosed in dietary supplements and nutraceutical and
cosmeceutical products.
Georg Thieme Verlag KG Stuttgart · New York.
DOI: 10.1055/s-0042-110179
362. Mol Med Rep. 2016 Aug;14(2):1809-16. doi: 10.3892/mmr.2016.5408. Epub 2016 Jun
17.
Soy milk digestion extract inhibits progression of prostate cancer cell growth
via regulation of prostate cancer-specific antigen and cell cycle-regulatory
genes in human LNCaP cancer cells.
Kang NH(1), Shin HC(1), Oh S(1), Lee KH(1), Lee YB(1), Choi KC(2).
Author information:
(1)Department of Nutrition and Functional Food Research, Central Research
Institute, Dr Chung's Food Co., Ltd., Cheongju, Chungbuk 361-782, Republic of
Korea.
(2)Laboratory of Biochemistry and Immunology, College of Veterinary Medicine,
Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.
Soy milk, which is produced from whole soybeans, contains a variety of

biologically active components. Isoflavones are a class of soy-derived
phytoestrogens with beneficial effects, among which genistein (GEN) has been
previously indicated to reduce the risk of prostate cancer. The present study
evaluated the effects of soy milk digestion extract (SMD) on the progression of
prostate cancer via the estrogen receptor (ER)β in human LNCaP prostate cancer
cells. To evaluate the effects of SMD (daizein, 1.988 mg/100g, glycitein,
23.537 mg/100 g and GEN, 0.685 mg/100g) on cell proliferation, LNCaP cells were
cultured in media containing vehicle (0.1% dimethyl sulfoxide), 17β-estradiol
(E2; 2.7x10-7 mg/ml), GEN (2.7x10-2 mg/ml) of SMD (total aglycon concentration,
0.79 mg/ml), after which the cell viability was examined using an MTT assay. The
cell viability was significantly elevated by E2 (by 45±0.18%), while it was
markedly reduced by GEN (73.2±0.03%) or SMD (74.8±0.09%). Semi-quantitative
reverse transcription polymerase chain reaction analysis was performed to assess
the mRNA expression levels of target genes, including ERβ, prostate
cancer-specific antigen (PSA) and cell cycle regulators p21, Cyclin D1 and
cyclin-dependent kinase (CDK)4. The expression of ERβ was almost completely
diminished by E2, whereas it was significantly elevated by SMD. In addition, the
expression levels of PSA were considerably reduced by SMD. The expression of p21
was significantly elevated by SMD, while it was markedly reduced by E2. Of note,
the expression levels of Cyclin D1 and CDK4 were considerably elevated by E2,
while being significantly reduced by GEN and SMD. All of these results indicated
that SMD may inhibit the proliferation of human prostate cancer cells via
regulating the expression of ERβ, PSA, p21, Cyclin D1 and CDK4 in an
ER-dependent manner.
DOI: 10.3892/mmr.2016.5408
363. Nutrients. 2016 Jun 10;8(6):361. doi: 10.3390/nu8060361.
Isoflavones: Anti-Inflammatory Benefit and Possible Caveats.
Yu J(1), Bi X(2), Yu B(3), Chen D(4).
Author information:
(1)Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130,
China. yujie@sicau.edu.cn.
China. zsjg214@163.com.
China. ybingtian@163.com.
China. dwchen@sicau.edu.cn.
Inflammation, a biological response of body tissues to harmful stimuli, is also

known to be involved in a host of diseases, such as obesity, atherosclerosis,
rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids
that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory
properties. Increasing evidence has highlighted the potential for isoflavones to
prevent the chronic diseases in which inflammation plays a key role, though the
underlying mechanisms remain unclear. Recently, some studies have raised
concerns about isoflavones induced negative effects like carcinogenesis, thymic
involution, and immunosuppression. Therefore, this review aims to summarize the
anti-inflammatory effects of isoflavones, unravel the underlying mechanisms, and
present the potential health risks.
DOI: 10.3390/nu8060361
PMCID: PMC4924202
364. Int Urol Nephrol. 2016 Sep;48(9):1453-60. doi: 10.1007/s11255-016-1335-7. Epub

2016 Jun 4.
Relationship of serum levels and dietary intake of isoflavone, and the novel
bacterium Slackia sp. strain NATTS with the risk of prostate cancer: a
case-control study among Japanese men.
Nagata Y(1), Sugiyama Y(2), Fukuta F(3), Takayanagi A(3), Masumori N(3),
Tsukamoto T(3), Akasaka H(4), Ohnishi H(2)(4), Saitoh S(5), Miura T(4), Moriyama
K(6), Tsuji H(6), Akaza H(7), Mori M(2).
Author information:
(1)Department of Public Health, Sapporo Medical University School of Medicine,
West-17, South-1, Chuo-ku, Sapporo, 060-8556, Japan. ynagata@sapmed.ac.jp.
West-17, South-1, Chuo-ku, Sapporo, 060-8556, Japan.
(3)Department of Urology, Sapporo Medical University School of Medicine,
(4)Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical
University School of Medicine, West-17, South-1, Chuo-ku, Sapporo, 060-8556,
Japan.
(5)Department of Nursing, Sapporo Medical University School of Health Sciences,
(6)Yakult Central Institute for Microbiological Research, Izumi 5-11, Kunitachi,
Tokyo, 186-0012, Japan.
(7)Research Center for Advanced Science and Technology, The University of Tokyo,
Komaba 4-6-1, Meguro-ku, Tokyo, 153-8904, Japan.
PURPOSE: Isoflavones may play a role in the prevention of hormone-related

cancers. Equol is an isoflavone metabolized from daidzein in the presence of
certain intestinal bacteria. Slackia sp. strain NATTS, a newly identified
equol-producing bacterium, was recently isolated from human feces in Japan. We
investigated the association of serum levels and dietary intake of isoflavones
and Slackia sp. strain NATTS with the risk of prostate cancer in a case-control
study among Japanese men.
METHODS: Fifty-six patients with newly diagnosed prostate cancer and 56 hospital
controls were enrolled in this study. Isoflavones were assessed by measurement
of serum levels and administration of a food frequency questionnaire. Slackia
sp. strain NATTS in feces was also measured. The odds ratios (ORs) and 95 %
confidence intervals (CIs) for prostate cancer were then determined using a
logistic regression model.
RESULTS: The adjusted ORs for prostate cancer in comparison with the highest to
lowest categories were 0.06 (95 % CI 0.02-0.24) for serum genistein, 0.18 (95 %
CI 0.06-0.52) for daidzein, 0.16 (95 % CI 0.06-0.46) for glycitein, 0.52 (95 %
CI 0.22-1.22) for equol, 0.86 (95 % CI 0.30-2.48) for dietary genistein, and
0.80 (95 % CI 0.28-2.28) for dietary daidzein. The adjusted OR for prostate
cancer in comparison with values above versus below the median was 0.95 (95 % CI
0.42-2.16) for Slackia sp. strain NATTS.
CONCLUSION: Our study findings suggest that high serum levels of genistein,
daidzein, and glycitein are significantly associated with a decreased risk of
prostate cancer among Japanese men.
DOI: 10.1007/s11255-016-1335-7
365. Invest New Drugs. 2016 Oct;34(5):541-51. doi: 10.1007/s10637-016-0359-2. Epub

2016 May 18.
In vitro and in vivo antineoplastic and immunological effects of

pterocarpanquinone LQB-118.
Salustiano EJ(1)(2), Dumas ML(3), Silva-Santos GG(3), Netto CD(4)(5), Costa

PR(4), Rumjanek VM(3).
Author information:
(1)Laboratory of Tumor Immunology, Leopoldo de Meis Institute of Medical
Biochemistry (IBqM), Federal University of Rio de Janeiro (UFRJ), Avenida Carlos
Chagas Filho 373, Bloco H, 2° andar sala 003 Cidade Universitária, Rio de
Janeiro, RJ, 21941-590, Brazil. salustiano@bioqmed.ufrj.br.
(2)Laboratory of Bioorganic Chemistry, Institute for Natural Products Research,
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
salustiano@bioqmed.ufrj.br.
(3)Laboratory of Tumor Immunology, Leopoldo de Meis Institute of Medical
Biochemistry (IBqM), Federal University of Rio de Janeiro (UFRJ), Avenida Carlos
Chagas Filho 373, Bloco H, 2° andar sala 003 Cidade Universitária, Rio de
Janeiro, RJ, 21941-590, Brazil.
(4)Laboratory of Bioorganic Chemistry, Institute for Natural Products Research,
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
(5)Laboratory of Chemistry, Macaé Institute of Metrology and Technology, Federal
University of Rio de Janeiro, Professor Aloísio Teixeira Macaé Campus, Macaé,
RJ, Brazil.
Cancer is a malignancy of worldwide prevalence, and although new therapeutic

strategies are under investigation, patients still resort to reductive or
palliative chemotherapy. Side effects are a great concern, since treatment can
render patients susceptible to infections or secondary cancers. Thus, design of
safer chemotherapeutic drugs must consider the risk of immunotoxicity.
Pterocarpans are natural isoflavones that possess immunomodulatory and
antineoplastic properties. Ubiquitous in nature, quinones are present in
chemotherapeutic drugs such as doxorubicin and mitoxantrone. Our group has
patented a hybrid molecule, the pterocarpanquinone LQB-118, and demonstrated its
antineoplastic effect in vitro. In this report we describe its antineoplastic
effect in vivo and assess its toxicity toward the immune system. Treated mice
presented no changes in weight of primary and secondary organs of the immune
system nor their cellular composition. Immunophenotyping showed that treatment
increased CD4(+) thymocytes and proportionally reduced the CD4(+)CD8(+)
subpopulation in the thymus. No significant changes were observed in T CD8(+)
peripheral lymphocytes nor was the activation of fresh T cells affected after
treatment. LQB-118 induced apoptosis in murine tumor cells in vitro, being
synergistic with the autophagy promoter rapamycin. Furthermore, treatment
significantly reduced ascites or solid Ehrlich and B16F10 melanoma growth in
vivo, and ameliorated side effects such as cachexia. Based on its favorable
preclinical profile and considering previous results obtained in vitro, this
drug emerges as a promising candidate for further development.
DOI: 10.1007/s10637-016-0359-2
366. Forsch Komplementmed. 2016;23(2):75-80. doi: 10.1159/000444735. Epub 2016 Apr
12.
Impact of Soy Foods on the Development of Breast Cancer and the Prognosis of
Breast Cancer Patients.
Messina M.
The relationship between soy food intake and breast cancer has been rigorously
investigated for more than 25 years. The identification of isoflavones as
possible chemopreventive agents helped fuel this line of investigation. These
diphenolic compounds, which are found in uniquely-rich amounts in soy beans,
possess both estrogen-dependent and -independent properties that potentially
inhibit the development of breast cancer. Observational studies show that among
Asian women higher soy consumption is associated with an approximate 30%
reduction in risk of developing breast cancer. However, evidence suggests that
for soy to reduce breast cancer risk consumption must occur early in life, that
is during childhood and/or adolescence. Despite the interest in the role of soy
in reducing breast cancer risk concerns have arisen that soy foods, because they
contain isoflavones, may increase the likelihood of high-risk women developing
breast cancer and worsen the prognosis of breast cancer patients. However,
extensive clinical and epidemiologic data show these concerns to be unfounded.
Clinical trials consistently show that isoflavone intake does not adversely
affect markers of breast cancer risk, including mammographic density and cell
proliferation. Furthermore, prospective epidemiologic studies involving over
11,000 women from the USA and China show that postdiagnosis soy intake
statistically significantly reduces recurrence and improves survival.
© 2016 S. Karger GmbH, Freiburg.
DOI: 10.1159/000444735
367. Nutr Cancer. 2016 May-Jun;68(4):554-9. doi: 10.1080/01635581.2016.1158294.

Epub
2016 May 4.
The Effect of Reduced Dietary Fat and Soy Supplementation on Circulating

Adipocytokines in Postmenopausal Women: A Randomized Controlled 2-Month Trial.
Nadadur M(1), Stanczyk FZ(2), Tseng CC(3), Kim L(1), Wu AH(3).
Author information:
(1)a Department of Obstetrics and Gynecology , Keck School of Medicine of USC ,
Los Angeles , California.
(2)b Departments of Obstetrics and Gynecology and Preventive Medicine , Keck
School of Medicine of USC , Los Angeles , California.
(3)c Department of Preventive Medicine , Keck School of Medicine of USC , Los
Angeles , California.
The reduced risk of breast cancer observed in Asia has been linked with diets
rich in soy foods, and observational studies suggest that regular soy food
intake is related to lower circulating levels of some inflammatory markers which
have been implicated in breast cancer risk. However, short-term intervention
studies with soy-based diets in small numbers of women have shown few
significant changes in adipocytokine levels. This 8-wk dietary intervention
study in 57 healthy postmenopausal women investigated whether soy food
supplementation (50 mg isoflavones or 15 g soy protein in the form of tofu) or a
very low-fat diet (11.3% of total energy), similar to the traditional Asian
diet, is associated with beneficial effects on serum levels of the following
adipocytokines: TNF-α, IL-6, adiponectin, and resistin. We found no
statistically significant changes in the levels of these adipocytokines in
association with the very low-fat diet or soy supplementation. Only the change
in TNF-α levels between the very low-fat and control diet groups had borderline
statistical significance. We conclude that ingestion of a very low-fat diet or a
soy food supplemented diet for 8 wk does not significantly alter important
circulating adipocytokines.
DOI: 10.1080/01635581.2016.1158294
PMCID: PMC7580879
368. Food Sci Biotechnol. 2016 Apr 30;25(2):517-524. doi: 10.1007/s10068-016-0072-

0.
eCollection 2016.
Influence of water-soluble extracts of long-term fermented Doenjang on bone

metabolism bioactivity and breast cancer suppression.
Seol JY(1), Youn YN(1), Koo M(2)(3), Kim HJ(2)(3), Choi SY(1).
Author information:
(1)1Division of Biological Science, Sookmyung Women's University, Seoul, 04310
Korea.
(2)2Korea Food Research Institute, Seongnam, Gyeonggi, 13539 Korea.
(3)3Department of Food Biotechnology, Korea University of Science and
Technology, Daejeon, 34113 Korea.
Anti-cancer effects of doenjang extracts are usually studied based on methanol

extraction focusing on isoflavones, the principal extracted components. In this
syudy, effects of water-soluble extracts of long-term fermented doenjang
containing water-soluble low Mw peptides produced by microorganisms were
studied. Doenjang extracts had effects which arrested the cell cycle, inhibited
proliferation, and caused consequential apoptosis in breast cancer cells.
Doenjang water-soluble extracts increased bone density via activation of
osteoblast differentiation and suppression of osteoclast differentiation.
Effects increased as the fermentation period extended because the doenjang
fermentation period influenced extract contents. The value and utility of
doenjang as a functional food should be considered.
DOI: 10.1007/s10068-016-0072-0
PMCID: PMC6049206
PMID: 30263300
369. J Nat Prod. 2016 May 27;79(5):1429-38. doi: 10.1021/acs.jnatprod.6b00173. Epub

2016 Apr 21.
Efficient Synthesis of Glaziovianin A Isoflavone Series from Dill and Parsley

Extracts and Their in Vitro/in Vivo Antimitotic Activity.
Semenov VV(1), Tsyganov DV(1), Semenova MN(2)(3), Chuprov-Netochin RN(4),

Raihstat MM(1), Konyushkin LD(1), Volynchuk PB(4), Marusich EI(4), Nazarenko
VV(4), Leonov SV(4)(5), Kiselyov AS(4).
Author information:
(1)N. D. Zelinsky Institute of Organic Chemistry, RAS , Leninsky Prospect, 47,
119991, Moscow, Russian Federation.
(2)Institute of Developmental Biology, RAS , Vavilov Street, 26, 119334, Moscow,
Russian Federation.
(3)Chemical Block Ltd. , 3 Kyriacou Matsi, 3723, Limassol, Cyprus.
(4)Life Sciences Center, Moscow Institute of Physics and Technology ,
Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
(5)Institute of Cell Biophysics, RAS , Institutskaya Street, 3, Pushchino,
Moscow Region 142290, Russian Federation.
A concise six-step protocol for the synthesis of isoflavone glaziovianin A (GVA)

and its alkoxyphenyl derivatives 9 starting with readily available plant
metabolites from dill and parsley seeds was developed. The reaction sequence
involved an efficient conversion of the key intermediate epoxides 7 into the
respective β-ketoaldehydes 8 followed by their Cu(I)-mediated cyclization into
the target series 9. The biological activity of GVA and its derivatives was
evaluated using a panel of seven human cancer cell lines and an in vivo sea
urchin embryo assay. Both screening platforms confirmed the antimitotic effect
of the parent GVA (9cg) and its alkoxy derivatives. Structure-activity
relationship studies suggested that compounds 9cd and 9cf substituted with
trimethoxy- and dillapiol-derived B-rings, respectively, were less active than
the parent 9cg. Of the evaluated human cancer cell lines, the A375 melanoma cell
line was the most sensitive to the tested molecules. Notably, the target
compounds were not cytotoxic against human peripheral blood mononuclear cells up
to 10 μM concentration. Phenotypic readouts from the sea urchin assay
unequivocally suggest a direct microtubule-destabilizing effect of isoflavones
9cg, 9cd, and 9cf.
370. Cancer Sci. 2016 Jul;107(7):1022-8. doi: 10.1111/cas.12948. Epub 2016 Jun 13.
Equol inhibits prostate cancer growth through degradation of androgen receptor

by S-phase kinase-associated protein 2.
Itsumi M(1), Shiota M(1), Takeuchi A(1), Kashiwagi E(1), Inokuchi J(1),
Tatsugami K(1), Kajioka S(1), Uchiumi T(2), Naito S(1)(3), Eto M(1), Yokomizo
A(1).
Author information:
(1)Department of Urology, Graduate School of Medical Sciences, Kyushu
University, Fukuoka, Japan.
(2)Department of Clinical Chemistry and Laboratory Medicine, Graduate School of
Medical Sciences, Kyushu University, Fukuoka, Japan.
(3)Department of Urology, Harasanshin Hospital, Fukuoka, Japan.
Chemopreventive and potential therapeutic effects of soy isoflavones have been

shown to be effective in numerous preclinical studies as well as clinical
studies in prostate cancer. Although the inhibition of androgen receptor
signaling has been supposed as one mechanism underlying their effects, the
precise mechanism of androgen receptor inhibition remains unclear. Thus, this
study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed
androgen receptor as well as prostate-specific antigen expression most potently
in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen
receptor expression and activity was less prominent in castration-resistant CxR
and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular
apoptosis was induced by equol in LNCaP cells, but less so in CxR and 22Rv1
cells. We revealed that the proteasome pathway through S-phase kinase-associated
protein 2 (Skp2) was responsible for androgen receptor suppression. Taken
together, soy isoflavones, especially equol, appear to be promising as
chemopreventive and therapeutic agents for prostate cancer based on the fact
that equol augments Skp2-mediated androgen receptor degradation. Moreover,
because Skp2 expression was indicated to be crucial for the effect of soy
isoflavones, soy isoflavones may be applicable for precancerous and cancerous
prostates.
© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd
on behalf of Japanese Cancer Association.
DOI: 10.1111/cas.12948
PMCID: PMC4946716
371. Oncotarget. 2016 May 3;7(18):26617-27. doi: 10.18632/oncotarget.8562.
Dietary intake of flavonoid subclasses and risk of colorectal cancer: evidence

from population studies.
He X(1)(2), Sun LM(1)(2).
Author information:
(1)Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang
University Medical School, Hangzhou 310016, China.
(2)Institute of Gastroenterology, Zhejiang University (IGZJU), Hangzhou 310016,
China.
OBJECTIVE: To systematically evaluate the relationship between flavonoids intake

and colorectal cancer risk by conducting a meta-analysis.
RESULTS: Our meta-analysis included 18 studies involving 16,917 colorectal
cancer cases in 559,486 participants in relations to flavonoids intake during
six to twenty-six years of follow-up. Our results indicated that specific
flavonoid subclasses, such as procyanidins (OR = 0.75; 95% CI, 0.66-0.86) and
isoflavones (OR = 0.87; 95% CI, 0.78-0.98), showed protective effects against
colorectal cancer risk. There was no enough evidence indicating that increased
consumption of total flavonoids were significantly associated with reduced risk
of colorectal cancer (OR = 0.94, 95% CI, 0.81-1.09). There was no publication
bias across studies.
METHODS: We performed a systematic search of PubMed, Web of Science and the
Cochrane Library databases for relevant articles before December 2015. A
random-effects model was used to estimate summary odds ratios and 95% confidence
intervals (CIs) for associations between flavonoids and colorectal cancer risk.
We assessed heterogeneity among studies by the Cochran Q and I2 statistics.
CONCLUSIONS: Our meta-analysis provides comprehensive evidence and partly
supported the hypothesis that higher habitual intake of foods rich in
procyanidins and isoflavones may potentially decrease colorectal cancer
incidence. More prospective studies are warranted to verify this protective
association.
DOI: 10.18632/oncotarget.8562
PMCID: PMC5042003
Conflict of interest statement: No potential competing interests.

372. Curr Med Chem. 2016;23(13):1370-89. doi: 10.2174/0929867323666160406120711.
Modulation of Expression and Activity of ABC Transporters by the Phytoestrogen

Genistein. Impact on Drug Disposition.
Rigalli JP, Ciriaci N, Mottino AD, Catania VA, Ruiz ML(1).
Author information:
(1)Institute of Experimental Physiology, Faculty of Biochemical and
Pharmaceutical Science, Rosario National University, Suipacha 570, 2000 Rosario,
Argentina. ruiz@ifise-conicet.gov.ar.
ATP binding cassette (ABC) transporters are involved in drug absorption,

distribution and elimination. They also mediate multidrug resistance in cancer
cells. Isoflavones, such as genistein (GNT), belong to a class of
naturally-occurring compounds found at high concentrations in commonly consumed
soya based-foods and dietary supplements. GNT and its metabolites interact with
ABC transporters as substrates, inhibitors and/or modulators of their
expression. This review compiles information about regulation of ABC
transporters by GNT with special emphasis on the three major groups of ABC
transporters involved in excretion of endo- and xenobiotics as follows:
Pglycoprotein (MDR1, ABCB1), a group of multidrug resistance associated proteins
(MRPs, ABCC subfamily) and ABCG2 (BCRP), an ABC half-transporter. The impact of
these regulations on potential GNT-drug interactions is further considered.
DOI: 10.2174/0929867323666160406120711
373. Nutr Cancer. 2016 May-Jun;68(4):622-33. doi: 10.1080/01635581.2016.1154578.

Epub
2016 Apr 4.
Glycone-rich Soy Isoflavone Extracts Promote Estrogen Receptor Positive Breast

Cancer Cell Growth.
Johnson KA(1), Vemuri S(1), Alsahafi S(1), Castillo R(1), Cheriyath V(1).
Author information:
(1)a Department of Biological and Environmental Sciences , Texas A&M
University-Commerce , Commerce , Texas , USA.
Due to the association of hormone replacement therapy (HRT) with breast cancer
risk, estrogenically active soy isoflavones are considered as an HRT alternative
to alleviate menopausal symptoms. However, several recent reports challenged the
health benefits of soy isoflavones and associated them with breast cancer
promotion. While glyconic isoflavones are the major constituents of soybean
seeds, due to their low cell permeability, they are considered to be
biologically inactive. The glyconic isoflavones may exert their effects on
membrane-bound estrogen receptors or could be converted to aglycones by
extracellular β-glucosidases. Therefore, we hypothesized that despite their low
cell permeability, soybean cultivars with high glyconic isoflavones may promote
breast cancer cell growth. To test this, composition and estrogenic activity of
isoflavones from 54 commercial soybean cultivars were determined. Soybean seeds
produced in identical climate and growth conditions were used to minimize the
effects of extraneous factors on isoflavone profile and concentrations. The
glyconic daidzin concentration negatively correlated with genistin and with
other aglycones. Relative to control, isoflavone extracts from 51 cultivars were
estrogenic and promoted the growth of estrogen receptor positive (ER+) breast
cancer cell line MCF-7 from 1.14 to 4.59 folds and other three cultivars
slightly reduced the growth. Among these, extracts from three cultivars were
highly estrogenic and promoted MCF-7 cell growth by 2.59-4.64 folds (P<0.005).
Among six isoflavones, daidzin was positively associated with MCF-7 cell growth
(P<0.005, r = 0.13966), whereas the negative correlation between genistin and
MCF-7 cell growth was nearly significant (P≤0.0562, r = -0.026141). Furthermore,
in drug interaction studies daidzin-rich isoflavone extracts antagonized
tamoxifen, an ER inhibitor. Taken together, our results suggest that the
glyconic daidzin-rich soy isoflavone extracts may exert estrogenic effects and
promote ER+ breast cancer growth.
DOI: 10.1080/01635581.2016.1154578
374. Cancer Prev Res (Phila). 2016 May;9(5):385-95. doi:

10.1158/1940-6207.CAPR-15-0165. Epub 2016 Mar 22.
Effects of Pubertal Exposure to Dietary Soy on Estrogen Receptor Activity in the

Breast of Cynomolgus Macaques.
Dewi FN(1), Wood CE(2), Willson CJ(2), Register TC(2), Lees CJ(2), Howard TD(3),
Huang Z(4), Murphy SK(4), Tooze JA(5), Chou JW(5), Miller LD(6), Cline JM(2).
Author information:
(1)Department of Pathology, Section on Comparative Medicine, Wake Forest School
of Medicine, Winston-Salem, North Carolina. Primate Research Center, Bogor
Agricultural University, Bogor, Indonesia. fitriya.dewi@gmail.com
fitriya.dewi@cbn.net.id.
(2)Department of Pathology, Section on Comparative Medicine, Wake Forest School
of Medicine, Winston-Salem, North Carolina.
(3)Center for Genomics and Personalized Medicine Research, Wake Forest School of
Medicine, Winston-Salem, North Carolina.
(4)Department of Obstetrics and Gynecology, Division of Gynecologic Oncology,
Duke University School of Medicine, Durham, North Carolina.
(5)Department of Biostatistical Sciences, Wake Forest School of Medicine,
Winston-Salem, North Carolina.
(6)Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem,
North Carolina.
Endogenous estrogens influence mammary gland development during puberty and

breast cancer risk during adulthood. Early-life exposure to dietary or
environmental estrogens may alter estrogen-mediated processes. Soy foods contain
phytoestrogenic isoflavones (IF), which have mixed estrogen agonist/antagonist
properties. Here, we evaluated mammary gland responses over time in pubertal
female cynomolgus macaques fed diets containing either casein/lactalbumin (n =
12) or soy protein containing a human-equivalent dose of 120 mg IF/day (n = 17)
for approximately 4.5 years spanning menarche. We assessed estrogen receptor
(ER) expression and activity, promoter methylation of ERs and their downstream
targets, and markers of estrogen metabolism. Expression of ERα and classical ERα
response genes (TFF1, PGR, and GREB1) decreased with maturity, independent of
diet. A significant inverse correlation was observed between TFF1 mRNA and
methylation of CpG sites within the TFF1 promoter. Soy effects included lower
ERβ expression before menarche and lower mRNA for ERα and GREB1 after menarche.
Expression of GATA-3, an epithelial differentiation marker that regulates
ERα-mediated transcription, was elevated before menarche and decreased after
menarche in soy-fed animals. Soy did not significantly alter expression of other
ER activity markers, estrogen-metabolizing enzymes, or promoter methylation for
ERs or ER-regulated genes. Our results demonstrate greater ER expression and
activity during the pubertal transition, supporting the idea that this life
stage is a critical window for phenotypic modulation by estrogenic compounds.
Pubertal soy exposure decreases mammary ERα expression after menarche and exerts
subtle effects on receptor activity and mammary gland differentiation. Cancer
Prev Res; 9(5); 385-95. ©2016 AACR.
DOI: 10.1158/1940-6207.CAPR-15-0165
PMCID: PMC4932899
Conflict of interest statement: Authors’ disclosure: The authors have no

conflicts of interest to declare. Soy protein isolate was donated by Solae, LLC
(St. Louis, MO).
375. Curr Oncol. 2016 Feb;23(1):e17-23. doi: 10.3747/co.23.2835. Epub 2016 Feb 18.
Genetic polymorphisms of insulin-like growth factor 1 and insulin-like growth

factor binding protein 3, xenoestrogen, phytoestrogen, and premenopausal breast
cancer.
Li H(1), Zhao M(1), Wang Q(2), Liu L(3), Qi YN(1), Li JY(1).
Author information:
(1)Department of Epidemiology and Biostatistics, West China School of Public
Health, Sichuan University, Chengdu, Sichuan, P.R.C.;
(2)Department of Health Service Management, Public Health School, Sun Yat-Sen
University, Guangzhou, Guangdong, P.R.C.;
(3)The Comprehensive Guidance Center of Women's Health, Chengdu Women's and
Children's Central Hospital, Chengdu, Sichuan, P.R.C.
BACKGROUND: Previous studies suggest a combined effect of insulin-like growth

factor 1 (igf-1) and igf binding protein 3 (igfbp-3) gene polymorphisms,
xenoestrogen, and phytoestrogen on the igf-1 signalling pathway and serum
concentrations in the igf system, which are associated with premenopausal breast
cancer (bca) risk.
METHODS: Between 2010 and 2012, our study recruited 140 premenopausal bca
patients and 160 community-based premenopausal control subjects. Participants
were surveyed about oral contraceptive (oc) use, dietary habits, and other bca
risk factors. TaqMan assays were used to determine igf-1 rs1520220 and igfbp-3
rs2854744 genotypes. Daily intakes of energy-adjusted soy isoflavones (easis)
were calculated by the residual method. Multivariate logistic regression was
applied to estimate the adjusted odds ratios (ors) and 95% confidence intervals
(cis) of the igf-1 rs1520220 and igfbp-3 rs2854744 genotypes, oc use, and intake
of easis. Stratified analyses were performed to detect the gene-environment
combined effect, and multivariate logistic regression was used to estimate
interaction coefficients (iors) by the multiplicative model, with 95% cis. The
delta method was used to calculate interaction coefficients by the additive
model [relative excess risk of interaction (reri), attributable proportions of
interaction (apis)] and 95% cis.
RESULTS: The igf-1 and igfbp-3 genotypes, oc use, and easis were not found to be
associated with bca risk (p > 0.05). Stratified analysis showed that the risk of
bca was markedly increased in women carrying the igfbp-3C allele and using ocs
compared with women either carrying the igfbp-3C allele or using ocs (or: 3.02;
95% ci: 1.04 to 8.79). The interaction coefficients ior, reri, and api were 4.89
(95% ci: 1.09 to 21.90), 2.42 (95% ci: -0.76 to 5.61), and 0.80 (95% ci: 0.46 to
1.67) respectively.
CONCLUSIONS: The igfbp-3 rs2854744 polymorphism and oc use might synergistically
increase premenopausal bca risk.
DOI: 10.3747/co.23.2835
PMCID: PMC4754064
PMID: 26966408
376. PLoS One. 2016 Mar 9;11(3):e0151134. doi: 10.1371/journal.pone.0151134.

eCollection 2016.
Association among Dietary Flavonoids, Flavonoid Subclasses and Ovarian Cancer

Risk: A Meta-Analysis.
Hua X(1), Yu L(2), You R(1), Yang Y(1), Liao J(1), Chen D(1), Yu L(1).
Author information:
(1)Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, 430022, PR China.
(2)Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical
College, Huazhong University of Science and Technology, Wuhan, 430022, PR China.
BACKGROUND: Previous studies have indicated that intake of dietary flavonoids or

flavonoid subclasses is associated with the ovarian cancer risk, but presented
controversial results. Therefore, we conducted a meta-analysis to derive a more
precise estimation of these associations.
METHODS: We performed a search in PubMed, Google Scholar and ISI Web of Science
from their inception to April 25, 2015 to select studies on the association
among dietary flavonoids, flavonoid subclasses and ovarian cancer risk. The
information was extracted by two independent authors. We assessed the
heterogeneity, sensitivity, publication bias and quality of the articles. A
random-effects model was used to calculate the pooled risk estimates.
RESULTS: Five cohort studies and seven case-control studies were included in the
final meta-analysis. We observed that intake of dietary flavonoids can decrease
ovarian cancer risk, which was demonstrated by pooled RR (RR = 0.82, 95% CI =
0.68-0.98). In a subgroup analysis by flavonoid subtypes, the ovarian cancer
risk was also decreased for isoflavones (RR = 0.67, 95% CI = 0.50-0.92) and
flavonols (RR = 0.68, 95% CI = 0.58-0.80). While there was no compelling
evidence that consumption of flavones (RR = 0.86, 95% CI = 0.71-1.03) could
decrease ovarian cancer risk, which revealed part sources of heterogeneity. The
sensitivity analysis indicated stable results, and no publication bias was
observed based on the results of Funnel plot analysis and Egger's test (p =
0.26).
CONCLUSIONS: This meta-analysis suggested that consumption of dietary flavonoids
and subtypes (isoflavones, flavonols) has a protective effect against ovarian
cancer with a reduced risk of ovarian cancer except for flavones consumption.
Nevertheless, further investigations on a larger population covering more
flavonoid subclasses are warranted.
PMCID: PMC4784737

that no competing interests exist.
377. J Food Sci. 2016 Apr;81(4):H1016-23. doi: 10.1111/1750-3841.13266. Epub 2016

Mar
8.
Innovative Soaking and Grinding Methods and Cooking Affect the Retention of
Isoflavones, Antioxidant and Antiproliferative Properties in Soymilk Prepared
from Black Soybean.
Tan Y(1)(2), Chang SK(2), Zhang Y(2).
Author information:
(1)Dept. of Chinese Medicine, Shaanxi Univ. of Chinese Medicine, Xianyang,
Shaanxi, 712046, P.R. of China.
(2)Dept. of Food Science, Nutrition and Health Promotion, Mississippi State
Univ, MS State, Miss., 39762, U.S.A.
This study's objective was to characterize the effect of traditional and 3 newly
devised (soaking+grinding) methods combined with cooking on the content and
composition of phenolic substances, antioxidant, and antiproliferative
properties of soymilk prepared from black soybean. Phenolic substances and
antioxidant profile were characterized and antiproliferation of prostate cancer
DU145 cells was conducted using a cell culture assay. Results indicated Grinding
Method 4 produced significantly (P < 0.05) higher total phenolic content (TPC),
total flavonoid content (TFC), condensed tannin content (CTC), and total
isoflavone content in both raw and cooked black soymilk as compared to Method 1.
Cooking soymilk reduced 23% to 38% of total phenolic substances. Raw black
soymilk produced by Method 4 displayed the highest antioxidant capability, which
was determined using ORAC, FRAP, and DPPH assays, and a higher antiprostate cell
proliferation ability. Cooking only slightly reduced the potency to inhibit
DU145 prostate cancer cells as IC50 value was increased from the average of
about 4.0 mg/mL of raw soymilk extracts to 5.5 mg/mL of cooked soymilk extracts
of all grinding methods. Overall, total isoflavone content was the only
component that was negatively correlated with IC50 value (r = -0.93, P < 0.05)
which indicates the ability to inhibit prostate cancer cell is associated with
the increase in total isoflavone content, not with any other phenolic substances
or antioxidant properties.
© 2016 Institute of Food Technologists®
DOI: 10.1111/1750-3841.13266
378. Br J Nutr. 2016 May;115(9):1607-15. doi: 10.1017/S0007114516000581. Epub 2016

Mar 7.
Urine phyto-oestrogen metabolites are not significantly associated with risk of

type 2 diabetes: the Singapore Chinese health study.
Talaei M(1), Lee BL(1), Ong CN(1), van Dam RM(1), Yuan JM(2), Koh WP(3), Pan
A(4).
Author information:
(1)1Saw Swee Hock School of Public Health,National University of Singapore and
National University Health System,Singapore 117549,Singapore.
(2)4Division of Cancer Control and Population Sciences,University of Pittsburgh
Cancer Institute,Pittsburgh,PA 15232,USA.
(3)6Duke-NUS Graduate Medical School,Singapore 169857,Singapore.
(4)7Department of Epidemiology and Biostatistics,MOE Key Laboratory of
Environment and Health,School of Public Health,Tongji Medical College,Huazhong
University of Science and Technology,Wuhan,Hubei 430030,People's Republic of
China.
We evaluated the relationship between urine concentrations of phyto-oestrogens

(isoflavones and lignans) and risk of incident type 2 diabetes in middle-aged
and elderly Chinese residing in Singapore. Urine metabolites of isoflavones and
lignans were assayed by HPLC among 564 diabetes cases and 564 matched controls
in a case-control study nested within the Singapore Chinese Health Study cohort.
Participants were free of diagnosed diabetes, CVD and cancer at morning urine
collections during 1999-2004. Cases were participants who reported to have
physician-diagnosed diabetes at follow-up visits during 2006-2010, whereas
controls were randomly selected among those who remained free of diabetes and
were matched to the index cases by age, sex, dialect group and date of urine
collection. Conditional logistic regression models were used to calculate OR and
95 % CI with adjustment for potential confounders. The mean age of the
participants at the time of urine collection was 59·8 years, and the average
interval between urine collection and diabetes diagnosis was 4·0 years. The
multivariate-adjusted OR for diabetes were 1·00 (reference), 0·76 (95 % CI 0·52,
1·11), 0·78 (95 % CI 0·53, 1·14) and 0·79 (95 % CI 0·54, 1·15) across quartiles
of urine isoflavones (P for trend=0·54), and were 1·00 (reference), 0·87 (95 %
CI 0·60, 1·27), 1·10 (95 % CI 0·77, 1·56) and 0·93 (95 % CI 0·63, 1·37) for
lignans (P for trend=0·93). The results were similar in men and women, as well
as for individual metabolites of isoflavones (genistein, daidzein, glycitin and
equol) or lignans (enterodiol and enterolactone). The present study did not find
a significant association between urine phyto-oestrogen metabolites and risk of
type 2 diabetes in Chinese adults.
DOI: 10.1017/S0007114516000581
PMCID: PMC5772653
Conflict of interest statement: The authors declare that there are no conflicts
of interest.
379. Gynecol Endocrinol. 2016 Jun;32(6):427-30. doi: 10.3109/09513590.2016.1152240.

Epub 2016 Mar 4.
Consensus: soy isoflavones as a first-line approach to the treatment of

menopausal vasomotor complaints.
Schmidt M(1), Arjomand-Wölkart K(2), Birkhäuser MH(3), Genazzani AR(4), Gruber

DM(5), Huber J(5), Kölbl H(5), Kreft S(6), Leodolter S(5), Linsberger D(5),
Metka M(5), Simoncini T(7), Vrabic Dezman L(8).
Author information:
(1)a International Society for Phytosciences , Mattsies , Germany .
(2)b Institut Für Pharmazeutische Wissenschaften, Karl-Franzens-Universität Graz
, Graz , Austria .
(3)c Gynaecological Endocrinonoly and Reproductive Medicine, Medical Faculty,
University of Berne , Basel , Switzerland .
(4)d Department of Gynaecology and Obstetrics , European Society of Gynecology,
University of Pisa , Pisa , Italy .
(5)e 1st Department of Gynaeology and Obstetrics, University of Vienna , Wien ,
Austria .
(6)f Chair of Pharmacognostic and Phytochemical Laboratory, Faculty of Pharmacy,
University of Ljubljana , Ljubljana , Slovenia .
(7)g Division of Obstetrics and Gynadecology , Department of Clinical and
Experimental Medicine, Università Di Pisa , Pisa , Italy , and.
(8)h Slovenian Menopause Society , Kranj , Slovenia.
The association between an increased uptake of isoflavones and a reduced
frequency of menopausal hot flushes was first described in 1992, based on a
lower incidence of hot flushes in countries with a high consumption of soy.
Since then, numerous clinical trials with various sources of isoflavones
including soy and red clover have been presented, with practically all of the
studies with adequate design delivering an outcome in favour of isoflavone
supplementation. An in-depth risk assessment (EFSA 2015) concludes that the
amply available human data does not indicate any suspected harmful effects from
a potential interaction of isoflavones with hormone-sensitive tissues in the
mammary gland, the uterus and the thyroid gland. Safety was ascertained with
long-term intake of up to 150 mg isoflavones per day ingested for the duration
of at least 3 years. Moreover, high isoflavone intake was found to have
preventive effects with respect to breast cancer. Clinical findings indicate
potential benefits of isoflavone exposure even during breast cancer treatment
with tamoxifen or anastrozole.
DOI: 10.3109/09513590.2016.1152240
380. BJU Int. 2016 Apr;117 Suppl 4(Suppl 4):17-34. doi: 10.1111/bju.13361. Epub
2016
Feb 22.
Phytotherapeutic interventions in the management of biochemically recurrent

prostate cancer: a systematic review of randomised trials.
van Die MD(1), Bone KM(2)(3), Emery J(1), Williams SG(1)(4), Pirotta MV(1),
Paller CJ(5).
Author information:
(1)Department of General Practice, University of Melbourne, Parkville, Vic.,
Australia.
(2)Integria (MediHerb), Warwick, Qld, Australia.
(3)New York Chiropractic College, Seneca Falls, NY, USA.
(4)Peter MacCallum Cancer Centre, East Melbourne, Vic., Australia.
(5)The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,
Baltimore, MD, USA.
OBJECTIVE: To evaluate the evidence from randomised trials for the efficacy and
safety of phytotherapeutic interventions in the management of biochemically
recurrent (BCR) prostate cancer, indicated by prostate-specific antigen (PSA)
progression, numbers progressing to/time to initiation of androgen-deprivation
therapy or salvage therapy.
PATIENTS AND METHODS: MEDLINE (Ovid), EMBASE (Ovid), AMED (Ovid), CINAHL (EBSCO)
and the Cochrane Library databases were searched. Clinical trials investigating
phytotherapeutic interventions as dietary supplements or dietary components,
including multi-component herbal formulations, in men with BCR prostate cancer
were located. Eight of nine authors contacted for further information responded.
Methodological quality was assessed using the Cochrane Collaboration's risk of
bias assessment tool. The Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statement for reporting systematic reviews was followed.
RESULTS: Of 23 full-text articles assessed for eligibility, five met the
criteria for inclusion. Two studies were placebo controlled; two were active
control trials; and one a high-/low-dose trial. The interventions were
administered as isolated phytochemicals (sulphoraphane), phytotherapeutic
extracts [Pomi-T (pomegranate, turmeric, green tea and broccoli sprout extract),
soy, lycopene, and POMx (pomegranate extract)], or plant-derived dietary items
(soy and lycopene). All studies found serum PSA levels to stabilise, decrease or
rise more slowly in a significant number of men, and three studies reported
stabilising or lengthening of PSA-doubling time. Studies were generally of good
quality, but sample sizes were predominantly small, and durations short.
CONCLUSIONS: High-quality studies in this area are lacking. Sulphoraphane,
lycopene, soy isoflavones, POMx, and Pomi-T are safe and well tolerated. There
is limited evidence that they can affect PSA dynamics. No recommendation can be
made for the use of these agents in managing prostate cancer morbidity and
mortality until high-quality, fully powered studies are available.
Recommendations are made for improving reproducibility and translation of
findings with regard to study population, study endpoints, design, and the
reporting of phytotherapeutic interventions.
© 2016 The Authors BJU International © 2016 BJU International Published by John
Wiley & Sons Ltd.
DOI: 10.1111/bju.13361
PMCID: PMC8631186
Conflict of interest statement: Conflict of Interest Prof. Kerry Bone works as a

consultant director of Research and Development for MediHerb (Integria)
Australia, manufacturers of herbal medicines. He and Dr Diana van Die are
in-laws.
381. Nat Prod Commun. 2015 Dec;10(12):2179-88.
Synergistic Effects of Dietary Natural Products as Anti-Prostate Cancer Agents.
Vue B, Zhang S, Chen QH.
This review is to describe synergistic effects of various combinations of

dietary natural products including curcumin, quercetin, soybean isoflavones,
silibinin, and EGCG that have potential for the treatment of prostate cancer.
These data can provide valuable insights into the future rational design and
development of synergistic and/or hybrid agents for potential treatment of
prostate cancer.
382. Biometals. 2016 Apr;29(2):299-310. doi: 10.1007/s10534-016-9916-6. Epub 2016

Feb
12.
Simulating hypoxia-induced acidic environment in cancer cells facilitates

mobilization and redox-cycling of genomic copper by daidzein leading to
pro-oxidant cell death: implications for the sensitization of resistant hypoxic
cancer cells to therapeutic challenges.
Ullah MF(1)(2), Ahmad A(3)(4), Bhat SH(5), Khan HY(3), Zubair H(3), Sarkar
FH(4), Hadi SM(3).
Author information:
(1)Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002,
India. m.ullah@ut.edu.sa.
(2)Laboratory of Phytomedicine & Therapeutics, Prince Fahd Research Chair,
Department of Medical Laboratory Technology, Faculty of Applied Medical
Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia. m.ullah@ut.edu.sa.
(3)Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002,
India.
(4)Department of Pathology, Karmanos Cancer Institute, Wayne State University
School of Medicine, Detroit, MI, USA.
(5)Laboratory of Phytomedicine & Therapeutics, Prince Fahd Research Chair,
Department of Medical Laboratory Technology, Faculty of Applied Medical
Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia.
This study was conducted to investigate the mechanism of action involved in the
anti-cancer activity of daidzein and identification of cancer specific
micro-environment as therapeutic target of this secondary metabolite derived
from soy. Our data indicated that daidzein induces cellular DNA breakage,
anti-proliferative effects and apoptosis in a concentration-dependent manner. We
demonstrated that such a daidzein-induced anti-cancer action involves a
copper-dependant pathway in which endogenous copper is mobilized by daidzein and
redox-cycled to generate reactive oxygen species which act as an upstream signal
leading to pro-oxidant cell death. Further in the context of hypoxia being a
resistant factor against standard therapies and that an effect secondary to
hypoxia is the intracellular acidification, we show that the anticancer activity
of daidzein is modulated positively in acidic pH but copper-specific chelator is
still able to inhibit daidzein activity. Moreover, an experimental setup of
hypoxia mimic (cobalt chloride) revealed an enhanced sensitivity of cancer cells
to the cytotoxic effects of daidzein which was neutralized in the presence of
neocuproine. The findings support a paradigm shift from the conventional
antioxidant property of dietary isoflavones to molecules capable of initiating a
pro-oxidant signaling mediated by reactive oxygen species. Further, the clinical
relevance of such an action mechanism in cancer chemoprevention is also
proposed. This study identified endogenous copper as a molecular target and
acidic pH as a modulating factor for the therapeutic activity of daidzein
against cancer. The evidence presented highlights the potential of dietary
agents as adjuvants to standard therapeutic regimens.
DOI: 10.1007/s10534-016-9916-6
383. Arch Toxicol. 2016 Aug;90(8):1907-16. doi: 10.1007/s00204-016-1674-2. Epub

2016
Feb 9.
Soy isoflavone exposure through all life stages accelerates

17β-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden,
in ACI rats.
Möller FJ(1), Pemp D(2), Soukup ST(3), Wende K(4), Zhang X(4), Zierau O(4),
Muders MH(5), Bosland MC(6), Kulling SE(3), Lehmann L(2), Vollmer G(4).
Author information:
(1)Department of Molecular Cell Physiology and Endocrinology, Institute for
Zoology, Technische Universität Dresden, 01062, Dresden, Germany.
frank.moeller@tu-dresden.de.
(2)Department of Food Chemistry, Institute for Pharmacy and Food Chemistry,
Universität Würzburg, 97074, Würzburg, Germany.
Rubner-Institut, 76131, Karlsruhe, Germany.
(4)Department of Molecular Cell Physiology and Endocrinology, Institute for
Zoology, Technische Universität Dresden, 01062, Dresden, Germany.
(5)Institute for Pathology, University Clinic Carl Gustav Carus, Technische
Universität Dresden, 01307, Dresden, Germany.
Chicago, Chicago, IL, 60612, USA.
There is an ongoing debate whether the intake of soy-derived isoflavones (sISO)

mediates beneficial or adverse effects with regard to breast cancer risk.
Therefore, we investigated whether nutritional exposure to a sISO-enriched diet
from conception until adulthood impacts on 17β-estradiol (E2)-induced
carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats
were exposed to dietary sISO from conception until postnatal day 285. Silastic
tubes containing E2 were used to induce MG tumorigenesis. Body weight, food
intake, and tumor growth were recorded weekly. At necropsy, the number,
position, size, and weight of each tumor were determined. Plasma samples
underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence
and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed
rats compared to the control rats. Time-to-tumor onset was shortened from 25 to
20 weeks, and larger tumors developed in the sISO-exposed rats. The histological
phenotype of the MG tumors was independent of the sISO diet received, and it
included both comedo and cribriform phenotypes. Morphological analyses of the
whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure
to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the
time-to-tumor was significantly shortened.
DOI: 10.1007/s00204-016-1674-2
384. Chin Med J (Engl). 2016 Feb 5;129(3):341-7. doi: 10.4103/0366-6999.174488.
Isoflavones and Prostate Cancer: A Review of Some Critical Issues.
Zhang HY, Cui J, Zhang Y, Wang ZL, Chong T, Wang ZM(1).
Author information:
(1)Department of Urology, Second Affiliated Hospital of Xi'an Jiaotong
University, Xi'an, Shaanxi 710004, China.
OBJECTIVE: The purpose of this review is to discuss some critical issues of

isoflavones protective against the development of prostate cancer (PCa).
DATA SOURCES: Data cited in this review were obtained primarily from PubMed and
Embase from 1975 to 2015.
STUDY SELECTION: Articles were selected with the search terms "isoflavone",
"Phytoestrogen", "soy", "genistin", and "PCa ".
RESULTS: Isoflavones do not play an important role on prostate-specific antigen
levels reduction in PCa patients or healthy men. The effect of isoflavones on
sex hormone levels and PCa risk may be determined by equol converting bacteria
in the intestine, specific polymorphic variation and concentrations of
isoflavones. The intake of various types of phytoestrogens with lower
concentrations in the daily diet may produce synergistic effects against PCa.
Moreover, prostate tissue may concentrate isoflavones to potentially
anti-carcinogenic levels. In addition, it is noteworthy that isoflavones may act
as an agonist in PCa.
CONCLUSIONS: Isoflavones play a protective role against the development of PCa.
However, careful consideration should be given when isoflavones are used in the
prevention and treatment of PCa.
DOI: 10.4103/0366-6999.174488
PMCID: PMC4799580
385. Antioxidants (Basel). 2015 Mar 26;4(2):248-68. doi: 10.3390/antiox4020248.
Mechanisms of Photoaging and Cutaneous Photocarcinogenesis, and Photoprotective

Strategies with Phytochemicals.
Bosch R(1)(2), Philips N(3), Suárez-Pérez JA(4)(5), Juarranz A(6), Devmurari

A(7), Chalensouk-Khaosaat J(8), González S(9)(10).
Author information:
(1)Department of Dermatology, Virgen de la Victoria University Hospital, Málaga
29010, Spain. ricardobosch@aedv.es.
(2)Dermatology and Medicine Department, University of Málaga, Málag 29071,
Spain. ricardobosch@aedv.es.
(3)School of Natural Sciences, Fairleigh Dickinson University, 1000 River Road,
Teaneck, NJ 07666, USA. nphilips@fdu.edu.
(4)Department of Dermatology, Virgen de la Victoria University Hospital, Málaga
29010, Spain. jasuape@hotmail.com.
(5)Dermatology and Medicine Department, University of Málaga, Málag 29071,
Spain. jasuape@hotmail.com.
(6)Biology Department, Universidad Autónoma de Madrid, Madrid 28903, Spain.
angeles.juarranz@uam.es.
Teaneck, NJ 07666, USA. avaniben@student.fdu.edu.
Teaneck, NJ 07666, USA. jovinna.ck323@yahoo.com.
(9)Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY
10022, USA. gonzals6@mskcc.org.
(10)Ramon y Cajal Hospital, Alcala University, Madrid 28034, Spain.
gonzals6@mskcc.org.
Photoaging and photocarcinogenesis are primarily due to solar ultraviolet (UV)

radiation, which alters DNA, cellular antioxidant balance, signal transduction
pathways, immunology, and the extracellular matrix (ECM). The DNA alterations
include UV radiation induced thymine-thymine dimers and loss of tumor suppressor
gene p53. UV radiation reduces cellular antioxidant status by generating
reactive oxygen species (ROS), and the resultant oxidative stress alters signal
transduction pathways such as the mitogen-activated protein kinase (MAPK), the
nuclear factor-kappa beta (NF-κB)/p65, the janus kinase (JAK), signal
transduction and activation of transcription (STAT) and the nuclear factor
erythroid 2-related factor 2 (Nrf2). UV radiation induces pro-inflammatory genes
and causes immunosuppression by depleting the number and activity of the
epidermal Langerhans cells. Further, UV radiation remodels the ECM by increasing
matrixmetalloproteinases (MMP) and reducing structural collagen and elastin. The
photoprotective strategies to prevent/treat photoaging and photocarcinogenesis
include oral or topical agents that act as sunscreens or counteract the effects
of UV radiation on DNA, cellular antioxidant balance, signal transduction
pathways, immunology and the ECM. Many of these agents are phytochemical
derivatives and include polyphenols and non-polyphenols. The flavonoids are
polyphenols and include catechins, isoflavones, proanthocyanidins, and
anthocyanins, whereas the non-flavonoids comprise mono phenolic acids and
stilbenes. The natural sources of polyphenols include tea, cocoa, grape/wine,
soy, pomegranate, and Polypodium leucotomos. The non-phenolic phytochemicals
include carotenoids, caffeine and sulphoraphance (SFN). In addition, there are
other phytochemical derivatives or whole extracts such as baicalin, flavangenol,
raspberry extract, and Photomorphe umbellata with photoprotective activity
against UVB radiation, and thereby carcinogenesis.
DOI: 10.3390/antiox4020248
PMCID: PMC4665475
PMID: 26783703
386. J Res Med Sci. 2015 Sep;20(9):893-900. doi: 10.4103/1735-1995.170627.
Dietary isoflavones and gastric cancer: A brief review of current studies.
Golpour S(1), Rafie N(1), Safavi SM(1), Miraghajani M(1).
Author information:
(1)Department of Community Nutrition, Food Security Research Center, Isfahan
University of Medical Sciences, Isfahan, Iran; Department of Community
Nutrition, School of Nutrition and Food Science, Isfahan University of Medical
Sciences, Isfahan, Iran.
BACKGROUND: Although several in vitro and animal studies have suggested that
isoflavones might exert inhibitory effects on gastric carcinogenesis,
epidemiologic studies have reported inconclusive results in this field. The aim
of this brief review was to investigate whether such an association exists among
dietary isoflavones and gastric cancer incidence, prevention, and mortality in
epidemiologic studies.
MATERIALS AND METHODS: We conducted a search of PubMed, Google Scholar,
Cochrane, Science direct, and Iranian Scientific Databases including Scientific
Information Database and IranMedex Database (up to November 2014) using common
keywords for studies that focused on dietary isoflavones and gastric cancer
risk.
RESULTS: A total of nine epidemiologic studies consisting of five case-controls,
three prospective cohorts, and one ecologic study were included in this review.
An inverse association between dietary isoflavones and gastric cancer was shown
in only one case-control and one ecologic study.
CONCLUSION: In summary, whether anticarcinogenic properties of isoflavones are
established, research found no substantial correlation in this field. There are
insufficient studies to draw any firm conclusions about the relationship between
isoflavones intake and the risk of gastric cancer. Hence, further evidence from
cohort and trial studies are needed.
DOI: 10.4103/1735-1995.170627
PMCID: PMC4696376
PMID: 26759578
387. Biol Pharm Bull. 2016;39(4):631-5. doi: 10.1248/bpb.b15-00767. Epub 2016 Jan
9.
Bioassay-Guided Isolation of Two Flavonoids from Derris scandens with

Topoisomerase II Poison Activity.
Sangmalee S(1), Laorpaksa A, Sritularak B, Sukrong S.
Author information:
(1)Department of Pharmacognosy and Pharmaceutical Botany, Unit Cell for Research
and Development of Herbal Medicines, Biomaterials and Dental Material for Dental
Care and Therapy.
Derris scandens (ROXB.) BENTH. (Fabaceae) is used as an alternative treatment

for cancer in Thai traditional medicine. Investigation of the topoisomerase II
(Top2) poison of compounds isolated from this plant may reveal new drug leads
for the treatment of cancer. Bioassay-guided isolation was performed on an
extract of D. scandens stems using a yeast cell-based assay. A yeast strain
expressing the top2-1 temperature-sensitive mutant was used to assay Top2
activity. At the permissive temperature of 25°C, yeast cells were highly
sensitive to Top2 poison agents. At the semi-permissive temperature of 30°C,
where enzyme activity was present but greatly diminished, cells displayed only
marginal sensitivity. The bioassay-guided fractionation of the extract led to
the isolation of two known isoflavones: 5,7,4'-trihydroxy-6,8-diprenylisoflavone
(1) and lupalbigenin (2). These two compounds also displayed cytotoxicity
against three different cancer cell lines, KB, MCF-7 and NCI-H187. In
conclusion, Top2 poison agents from D. scandens are reported for the first time,
substantiating the use of D. scandens in Thai traditional medicine for cancer
treatment.
DOI: 10.1248/bpb.b15-00767
388. Menopause. 2016 May;23(5):556-64. doi: 10.1097/GME.0000000000000569.
Use of hormone therapy and isoflavones and mammographic density in Spain.
Isidoro B(1), Lope V, Whelan D, Pedraz C, Sánchez-Contador C, Santamariña C,

Moreo P, Vidal C, Salas-Trejo D, Ederra M, Aragonés N, Pérez-Gómez B, Pollán M.
Author information:
(1)1Cancer and Environmental Epidemiology Unit, National Center for
Epidemiology, Carlos III Institute of Health, Madrid, Spain 2Department of
Preventive Medicine, HM Hospitals, Madrid, Spain 3Consortium for Biomedical
Research in Epidemiology and Public Health (CIBER Epidemiología y Salud Pública,
CIBERESP, Spain 4Cancer Epidemiology Research Group, Oncology and Hematology
Area, IIS Puerta de Hierro (IDIPHIM), Madrid, Spain 5Castile-León Breast Cancer
Screening Programme, General Directorate Public Health SACYL, Burgos,
Castile-León, Spain 6Balearic Islands Breast Cancer Screening Programme, Health
Promotion for Women and Childhood, General Directorate Public Health and
Participation, Regional Authority of Health and Consumer Affairs, Balearic
Islands, Palma de Mellorca, Spain 7Galicia Breast Cancer Screening Programme,
Regional Authority of Health, Galicia Regional Government, Corunna, Spain
8Aragon Breast Cancer Screening Programme, Health Service of Aragon, Zaragoza,
Spain 9Cancer Prevention and Control Unit, Catalan Institute of Oncology (ICO),
Barcelona, Spain 10Valencia Breast Cancer Screening Programme, General
Directorate Public Health, Valencia, Spain 11FISABIO, Valencia, Spain 12Navarra
Breast Cancer Screening Programme, Public Health Institute, Pamplona, Spain.
OBJECTIVE: The use of some forms of hormone therapy (HT) is associated with an
increase in mammographic density-a major risk factor for breast cancer. The role
of isoflavones, however, is unclear. Here, we quantify the prevalence of HT and
isoflavone use among postmenopausal Spanish women, determine associated risk
factors, and explore the relationship between these therapies and mammographic
density.
METHODS: This cross-sectional study included 2,754 postmenopausal women who
underwent breast cancer screening in seven geographical areas. Mammographic
density was evaluated using Boyd's semiquantitative scale. Multinomial logistic
regression models were adjusted to assess risk factors associated with both
therapies. Ordinal regression models were fitted to study the association
between HT and isoflavone consumption with mammographic density.
RESULTS: The prevalence of ever-use of HT was 12%, whereas that of the current
use was 2.3%. Isoflavone lifetime prevalence was 3.7%, and current use was 1.7%.
The most common HT types were tibolone and estrogens. Surgical menopause, oral
contraceptive use, educational level, population density, and years since
menopause were positively associated with HT, whereas body mass index and parity
were inversely associated. Mammographic density was not associated with current
or past HT use. However, women who reported having consumed isoflavones in the
past and those who started their use after menopause had a higher mammographic
density when compared with never-users (odds ratio 1.98, 95% CI 1.21-3.25,
P = 0.007; and odds ratio 1.60, 95% CI 1.01-2.53, P = 0.045 respectively).
CONCLUSIONS: Our results show a low prevalence of HT and isoflavone use in
postmenopausal Spanish women. In this population, HT use was not associated with
mammographic density, whereas some categories of isoflavone users had higher
density.
DOI: 10.1097/GME.0000000000000569
389. Recent Pat Food Nutr Agric. 2016;8(2):91-98. doi:

10.2174/2212798408666160620090519.
Bioconversion of Isoflavones into Bioactive Equol: State of the Art.
Lopes DB, de Avila ARA, de Queiros LD, Macedo JA, Macedo GA(1).
Author information:
(1)Laboratory of Bioprocess, Department of Food and Nutrition, Food Engineering
Faculty, University of Campinas (UNICAMP), P.O. Box 6121, Barão Geraldo,
Campinas-SP, Brazil..
BACKGROUND: Soy isoflavones, an important class of phytoestrogens, are suggested

to be responsible for a number of biological activities associated with health
benefits, including defense against various chronic diseases, including breast
and prostate cancer, cardiovascular disorders, and osteoporosis, and they may
alleviate the symptoms of menopause.
METHODS: However, current researches (including patents) have shown that the
clinical efficacy of these phenolic compounds is related to the ability of an
individual to biotransform isoflavones into equol, which is a metabolite of
daidzein formed exclusively by the intestinal microbiota.
RESULTS: This biologically active metabolite presents greater effects than other
isoflavones; however, only about 30-50 % of people have a microbiota that is
able to produce equol from dietary daidzein. Concern has recently grown about
applications to improve the production of this metabolite.
CONCLUSION: This paper summarizes the metabolism of equol, its production, and
clinical implications.

DOI: 10.2174/2212798408666160620090519
390. J Thorac Oncol. 2015 Dec;10(12):1703-12. doi: 10.1097/JTO.0000000000000677.
Soy Isoflavones Promote Radioprotection of Normal Lung Tissue by Inhibition of

Radiation-Induced Activation of Macrophages and Neutrophils.
Abernathy LM(1), Fountain MD, Rothstein SE, David JM, Yunker CK, Rakowski J,
Lonardo F, Joiner MC, Hillman GG.
Author information:
(1)*Department of Immunology and Microbiology, †Division of Radiation Oncology,
Department of Oncology, and ‡Department of Pathology, Wayne State University
School of Medicine, Detroit, Michigan.
INTRODUCTION: Radiation therapy for lung cancer is limited by toxicity to normal

lung tissue that results from an inflammatory process, leading to pneumonitis
and fibrosis. Soy isoflavones mitigate inflammatory infiltrates and
radiation-induced lung injury, but the cellular immune mediators involved in the
radioprotective effect are unknown.
METHODS: Mice received a single dose of 10 Gy radiation delivered to the lungs
and daily oral treatment of soy isoflavones. At different time points, mice were
either processed to harvest bronchoalveolar lavage fluid for differential cell
counting and lungs for flow cytometry or immunohistochemistry studies.
RESULTS: Combined soy and radiation led to a reduction in infiltration and
activation of alveolar macrophages and neutrophils in both the bronchoalveolar
and lung parenchyma compartments. Soy treatment protected F4/80CD11c
interstitial macrophages, which are known to play an immunoregulatory role and
are decreased by radiation. Furthermore, soy isoflavones reduced the levels of
nitric oxide synthase 2 expression while increasing arginase-1 expression after
radiation, suggesting a switch from proinflammatory M1 macrophage to an
anti-inflammatory M2 macrophage phenotype. Soy also prevented the influx of
activated neutrophils in lung caused by radiation.
CONCLUSIONS: Soy isoflavones inhibit the infiltration and activation of
macrophages and neutrophils induced by radiation in lungs. Soy
isoflavones-mediated modulation of macrophage and neutrophil responses to
radiation may contribute to a mechanism of resolution of radiation-induced
chronic inflammation leading to radioprotection of lung tissue.
DOI: 10.1097/JTO.0000000000000677
PMCID: PMC6876621
Conflict of interest statement: Conflict of Interest: No financial disclosures.
391. Molecules. 2015 Dec 22;21(1):E13. doi: 10.3390/molecules21010013.
Soy Isoflavones and Breast Cancer Cell Lines: Molecular Mechanisms and Future
Perspectives.
Uifălean A(1)(2), Schneider S(3), Ionescu C(4), Lalk M(5), Iuga CA(6).
Author information:
(1)Department of Pharmaceutical Analysis, Faculty of Pharmacy, Iuliu Hațieganu
Romania. alina.uifalean@umfcluj.ro.
Street 4, Greifswald 17487, Germany. alina.uifalean@umfcluj.ro.
Street 4, Greifswald 17487, Germany. stefanie.schneider1@uni-greifswald.de.
(4)Department of Pharmaceutical Biochemistry and Clinical Laboratory, Faculty of
Pharmacy, Iuliu Hațieganu University of Medicine and Pharmacy, Louis Pasteur
Street 6, Cluj-Napoca 400349, Romania. corina.ionescu@umfcluj.ro.
Street 4, Greifswald 17487, Germany. lalk@uni-greifswald.de.
(6)Department of Pharmaceutical Analysis, Faculty of Pharmacy, Iuliu Hațieganu
Romania. iugac@umfcluj.ro.
The potential benefit of soy isoflavones in breast cancer chemoprevention, as
suggested by epidemiological studies, has aroused the interest of numerous
scientists for over twenty years. Although intensive work has been done in this
field, the preclinical results continue to be controversial and the molecular
mechanisms are far from being fully understood. The antiproliferative effect of
soy isoflavones has been commonly linked to the estrogen receptor interaction,
but there is growing evidence that other pathways are influenced as well. Among
these, the regulation of apoptosis, cell proliferation and survival, inhibition
of angiogenesis and metastasis or antioxidant properties have been recently
explored using various isoflavone doses and various breast cancer cells. In this
review, we offer a comprehensive perspective on the molecular mechanisms of
isoflavones observed in in vitro studies, emphasizing each time the dose-effect
relationship and estrogen receptor status of the cells. Furthermore, we present
future research directions in this field which could provide a better
understanding of the inner molecular mechanisms of soy isoflavones in breast
cancer.
PMCID: PMC6273223
392. J Med Food. 2016 Jan;19(1):1-14. doi: 10.1089/jmf.2015.0045. Epub 2015 Dec 15.
Soy Isoflavones and Osteoporotic Bone Loss: A Review with an Emphasis on

Modulation of Bone Remodeling.
Zheng X(1), Lee SK(2), Chun OK(1).
Author information:
(1)1 Department of Nutritional Sciences, University of Connecticut , Storrs,
Connecticut, USA.
(2)2 Center on Aging, University of Connecticut Health Center , Farmington,
Connecticut, USA.
Osteoporosis is an age-related disorder that affects both women and men,

although estrogen deficiency induced by menopause accelerates bone loss in older
women. As the demographic shifts to a more aged population, a growing number of
men and women will be afflicted with osteoporosis. Since the current drug
therapies available have multiple side effects, including increased risk of
developing certain types of cancer or complications, a search for potential
nonpharmacologic alternative therapies for osteoporosis is of prime interest.
Soy isoflavones (SI) have demonstrated potential bone-specific effects in a
number of studies. This article provides a systematic review of studies on
osteoporotic bone loss in relation to SI intake from diet or supplements to
comprehensively explain how SI affect the modulation of bone remodeling.
Evidence from epidemiologic studies supports that dietary SI attenuate
menopause-induced osteoporotic bone loss by decreasing bone resorption and
stimulating bone formation. Other studies have also illustrated that bone
site-specific trophic and synergistic effects combined with exercise
intervention might contribute to improve the bioavailability of SI or strengthen
the bone-specific effects. To date, however, the effects of dietary SI on
osteoporotic bone loss remain inconclusive, and study results vary from study to
study. The current review will discuss the potential factors that result in the
conflicting outcomes of these studies, including dosages, intervention
materials, study duration, race, and genetic differences. Further well-designed
studies are needed to fully understand the underlying mechanism and evaluate the
effects of SI on osteoporosis in humans.
DOI: 10.1089/jmf.2015.0045
PMCID: PMC4717511
393. Curr Cancer Drug Targets. 2016;16(5):455-65. doi:

10.2174/1568009616666151207105720.
S-equol, a Secondary Metabolite of Natural Anticancer Isoflavone Daidzein,

Inhibits Prostate Cancer Growth In Vitro and In Vivo, Though Activating the
Akt/FOXO3a Pathway.
Lu Z, Zhou R, Kong Y, Wang J, Xia W, Guo J, Liu J, Sun H, Liu K, Yang J, Mi M,

Xu H(1).
Author information:
(1)Department of Nutrition, Daping Hospital and Research Institute of Surgery,
Third Military Medical University, Chongqing 400042, China.
hongxiaxu@tmmu.edu.cn.
Forkhead box O3 (FOXO3a) is a transcription factor with tumor suppressor

functions that plays an important role in prostate cancer. Daidzein, one of the
soy isoflavones present in soy-based foods, has been shown to exert anti-tumor
effects in vitro and in vivo. We herein investigated the inhibitory effects of
S-equol, an isoflavandiol metabolized from daidzein by bacterial flora in the
intestines, on the LnCaP, DU145 and PC3 human prostate cancer cell lines. Our
results showed that S-equol and R-equol inhibited the growth of all three cell
lines. Additional studies revealed that S-equol caused cell cycle arrest in the
G2/M phase in PC3 cells by downregulating Cyclin B1 and CDK1 and upregulating
CDK inhibitors (p21 and p27), as well as inducing apoptosis by upregulating Fas
ligand (FasL) and the expression of proapoptotic Bim. Additionally, S-equol
increased the expression of FOXO3a, decreased the expression of p-FOXO3a and
enhanced the nuclear stability of FOXO3a. S-equol also decreased the expression
of MDM2, which serves as an E3 ubiquitin ligase for p-FOXO3a, thus preventing
p-FOXO3a degradation by the proteasome. Mechanistic studies showed that S-equol
targeted the Akt/FOXO3a pathway, which is important for prostate cancer cell
survival, cell cycle progression and apoptosis. Moreover, treatment with S-equol
inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. Overall, the
data from the present study demonstrate that S-equol has significant
anti-prostate cancer activities in vitro and in vivo, and indicate that its
anticancer effects were likely associated with the activation of FOXO3a via an
Akt-specific pathway and inhibitory effects on MDM2 expression. The results not
only provide a better understanding of the molecular mechanisms of this unique
secondary metabolite of a natural anti-cancer compound, but also provide a basis
for the development of daidzein and its analogs as novel anticancer agents.
DOI: 10.2174/1568009616666151207105720
394. Climacteric. 2016;19(1):77-84. doi: 10.3109/13697137.2015.1094783. Epub 2015

Nov
25.
Effects of early and late treatment with soy isoflavones in the mammary gland of
ovariectomized rats.
Santos MA(1), Florencio-Silva R(2), Teixeira CP(2), Sasso GR(2), Marinho DS(2),
Simões RS(3), Simões MJ(2), Carbonel AF(2).
Author information:
(1)a Universidade Federal De São Paulo , São Paulo ;
(2)b Morphology and Genetics , Universidade Federal De São Paulo , São Paulo ;
(3)c Gynecology, Universidade De São Paulo , São Paulo , Brazil.
INTRODUCTION: Soy isoflavones have been shown to be an alternative to hormone

therapy at menopause, without causing side-effects such as breast cancer.
However, the effects of early and late treatment with isoflavones on the mammary
gland remain controversial.
OBJECTIVE: To investigate the effects of early and late treatment with soy
isoflavones on the mammary gland of ovariectomized rats.
METHODS: Thirty 3-month-old rats were ovariectomized and divided equally into
groups: Control, treated with vehicle solution; or with 150 mg/kg/body weight of
isoflavones by gavage; or subcutaneously treated with 10 μg/kg/body weight with
17β-estradiol. Treatments started 3 days (early treatment) or 30 days (late
treatment) after ovariectomy and lasted for 30 consecutive days. Thereafter, the
animals were euthanized and the mammary glands were removed and processed for
paraffin embedding. Sections were stained with hematoxylin and eosin for
histomorphometry or subjected to immunohistochemical detection of Ki-67 and
VEGF-A.
RESULTS: The ductal, lobular and total epithelial fractions were similar between
controls and the early/late isoflavone groups, but they were significantly
higher in the groups treated with estradiol. In both epithelial and stromal
regions, the immunoreactivity of VEGF-A and the percentage of Ki-67-positive
cells were significantly higher in the groups treated with estradiol, while they
were similar in the early/late isoflavone groups and control groups.
CONCLUSION: Our results indicate that early and late treatment with soy
isoflavones at the dose of 150 mg/kg/body weight does not show proliferative and
angiogenic effects on the mammary gland of ovariectomized rats.
DOI: 10.3109/13697137.2015.1094783
395. PLoS One. 2015 Nov 17;10(11):e0143228. doi: 10.1371/journal.pone.0143228.

eCollection 2015.
Isoflavone and Soyfood Intake and Colorectal Cancer Risk: A Case-Control Study
in Korea.
Shin A(1), Lee J(2), Lee J(1)(3), Park MS(4), Park JW(5), Park SC(6), Oh JH(6),
Kim J(2).
Author information:
Medicine, Seoul, 110-799, Republic of Korea.
(2)Molecular Epidemiology Branch, National Cancer Center, Goyang-si, 410-769,
Republic of Korea.
(3)Department of Nutritional Science and Food Management, Ewha Womans
University, Seoul, 120-750, Republic of Korea.
(4)Gachon University College of Nursing, Incheon, 406-799, Republic of Korea.
(5)Department of Surgery, Seoul National University College of Medicine and
Hospital, Seoul, 110-799, Republic of Korea.
(6)Center for Colorectal Cancer, National Cancer Center, Goyang-si, 410-769,
Republic of Korea.
We aimed to assess the relationship between dietary soyfood and isoflavone
intake and colorectal cancer risk in a case-control study. A total of 901
colorectal cancer cases and 2669 controls were recruited at the National Cancer
Center, Korea. A semi-quantitative food frequency questionnaire was used to
assess the usual dietary habits, and the isoflavone intake level was estimated
from five soyfood items. A high intake of total soy products, legumes, and
sprouts was associated with a reduced risk for colorectal cancer in men and
women, although the middle quartiles of intake of total soy products were
associated with an elevated risk. In contrast, a high intake of fermented soy
paste was associated with an elevated risk for colorectal cancer in men. The
groups with the highest intake quartiles of isoflavones showed a decreased risk
for colorectal cancer compared to their counterparts with the lowest intake
quartiles in men (odds ratio (OR): 0.67, 95% confidence interval (CI):
0.51-0.89) and women (OR: 0.65, 95% CI: 0.43-0.99). The reduced risk for the
highest intake groups persisted for distal colon cancer in men and rectal cancer
in women. The association between soyfood intake and colorectal cancer risk was
more prominent among post-menopausal women than pre-menopausal women. In
conclusion, a high intake of total soy products or dietary isoflavones was
associated with a reduced risk for overall colorectal cancer, and the
association may be more relevant to distal colon or rectal cancers.
PMCID: PMC4648565

that no competing interests exist.
396. BMC Cancer. 2015 Nov 16;15:905. doi: 10.1186/s12885-015-1914-5.
Induction of proto-oncogene BRF2 in breast cancer cells by the dietary soybean

isoflavone daidzein.
Koo J(1), Cabarcas-Petroski S(2), Petrie JL(3), Diette N(1), White RJ(3),
Schramm L(4).
Author information:
(1)Department of Biological Sciences, St. John's University, Queens, New York,
11439, USA.
(2)Pennsylvania State University, Beaver Campus, Monaca, PA, 15061, USA.
(3)Department of Biology, University of York, Heslington, York, YO10 5DD, UK.
(4)Department of Biological Sciences, St. John's University, Queens, New York,
11439, USA. schramml@stjohns.edu.
BACKGROUND: BRF2 is a transcription factor required for synthesis of a small

group of non-coding RNAs by RNA polymerase III. Overexpression of BRF2 can
transform human mammary epithelial cells. In both breast and lung cancers, the
BRF2 gene is amplified and overexpressed and may serve as an oncogenic driver.
Furthermore, elevated BRF2 can be independently prognostic of unfavorable
survival. Dietary soy isoflavones increase metastasis to lungs in a model of
breast cancer and a recent study reported significantly increased cell
proliferation in breast cancer patients who used soy supplementation. The soy
isoflavone daidzein is a major food-derived phytoestrogen that is structurally
similar to estrogen. The putative estrogenic effect of soy raises concern that
high consumption of soy foods by breast cancer patients may increase tumor
growth.
METHODS: Expression of BRF2 RNA and protein was assayed in ER-positive or
-negative human breast cancer cells after exposure to daidzein. We also measured
mRNA stability, promoter methylation and response to the demethylating agent
5-azacytidine. In addition, expression was compared between mice fed diets
enriched or deprived of isoflavones.
RESULTS: We demonstrate that the soy isoflavone daidzein specifically stimulates
expression of BRF2 in ER-positive breast cancer cells, as well as the related
factor BRF1. Induction is accompanied by increased levels of non-coding RNAs
that are regulated by BRF2 and BRF1. Daidzein treatment stabilizes BRF2 and BRF1
mRNAs and selectively decreases methylation of the BRF2 promoter. Functional
significance of demethylation is supported by induction of BRF2 by the
methyltransferase inhibitor 5-azacytidine. None of these effects are observed in
an ER-negative breast cancer line, when tested in parallel with ER-positive
breast cancer cells. In vivo relevance is suggested by the significantly
elevated levels of BRF2 mRNA detected in female mice fed a high-isoflavone
commercial diet. In striking contrast, BRF2 and BRF1 mRNA levels are suppressed
in matched male mice fed the same isoflavone-enriched diet.
CONCLUSIONS: The BRF2 gene that is implicated in cancer can be induced in human
breast cancer cells by the isoflavone daidzein, through promoter demethylation
and/or mRNA stabilization. Dietary isoflavones may also induce BRF2 in female
mice, whereas the converse occurs in males.
DOI: 10.1186/s12885-015-1914-5
PMCID: PMC4647806
397. Front Oncol. 2015 Oct 21;5:238. doi: 10.3389/fonc.2015.00238. eCollection

2015.
Radiation-Induced Esophagitis is Mitigated by Soy Isoflavones.
Fountain MD(1), Abernathy LM(1), Lonardo F(2), Rothstein SE(3), Dominello MM(3),
Yunker CK(3), Chen W(3), Gadgeel S(3), Joiner MC(3), Hillman GG(1).
Author information:
(1)Department of Immunology and Microbiology, Karmanos Cancer Institute, Wayne
State University School of Medicine , Detroit, MI , USA ; Department of
Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine ,
Detroit, MI , USA.
(2)Department of Pathology, Karmanos Cancer Institute, Wayne State University
School of Medicine , Detroit, MI , USA.
(3)Department of Oncology, Karmanos Cancer Institute, Wayne State University
School of Medicine , Detroit, MI , USA.
INTRODUCTION: Lung cancer patients receiving radiotherapy present with acute

esophagitis and chronic fibrosis, as a result of radiation injury to esophageal
tissues. We have shown that soy isoflavones alleviate pneumonitis and fibrosis
caused by radiation toxicity to normal lung. The effect of soy isoflavones on
esophagitis histopathological changes induced by radiation was investigated.
METHODS: C57BL/6 mice were treated with 10 Gy or 25 Gy single thoracic
irradiation and soy isoflavones for up to 16 weeks. Damage to esophageal tissues
was assessed by hematoxylin-eosin, Masson's Trichrome and Ki-67 staining at 1,
4, 10, and 16 weeks after radiation. The effects on smooth muscle cells and
leukocyte infiltration were determined by immunohistochemistry using anti-αSMA
and anti-CD45, respectively.
RESULTS: Radiation caused thickening of esophageal tissue layers that was
significantly reduced by soy isoflavones. Major radiation alterations included
hypertrophy of basal cells in mucosal epithelium and damage to smooth muscle
cells in muscularis mucosae as well as disruption of collagen fibers in lamina
propria connective tissue with leukocyte infiltration. These effects were
observed as early as 1 week after radiation and were more pronounced with a
higher dose of 25 Gy. Soy isoflavones limited the extent of tissue damage
induced by radiation both at 10 and 25 Gy.
CONCLUSION: Soy isoflavones have a radioprotective effect on the esophagus,
mitigating the early and late effects of radiation injury in several esophagus
tissue layers. Soy could be administered with radiotherapy to decrease the
incidence and severity of esophagitis in lung cancer patients receiving thoracic
radiation therapy.
DOI: 10.3389/fonc.2015.00238
PMCID: PMC4617099
PMID: 26557504
398. Asian Pac J Cancer Prev. 2015;16(15):6527-34. doi:

10.7314/apjcp.2015.16.15.6527.
Association between Smoking Status and Food and Nutrient Consumption in

Japanese: a Large-Scale Cross-Sectional Study.
Endoh K(1), Kuriki K, Kasezawa N, Tohyama K, Goda T.
Author information:
(1)Laboratory of Public Health, Division of Nutritional Sciences, School of Food
and Nutritional Sciences, University of Shizuoka, Shizuoka City, Japan E-mail :
kuriki@u-shizuoka-ken.ac.jp.
BACKGROUND: In Japan, in comparison with the rest of the world the death rate of
lung cancer is low although the smoking rate is relatively high. This is the
so-called "Japanese smoking paradox". A healthy diet is proposed to attenuate
the risk without quitting smoking. We here examined the relationships between
smoking status (SS) and the consumption of food and nutrient in Japan.
MATERIALS AND METHODS: Totals of 5,587 men and 2,718 women were divided into
three (non-smokers, smokers and heavy smokers) and two (non-smokers and smokers)
groups, respectively, according to pack-year, which represents the amount of
smoking over a long period. Food and nutrient consumption was estimated with a
validated food frequency questionnaire. Using general linear models, food and
nutrient consumption was estimated for each group in men and women, separately.
RESULTS: In men, SS was positively related to consumption of rice, 3 alcoholic
beverages, carbohydrate, alcohol and other 8 foods/nutrients (p<0.05 for all)
and negatively to those of protein animal, fat, fatty acids, dietary fiber,
isoflavones and 36 other foods/nutrients (p<0.05 for all). In women, SS was
positively associated with intake of 13 foods/nutrients, while being negatively
associated with those of rice, energy, dietary fiber, and 14 other
foods/nutrients (p<0.05 for all).
CONCLUSIONS: Our results support lower intake of vegetables and fruits rich in
antioxidants, which are thought as preventive factors for many diseases, in
smokers.
DOI: 10.7314/apjcp.2015.16.15.6527
399. Br J Nutr. 2015 Nov 28;114(10):1694-701. doi: 10.1017/S0007114515003359. Epub

2015 Sep 15.
Urinary isoflavonoids and risk of type 2 diabetes: a prospective investigation

in US women.
Ding M(1), Franke AA(2), Rosner BA(3), Giovannucci E(1), van Dam RM(1), Tworoger
SS(3), Hu FB(1), Sun Q(1).
Author information:
(1)1Department of Nutrition,Harvard School of Public Health,Boston,MA 02115,USA.
(2)2Department of Food Science and Human Nutrition,College of Tropical
Agriculture and Human Resources,University of Hawai'i Cancer Center,Honolulu,HI
96813,USA.
(3)3Channing Division of Network Medicine,Brigham and Women's Hospital and
Harvard Medical School,Boston,MA 02115,USA.
To examine the association between urinary excretion of isoflavonoids and risk

of type 2 diabetes (T2D), we conducted a nested case-control study among 1111
T2D pairs identified during 1995-2008 in the Nurses' Health Study (NHS) and
NHSII, who were free of diabetes, CVD and cancer at urine sample collection.
Urinary excretion of daidzein and genistein, as well as their metabolites
O-desmethylangolensin (O-DMA), dihydrogenistein (DHGE) and dihydrodaidzein
(DHDE) was assayed using liquid chromatography MS. Self-reported T2D incident
cases were confirmed using a validated questionnaire. Higher urinary excretion
of daidzein and genistein was associated with a lower risk of T2D in the
combined cohorts. Comparing extreme tertiles of the urinary markers, the OR of
T2D were 0·71 (95 % CI 0·55, 0·93) for daidzein and 0·74 (95 % CI 0·56, 0·97)
for genistein, although the test for linear trend was not significant for
genistein (P trend=0·03 and 0·15, respectively). DMA, DHDE and DHGE were
non-significantly associated with a lower T2D risk. The inverse association of
daidzein with T2D risk was stronger among post-menopausal women who did not use
hormone replacement therapy (P interaction=0·001): the OR was 0·58 (95 % CI
0·34, 0·97) comparing extreme tertiles among these women. In conclusion, urinary
excretion of isoflavones was associated with a lower T2D risk in US women,
especially among post-menopausal women who did not use hormone. Further research
is warranted to replicate these observations among western populations with
similarly low overall isoflavone intake.
DOI: 10.1017/S0007114515003359
PMCID: PMC4762594
Conflict of interest statement: Competing Interests None of the authors had any
financial or personal conflict of interest to disclose.
400. Mater Sci Eng C Mater Biol Appl. 2015 Dec 1;57:49-57. doi:
10.1016/j.msec.2015.07.012. Epub 2015 Jul 14.
Synthesis and functionalization of silica-based nanoparticles with fluorescent

biocompounds extracted from Eysenhardtia polystachya for biological
applications.
Ferreira G(1), Hernandez-Martinez AR(1), Pool H(2), Molina G(1), Cruz-Soto M(3),
Luna-Barcenas G(2), Estevez M(4).
Author information:
(1)Centro de Física Aplicada y Tecnología Avanzada (CFATA), Universidad Nacional
Autónoma de México, Campus Juriquilla, Blvd. Juriquilla 3000, Juriquilla,
Querétaro, Mexico.
(2)Centro de Investigación y Estudios Avanzados del IPN (CINVESTAV), Unidad
Querétaro, Libramiento Norponiente #2000, Real de Juriquilla, C.P. 76230
Querétaro, Mexico.
(3)Universidad del Valle de México, Campus Querétaro, Blvd. Juriquilla 3000,
Juriquilla, Querétaro, Mexico.
(4)Centro de Física Aplicada y Tecnología Avanzada (CFATA), Universidad Nacional
Autónoma de México, Campus Juriquilla, Blvd. Juriquilla 3000, Juriquilla,
Querétaro, Mexico. Electronic address: miries@fata.unam.mx.
Several types of dyes or fluorophores are used for the detection of interactions
between drug carriers and cells, within biomedicine field. However, many of them
have a certain level of toxicity and instability affecting their biological
properties. Different studies have demonstrated that nanoparticles (NPs) have
interesting properties that could be used to stabilize diverse biomolecules,
including dyes. Here, we report the synthesis of a novel nanosystem by the
functionalization of silica NPs using biocompounds extracted from Mexican tree
"Palo azul" (Eysenhardtia polystachya) and APTES as a coupling agent. Particle
size, electrical properties, and morphology of the novel nanosystem were
analyzed. The extracted biocompounds presented fluorescence which prevails over
time, even after nanosystem formation and apparent cellular internalization.
These were detected using MCF-7 cells visualized by confocal laser-scanning
microscopy (CLSM), finding that the nanosystem was able to internalize into
cells and act as a fluorescent biomarker. By this method, our novel nanosystem
opens the possibilities to obtain sensitive data in a noninvasive manner for
biological applications, such as early-stage cancer diagnosis, drug delivery,
and pathogen detection.
DOI: 10.1016/j.msec.2015.07.012
401. Fitoterapia. 2015 Dec;107:1-14. doi: 10.1016/j.fitote.2015.08.015. Epub 2015

Sep
5.
Belamcandae chinensis rhizome--a review of phytochemistry and bioactivity.
Woźniak D(1), Matkowski A(2).
Author information:
(1)Department of Pharmaceutical Biology and Botany, Medical University of
Wroclaw, ul. Borowska 211, PL-50556 Wroclaw, Poland. Electronic address:
pharmaceutical.biology@wp.eu.
(2)Department of Pharmaceutical Biology and Botany, Medical University of
Wroclaw, ul. Borowska 211, PL-50556 Wroclaw, Poland.
Belamcandae chinensis rhizoma, is a rhizome of Iris domestica (syn. Belamcanda

chinensis). Under the Chinese name she gan, it is extensively used in
Traditional Chinese Medicine and other East Asian phytotherapy systems.
Recently, the monograph of Belamcandae chinensis rhizoma has been included in
the European Pharmacopeia. This review provides a comprehensive summary and
systematizes the literature data on ethnobotanical uses, chemical constituents
and biological effects of Belamcandae chinensis rhizoma and its components. The
main group of phytochemicals identified in the dried rhizoma are polyphenols
such as isoflavones, xanthone glycosides, stilbenes, simple phenols and
quinones. Another characteristic class of substances are triterpenopid iridals.
The most typical traditional usage of Belamcandae chinensis rhizoma is for
healing respiratory diseases but most of pharmacological research so far has
been focused on isoflavones and their estrogenic properties. In pharmacological
research, it has been mainly considered as a source of tectorigenin--a
phytoestrogene with therapeutic potential in hormone-dependent cancer. The most
active isoflavones are tectoridin, tectorigenin and irigenin. The available
literature indicates that Belamcandae chinensis rhizoma can prevent excessive
oxidation of biomolecules based on various antioxidant mechanisms: transition
metal ions reduction, inhibition of lipid peroxidation, free radicals
scavenging. The other biological activities proven by a number of in vitro
studies include: antimutagenic,anti-inflammatory, anti-angiogenic, hypoglycemic.
In conclusion, the knowledge about Belamcandae chinensis rhizoma has been
growing rapidly in the recent years,but there are still significant gaps in our
understanding of its bioactivity, therapeutic value, and roles played by each of
the numerous phytochemicals.
DOI: 10.1016/j.fitote.2015.08.015
402. Int J Clin Exp Pathol. 2015 Jul 1;8(7):7809-17. eCollection 2015.
Inhibitory effects of O-methylated isoflavone glycitein on human breast cancer

SKBR-3 cells.
Zhang B(1), Su JP(2), Bai Y(1), Li J(1), Liu YH(1).
Author information:
(1)Department of Surgical Oncology, Cangzhou Central Hospital Cangzhou, China.
(2)Department of Endocrinology, Cangzhou People's Hospital Cangzhou, China.
Glycitein is an O-methylated isoflavone which accounts for 5-10% of the total

isoflavones in soy food products. Cell proliferation studies on the dietary
phytoestrogen, glycitein against human breast carcinoma SKBR-3 cells showed that
glycitein exhibits biphasic regulation on SKBR-3 cells. At concentrations of
less than 10 mg/mL, cells respond to glycitein by increasing cell growth and de
novo DNA synthesis whereas the addition of glycitein at concentrations greater
than 30 mg/mL significantly inhibited cell growth and DNA synthesis in a
dose-dependent manner. Cells treated with 60 mg/mL of glycitein did not regain
normal growth after treatment was stopped. Glycitein was found to be cytostatic
at low concentrations and cytotoxic at higher concentrations. Treatment with 100
mg/mL of glycitein severely altered the cell morphology. Collective results
showed that glycitein damaged the cell membranes by increasing membrane
permeability and suggested possible mechanisms of the action of dietary
phytoestrogens on human breast carcinoma SKBR-3 cells.
PMCID: PMC4555673
403. Enzymes. 2015;37:193-221. doi: 10.1016/bs.enz.2015.05.004. Epub 2015 Jul 23.
The Role of Soy Phytoestrogens on Genetic and Epigenetic Mechanisms of Prostate

Cancer.
Karsli-Ceppioglu S(1), Ngollo M(2), Judes G(2), Penault-LLorca F(2), Bignon

YJ(2), Guy L(3), Bernard-Gallon D(4).
Author information:
(1)Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Marmara
University, Istanbul, Turkey; Department of Oncogenetics, Centre Jean
Perrin-CBRV, Clermont-Ferrand, France; EA 4677 "ERTICA," University of Auvergne,
Clermont-Ferrand, France.
(2)Department of Oncogenetics, Centre Jean Perrin-CBRV, Clermont-Ferrand,
France; EA 4677 "ERTICA," University of Auvergne, Clermont-Ferrand, France.
(3)EA 4677 "ERTICA," University of Auvergne, Clermont-Ferrand, France;
Department of Urology, CHU Gabriel Montpied, Clermont-Ferrand, France.
(4)Department of Oncogenetics, Centre Jean Perrin-CBRV, Clermont-Ferrand,
France; EA 4677 "ERTICA," University of Auvergne, Clermont-Ferrand, France.
Electronic address: Dominique.BERNARD-GALLON@cjp.fr.
Soy phytoestrogens are dietary components with considerable effects on reducing

the incidence of prostate cancer. Epidemiological studies demonstrated that
occurrence of prostate cancer is relatively low in Asia and Southern Europe, a
status associated with consuming of soy isoflavones, such as genistein,
daidzein, and glycitein. Soy phytoestrogens exert their activity on molecular
mechanisms, including cell-cycle control, induction of apoptosis, inhibition of
angiogenesis, and metastasis. In addition, they have antioxidant activity and
show regulatory effect on the expression of genes involved in DNA damage and
repair. Furthermore, the epigenetic regulation of gene expression can be
modified by soy phytoestrogens. They show regulatory effects on gene activity by
altering DNA methylation and/or histone modification patterns. In this chapter,
we discuss the role of soy phytoestrogens on the genetic and epigenetic
mechanisms of prostate cancer. We attempt to provide further insight in order to
understand the underlying mechanisms of protective effects of soy phytoestrogens
in preventing prostate cancer.
© 2015 Elsevier Inc. All rights reserved.
DOI: 10.1016/bs.enz.2015.05.004
PMID: 26298461
404. Cancer Prev Res (Phila). 2015 Nov;8(11):1036-44. doi:

10.1158/1940-6207.CAPR-14-0464. Epub 2015 Aug 14.
Consumption of soy isoflavone enriched bread in men with prostate cancer is

associated with reduced proinflammatory cytokines and immunosuppressive cells.
Lesinski GB(1), Reville PK(2), Mace TA(2), Young GS(3), Ahn-Jarvis J(4),
Thomas-Ahner J(2), Vodovotz Y(5), Ameen Z(2), Grainger E(2), Riedl K(5),
Schwartz S(5), Clinton SK(1).
Author information:
(1)Department of Internal Medicine, Division of Medical Oncology, The Arthur G.
James and Richard Solove Research Institute, Columbus, Ohio. The Ohio State
University Comprehensive Cancer Center, Columbus, Ohio.
Gregory.Lesinski@osumc.edu steven.clinton@osumc.edu.
(2)Department of Internal Medicine, Division of Medical Oncology, The Arthur G.
James and Richard Solove Research Institute, Columbus, Ohio.
(3)Center for Biostatistics, The Ohio State University, Columbus, Ohio.
(4)College of Food, Agricultural and Environmental Science, Department of Food
Science and Technology, The Ohio State University, Columbus, Ohio.
(5)The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
College of Food, Agricultural and Environmental Science, Department of Food
Science and Technology, The Ohio State University, Columbus, Ohio.
We hypothesized that soy phytochemicals may have immunomodulatory properties

that may affect prostate carcinogenesis and progression. A randomized, phase II
trial was conducted in 32 patients with prostate cancer with asymptomatic
biochemical recurrence but no measurable disease on standard staging studies.
Patients were randomized to two slices of soy bread (34 mg isoflavones/slice) or
soy bread containing almond powder daily as a source of β-glucosidase. Flow
cytometry and bioplex assays were used to measure cytokines or immune cell
phenotype in blood at baseline (day 0) and following intervention (day 56).
Adequate blood samples were available at enrollment and day 56 and evaluated.
Multiple plasma cytokines and chemokines were significantly decreased on day 56
versus baseline. Subgroup analysis indicated reduced TH1 (P = 0.028) and
myeloid-derived suppressor cell (MDSC)-associated cytokines (P = 0.035). TH2 and
TH17 cytokines were not significantly altered. Phenotypic analysis revealed no
change in CD8(+) or CD4(+) T cells but showed increased CD56(+) natural killer
(NK) cells (P = 0.038). The percentage of cells with a T regulatory cell
phenotype (CD4(+)CD25(+)FoxP3(+)) was significantly decreased after 56 days of
soy bread (P = 0.0136). Significantly decreased monocytic
(CD33(+)HLADR(neg)CD14(+)) MDSC were observed in patients consuming soy bread (P
= 0.0056). These data suggest that soy bread modulates systemic soluble and
cellular biomarkers consistent with limiting inflammation and suppression of
MDSCs. Additional studies to elucidate impact on the carcinogenic process or as
a complement to immune-based therapy are required.
DOI: 10.1158/1940-6207.CAPR-14-0464
PMCID: PMC4633400
Conflict of interest statement: Conflict of Interest: There are no conflicts of

interest related to this work.
405. Cancer Prev Res (Phila). 2015 Oct;8(10):942-51. doi:

10.1158/1940-6207.CAPR-15-0125. Epub 2015 Aug 14.
Double-Blind Randomized 12-Month Soy Intervention Had No Effects on Breast MRI

Fibroglandular Tissue Density or Mammographic Density.
Wu AH(1), Spicer D(2), Garcia A(3), Tseng CC(4), Hovanessian-Larsen L(5), Sheth
P(5), Martin SE(6), Hawes D(6), Russell C(2), MacDonald H(2), Tripathy D(7), Su
MY(8), Ursin G(9), Pike MC(10).
Author information:
(1)Department of Preventive Medicine, University of Southern California Keck
School of Medicine, Los Angeles, California. annawu@usc.edu.
(2)Department of Medicine, University of Southern California Keck School of
Medicine, Los Angeles, California.
(3)Hematology Oncology, Louisiana State University, New Orleans, Louisiana.
School of Medicine, Los Angeles, California.
(5)Department of Radiology, University of Southern California Keck School of
(6)Department of Pathology, University of Southern California Keck School of
(7)MBreast Medical Oncology, The University of Texas MD Anderson Cancer Center,
Houston, Texas.
(8)Tu and Yuen Center for Functional Onco-Imaging, University of California,
Irvine, Irvine, California.
School of Medicine, Los Angeles, California. Department of Nutrition, University
of Oslo, Oslo, Norway. Cancer Registry of Norway, Oslo, Oslo, Norway.
School of Medicine, Los Angeles, California. Department of Epidemiology and
Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
Soy supplementation by patients with breast cancer remains controversial. No

controlled intervention studies have investigated the effects of soy
supplementation on mammographic density in patients with breast cancer. We
conducted a double-blind, randomized, placebo-controlled intervention study in
previously treated patients with breast cancer (n = 66) and high-risk women (n =
29). We obtained digital mammograms and breast MRI scans at baseline and after
12 months of daily soy (50 mg isoflavones per day; n = 46) or placebo (n = 49)
tablet supplementation. The total breast area (MA) and the area of mammographic
density (MD) on the mammogram were measured using a validated computer-assisted
method, and mammographic density percent (MD% = 100 × MD/MA) was determined. A
well-tested computer algorithm was used to quantitatively measure the total
breast volume (TBV) and fibroglandular tissue volume (FGV) on the breast MRI,
and the FGV percent (FGV% = 100 × FGV/TBV) was calculated. On the basis of
plasma soy isoflavone levels, compliance was excellent. Small decreases in MD%
measured by the ratios of month 12 to baseline levels were seen in the soy
(0.95) and the placebo (0.87) groups; these changes did not differ between the
treatments (P = 0.38). Small decreases in FGV% were also found in both the soy
(0.90) and the placebo (0.92) groups; these changes also did not differ between
the treatments (P = 0.48). Results were comparable in patients with breast
cancer and high-risk women. We found no evidence that soy supplementation would
decrease mammographic density and that MRI might be more sensitive to changes in
density than mammography.
DOI: 10.1158/1940-6207.CAPR-15-0125
PMCID: PMC4596769
406. Cancer Prev Res (Phila). 2015 Nov;8(11):1045-54. doi:

10.1158/1940-6207.CAPR-14-0465. Epub 2015 Aug 14.
Isoflavone pharmacokinetics and metabolism after consumption of a standardized

soy and soy-almond bread in men with asymptomatic prostate cancer.
Ahn-Jarvis JH(1), Clinton SK(2), Grainger EM(3), Riedl KM(4), Schwartz SJ(4),
Lee ML(5), Cruz-Cano R(5), Young GS(6), Lesinski GB(7), Vodovotz Y(4).
Author information:
(1)Department of Food Science and Technology, College of Food, Agricultural, and
Environmental Sciences, The Ohio State University, Columbus, Ohio.
(2)Division of Medical Oncology, Department of Internal Medicine, The Arthur G.
James and Richard Solove Research Institute, The Ohio State University,
Columbus, Ohio. The Ohio State University Comprehensive Cancer Center, Columbus,
Ohio. steven.clinton@osumc.edu.
(3)The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
(4)Department of Food Science and Technology, College of Food, Agricultural, and
Environmental Sciences, The Ohio State University, Columbus, Ohio. The Ohio
State University Comprehensive Cancer Center, Columbus, Ohio.
(5)Department of Epidemiology and Biostatistics at the University of Maryland,
College Park, Maryland.
(6)Center for Biostatistics at The Ohio State University College of Medicine,
Columbus, Ohio.
(7)Division of Medical Oncology, Department of Internal Medicine, The Arthur G.
James and Richard Solove Research Institute, The Ohio State University,
Columbus, Ohio. The Ohio State University Comprehensive Cancer Center, Columbus,
Ohio.
Epidemiologic associations suggest that populations consuming substantial

amounts of dietary soy exhibit a lower risk of prostate cancer. A 20-week
randomized, phase II, crossover trial was conducted in 32 men with asymptomatic
prostate cancer. The crossover involved 8 weeks each of soy bread (SB) and
soy-almond bread (SAB). The primary objective was to investigate isoflavone
bioavailability and metabolite profile. Secondary objectives include safety,
compliance, and assessment of biomarkers linked to prostate carcinogenesis. Two
distinct SBs were formulated to deliver approximately 60 mg aglycone equivalents
of isoflavones per day. The isoflavones were present as aglycones (∼78% as
aglycones) in the SAB whereas in the standard SB predominantly as glucosides
(18% total isoflavones as aglycones). Compliance to SB (97% ± 4%) and SAB (92% ±
18%) was excellent; toxicity was rare and limited to grade 1 gastrointestinal
complaints. Pharmacokinetic studies between SB and SAB showed modest
differences. Peak serum concentration time (Tmax) was significantly faster with
SAB meal compared with SB in some isoflavonoids, and AUC0 to 24 h of
dihydrodaidzein and O-desmethylangolensin was significantly greater after an SB
meal. An exploratory cluster analysis was used to identify four
isoflavone-metabolizing phenotypes. Insulin-like growth factor-binding protein
increased significantly by 41% (P = 0.024) with soy intervention. Findings from
this study provide the necessary framework to study isoflavone-metabolizing
phenotypes as a strategy for identification of individuals that might benefit or
show resistance to cancer preventive strategies using dietary soy. A
standardized SB used for future large-scale randomized clinical trials to affect
human prostate carcinogenesis is feasible.
DOI: 10.1158/1940-6207.CAPR-14-0465
PMCID: PMC4633369
Conflict of interest statement: Conflict of Interest: There are no conflicts of

interest related to this work.
407. Am J Clin Nutr. 2015 Sep;102(3):680-6. doi: 10.3945/ajcn.115.111591. Epub 2015

Aug 5.
Dietary isoflavones, urinary isoflavonoids, and risk of ischemic stroke in

women.
Yu D(1), Shu XO(1), Li H(2), Yang G(1), Cai Q(1), Xiang YB(2), Ji BT(3), Franke
AA(4), Gao YT(2), Zheng W(1), Zhang X(5).
Author information:
School of Medicine, Nashville, TN;
(2)Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University
School of Medicine, Shanghai, China;
(3)Division of Cancer Epidemiology and Genetics, National Cancer Institute/NIH,
Bethesda, MD; and.
(4)University of Hawaii Cancer Center, Honolulu, HI.
School of Medicine, Nashville, TN; xianglan218@gmail.com.
BACKGROUND: Hormone therapy has been shown to increase risk of ischemic stroke
in women. Plant-derived estrogens, particularly soy isoflavones, are known to
have some estrogenic effects and have been marketed as natural alternatives to
hormone therapy. Concerns have been raised about whether high isoflavone
exposure may be related to ischemic stroke risk as well.
OBJECTIVE: We examined the dietary intake of isoflavones and the urinary
excretion of isoflavonoids in relation to risk of ischemic stroke in women.
DESIGN: A prospective cohort study was conducted in 66,832 Chinese women (aged
40-70 y) who had no cardiovascular disease or cancer at baseline. Usual dietary
intakes were assessed via in-person interviews with the use of a validated
food-frequency questionnaire. Incident strokes were ascertained during follow-up
home visits and confirmed by medical records. We also conducted a nested
case-control study in postmenopausal women who had never used hormone therapy,
including 1422 incident ischemic stroke cases and 1422 controls individually
matched by age, date and time of urine sample collection, time since last meal,
and use of antibiotics. Urinary isoflavonoids were measured with the use of
high-performance liquid chromatography coupled with mass spectrometry.
RESULTS: During a mean follow-up of 10 y, 3110 incident ischemic strokes were
verified. Dietary isoflavone intake was associated with increased risk of
ischemic stroke; multivariable-adjusted HRs from lowest to highest quintiles
were 1.00, 1.05, 1.10, 1.11, and 1.24, respectively (95% CI: 1.08, 1.42; P-trend
= 0.002). In the case-control study, a similar positive association was observed
for dietary isoflavones, but no significant associations were shown for the
urinary isoflavonoid concentration [OR: 1.01 (95% CI: 0.77, 1.32) for comparison
of extreme quintiles].
CONCLUSIONS: A habitually high intake of soy isoflavones may be associated with
a modest but significant increase in risk of ischemic stroke in women. However,
no association was shown for the urinary excretion of isoflavonoids.
DOI: 10.3945/ajcn.115.111591
PMCID: PMC4548177
408. Food Funct. 2015 Sep;6(9):3091-7. doi: 10.1039/c5fo00374a.
Calycosin induces apoptosis by the regulation of ERβ/miR-17 signaling pathway in

human colorectal cancer cells.
Chen J(1), Zhao X, Li X, Wu Y.
Author information:
(1)School of Basic Medical Sciences, Guilin Medical University, Guilin 541004,
China.
Prior studies have suggested that a high intake of isoflavonoids is associated

with a protective effect against hormone-related cancers, such as colorectal
cancer (CRC). Calycosin, a main component of isoflavones, has been shown to
suppress the growth of hormone-dependent tumors through an ERβ-mediated
signaling pathway. However, the effects of calycosin on CRC remain unclear. In
this study, we aimed to investigate the anti-tumor activities of calycosin on
CRC and its potential mechanism. HCT-116 cells were treated with calycosin. Cell
proliferation, apoptosis and invasiveness were measured by MTT assay, flow
cytometry and transwell invasion assay, respectively. mRNA levels of ER beta
(ERβ) and miR-17 were quantified by real-time PCR. Protein expressions of ERβ
and phosphatase and tensin homolog deleted on chromosome ten (PTEN) were
determined by western blotting. We found that calycosin significantly induced
apoptosis, and inhibited proliferation and invasiveness of HCT-116 cells in a
dose-dependent manner. In addition, ERβ expression significantly increased in
calycosin-treated HCT-116 cells, followed by a decrease of miR-17, and
up-regulation of PTEN. Our results indicate that calycosin has an inhibitory
effect on CRC, which might be obtained by ERβ-mediated regulation of miR-17 and
PTEN expression.
DOI: 10.1039/c5fo00374a
409. Oxid Med Cell Longev. 2015;2015:504253. doi: 10.1155/2015/504253. Epub 2015
Jun
9.
Role of Polyphenols and Other Phytochemicals on Molecular Signaling.
Upadhyay S(1), Dixit M(1).
Author information:
(1)Laboratory of Vascular Biology, Department of Biotechnology, Bhupat and Jyoti
Mehta School of Biosciences and Bioengineering Building, Indian Institute of
Technology, Madras, Chennai, Tamil Nadu 600036, India.
Optimized nutrition through supplementation of diet with plant derived

phytochemicals has attracted significant attention to prevent the onset of many
chronic diseases including cardiovascular impairments, cancer, and metabolic
disorder. These phytonutrients alone or in combination with others are believed
to impart beneficial effects and play pivotal role in metabolic abnormalities
such as dyslipidemia, insulin resistance, hypertension, glucose intolerance,
systemic inflammation, and oxidative stress. Epidemiological and preclinical
studies demonstrated that fruits, vegetables, and beverages rich in carotenoids,
isoflavones, phytoestrogens, and phytosterols delay the onset of atherosclerosis
or act as a chemoprotective agent by interacting with the underlying
pathomechanisms. Phytochemicals exert their beneficial effects either by
reducing the circulating levels of cholesterol or by inhibiting lipid oxidation,
while others exhibit anti-inflammatory and antiplatelet activities.
Additionally, they reduce neointimal thickening by inhibiting proliferation of
smooth muscle cells and also improve endothelium dependent vasorelaxation by
modulating bioavailability of nitric-oxide and voltage-gated ion channels.
However, detailed and profound knowledge on specific molecular targets of each
phytochemical is very important to ensure safe use of these active compounds as
a therapeutic agent. Thus, this paper reviews the active antioxidative,
antiproliferative, anti-inflammatory, or antiangiogenesis role of various
phytochemicals for prevention of chronic diseases.
DOI: 10.1155/2015/504253
PMCID: PMC4477245
410. Curr Drug Metab. 2015;16(2):124-40. doi: 10.2174/138920021602150713114921.
Interaction of Isoflavones with the BCRP/ABCG2 Drug Transporter.
Bircsak KM, Aleksunes LM(1).
Author information:
(1)Dept. of Pharmacology and Toxicology, Rutgers University, 170 Frelinghuysen
Rd. Piscataway, NJ 08854, USA. aleksunes@eohsi.rutgers.edu.
This review will provide a comprehensive overview of the interactions between
dietary isoflavones and the ATP-binding cassette (ABC) G2 efflux transporter,
which is also named the breast cancer resistance protein (BCRP). Expressed in a
variety of organs including the liver, kidneys, intestine, and placenta, BCRP
mediates the disposition and excretion of numerous endogenous chemicals and
xenobiotics. Isoflavones are a class of naturallyoccurring compounds that are
found at high concentrations in commonly consumed foods and dietary supplements.
A number of isoflavones, including genistein and daidzein and their metabolites,
interact with BCRP as substrates, inhibitors, and/or modulators of gene
expression. To date, a variety of model systems have been employed to study the
ability of isoflavones to serve as substrates and inhibitors of BCRP; these
include whole cells, inverted plasma membrane vesicles, in situ organ perfusion,
as well as in vivo rodent and sheep models. Evidence suggests that BCRP plays a
role in mediating the disposition of isoflavones and in particular, their
conjugated forms. Furthermore, as inhibitors, these compounds may aid in
reversing multidrug resistance and sensitizing cancer cells to chemotherapeutic
drugs. This review will also highlight the consequences of altered BCRP
expression and/or function on the pharmacokinetics and toxicity of chemicals
following isoflavone exposure.
DOI: 10.2174/138920021602150713114921
PMCID: PMC4713194
Conflict of interest statement: Conflicts of Interest The authors declare no

conflicts of interest. This work was supported by the National Institutes of
Environmental Health Sciences (Grants ES020522, ES005022, ES007148, ES021800,
DK093903), a component of the National Institutes of Health. Kristin Bircsak is
supported by predoctoral fellowships from the American Foundation for
Pharmaceutical Education and Pharmaceutical Research and Manufacturers of
America.
411. Ann Epidemiol. 2015 Oct;25(10):730-5.e2. doi: 10.1016/j.annepidem.2015.05.010.

Epub 2015 Jun 5.
Dietary flavonoid intake and Barrett's esophagus in western Washington State.
Petrick JL(1), Steck SE(2), Bradshaw PT(3), Chow WH(4), Engel LS(5), He K(6),
Risch HA(7), Vaughan TL(8), Gammon MD(5).
Author information:
(1)Department of Epidemiology, University of North Carolina, Chapel Hill.
Electronic address: jessica.petrick@unc.edu.
(2)Department of Epidemiology and Biostatistics, University of South Carolina,
Columbia.
(3)Department of Nutrition, University of North Carolina, Chapel Hill.
(4)Department of Epidemiology, The University of Texas MD Anderson Cancer
Center, Houston.
(5)Department of Epidemiology, University of North Carolina, Chapel Hill.
(6)Department of Epidemiology and Biostatistics, Indiana University,
Bloomington.
(7)Department of Chronic Disease Epidemiology, Yale School of Public Health, New
Haven, CT.
(8)Division of Public Health Sciences, Fred Hutchinson Cancer Research Center,
Seattle, WA.
PURPOSE: Flavonoids, concentrated in fruits and vegetables, demonstrate in

experimental studies chemopreventive properties in relation to Barrett's
esophagus (BE), a precursor lesion for esophageal adenocarcinoma. One
case-control investigation reported an inverse association between isoflavone
intake and odds of BE, yet no epidemiologic study has considered other flavonoid
classes, which are more commonly consumed by Americans.
METHODS: We examined intake of total flavonoids, six flavonoid classes, and
lignans among case-control study participants in western Washington State. Food
frequency questionnaires were self-completed by BE cases with specialized
intestinal metaplasia (n = 170) and matched controls (n = 183).
RESULTS: In logistic regression models adjusted for age, sex, body mass index,
and energy intake, the odds ratio (OR) for specialized intestinal metaplasia BE
associated with anthocyanidin intake was 0.49 (95% confidence interval:
0.30-0.80, for quartiles 2-4 combined vs. quartile 1), for which wine and fruit
juice were major dietary sources. More moderate decreased ORs were noted for
flavanones, flavonols, isoflavones, and lignans. A modest increased OR was
observed for flavones, for which pizza was the main dietary source in our
population.
CONCLUSIONS: Our findings of an inverse association between anthocyanidins and
odds of BE suggest that adequate dietary intake of these compounds may lower
risk of this cancer precursor lesion.
DOI: 10.1016/j.annepidem.2015.05.010
PMCID: PMC4567908
412. Asian Pac J Cancer Prev. 2015;16(12):4987-91. doi:

10.7314/apjcp.2015.16.12.4987.
Associations of Serum Isoflavone, Adiponectin and Insulin Levels with Risk for
Epithelial Ovarian Cancer: Results of a Case-control Study.
Otokozawa S(1), Tanaka R, Akasaka H, Ito E, Asakura S, Ohnishi H, Saito S, Miura

T, Saito T, Mori M.
Author information:
(1)Department of Public Health, Sapporo Medical University School of Health
Sciences, Sapporo, Japan E-mail : mitsurum@sapmed.ac.jp.
BACKGROUND: The aim of this study was to examine the association of serum
isoflavones, adiponectin, and insulin levels with ovarian cancer risk.
MATERIALS AND METHODS: We gathered cases with histologically confirmed
epithelial ovarian cancer at Sapporo Medical University Hospital from October
2010 to September 2012. Potential controls were recruited from female inpatients
without any history of cancer or diabetes mellitus in different wards of the
same hospital over the same period of time. Serum isoflavones, adiponectin, and
insulin levels were measured in order to estimate associations with ovarian
cancer risk in a case-control study. Data from 71 cases and 80 controls were
analyzed with a logistic regression model adjusting for known risk factors.
RESULTS: A significant reduction in ovarian cancer risk was observed for the
high tertile of serum daidzein level versus the low (Ptrend<0.001). A
significant reduction in ovarian cancer risk was also observed for the high
tertile of serum glycitein level versus the low (Ptrend=0.005). Furthermore, a
significant reduction in ovarian cancer risk was observed for the high tertile
of serum adiponectin level versus the low (Ptrend=0.004). Conversely, serum
insulin level showed significantly elevated risk for ovarian cancer with the
high tertile versus the low Ptrend<0.001).
CONCLUSIONS: Decreased serum isoflavones levels, such as those for daidzein and
glycitein, decreased serum adiponectin levels, and increased serum insulin
levels could be shown to be associated with elevated risk of ovarian cancer.
DOI: 10.7314/apjcp.2015.16.12.4987
413. BMC Complement Altern Med. 2015 Jul 3;15:212. doi: 10.1186/s12906-015-0734-0.
The flavonoid beverage Haelan 951 induces growth arrest and apoptosis in
pancreatic carcinoma cell lines in vitro.
Rothe J(1), Wakileh M(2), Dreißiger K(3), Weber H(4).
Author information:
(1)Institute of Clinical Chemistry and Laboratory Medicine, University of
Rostock, Ernst-Heydemann-Straße 6, 18057, Rostock, Germany.
juliane.rothe88@gmx.de.
michael.wakileh@med.uni-rostock.de.
katrin.dreissiger@med.uni-rostock.de.
heike.weber@med.uni-rostock.de.
BACKGROUND: A major challenge in pancreatic cancer treatment is the resistance

of human pancreatic cancer cells to apoptosis. Soy isoflavones and calpain
inhibition have been suggested to exert inhibitory effects on cancer development
and progression. We investigated the effects of the isoflavone containing
beverage Haelan 951 and the calpain inhibitor PD150606 on the viability, growth
and apoptosis of the human pancreatic cancer cell lines CAPAN-1 and BxPC-3, on
the rat pancreatic cancer cell line AR42J, and on human fibroblasts as the
control cell line.
METHODS: Cellular viability and proliferation were determined using the LDH
cytotoxicity and WST-1 assay, respectively. Apoptosis was detected by flow
cytometric analyses of Annexin V-FITC labeled-cells, TUNEL assay and caspase
activation. Student's t test or Mann-Whitney Rank Sum test were used to compare
the data.
RESULTS: Haelan concentrations lower than 8% showed no cytotoxic effects,
whereas higher concentrations led to necrosis. Eight percent Haelan induced
significant growth inhibition of CAPAN-1 and BxPC-3 cell lines by 30% and 35%,
respectively, compared with the control. The proliferation rate of AR42J cells
decreased by 50%, whereas the fibroblasts remained unaffected. An 1.1-fold
increase in apoptosis was found in CAPAN-1 cells, whereas the number of
apoptotic BxPC-3 cells was elevated 2-fold. The number of apoptotic AR42J cells
and fibroblasts was elevated 1.5-fold, each. Inhibition of calpain activity
amplified the Haelan-induced growth inhibition of CAPAN-1 and BxPC-3 cells, but
failed to amplify the growth inhibition of Haelan-treated AR42J cells. In
fibroblasts, calpain inhibition induced Haelan-independent growth inhibition.
Calpain inhibition also amplified the Haelan-induced apoptotic activity in all
cancer cell lines, but exerted no further effect in fibroblasts.
CONCLUSIONS: The proliferation-inhibiting and apoptosis-inducing effects of
Haelan are highly dependent on cell type and concentration administered. The
results show for the first time that Haelan may be a promising candidate in the
treatment of human pancreatic cancer, and its anticancer activity may be
potentiated when administered with calpain inhibitors.
DOI: 10.1186/s12906-015-0734-0
PMCID: PMC4490641
414. Recent Pat Food Nutr Agric. 2015;7(2):92-9. doi:

10.2174/2212798407666150629123957.
Immunomodulatory Effects of Soybeans and Processed Soy Food Compounds.
Tezuka H(1), Imai S.
Author information:
(1)Department of Biodefense Research, Medical Research Institute, Tokyo Medical
and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
tezco.bre@mri.tmd.ac.jp.
Inflammation is an immune response against both internal and external antigens

in organisms, particularly in mammals, and includes both uncontrolled chronic
and low-grade inflammations. Uncontrolled chronic inflammation often leads to
severe diseases such as vascular disease, arthritis, cancer, diabete, allergy,
and autoimmunity. On the other hand, low-grade inflammation is recognized as a
relationship between obesity and risk of metabolic syndrome. Elevated production
of pro-inflammatory cytokines and mediators is commonly observed in patients
with uncontrolled or low-grade inflammation-associated diseases. Plants have
been generated phytochemicals to overcome inflammations and infections through
evolution. Phytochemicals belong to alkaloids, polyphenols, flavonoids,
coumarins, and terpenoids. The consumption of soybeans plays a role in immune
modulation through their components such as isoflavones, saponins, and
anthocyanins. Recently, it was reported that the application of phytochemicals
into patients with inflammatory diseases improves their symptoms. Therefore, it
is important to identify novel phytochemicals with immunomodulatory activities.
This review introduces and discusses recent advances and patents regarding
soybean or processed soy food compounds which exhibit immunomodulatory activity
in immune diseases, particularly allergy, by mediating the suppression of
inflammatory pathways.
DOI: 10.2174/2212798407666150629123957
415. Anticancer Res. 2015 Jun;35(6):3167-73.
Genistein Suppresses Growth of Human Uterine Sarcoma Cell Lines via Multiple
Mechanisms.
Yeh CC(1), Fan Y(1), Jiang L(1), Yang YL(2), He B(2), You L(2), Mann M(3).
Author information:
(1)Translational Research Laboratory, University of California San Francisco,
San Francisco, CA, U.S.A.
(2)Thoracic Oncology Laboratory, Department of Surgery, University of California
San Francisco, San Francisco, CA, U.S.A.
(3)Translational Research Laboratory, University of California San Francisco,
San Francisco, CA, U.S.A. Michael.Mann@ucsfmedctr.org.
BACKGROUND: The estrogen-like soy isoflavone genistein can suppress the growth
of a number of different types of cancer cells, but its effect on uterine
sarcoma is unknown.
MATERIALS AND METHODS: The impact of genistein on the proliferation of three
uterine sarcoma cell lines, MES-SA, MES-SA-Dx5 and SK-UT-1, was evaluated.
TOPflash luciferase reporter assay and western blotting were used to assess the
influence of genistein on cellular signaling; DNA fragmentation was assessed as
a measure of genistein-induced apoptosis.
RESULTS: Genistein inhibited the proliferation of all three cell lines, with
half-maximal inhibitory concentrations of 19.2 μM, 13.1 μM and 9.3 μM for
SK-UT-1, MES-SA-Dx5, and MES-SA, respectively. This inhibitory activity was
accompanied by induction of DNA fragmentation at 48 h. Western blot analyses
revealed three major expression patterns: induction of p53 and Dickkopf-related
protein 1 (DKK1) and suppression of histone deacetylase 4/5/7 (HDAC4/5/7),
dishevelled protein (DVL), BAX, survivin and phosphorylated mitogen-activated
protein kinase kinase (phospho-MEK) in all three lines; suppression of p27 and
β-catenin in the more resistant lines MES-SA-Dx5 and SK-UT-1; and suppression of
Protein kinase B (AKT) and extracellular signal-regulated kinases (ERKs)
phosphorylation and activation of caspase-3 in the parental derived lines MES-SA
and MES-SA-Dx5. Down-regulation of β-catenin expression also coincided with
decreases in TOPflash activity.
CONCLUSION: Genistein reduces sarcoma cell numbers through inhibition of
proliferative signaling and through induction of programmed or non-programmed
cell death. Genistein-mediated signaling changes were unique in each individual
cell line, and the differential signaling responses in these three cell lines
may contribute to their different levels of susceptibility to this compound.
Copyright© 2015 International Institute of Anticancer Research (Dr. John G.

Delinassios), All rights reserved.
416. Int J Mol Sci. 2015 May 22;16(5):11728-49. doi: 10.3390/ijms160511728.
Soy and breast cancer: focus on angiogenesis.
Varinska L(1), Gal P(2)(3)(4)(5), Mojzisova G(6), Mirossay L(7), Mojzis J(8).
Author information:
(1)Department of Pharmacology, P.J. Šafárik University, Faculty of Medicine,
Trieda SNP 1, 040 11 Košice, Slovakia. lenka.varinska@upjs.sk.
Trieda SNP 1, 040 11 Košice, Slovakia. peter.gal@upjs.sk.
(3)Department for Biomedical Research, East-Slovak Institute of Cardiovascular
Diseases, Ondavská 8, 040 11 Košice, Slovakia. peter.gal@upjs.sk.
(4)Department of Pharmacognosy and Botany, Faculty of Pharmacy, Commenius
University, Odbojárov 10, 832 10 Bratislava, Slovakia. peter.gal@upjs.sk.
(5)Institute of Anatomy, 1st Faculty of Medicine, Charles University, U
nemocnice 3, 128 00 Prague, Czech Republic. peter.gal@upjs.sk.
(6)Department of Experimental Medicine, P.J. Šafárik University, Faculty of
Medicine, Trieda SNP-1, 040 11 Košice, Slovakia. gabriela.mojzisova@upjs.sk.
Trieda SNP 1, 040 11 Košice, Slovakia. ladislav.mirossay@upjs.sk.
Trieda SNP 1, 040 11 Košice, Slovakia. jan.mojzis@upjs.sk.
Epidemiological studies have revealed that high consumption of soy products is

associated with low incidences of hormone-dependent cancers, including breast
and prostate cancer. Soybeans contain large amounts of isoflavones, such as the
genistein and daidzain. Previously, it has been demonstrated that genistein, one
of the predominant soy isoflavones, can inhibit several steps involved in
carcinogenesis. It is suggested that genistein possesses pleiotropic molecular
mechanisms of action including inhibition of tyrosine kinases, DNA topoisomerase
II, 5α-reductase, galectin-induced G2/M arrest, protein histidine kinase, and
cyclin-dependent kinases, modulation of different signaling pathways associated
with the growth of cancer cells (e.g., NF-κB, Akt, MAPK), etc. Moreover,
genistein is also a potent inhibitor of angiogenesis. Uncontrolled angiogenesis
is considered as a key step in cancer growth, invasion, and metastasis.
Genistein was found to inhibit angiogenesis through regulation of multiple
pathways, such as regulation of VEGF, MMPs, EGFR expressions and NF-κB,
PI3-K/Akt, ERK1/2 signaling pathways, thereby causing strong antiangiogenic
effects. This review focuses on the antiangiogenic properties of soy
isoflavonoids and examines their possible underlying mechanisms.
DOI: 10.3390/ijms160511728
PMCID: PMC4463727

May 21.
Anticarcinogenic Effects of Dietary Phytoestrogens and Their Chemopreventive

Mechanisms.
Hwang KA(1), Choi KC.
Author information:
(1)a Laboratory of Biochemistry and Immunology, College of Veterinary Medicine,
Chungbuk National University , Cheongju , Chungbuk , Republic of Korea.
Phytoestrogens are phenolic compounds derived from plants and exert an

estrogenic as well as an antiestrogenic effect and also various biological
efficacies. Chemopreventive properties of phytoestrogens has emerged from
epidemiological observations indicating that the incidence of some cancers
including breast and prostate cancers is much lower in Asian people, who consume
significantly higher amounts of phytoestrogens than Western people. There are 4
main classes of phytoestrogens: isoflavones, stilbenes, coumestans, and lignans.
Currently, resveratrol is recognized as another major phytoestrogen present in
grape and red wine and has been studied in many biological studies.
Phytoestrogens have biologically diverse profitabilities and advantages such as
low cytotoxicity to patients, lack of side effects in clinical trials, and
pronounced benefits in a combined therapy. In this review, we highlighted the
effects of genistein, daidzein, and resveratrol in relation with their
anticarcinogenic activity. A lot of in vitro and in vivo results on their
chemopreventive properties were presented along with the underlying mechanisms.
Besides well-known mechanisms such as antioxidant property and apoptosis, newly
elucidated anticarcinogenic modes of action including epigenetic modifications
and topoisomerase inhibition have been provided to examine the possibility of
phytoestrogens as promising reagents for cancer chemoprevention and/or treatment
and to suggest the importance of plant-based diet of phytoestrogens.
DOI: 10.1080/01635581.2015.1040516
418. Int J Mol Sci. 2015 May 13;16(5):10907-20. doi: 10.3390/ijms160510907.
Possibility of breast cancer prevention: use of soy isoflavones and fermented

soy beverage produced using probiotics.
Takagi A(1), Kano M(2), Kaga C(3).
Author information:
(1)Pharmaceutical Research Laboratory, Yakult Central Institute, Tokyo 186-8650,
Japan. akimitsu-takagi@yakult.co.jp.
(2)Food Research Laboratory, Yakult Central Institute, Tokyo 186-8650, Japan.
mitsuyoshi-kano@yakult.co.jp.
(3)Food Research Laboratory, Yakult Central Institute, Tokyo 186-8650, Japan.
chiaki-kaga@yakult.co.jp.
The various beneficial effects of soybeans, which are rich in phytochemicals,

have received much attention because of increasing health awareness. Soy milk
that has been fermented using lactic acid bacteria has been used to prepare
cheese-like products, tofu (bean-curd), and yogurt-type products. However, the
distinct odor of soybeans has limited the acceptance of such foods, particularly
in Western countries. In Japan, while tofu and soy milk have long been
habitually consumed, the development of novel, palatable food products has not
been easy. The unpleasant odor of soy milk and the absorption efficiency for
isoflavones can be improved using a recently developed fermented soy milk
beverage. Cancer has been the leading cause of death, and breast cancer is the
most common malignancy among women. The most common type of breast cancer is
estrogen-dependent, and the anti-estrogenic effects of isoflavones are known.
The present review focuses on the characteristics of soy milk fermented using
probiotics, an epidemiological study examining the incidence of breast cancer
and soy isoflavone consumption, and a non-clinical study examining breast cancer
prevention using fermented soy milk beverage.
DOI: 10.3390/ijms160510907
PMCID: PMC4463682
419. Int Urol Nephrol. 2015 Jun;47(6):965-70. doi: 10.1007/s11255-015-0981-5. Epub

2015 May 14.
Plasma genistein and risk of prostate cancer in Chinese population.
Wu Y(1), Zhang L, Na R, Xu J, Xiong Z, Zhang N, Dai W, Jiang H, Ding Q.
Author information:
(1)Department of Urology, Huashan Hospital, Fudan University, 12 Mid-Wulumuqi
Road, Shanghai, China.
OBJECTIVES: Genistein is one of the main soy isoflavones in our daily diet.
There were studies proving that high-dietary intake of genistein may relate to
the low morbidity and mortality of prostate cancer (PCa) in the Asian
population. Since there were few studies of plasma genistein level in the
Chinese population, we performed this study to preliminarily evaluate the
associations among plasma genistein, epidemiologic factors and PCa in a Chinese
population.
METHODS: Between 2012 and 2013, 100 men over the age of 40 underwent prostate
biopsy for PCa at Huashan Hospital, Shanghai, China. Clinical information,
epidemiologic information and blood samples were collected prior to biopsy for
each patient. All patients underwent 10-core ultrasound-guided transperineal
prostate biopsy, and the pathology results were collected after biopsy. We
measured the plasma genistein concentration of the blood samples and analyzed
the results along with the clinical and epidemiologic information.
RESULTS: Among the 100 patients, 46 (46.0 %) were diagnosed with PCa. The median
plasma genistein concentration of non-PCa patients (728.6 ng/ml) was
significantly higher than that of PCa patients (513.0 ng/ml) (P < 0.05). In the
univariate analysis, we found that age and smoking history were related to PCa
(P < 0.05). In the multivariate analysis, we found that age, smoking history and
plasma genistein were related to PCa (P < 0.05). The age-adjusted odds ratio of
PCa risk comparing plasma genistein level above median to that below median was
0.31 (95 % CI 0.13-0.71).
CONCLUSION: Our study suggested that high concentration of plasma genistein
level may contribute to the low incidence of prostate cancer in Chinese
population.
DOI: 10.1007/s11255-015-0981-5
PMCID: PMC4445252
420. Eur J Nutr. 2016 Apr;55(3):1029-40. doi: 10.1007/s00394-015-0917-y. Epub 2015

May 6.
Urinary phytoestrogens and cancer, cardiovascular, and all-cause mortality in

the continuous National Health and Nutrition Examination Survey.
Reger MK(1)(2), Zollinger TW(1), Liu Z(3), Jones J(4), Zhang J(5)(6).
Author information:
Public Health, 714 N Senate Avenue, Suite EF250F, Indianapolis, IN, 46202, USA.
(2)College of Health Professions, Ferris State University, Big Rapids, MI, USA.
(3)Department of Biostatistics, Indiana University Richard M. Fairbanks School
of Public Health and School of Medicine, Indianapolis, IN, USA.
(4)Department of Health Informatics, School of Informatics and Computing,
Indiana University-Purdue University Indianapolis, Indianapolis, IN, USA.
Public Health, 714 N Senate Avenue, Suite EF250F, Indianapolis, IN, 46202, USA.
JZ21@iu.edu.
(6)Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN,
USA. JZ21@iu.edu.
PURPOSE: Experimental studies suggest that phytoestrogen intake alters cancer

and cardiovascular risk. This study investigated the associations of urinary
phytoestrogens with total cancer (n = 79), cardiovascular (n = 108), and
all-cause (n = 290) mortality among 5179 participants in the continuous National
Health and Nutrition Examination Survey (1999-2004).
METHODS: Urinary phytoestrogens were measured using high-performance liquid
chromatography with tandem mass spectrometric detection. Survival analysis was
performed to evaluate hazard ratios (HRs) and 95 % confidence intervals (CIs)
for each of the three outcomes in relation to urinary phytoestrogens.
RESULTS: After adjustment for confounders, higher urinary concentrations of
total enterolignans were associated with a reduced risk of death from
cardiovascular disease (HR for tertile 3 vs. tertile 1 0.48; 95 % CI 0.24,
0.97), whereas higher urinary concentrations of total isoflavones (HR for
tertile 3 vs. tertile 1 2.14; 95 % CI 1.03, 4.47) and daidzein (HR for tertile 3
vs. tertile 1 2.05; 95 % CI 1.02, 4.11) were associated with an increased risk.
A reduction in all-cause mortality was observed for elevated urinary
concentrations of total enterolignans (HR for tertile 3 vs. tertile 1 0.65; 95 %
CI 0.43, 0.96) and enterolactone (HR for tertile 3 vs. tertile 1 0.65; 95 % CI
0.44, 0.97).
CONCLUSIONS: Some urinary phytoestrogens were associated with cardiovascular and
all-cause mortality in a representative sample of the US population. This is one
of the first studies that used urinary phytoestrogens as biomarkers of their
dietary intake to evaluate the effect of these bioactive compounds on the risk
of death from cancer and cardiovascular disease.
DOI: 10.1007/s00394-015-0917-y
421. Avicenna J Med Biotechnol. 2015 Jan-Mar;7(1):16-21.
Effects of Combined Soy Isoflavone Extract and Docetaxel Treatment on Murine 4T1
Breast Tumor Model.
Hejazi E(1), Nasrollahzadeh J(1), Fatemi R(2), Barzegar-Yar Mohamadi L(3),

Saliminejad K(4), Amiri Z(5), Kimiagar M(1), Houshyari M(6), Tavakoli M(2),
Idali F(2).
Author information:
(1)Department of Clinical Nutrition and Dietetics, School of Nutrition Sciences
and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran,
Iran.
(2)Reproductive Immunology Research Center, Avicenna Research Institute, ACECR,
Tehran, Iran.
(3)Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR,
Tehran, Iran.
(4)Reproductive Biotechnology Research Center, Avicenna Research Institute,
ACECR, Tehran, Iran.
(5)Department of Basic Sciences and Cellular and Molecular Nutrition, School of
Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical
(6)Department of Radiation Oncology, Shohada Tajrish Hospital, Shahid Beheshti
University of Medical Sciences, Tehran, Iran.
BACKGROUND: Emergence of drug resistance has brought major problems in

chemotherapy. Using nutrients in combination with chemotherapy could be
beneficial for improvement of sensitivity of tumors to drug resistance.
Soybean-derived isoflavones have been suggested as chemopreventive agents for
certain types of cancer, particularly breast cancer. In this study, the
synergistic effects of soy isoflavone extract in combination with docetaxel in
murine 4T1 breast tumor model were investigated.
METHODS: In this study, mice were divided into 4 groups (15 mice per group) of
control, the dietary Soy Isoflavone Extract (SIE, 100 mg/kg diet), the Docetaxel
(DOCE, 10 mg/kg) injection and the combination of dietary soy isoflavone extract
and intravenous docetaxel injection (DOCE+SIE). After 3 injections of docetaxel
(once a week), 7 mice were sacrificed to analyze MKI67 gene and protein
expressions and the rest were monitored for diet consumption, tumor growth and
survival rates.
RESULTS: In DOCE+SIE group, diet consumption was significantly higher than DOCE
group. While lifespan showed a trend towards improvement in DOCE+SIE group, no
significant difference was observed among the 4 studied groups. Tumor volume was
not significantly affected in treated groups. A lower but not significant MKI67
protein expression was detected in western blot in DOCE+SIE group. The mRNA
expression was not significantly different among groups.
CONCLUSION: The results suggest that the combination of soy isoflavone as an
adjunct to docetaxel chemotherapy can be effective in improving diet consumption
in breast cancer.
PMCID: PMC4388885
PMID: 25926948
422. J Food Sci Technol. 2015 May;52(5):2522-9. doi: 10.1007/s13197-014-1396-5.

Epub
2014 May 16.
Functional components and medicinal properties of food: a review.
Abuajah CI(1), Ogbonna AC(1), Osuji CM(2).
Author information:
(1)Department of Food Science and Technology, University of Uyo, PMB 1017 Uyo,
Nigeria.
(2)Department of Food Science and Technology, Federal University of Technology,
PMB 1526 Owerri, Nigeria.
Research has proved a relationship between functional components of food, health

and well-being. Thus, functional components of food can be effectively applied
in the treatment and prevention of diseases. They act simultaneously at
different or identical target sites with the potential to impart physiological
benefits and promotion of wellbeing including reducing the risk of cancer,
cardiovascular disease, osteoporosis, inflammation, type II diabetes, and other
chronic degenerative diseases, lowering of blood cholesterol, neutralization of
reactive oxygen species and charged radicals, anticarcinogenic effect,
low-glycaemic response, etc. Previously, it was thought that functional
ingredients such as non-starchy carbohydrates including soluble and insoluble
dietary fibres, fucoidan; antioxidants including polyphenols, carotenoids,
tocopherols, tocotrienols, phytosterols, isoflavones, organosulphur compounds;
plant sterols and soy phytoestrogens occur only in plant foods (whole grains,
fruits, and vegetables) as phytochemicals. However, probiotics, prebiotics,
conjugated linolenic acid, long-chain omega-3, -6 and -9-polyunsaturated fatty
acids, and bioactive peptides have proved that functional components are equally
available in animal products such as milk, fermented milk products and
cold-water fish. The way a food is processed affects its functional components.
Many processing techniques have been found to lower the concentration of
functional components in food. Conversely, other techniques were found to
increase them. Hence, in a time when the role of a healthy diet in preventing
non-communicable diseases is well accepted, the borderline between food and
medicine is becoming very thin.
DOI: 10.1007/s13197-014-1396-5
PMCID: PMC4397330
PMID: 25892752
423. Crit Rev Food Sci Nutr. 2016 Aug 17;56(11):1826-43. doi:
10.1080/10408398.2013.789823.
Bioactivation of Phytoestrogens: Intestinal Bacteria and Health.
Landete JM(1), Arqués J(1), Medina M(1), Gaya P(1), de Las Rivas B(2), Muñoz
R(2).
Author information:
(1)a Departamento de Tecnología de Alimentos , Instituto Nacional de
Investigación y Tecnología Agraria y Alimentaria (INIA) . Madrid , Spain.
(2)b Departamento de Biotecnología Bacteriana , Instituto de Ciencia y
Tecnología de Alimentos y Nutrición (ICTAN), Consejo Superior de Investigaciones
Científicas (CSIC) , Madrid , Spain.
Phytoestrogens are polyphenols similar to human estrogens found in plants or

derived from plant precursors. Phytoestrogens are found in high concentration in
soya, flaxseed and other seeds, fruits, vegetables, cereals, tea, chocolate,
etc. They comprise several classes of chemical compounds (stilbenes, coumestans,
isoflavones, ellagitannins, and lignans) which are structurally similar to
endogenous estrogens but which can have both estrogenic and antiestrogenic
effects. Although epidemiological and experimental evidence indicates that
intake of phytoestrogens in foods may be protective against certain chronic
diseases, discrepancies have been observed between in vivo and in vitro
experiments. The microbial transformations have not been reported so far in
stilbenes and coumestans. However, isoflavones, ellagitanins, and lignans are
metabolized by intestinal bacteria to produce equol, urolithins, and
enterolignans, respectively. Equol, urolithin, and enterolignans are more
bioavailable, and have more estrogenic/antiestrogenic and antioxidant activity
than their precursors. Moreover, equol, urolithins and enterolignans have
anti-inflammatory effects and induce antiproliferative and apoptosis-inducing
activities. The transformation of isoflavones, ellagitanins, and lignans by
intestinal microbiota is essential to be protective against certain chronic
diseases, as cancer, cardiovascular disease, osteoporosis, and menopausal
symptoms. Bioavailability, bioactivity, and health effects of dietary
phytoestrogens are strongly determined by the intestinal bacteria of each
individual.
DOI: 10.1080/10408398.2013.789823

Mar
31.
Biotransformed soybean extract induces cell death of estrogen-dependent breast

cancer cells by modulation of apoptotic proteins.
Stocco B(1), Toledo KA, Fumagalli HF, Bianchini FJ, Fortes VS, Fonseca MJ, Toloi
MR.
Author information:
(1)a Faculty of Pharmaceutical Sciences of Ribeirão Preto, Laboratory of
Clinical Cytology, University of São Paulo , Brazil.
The process of soybean biotransformation increases the quantity of isoflavones

(daidzein and genistein), which besides being considered an alternative to
estroprogestive hormone replacement therapy (HRT), are able of hindering the
growth and development of tumor cells. We investigated the effects of soybean
extract biotransformed by fungus on estrogen-dependent (MCF-7) and nondependent
(SK-BR-3) breast cell lines. Cells were treated with different concentrations of
biotransformed (BSE) and nonbiotransformed soybean extract (SE), or daidzein (D)
and genistein (G) patterns isolated and in combination (D + G). Afterwards, we
analyzed cell viability by MTT assay, phosphatidylserine exposure and cell
permeability by flow cytometry; expression of apoptotic proteins by Western
blotting. BSE promoted reduction in cell viability and increase in DNA
degradation in both cell lines. In addition, we verified increase in cell
permeability and in the expression of phosphatidylserine, as well as modulation
in the expression of apoptotic proteins in MCF-7 cells. The cells did not show
any signs of cell death when incubated with the controls (D, G, and D + G).
Unknown components found in the BSE induce cell death by apoptosis and necrosis,
mainly in MCF-7 cells. These processes depend on the activation of caspase-3 and
involve an increase in the expression of proapoptotic molecules.
DOI: 10.1080/01635581.2015.1015744
425. Mol Nutr Food Res. 2015 Aug;59(8):1419-30. doi: 10.1002/mnfr.201500028. Epub
2015 Jun 26.
Isoflavones in soy flour diet have different effects on whole-genome expression

patterns than purified isoflavone mix in human MCF-7 breast tumors in
ovariectomized athymic nude mice.
Liu Y(1), Hilakivi-Clarke L(2), Zhang Y(1), Wang X(3), Pan YX(1), Xuan J(3),
Fleck SC(4), Doerge DR(4), Helferich WG(1).
Author information:
(1)Department of Food Science and Human Nutrition, University of Illinois,
Urbana-Champaign, IL, USA.
(2)Department of Oncology, Georgetown University Medical Center, Washington, DC,
USA.
(3)Bradley Department of Electrical and Computer Engineering, Virginia
Polytechnic Institute and State University, Arlington, VA, USA.
(4)Division of Biochemical Toxicology, National Center for Toxicological
Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
SCOPE: Soy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor
growth in athymic nude mice, indicating that other bioactive compounds in soy
can negate the estrogenic properties of isoflavones. The underlying signal
transduction pathways to explain the protective effects of soy flour consumption
were studied here.
METHODS AND RESULTS: Ovariectomized athymic nude mice inoculated with MCF-7
human breast cancer cells were fed either Soy flour diet (MS) or purified
isoflavone mix diet (MI), both with equivalent amounts of genistein. Positive
controls received estradiol pellets and negative controls received sham pellets.
GeneChip Human Genome U133 Plus 2.0 Array platform was used to evaluate gene
expressions, and results were analyzed using bioinformatics approaches. Tumors
in MS-fed mice exhibited higher expression of tumor growth suppressing genes
ATP2A3 and BLNK and lower expression of oncogene MYC. Tumors in MI-fed mice
expressed a higher level of oncogene MYB and a lower level of MHC-I and MHC-II,
allowing tumor cells to escape immunosurveillance. MS-induced gene expression
alterations were predictive of prolonged survival among
estrogen-receptor-positive breast cancer patients, whilst MI-induced gene
changes were predictive of shortened survival.
CONCLUSION: Our findings suggest that dietary soy flour affects gene expression
differently than purified isoflavones, which may explain why soy foods prevent
isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice.
DOI: 10.1002/mnfr.201500028
PMCID: PMC5763549
Conflict of interest statement: Conflict of interest The authors have declared

no conflict of interest.
426. Enzyme Microb Technol. 2015 Apr;71:20-7. doi: 10.1016/j.enzmictec.2015.01.004.
Epub 2015 Jan 25.
Regioselectivity-driven evolution of CYP102D1 for improved synthesis of

3'-ortho-dihydroxyisoflavone.
Choi KY(1), Yang YH(2), Kim BG(3).
Author information:
(1)Department of Environmental Engineering, College of Engineering, Ajou
University, Suwon, Gyeonggi-do, South Korea. Electronic address:
kychoi@ajou.ac.kr.
(2)Department of Microbial Engineering, College of Engineering, Konkuk
University, South Korea.
(3)School of Chemical and Biological Engineering, Seoul National University,
Seoul, South Korea.
Daidzein is a major component of isoflavones, and its hydroxylated forms are

valuable phytochemicals with anti-cancer and anti-oxidant activity. Due to the
limitations of chemical synthesis of these hydroxylated structures, alternative
enzymatic synthesis has been attempted. Previously, several protein-engineering
approaches using CYP102D1 were investigated; these produced mutants with
daidzein hydroxylation activity and regioselectivity through rational design
(F96V/M246I) and saturation mutagenesis (A273H/G274E/T277G). However, the
generated mutants have low regioselectivity (F96V/M246I) or low hydroxylation
activity (A273H/G274E/T277G). Here, we characterized mutants capable of
catalyzing C3'-specific daidzein hydroxylation with enhanced hydroxylation
activity and regioselectivity. In order to obtain regioselectivity toward the
daidzein C3'-position, site-saturation mutagenesis on the substrate-binding
region of CYP102D1 F96V/M246I was investigated. A high-throughput screening
assay was then performed, based on O-dealkylation activity against the daidzein
analog substrate 4'-O-methyl-daidzein. This resulted in a mutant with more than
23-fold improved hydroxylation activity (55.6±17.9μM(-1)min(-1), or 48.4mg/L
titer) and regioselectivity over the 3'/6-position that was increased by
three-fold (from 0.9 to 2.6) compared with the F96V/M246I template enzyme.
Furthermore, we carried out docking simulation studies that could partially
explain the effects of these mutations on C3'-specific hydroxylation activity.
DOI: 10.1016/j.enzmictec.2015.01.004
427. Clin Exp Metastasis. 2015 Apr;32(4):323-33. doi: 10.1007/s10585-015-9709-2.

Epub
2015 Mar 8.
Dietary soy isoflavones increase metastasis to lungs in an experimental model of

breast cancer with bone micro-tumors.
Yang X(1), Belosay A, Hartman JA, Song H, Zhang Y, Wang W, Doerge DR, Helferich
WG.
Author information:
(1)Department of Food Science and Human Nutrition, University of Illinois at
Urbana-Champaign, 580 Bevier Hall, 905 S. Goodwin Ave, Urbana, IL, 61801, USA.
Bone is one of the most common sites for metastasis in breast cancer (BC).
Micro-metastasis in bone marrow was detected in 30% of patients with stage I,
II, or III BC at primary surgery and is a strong indicator of poor prognosis.
The role dietary soy isoflavones play in BC with bone micro-metastasis is
unclear. In this study, we examined the effects of genistein, daidzein,
(-)-equol or a mixture of soy isoflavones on BC with bone micro-metastasis using
an experimental model of murine mammary cancer 4T1 cells engineered with
luciferase. A small number (1000) of 4T1 cells were injected into the tibia of
female Balb/c mice to establish micro-tumors in bone. Soy isoflavones were
supplemented in the AIN-93G diet at 750 mg/kg and were provided to mice from 3
weeks before to 3 weeks after cell injection. Bioluminescent imaging was
conducted on day 2 (D2), D6, D8, D16 and D20 post cell injection and the results
indicated dietary soy isoflavones enhanced the growth of bone micro-tumors on
D8. Furthermore, dietary soy isoflavones stimulated metastatic tumor formation
in lungs and increased Ki-67 protein expression in these metastasized tumors. In
vitro, soy isoflavones (<10 µM) had limited effects on the growth, motility or
invasion of 4T1 cells. Thus, the in vivo stimulatory effect could be likely due
to systemic effects between the host, 4T1 tumors and soy isoflavones. In
conclusion, soy isoflavones stimulate BC with bone micro-metastasis in mice and
further investigations are needed regarding their consumption by BC survivors.
DOI: 10.1007/s10585-015-9709-2
PMCID: PMC5763566
Conflict of interest statement: Conflict of Interest: The authors declare that

428. Anticancer Drugs. 2015 Jul;26(6):599-611. doi: 10.1097/CAD.0000000000000224.
Isoflavone lupiwighteone induces cytotoxic, apoptotic, and antiangiogenic

activities in DU-145 prostate cancer cells.
Ren J(1), Huang Q, Xu Y, Yang M, Yang J, Hu K.
Author information:
(1)Department of Pharmacy, School of Pharmaceutical Engineering & Life Science,
Changzhou University, Changzhou, Jiangsu, People's Republic of China.
Isoflavones constitute a large series of compounds found in many plants. They

make up an important part of the diet and have a broad spectrum of biological
activities such as cytotoxic and antitumor effects. Lupiwighteone (Lup) is an
isoflavone-type compound. It is distributed widely in wild-growing plants such
as Glycyrrhiza glabra, Lupinus, and Lotus pedunculatus. On the basis of existing
research, Lup shows antioxidant and antimicrobial effects, but its antitumor
activity has not been reported as yet. This study aimed to examine the antitumor
activity of Lup, explore its antitumor mechanism in a human prostate carcinoma
cell line (DU-145), and evaluate its antiangiogenetic activity in the human
umbilical vein endothelial cell line (HUVEC). The results showed that Lup could
inhibit the growth of DU-145 and HUVEC cells in a concentration-dependent and
time-dependent manner by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide assay. Flow cytometry analysis indicated that Lup could induce cell
cycle arrest, cells apoptosis, mitochondrial membrane potential loss, and an
increase in intracellular reactive oxygen species of DU-145 cells. Upregulation
of Bax, cytochrome c, caspase-3, and PARP-1 protein expressions and
downregulation of Bcl-2, procaspase-9, and p-Akt protein expressions were
observed by western blot after the treatment of Lup. Furthermore, the effects of
Lup on the cellular behavior of HUVECs were also investigated. Altogether, our
data proved the anticancer and antiangiogenesis potential of Lup.
DOI: 10.1097/CAD.0000000000000224
429. Menopausal Symptoms: Comparative Effectiveness of Therapies [Internet].
Grant MD(1), Marbella A(1), Wang AT(1), Pines E(1), Hoag J(1), Bonnell C(1),
Ziegler KM(1), Aronson N(1).
Rockville (MD): Agency for Healthcare Research and Quality (US); 2015 Mar.
Report No.: 15-EHC005-EF.
AHRQ Comparative Effectiveness Reviews.
Author information:
(1)Blue Cross and Blue Shield Association Technology Evaluation Center,
Evidence-based Practice Center
OBJECTIVES: To systematically review and synthesize evidence evaluating the

comparative effectiveness of treatments for menopausal symptoms, along with
potential long-term benefits and harms of those treatments.
DATA SOURCES: The following electronic databases were searched through January
2014: MEDLINE®, Embase®, Cochrane Controlled Trials Register, and AMED Allied
and Complementary Medicine. Gray literature searches included
clinicaltrials.gov, the Food and Drug Administration Web site, and relevant
conference abstracts.
REVIEW METHODS: Menopausal symptom outcomes included: vasomotor, quality of
life, psychological, sexual function, urogenital, and sleep disturbance.
Randomized controlled trials provided the evidence base for symptom relief.
Standardized mean differences were calculated to allow pooling of outcomes from
varied measures. Network meta-analyses were performed when possible, along with
pairwise comparisons. Systematic reviews, cohort studies, and case-control
studies provided evidence for the following long-term benefits and harms:
breast, colon, endometrial, and ovarian cancer; coronary heart disease and
venous thromboembolic events; gallbladder disease; and osteoporotic fractures.
RESULTS: Evidence from 283 trials provided results for vasomotor symptoms (211
trials), quality of life (125 trials), psychological symptoms (108 trials),
sexual function (94 trials), urogenital atrophy (71 trials), and sleep
disturbance (56 trials). The most commonly studied agents were estrogens,
isoflavones, and selective serotonin reuptake
inhibitors/serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs). Estrogens
appeared to be the most effective treatment in relieving vasomotor symptoms and
were accompanied by better quality-of-life scores. SSRIs/SNRIs relieve vasomotor
symptoms less effectively than estrogens but were accompanied by the largest
improvement in global measures of psychological well-being. Estrogens
administered vaginally diminished pain during sex and testosterone increased
sexual activity. Measures of urogenital atrophy were improved with ospemifene
and vaginal or oral estrogens. Estrogens also improved sleep, but the effect
appeared to be modest. Over the long term, estrogen combined with progestogen
has both beneficial effects (fewer osteoporotic fractures) and harmful effects
(increased risk of breast cancer, gallbladder disease, venous thromboembolic
events, and stroke). Estrogens given alone do not appear to increase breast
cancer risk, although endometrial cancer risk is increased. There is limited
evidence on the long-term effects of most nonhormone treatments. No studies were
identified that examined the efficacy or safety of compounding practices for
hormone therapies.
CONCLUSIONS: Women experiencing symptoms of menopause can consider a number of
potential treatments of varying efficacy. From a large body of evidence, there
is considerable certainty that estrogens are the most effective treatment for
relieving vasomotor symptoms and are accompanied by the greatest improvement in
quality-of-life measures. For other common symptoms—psychological, urogenital,
and sleep disturbance—although estrogens are effective, some nonhormonal agents
compare favorably. Estrogens are accompanied by potential long-term harms that
require consideration. There is limited evidence on the potential consequences
of long-term use of nonhormonal agents when those agents are used to treat
menopausal symptoms.
PMID: 25905155
430. Mol Nutr Food Res. 2015 Jul;59(7):1274-91. doi: 10.1002/mnfr.201400866. Epub
2015 Mar 31.
Dietary phenolics against colorectal cancer--From promising preclinical results

to poor translation into clinical trials: Pitfalls and future needs.
Núñez-Sánchez MA(1), González-Sarrías A(1), Romo-Vaquero M(1), García-Villalba

R(1), Selma MV(1), Tomás-Barberán FA(1), García-Conesa MT(1), Espín JC(1).
Author information:
(1)Research Group on Quality, Safety and Bioactivity of Plant Foods, Department
of Food Science and Technology, CEBAS-CSIC, Murcia, Spain.
Colorectal cancer (CRC) remains a major cause of cancer death worldwide. Over
70% of CRC cases are sporadic and related to lifestyle. Epidemiological studies
inversely correlate CRC incidence with the intake of fruits and vegetables but
not with their phenolic content. Preclinical studies using in vitro (cell lines)
and animal models of CRC have reported anticancer effects for dietary phenolics
through the regulation of different markers and signaling pathways. Herein, we
review and contrast the evidence between preclinical studies and clinical trials
(patients with CRC or at risk, familial adenopolyposis or aberrant crypt foci)
investigating the protective effects of curcumin, resveratrol, isoflavones,
green tea extracts (epigallocatechin gallate), black raspberry powder
(anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger
extracts (gingerol derivatives), and pomegranate extracts (ellagitannins and
ellagic acid). To date, curcumin is the most promising polyphenol as possible
future adjuvant in CRC management. Overall, the clinical evidence of dietary
phenolics against CRC is still weak and the amounts needed to exert some effects
largely exceed common dietary doses. We discuss here the possible reasons behind
the gap between preclinical and clinical research (inconsistence of results,
lack of clinical endpoints, etc.), and provide an outlook and a roadmap to
approach this topic.
DOI: 10.1002/mnfr.201400866
431. Cancer Causes Control. 2015 Apr;26(4):571-80. doi: 10.1007/s10552-015-0534-3.

Epub 2015 Feb 17.
Soy isoflavone intake and bone mineral density in breast cancer survivors.
Baglia ML(1), Gu K, Zhang X, Zheng Y, Peng P, Cai H, Bao PP, Zheng W, Lu W, Shu
XO.
Author information:
(1)Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer
Center, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA.
PURPOSE: Low bone mineral density (BMD) is common among breast cancer survivors
due to acute estrogen deprivation. Soy food is a rich source of phytoestrogens,
namely isoflavones, known to have both estrogenic and anti-estrogenic effects.
The objective of the study was to assess the association between soy consumption
and BMD in breast cancer survivors, which has not previously been evaluated.
METHODS: Forearm BMD was evaluated using dual-energy X-ray absorptiometry at 60
months post-diagnosis for 1,587 participants of the Shanghai Breast Cancer
Survival Study. Soy intakes collected at 6, 18, and 36 months post-diagnosis
were averaged, and the association with BMD, osteopenia, and osteoporosis was
evaluated using linear and logistic regression.
RESULTS: The mean (standard deviation) intake of isoflavones was 48.1 (28.0)
mg/day. Soy intake was inversely associated with BMD and positively associated
with osteoporosis. Compared with the lowest quartile, the highest quartile of
soy isoflavone intake, ≥ 62.64 mg/day, was associated with a reduction of BMD by
1.95% [95% confidence interval (CI) -3.54, -0.36%] and an increased odds ratio
of 1.69 for osteoporosis (95% CI 1.09, 2.61). The inverse association was
predominantly seen among women who recently entered menopause (≤ 5 years).
CONCLUSION: In contrast to observations from general populations, high soy
intake (≥ 62.64 mg of soy isoflavone/day) was associated with lower proximal
forearm BMD among breast cancer survivors, particularly during the early years
of menopause. Our finding needs to be replicated, particularly in studies with
more comprehensive bone density evaluation.
DOI: 10.1007/s10552-015-0534-3
PMCID: PMC4368486
Conflict of interest statement: CONFLICT OF INTEREST The authors declare that

432. Br J Cancer. 2015 Mar 31;112(7):1291-300. doi: 10.1038/bjc.2015.25.
Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and
survival in the United States of America (USA).
Petrick JL(1), Steck SE(2), Bradshaw PT(3), Trivers KF(4), Abrahamson PE(5),
Engel LS(1), He K(6), Chow WH(7), Mayne ST(8), Risch HA(8), Vaughan TL(9),
Gammon MD(1).
Author information:
(1)Department of Epidemiology, CB 7435, University of North Carolina, Chapel
Hill, NC 27599-7435, USA.
(2)Department of Epidemiology and Biostatistics, University of South Carolina,
Columbia, SC, USA.
(3)Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
(4)Division of Cancer Prevention and Control, Centers for Disease Control,
Atlanta, GA, USA.
(5)Salmon Bay Consulting, Inc., Seattle, WA, USA.
(6)Department of Epidemiology and Biostatistics, Indiana University,
Bloomington, IN, USA.
(7)Department of Epidemiology, University of Texas MD Anderson Cancer Center,
Houston, TX, USA.
(8)Department of Chronic Disease Epidemiology, Yale School of Public Health and
Yale Cancer Center, New Haven, CT, USA.
(9)Division of Public Health Sciences, Fred Hutchinson Cancer Research Center,
Seattle, WA, USA.
BACKGROUND: Flavonoids, polyphenolic compounds concentrated in fruits and

vegetables, have experimentally demonstrated chemopreventive effects against
oesophageal and gastric cancer. Few epidemiologic studies have examined
flavonoid intake and incidence of these cancers, and none have considered
survival.
METHODS: In this USA multicentre population-based study, case participants
(diagnosed during 1993-1995 with oesophageal adenocarcinoma (OEA, n=274),
gastric cardia adenocarcinoma (GCA, n=248), oesophageal squamous cell carcinoma
(OES, n=191), and other gastric adenocarcinoma (OGA, n=341)) and
frequency-matched controls (n=662) were interviewed. Food frequency
questionnaire responses were linked with USDA Flavonoid Databases and available
literature for six flavonoid classes and lignans. Case participants were
followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs)
and hazard ratios (HRs) (95% confidence intervals (CIs)) were estimated,
comparing highest with lowest intake quartiles, using polytomous logistic and
proportional hazards regressions, respectively.
RESULTS: Little or no consistent association was found for total flavonoid
intake (main population sources: black tea, orange/grapefruit juice, and wine)
and incidence or survival for any tumour type. Intake of anthocyanidins, common
in wine and fruit juice, was associated with a 57% reduction in the risk of
incident OEA (OR=0.43, 95% CI=0.29-0.66) and OES (OR=0.43, 95% CI=0.26-0.70).
The ORs for isoflavones, for which coffee was the main source, were increased
for all tumours, except OES. Anthocyanidins were associated with decreased risk
of mortality for GCA (HR=0.63, 95% CI=0.42-0.95) and modestly for OEA (HR=0.87,
95% CI=0.60-1.26), but CIs were wide.
CONCLUSIONS: Our findings, if confirmed, suggest that increased dietary
anthocyanidin intake may reduce incidence and improve survival for these
cancers.
DOI: 10.1038/bjc.2015.25
PMCID: PMC4385952
433. Toxicol In Vitro. 2015 Jun;29(4):706-15. doi: 10.1016/j.tiv.2015.01.013. Epub

2015 Feb 7.
Deconjugation of soy isoflavone glucuronides needed for estrogenic activity.
Islam MA(1), Bekele R(2), Vanden Berg JH(2), Kuswanti Y(2), Thapa O(2), Soltani
S(2), van Leeuwen FX(2), Rietjens IM(2), Murk AJ(2).
Author information:
(1)Division of Toxicology, Wageningen University, 6703 HE Wageningen, The
Netherlands. Electronic address: arif.sau.agch@gmail.com.
(2)Division of Toxicology, Wageningen University, 6703 HE Wageningen, The
Netherlands.
Soy isoflavones (SIF) are present in the systemic circulation as conjugated

forms of which the estrogenic potency is not yet clear. The present study
provides evidence that the major SIF glucuronide metabolites in blood,
genistein-7-O-glucuronide (GG) and daidzein-7-O-glucuronide (DG), only become
estrogenic after deconjugation. The estrogenic potencies of genistein (Ge),
daidzein (Da), GG and DG were determined using stably transfected U2OS-ERα,
U2OS-ERβ reporter gene cells and proliferation was tested in T47D-ERβ cells
mimicking the ERα/ERβ ratio of healthy breast cells and inT47D breast cancer
cells. In all assays applied, the estrogenic potency of the aglycones was
significantly higher than that of their corresponding glucuronides. UPLC
analysis revealed that in U2OS and T47D cells, 0.2-1.6% of the glucuronides were
deconjugated to their corresponding aglycones. The resulting aglycone
concentrations can account for the estrogenicity observed upon glucuronide
exposure. Interestingly, under similar experimental conditions, rat breast
tissue S9 fraction was about 30 times more potent in deconjugating these
glucuronides than human breast tissue S9 fraction. Our study confirms that SIF
glucuronides are not estrogenic as such, and that the small % of deconjugation
in the cell is enough to explain the slight bioactivity observed for the
SIF-glucuronides. Species differences in deconjugation capacity should be taken
into account when basing risk-benefit assessment of these SIF for the human
population on animal data.
DOI: 10.1016/j.tiv.2015.01.013
434. Cell Physiol Biochem. 2015;35(2):722-8. doi: 10.1159/000369732. Epub 2015 Jan
30.
Calycosin and genistein induce apoptosis by inactivation of HOTAIR/p-Akt

signaling pathway in human breast cancer MCF-7 cells.
Chen J(1), Lin C, Yong W, Ye Y, Huang Z.
Author information:
(1)School of Basic Medical Sciences, Guilin Medical University, Guilin, China.
BACKGROUND: Calycosin and genistein are the two main components of isoflavones.
Previously, we reported that these compounds display antitumor activities in the
breast cancer cell lines MCF-7 and T47D. In the present study, we investigated
the mechanism of action of calycosin and genistein, and their respective
efficacies as potential therapies for the treatment of breast carcinoma in the
clinic.
METHODS: MCF-7 cells were treated with calycosin or genistein. Cell
proliferation and apoptosis were measured using CCK8 assay and Hoechst 33258.
The expression level of phosphorylated Akt protein was determined by western
blotting. Expression level of HOTAIR was quantified by real-time PCR.
RESULTS: Both calycosin and genistein inhibited proliferation and induced
apoptosis in MCF-7 breast cancer cells, especially after treatment with
calycosin. Treatment of MCF-7 cells with calycosin or genistein resulted in
decreased phosphorylation of Akt, and decreased expression of its downstream
target, HOTAIR.
CONCLUSION: Calycosin is more effective in inhibiting breast cancer growth in
comparison with genistein, through its regulation of Akt signaling pathways and
HOTAIR expression.
© 2015 S. Karger AG, Basel.
DOI: 10.1159/000369732
435. Cell Physiol Biochem. 2015;35(2):639-46. doi: 10.1159/000369725. Epub 2015 Jan
28.
Biochanin A promotes proliferation that involves a feedback loop of microRNA-375

and estrogen receptor alpha in breast cancer cells.
Chen J(1), Ge B, Wang Y, Ye Y, Zeng S, Huang Z.
Author information:
(1)School of Basic Medical Sciences, Guilin Medical University, Guilin, China.
BACKGROUND: Biochanin A and formononetin are O-methylated isoflavones that are

isolated from the root of Astragalus membranaceus, and have antitumorigenic
effects. Our previous studies found that formononetin triggered
growth-inhibitory and apoptotic activities in MCF-7 breast cancer cells. We
performed in vivo and in vitro studies to further investigate the potential
effect of biochanin A in promoting cell proliferation in estrogen receptor
(ER)-positive cells, and to elucidate underlying mechanisms.
METHODS: ERα-positive breast cancer cells (T47D, MCF-7) were treated with
biochanin A. The MTT assay and flow cytometry were used to assess cell
proliferation and apoptosis. mRNA levels of ERα, Bcl-2, and miR-375 were
quantified using real-time polymerase chain reaction. Compared with the control,
low biochanin A concentrations (2-6 μM) stimulated ERα-positive cell
proliferation (T47D, MCF-7). The more sensitive T47D cells were used to study
the relevant signaling pathway.
RESULTS: After treatment with biochanin A, ERα, miR-375, and Bcl-2 expression
was significantly upregulated. Additionally, in the in vivo studies, uterine
weight in ovariectomized mice treated with biochanin A increased significantly.
CONCLUSION: This study demonstrated that biochanin A promoted ERα-positive cell
proliferation through miR-375 activation and this mechanism is possibly
involving in a miR-375 and ERα feedback loop.
© 2015 S. Karger AG, Basel.
DOI: 10.1159/000369725
436. J Biol Chem. 2015 Mar 6;290(10):6047-57. doi: 10.1074/jbc.M114.617415. Epub

2015
Jan 15.
Equol, an isoflavone metabolite, regulates cancer cell viability and protein

synthesis initiation via c-Myc and eIF4G.
de la Parra C(1), Borrero-Garcia LD(2), Cruz-Collazo A(2), Schneider RJ(3),

Dharmawardhane S(4).
Author information:
(1)From the Department of Biochemistry, School of Medicine, University of Puerto
Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 and Department of
Microbiology and Radiation Oncology, NYU Cancer Institute, New York University
School of Medicine, New York, New York 10016.
Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 and.
(3)Department of Microbiology and Radiation Oncology, NYU Cancer Institute, New
York University School of Medicine, New York, New York 10016.
Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 and su.d@upr.edu.
Epidemiological studies implicate dietary soy isoflavones as breast cancer

preventives, especially due to their anti-estrogenic properties. However, soy
isoflavones may also have a role in promoting breast cancer, which has yet to be
clarified. We previously reported that equol, a metabolite of the soy isoflavone
daidzein, may advance breast cancer potential via up-regulation of the
eukaryotic initiation factor 4GI (eIF4GI). In estrogen receptor negative (ER-)
metastatic breast cancer cells, equol induced elevated levels of eIF4G, which
were associated with increased cell viability and the selective translation of
mRNAs that use non-canonical means of initiation, including internal ribosome
entry site (IRES), ribosome shunting, and eIF4G enhancers. These mRNAs typically
code for oncogenic, survival, and cell stress molecules. Among those mRNAs
translationally increased by equol was the oncogene and eIF4G enhancer, c-Myc.
Here we report that siRNA-mediated knockdown of c-Myc abrogates the increase in
cancer cell viability and mammosphere formation by equol, and results in a
significant down-regulation of eIF4GI (the major eIF4G isoform), as well as
reduces levels of some, but not all, proteins encoded by mRNAs that are
translationally stimulated by equol treatment. Knockdown of eIF4GI also markedly
reduces an equol-mediated increase in IRES-dependent mRNA translation and the
expression of specific oncogenic proteins. However, eIF4GI knockdown did not
reciprocally affect c-Myc levels or cell viability. This study therefore
implicates c-Myc as a potential regulator of the cancer-promoting effects of
equol via up-regulation of eIF4GI and selective initiation of translation on
mRNAs that utilize non-canonical initiation, including certain oncogenes.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M114.617415
PMCID: PMC4358247
437. J Cancer. 2015 Jan 1;6(1):9-18. doi: 10.7150/jca.10560. eCollection 2015.
Use of proteins as biomarkers and their role in carcinogenesis.
Zarogoulidis P(1), Tsakiridis K(2), Karapantzou C(3), Lampaki S(1), Kioumis

I(1), Pitsiou G(1), Papaiwannou A(1), Hohenforst-Schmidt W(4), Huang H(5),
Kesisis G(6), Karapantzos I(3), Chlapoutakis S(7), Korantzis I(6), Mpakas A(2),
Karavasilis V(7), Mpoukovinas I(8), Li Q(5), Zarogoulidis K(1).
Author information:
(1)1. Pulmonary-Oncology, ``G. Papanikolaou`` General Hospital, Aristotle
University of Thessaloniki, Thessaloniki, Greece;
(2)2. Thoracic Surgery Department, ``Saint Luke`` Private Hospital,
Thessaloniki, Greece;
(3)3. ORL-Oncology Unit, ``Saint Luke`` Private Hospital, Thessaloniki, Greece.
(4)4. II Medical Department, ``Coburg`` Regional Clinic, University of
Wuerzburg, Coburg, Germany.
(5)5. Department of Respiratory Diseases, Changhai Hospital/First Affiliated
Hospital of the Second Military Medical University, Shanghai, People's Republic
of China, China.
(6)6. Oncology Department, ``Saint Luke`` Private Hospital, Thessaloniki,
Greece;
(7)7. Cardiothoracic Surgery Department, University hospital of Ioannina,
Greece;
(8)9. Oncology Department, ``BioMedicine`` Private Clinic, Thessaloniki, Greece.
SUMMARY: Improved diagnostic methods and medical therapies are necessary for
early detection and treatment and an improved prognosis. It is thus vital to
both examine and evaluate the role of the various existing proteins as
biomarkers in carcinogenesis and to assess the contribution of these proteins in
anti-cancer activity, for consideration in therapeutic strategies. It is
essential to both examine and evaluate the role of the various existing proteins
as biomarkers in carcinogenesis and to assess the contribution of these proteins
in anti-cancer activity, for consideration in therapeutic strategies. The
purpose of this review is twofold. Firstly, it is to evaluate recent data about
which proteins can be utilized as biomarkers in carcinogenesis. The proteins
reviewed include: CPTP, IL-6, CCN, and S100. Secondly, it is to evaluate the
contribution of dietary proteins in cancer activity. Specifically, how whey
protein, soy proteins and lectin, a phytochemical could be useful in cancer
prevention and treatment.
RECENT FINDINGS: Whey protein, present in dairy products, is an excellent source
of the sulphur amino acid cysteine, the rate limiting substrate in glutathione
synthesis. Notably, this protein survives digestion and has been shown to have
anti-carcinogenic properties in animal studies. Lectins are phytochemicals
present in plant foods, and have active components which alters cancer
initiation, promotion and progression. Lectins have been characterized as a
useful tool in biochemistry, cell biology, immunology and in diagnostic and
therapeutic purposes in cancer research. Soy proteins contain various compounds,
including isoflavones, protease inhibitors and protein kinase inhibitors, which
have been proven effective in tumor growth inhibition. They have therefore, been
greatly emphasized in cancer prevention and treatment. It has been proved that
soy food consumption was associated with decreased risk of death and recurrence
of breast cancer. CPTP is a recently discovered protein whose main role is to
transport C1P, a pro-inflammatory molecule. The discovery of CPTP may shine a
light on the mechanism of inflammatory diseases, and hopefully offer a potential
target for therapeutic purposes in cancer research. Interleukin-6 is a
multifunctional cytokine that affects the activity of cancer cells. It is
involved in tumor growth, and elevated levels is associated with an increased
risk of cancer. S100B is a well-established biomarker for malignant melanoma,
and useful in assessing tumor load, stage and prognosis for patients with this
disease. Other members of this family of proteins include S100A4, which has been
associated with several malignancies and S100A2, which has been found to be
decreased in some cancers. CCN are a group of regulatory proteins, located in
the extracellular matrix (maricellular). They are involved in cellular adhesion,
mitogenesis, chemotaxis, cell survival, and wound healing. CCN proteins are also
able to modulate the signals of several proteins, which may also influence
skeletal development and angiogenesis. Many of the functions of these proteins
are thus also related to tumor growth. Furthermore, CCN interacts with estrogen
in the development of cancer, and is implicated in some breast and ovarian
cancers.
DOI: 10.7150/jca.10560
PMCID: PMC4278910
PMID: 25553084
Conflict of interest statement: Conflict of Interest: The author(s) confirm that

this article content has no conflicts of interest.
438. Cancer Epidemiol Biomarkers Prev. 2015 Mar;24(3):532-7. doi:

10.1158/1055-9965.EPI-14-1118. Epub 2014 Dec 26.
Plasma isoflavones and risk of primary liver cancer in Japanese women and men
with hepatitis virus infection: a nested case-control study.
Michikawa T(1), Inoue M(2), Sawada N(3), Tanaka Y(4), Yamaji T(3), Iwasaki M(3),
Shimazu T(3), Sasazuki S(3), Mizokami M(5), Tsugane S(3); , for the Japan Public
Health Center-based Prospective Study Group.
Author information:
(1)Environmental Epidemiology Section, Center for Environmental Health Sciences,
National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
Epidemiology and Prevention Group, Research Center for Cancer Prevention and
Screening, National Cancer Center, Tokyo, Japan.
(2)Epidemiology and Prevention Group, Research Center for Cancer Prevention and
Screening, National Cancer Center, Tokyo, Japan. Graduate School of Medicine,
The University of Tokyo, Tokyo, Japan. mnminoue@m.u-tokyo.ac.jp.
(3)Epidemiology and Prevention Group, Research Center for Cancer Prevention and
Screening, National Cancer Center, Tokyo, Japan.
(4)Department of Virology and Liver Unit, Nagoya City University Graduate School
of Medical Sciences, Mizuho-ku, Nagoya, Japan.
(5)The Research Center for Hepatitis and Immunology, National Center for Global
Health and Medicine, Ichikawa, Chiba, Japan.
BACKGROUND: Evidence suggests that estrogen plays a preventive role in primary

liver cancer development, and it might be thought that isoflavones, which are
structurally similar to estrogens and bind to estrogen receptors, are associated
with the risk of liver cancer. We investigated this suspected association by
measuring plasma concentrations of isoflavones in a nested case-control study of
a population-based prospective cohort in Japan.
METHODS: From 18,628 target participants ages 40 to 69 years who returned the
baseline questionnaire and provided blood samples, we selected those with either
hepatitis B or hepatitis C virus infection at baseline (n = 1,544). Among these,
90 (28 women and 62 men) were newly diagnosed with primary liver cancer from
1993 through 2006; they were matched with 175 controls (54 women and 121 men).
Plasma concentrations of isoflavones (genistein, daidzein, glycitein, and equol)
were measured using triple quadrupole tandem liquid chromatography-mass
spectrometry. The ORs of liver cancer development based on plasma concentrations
were estimated with a conditional logistic regression model.
RESULTS: Basically, distributions of plasma isoflavone concentrations did not
differ between the cases and controls. No statistically significant associations
of genistein, daidzein, glycitein, and equol with primary liver cancer risk were
found in either women or men.
CONCLUSIONS: In middle-aged Japanese women and men with hepatitis virus
infection, plasma isoflavones were unassociated with the occurrence of primary
liver cancer.
IMPACT: The role of isoflavones in liver carcinogenesis merits further study
using both biomarkers and data on dietary intake of isoflavones. Cancer
Epidemiol Biomarkers Prev; 24(3); 532-7. ©2014 AACR.
DOI: 10.1158/1055-9965.EPI-14-1118
439. Chin J Integr Med. 2018 Jul;24(7):551-560. doi: 10.1007/s11655-014-1960-x.

Epub
2014 Dec 10.
A Review on Pharmacological and Analytical Aspects of Naringenin.
Patel K(1), Singh GK(2), Patel DK(3).
Author information:
(1)G.L.A Institute of Pharmaceutical Research, Mathura, India.
(2)Department of Pharmaceutics, Institute of Technology, Banaras Hindu
University, Varanasi, 221005, India.
(3)Department of Pharmaceutics, Institute of Technology, Banaras Hindu
University, Varanasi, 221005, India. dkpatel.rs.phe@itbhu.ac.in.
Flavonoids are a widely distributed group of phytochemicals having benzo-pyrone

nucleus, and more than 4,000 different flavonoids have been described and
categorized into flavonols, flavones, flavanones, isoflavones, catechins and
anthocyanidins. Flavonoids occurs naturally in fruits, vegetables, nuts, and
beverages such as coffee, tea, and red wine, as well as in medical herbs.
Flavonoids are responsible for the different colors of plant parts and are
important constituents of the human diet. Flavanoids have different
pharmacological activities, such as antioxidant, anti-allergic, antibacterial,
anti-inflammatory, antimutagenic and anticancer activity. Naringenin belongs to
the flavanones and is mainly found in fruits (grapefruit and oranges) and
vegetables. Pharmacologically, it has anticancer, antimutagenic,
anti-inflammatory, antioxidant, antiproliferative and antiatherogenic
activities. Naringenin is used for the treatments of osteoporosis, cancer and
cardiovascular diseases, and showed lipid-lowering and insulin-like properties.
In the present review, detailed pharmacological and analytical aspects of
naringenin have been presented, which revealed the impressive pharmacological
profile and the possible usefulness in the treatment of different types of
diseases in the future. The information provided in this communication will act
as an important source for development of effective medicines for the treatment
of various disorders.
DOI: 10.1007/s11655-014-1960-x
440. Eur J Clin Nutr. 2015 Jan;69(1):134-42. doi: 10.1038/ejcn.2014.207. Epub 2014
Nov 5.
Red clover isoflavones enriched with formononetin lower serum LDL cholesterol-a
randomized, double-blind, placebo-controlled study.
Clifton-Bligh PB(1), Nery ML(2), Clifton-Bligh RJ(1), Visvalingam S(3), Fulcher

GR(1), Byth K(4), Baber R(5).
Author information:
(1)1] Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW,
Australia [2] Northern Clinical School, University of Sydney, St Leonards, NSW,
Australia.
(2)Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW,
Australia.
(3)Menopause Clinic, Royal North Shore Hospital, St Leonards, NSW, Australia.
(4)NHMRC Clinical Trials Centre, University of Sydney, St Leonards, NSW,
Australia.
(5)1] Northern Clinical School, University of Sydney, St Leonards, NSW,
Australia [2] Menopause Clinic, Royal North Shore Hospital, St Leonards, NSW,
Australia.
BACKGROUND: Although postmenopausal combined hormone replacement therapy reduces

the risk of hip fracture, long-term use may be associated with an increased risk
of breast cancer, and in women more than 10 years after menopause it is
associated with an increased risk of cardiovascular disease. Isoflavones,
because of preferential binding to estrogen receptor beta, may retain the
beneficial effects on bone but lessen the adverse effects on the breast.
OBJECTIVE: The objective of this study was to study the effects of an isoflavone
obtained from red clover (Rimostil) on bone mineral density, and on low-density
lipoprotein (LDL) cholesterol.
DESIGN: In a double-blind, randomized, placebo-controlled trial, 50 mg of
Rimostil was given to women who were menopausal for at least 1 year. Bone
mineral density of the spine, femoral neck and forearm and serum LDL cholesterol
were measured at baseline and at 6-month intervals. The duration of follow-up
was 2 years.
RESULTS: There was no beneficial effect of Rimostil on bone density at any site.
There was a 12% fall in serum LDL cholesterol in the Rimostil-treated arm, which
was significantly greater than the 2% drop seen in the control arm (P=0.005).
DOI: 10.1038/ejcn.2014.207
441. Crit Rev Food Sci Nutr. 2016 Jul 3;56(9):1501-18. doi:
10.1080/10408398.2013.772091.
Pharmacological Intervention through Dietary Nutraceuticals in Gastrointestinal

Neoplasia.
Ullah MF(1), Bhat SH(1), Husain E(1), Abu-Duhier F(1), Hadi SM(2), Sarkar FH(3),
Ahmad A(3).
Author information:
(1)a Prince Fahad Research Chair , Department of Medical Laboratory Technology,
Faculty of Applied Medical Sciences, University of Tabuk , Tabuk , Saudi Arabia.
(2)b Department of Biochemistry , Faculty of Life Sciences, Aligarh Muslim
University , Uttar Pradesh , India.
(3)c Department of Pathology , Karmanos Cancer Institute, Wayne State University
School of Medicine , Detroit , Michigan USA.
Neoplastic conditions associated with gastrointestinal (GI) tract are common

worldwide with colorectal cancer alone accounting for the third leading rate of
cancer incidence. Other GI malignancies such as esophageal carcinoma have shown
an increasing trend in the last few years. The poor survival statistics of these
fatal cancer diseases highlight the need for multiple alternative treatment
options along with effective prophylactic strategies. Worldwide geographical
variation in cancer incidence indicates a correlation between dietary habits and
cancer risk. Epidemiological studies have suggested that populations with high
intake of certain dietary agents in their regular meals have lower cancer rates.
Thus, an impressive embodiment of evidence supports the concept that dietary
factors are key modulators of cancer including those of GI origin. Preclinical
studies on animal models of carcinogenesis have reflected the pharmacological
significance of certain dietary agents called as nutraceuticals in the
chemoprevention of GI neoplasia. These include stilbenes (from red grapes and
red wine), isoflavones (from soy), carotenoids (from tomatoes), curcuminoids
(from spice turmeric), catechins (from green tea), and various other small plant
metabolites (from fruits, vegetables, and cereals). Pleiotropic action
mechanisms have been reported for these diet-derived chemopreventive agents to
retard, block, or reverse carcinogenesis. This review presents a prophylactic
approach to primary prevention of GI cancers by highlighting the translational
potential of plant-derived nutraceuticals from epidemiological, laboratory, and
clinical studies, for the better management of these cancers through consumption
of nutraceutical rich diets and their intervention in cancer therapeutics.
DOI: 10.1080/10408398.2013.772091
442. J Membr Biol. 2015 Feb;248(1):1-6. doi: 10.1007/s00232-014-9745-x. Epub 2014

Nov
2.
Membrane steroid receptor-mediated action of soy isoflavones: tip of the

iceberg.
Ajdžanović V(1), Medigović I, Živanović J, Mojić M, Milošević V.
Author information:
(1)Department of Cytology, Institute for Biological Research "Siniša Stanković",
University of Belgrade, Despot Stefan Blvd. 142, 11060, Belgrade, Serbia,
avlada@ibiss.bg.ac.rs.
Soy isoflavone's (genistein and daidzein in particular) biological significance

has been thoroughly studied for decades, so we started from the premise that
refreshed investigation approach in this field should consider identification of
their new molecular targets. In addition to recently described epigenetic
aspects of polyphenole action, the cell membrane constituents-mediated effects
of soy isoflavones are worthy of special attention. Accordingly, the expanding
concept of membrane steroid receptors and rapid signaling from the cell surface
may include the prominent role of these steroid-like compounds. It was observed
that daidzein strongly interacts with membrane estrogen receptors in adrenal
medullary cells. At low doses, daidzein was found to stimulate catecholamine
synthesis through extracellular signal-regulated kinase 1/2 or protein kinase A
pathways, but at high doses, it inhibited catecholamine synthesis and secretion
induced by acetylcholine. Keeping in mind that catecholamine excess can
contribute to the cardiovascular pathologies and that catecholamine lack may
lead to depression, daidzein application promises to have a wide range of
therapeutic effects. On the other hand, it was shown in vitro that genistein
inhibits LNCaP prostate cancer cells invasiveness by decreasing the membrane
fluidity along with immobilization of the androgen receptor containing membrane
lipid rafts, with down regulation of the androgen receptors and Akt signaling.
These data are promising in development of the molecular pharmacotherapy
pertinent to balanced soy isoflavone treatment of cardiovascular, psychiatric,
and steroid-related malignant diseases.
DOI: 10.1007/s00232-014-9745-x
443. Phytother Res. 2015 Feb;29(2):210-9. doi: 10.1002/ptr.5241. Epub 2014 Oct 7.
Isoflavones extracted from chickpea Cicer arietinum L. sprouts induce

mitochondria-dependent apoptosis in human breast cancer cells.
Chen H(1), Ma HR, Gao YH, Zhang X, Habasi M, Hu R, Aisa HA.
Author information:
(1)State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource
Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Urumqi, 830011, China; A Key Laboratory of Plant Resources
and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and
Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of
Chinese Academy of Sciences, Beijing, 100049, China.
Isoflavones are important chemical components of the seeds and sprouts of

chickpeas. We systematically investigated the effects of isoflavones extracted
from chickpea sprouts (ICS) on the human breast cancer cell lines SKBr3 and
Michigan Cancer Foundation-7 (MCF-7).
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that
ICS (10-60 µg/mL) significantly inhibited the proliferation of both cell lines
in a time-dependent and dose-dependent fashion. Wright-Giemsa staining as well
as annexin V-fluorescein isothiocyanate and propidium iodide (Annexin V/PI)
staining showed that ICS significantly increased cytoclasis and apoptotic body
formation. Quantitative Annexin V/PI assays further showed that the number of
apoptotic cells increased in a dose-dependent manner following ICS treatment.
Semiquantitative reverse transcription PCR showed that ICS increased the
expression of the apoptosis-promoting gene Bcl-2-associated X protein and
decreased the expression of the antiapoptotic gene Bcl-2. Western blot analysis
showed that treatment of SKBr3 and MCF-7 cells with ICS increased the expression
of caspase 7, caspase 9, P53, and P21 in a dose-dependent manner. Flow cytometry
assays using the fluorescent probe 3,3'-dihexyloxacarbocyanine iodide showed a
dose-dependent decrease in mitochondrial membrane potential following ICS
treatment. Treatment using ICS also induced a dose-dependent increase in
reactive oxygen species production. This is the first study to demonstrate that
ICS may be a chemopreventive or therapeutic agent against breast cancer.
Copyright © 2014 John Wiley & Sons, Ltd.
DOI: 10.1002/ptr.5241
444. Climacteric. 2015 Jun;18(3):389-98. doi: 10.3109/13697137.2014.964671. Epub

2014
Nov 27.
Soybean isoflavones attenuate the expression of genes related to endometrial

cancer risk.
Carbonel AA(1), Calió ML, Santos MA, Bertoncini CR, Sasso Gda S, Simões RS,
Simões MJ, Soares JM Jr.
Author information:
(1)Department of Morphology and Genetics, University Federal of São Paulo.
OBJECTIVE: We evaluated whether genistein or estrogen treatment has the same

effect when administered immediately or late to rats induced with menopause
using ovariectomy.
METHODS: Sixty adult female rats were divided into six treatment groups: GI =
vehicle immediately after ovariectomy; GII = vehicle 30 days after ovariectomy;
GIII = genistein immediately after ovariectomy; GIV = genistein 30 days after
ovariectomy; GV = estrogen immediately after ovariectomy; and GVI = estrogen 30
days after ovariectomy. All animals were treated for 30 consecutive days. At the
end of the treatment, part of the uteri was removed for subsequent histological
studies and another part was used to evaluate estrogen receptors 1 and 2, cell
proliferation (cyclin A1 and A2, cyclin D1, cyclin-dependent kinase inhibitors
1, 1B and 2, antigen identified by the monoclonal antibody Ki67) and
angiogenesis (vascular endothelial growth factor, VEGF-A) gene expression.
RESULTS: Late treatment after castration in rats resulted in more developed
endometrium, enhanced cell proliferation and estrogen-signalling pathways,
particularly the cyclin-related genes Ki67 and VEGF-A, compared to early
treatment. Interestingly, these same effects were less intense with genistein
compared to those induced by estrogen, especially when genistein was
administered late.
CONCLUSION: Our data show that isoflavone renders a lower risk of cancer when
compared to estrogen in treatments.
DOI: 10.3109/13697137.2014.964671
445. Gastric Cancer. 2015 Jul;18(3):495-503. doi: 10.1007/s10120-014-0396-5. Epub

2014 Jul 31.
Gene polymorphisms in the ornithine decarboxylase-polyamine pathway modify

gastric cancer risk by interaction with isoflavone concentrations.
Cho LY(1), Yang JJ, Ko KP, Ma SH, Shin A, Choi BY, Kim HJ, Han DS, Song KS, Kim
YS, Chang SH, Shin HR, Kang D, Yoo KY, Park SK.
Author information:
Medicine, 103 Daehakno, Jongno-Gu, Seoul, 110-799, Republic of Korea,
lisaycho@snu.ac.kr.
BACKGROUND: The study aimed to examine the association between genes encoding
molecules in the ornithine decarboxylase (ODC)-polyamine pathway (ODC1, AMD1,
NQO1, NOS2A, and OAZ2) and gastric cancer risk and whether the
gene-phytoestrogen interaction modifies gastric cancer risk.
METHODS: Among 76 gastric cancer cases and their 1:4 matched controls within the
Korean Multi-center Cancer Cohort, a total of 30 SNPs in five genes involved in
the ODC pathway were primarily analyzed. The second-stage genotyping in 388
matched case-control sets was conducted to reevaluate the significant SNPs
interacting with phytoestrogens during the primary analysis. The summary odds
ratios (ORs) [95 % confidence intervals (CIs)] for gastric cancer were
estimated. Interaction effects between the SNPs and plasma concentrations of
phytoestrogens (genistein, daidzein, equol, and enterolactone) were evaluated.
RESULTS: In the pooled analysis, NQO1 rs1800566 showed significant genetic
effects on gastric cancer without heterogeneity [OR 0.83 (95 % CI 0.70-0.995)]
and a greater decreased risk at high genistein/daidzein levels [OR 0.36 (95 %
CI 0.15-0.90) and OR 0.26 (95 % CI 0.10-0.64), respectively; p
interaction < 0.05]. Risk alleles of AMD1 rs1279599, AMD1 rs7768897, and OAZ2
rs7403751 had a significant gene-phytoestrogen (genistein and daidzein)
interaction effect to modify the development of gastric cancer. They had an
increased gastric cancer risk at low isoflavone levels, but a decreased risk at
high isoflavone levels (p interaction < 0.01).
CONCLUSIONS: Our findings suggest that common variants in the genes involved in
the ODC pathway may contribute to the risk of gastric cancer possibly by
modulating ODC polyamine biosynthesis or by interaction between isoflavones and
NQO1, OAZ2, and AMD1.
DOI: 10.1007/s10120-014-0396-5
446. Public Health Nutr. 2015 Jan;18(1):130-4. doi: 10.1017/S1368980013003443. Epub

2014 Mar 27.
Soya and isoflavone intakes associated with reduced risk of oesophageal cancer
in north-west China.
Tang L(1), Lee AH(1), Xu F(2), Zhang T(3), Lei J(4), Binns CW(1).
Author information:
(1)1School of Public Health,Curtin University,GPO Box U 1987,Perth,WA
6845,Australia.
(2)2National Drug and Alcohol Research Centre,University of New South
Wales,Sydney,New South Wales,Australia.
(3)3School of Medicine,Shihezi University,North 4 Road,Shihezi,Xinjiang,People's
Republic of China.
(4)4Xinjiang Tumour Hospital,Xinshi,Urumqi,Xinjiang,People's Republic of China.
OBJECTIVE: To ascertain the association between soya consumption, isoflavone

intakes and oesophageal cancer risk in remote north-west China, where the
incidence of oesophageal cancer is known to be high.
DESIGN: Case-control study. Information on habitual consumption of soya foods
and soya milk was obtained by personal interview. The intakes of isoflavones
were then estimated using the US Department of Agriculture nutrient database.
Logistic regression analyses were performed to assess the association between
soya consumption, isoflavone intakes and oesophageal cancer risk.
SETTING: Urumqi and Shihezi, Xinjiang Uyghur Autonomous Region, China.
SUBJECTS: Participants were 359 incident oesophageal cancer patients and 380
hospital-based controls.
RESULTS: The oesophageal cancer patients consumed significantly less (P < 0·001)
total soya foods (mean 57·2 (sd 119·0) g/d) and soya milk (mean 18·8 (sd 51·7)
ml/d) than the controls (mean 93·3 (sd 121·5) g/d and mean 35·7 (sd 73·0) ml/d).
Logistic regression analyses showed an inverse association between intake of
soya products and the risk of oesophageal cancer. The adjusted odds were OR =
0·33 (95 % CI 0·22, 0·49) and OR = 0·48 (95 % CI 0·31, 0·74) for consuming at
least 97 g of soya foods and 60 ml of soya milk daily (the highest tertiles of
consumption), respectively, relative to the lowest tertiles of consumption.
Similarly, inverse associations with apparent dose-response relationships were
found between isoflavone intakes and oesophageal cancer risk.
CONCLUSIONS: Habitual consumption of soya products appears to be associated with
reduced risk of oesophageal cancer in north-west China.
DOI: 10.1017/S1368980013003443
PMCID: PMC10271313
447. J Oncol Pharm Pract. 2015 Apr;21(2):128-31. doi: 10.1177/1078155214528552.

Epub
2014 Mar 17.
Soy food frequency questionnaire does not correlate with baseline isoflavone
levels in patients with bladder cancer.
Kolesar JM(1), Pomplun M(2), Havighurst T(3), Stublaski J(2), Wollmer B(2), Kim
K(3), Tangrea JA(4), Parnes HL(4), House MG(4), Gee J(5), Messing E(6), Bailey
HH(7).
Author information:
(1)School of Pharmacy, University of Wisconsin, Madison, WI, USA Carbone
Comprehensive Cancer Center, University of Wisconsin, Madison, WI, USA
jmkolesar@pharmacy.wisc.edu.
(2)Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI,
USA.
USA Department of Biostatistics and Medical Informatics, University of
Wisconsin, Madison, WI, USA.
(4)Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
(5)Institute of Urology, Lahey Clinic Medical Center, Burlington, MA, USA.
(6)University of Rochester Medical Center, Rochester, NY, USA.
USA School of Medicine and Public Health, University of Wisconsin, Madison, WI,
USA.
BACKGROUND: The isoflavone genistein, a natural soy product with receptor

tyrosine kinase-inhibiting activity, as well as phytoestrogenic and other
potential anticarcinogenic effects, is being studied as an anticancer agent.
Since isoflavones are commonly consumed in food products containing soy
proteins, a method to control for baseline isoflavone consumption is needed.
METHODS: HPLC was used to evaluate baseline plasma and urine concentrations of
isoflavone in fifty-four participants with bladder cancer enrolled on a phase II
chemoprevention study of G-2535. The soy food frequency questionnaire was used
to assess participant's baseline soy intake. The association between baseline
isoflavone concentrations and intakes for genistein and daidzein was assessed by
the Spearman's rank correlation coefficient.
RESULTS: The majority of participants had no detectable genistein or daidzein in
plasma at baseline. The median and range of values were 0 (0-1480) nmol/L for
genistein, and 0 (0-1260) nmol/L for daidzein. In urine, the median and range of
values were 91.0 (0-9030) nmol/L for genistein and 623 (0-100,000) nmol/L for
daidzein. The median and range of weekly estimated genistein intake was 0
(0-236) mg/wk; the median and range of weekly estimated daidzein intake was 0
(0-114) mg/wk. There was no relationship to soy intake as measured by the food
frequency questionnaire and baseline isoflavone levels in plasma or urine and
the Spearman's rank correlation coefficients were not significant.
CONCLUSION: The soy food frequency questionnaire did not correlate with plasma
or urine concentrations of either isoflavone.
IMPACT: Alternative methods for controlling for soy consumption, including
measuring plasma and urine concentrations, in isoflavone chemoprevention trials
should be considered.
© The Author(s) 2014 Reprints and permissions:

sagepub.co.uk/journalsPermissions.nav.
DOI: 10.1177/1078155214528552
PMCID: PMC4261043
448. Breast Cancer. 2015 Sep;22(5):452-61. doi: 10.1007/s12282-013-0502-2. Epub

2013
Oct 29.
Relationship of serum isoflavone, insulin and adiponectin levels with breast

cancer risk.
Minatoya M(1), Kutomi G, Asakura S, Otokozawa S, Sugiyama Y, Ohnishi H, Akasaka

H, Miura T, Mori M, Hirata K.
Author information:
Minami 1 Nishi 17, Chuo-ku, Sapporo, 060-8556, Japan, m.minatoya@sapmed.ac.jp.
BACKGROUND: Obesity is one of the well-known risk factors of breast cancer.

Accumulating evidence suggests that adiponectin, an obesity-related hormone, is
inversely associated with breast cancer risk, particularly in postmenopausal
women. Obesity is also associated with high levels of insulin. In addition,
studies have suggested that the soy isoflavones present in the traditional
Japanese diet have been associated with decreased risk of breast cancer.
However, there is no study that has assessed associations between serum levels
of isoflavones, insulin, adiponectin and the risk of breast cancer all together
with menopausal status.
METHODS: In a case-control study of 63 histologically confirmed breast cancer
patients and 76 controls, serum isoflavone, insulin, and high-molecular-weight
(HMW) adiponectin levels and breast cancer risk were examined for their
association with breast cancer risk after adjustment for various risk factors.
RESULTS: Women in the highest tertile of serum HMW adiponectin levels were
associated with a statistically significant decreased risk for breast cancer
compared with women in the lowest tertile [odds ratio (OR), 0.09; 95 %
confidence interval (CI) 0.03-0.33]. This association was observed in
postmenopausal women (OR 0.06; 95 % CI 0.01-0.28), but not in premenopausal
women. The observed associations were independent of possible effects of
insulin, body mass index, and known risk factors for breast cancer. Serum
isoflavones and insulin levels were not associated with breast cancer risk.
CONCLUSIONS: This study suggests that high serum HMW adiponectin levels are
significantly associated with a decreased risk for breast cancer. Our result
support the hypothesis that serum adiponectin may act as a potential biomarker
for breast cancer.
DOI: 10.1007/s12282-013-0502-2

Abstract Cancertiab Set

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Abstract Cancertiab Set

Uploaded by

Copyright:

Available Formats

1. Phytother Res. 2024 Apr 11. doi: 10.1002/ptr.8196. Online ahead of print.

Phytoestrogens: Chemistry, potential health benefits, and their medicinal

Phytoestrogens, also known as xenoestrogens, are secondary metabolites derived

2. Heliyon. 2024 Mar 27;10(7):e28616. doi: 10.1016/j.heliyon.2024.e28616.

Anti-cancer mechanisms of natural isoflavones against melanoma.

The incidence of skin-related neoplasms has generally increased in recent years.

© 2024 The Authors.

3. Front Nutr. 2024 Mar 21;11:1338392. doi: 10.3389/fnut.2024.1338392. eCollection

Changes in the consumption of isoflavones, omega-6, and omega-3 fatty acids in

BACKGROUND: Diets rich in minimally processed plant-based foods are recommended

Copyright © 2024 Lee, Campbell, Culakova, Blanchard, Wixom, Peppone and

4. Molecules. 2024 Mar 20;29(6):1377. doi: 10.3390/molecules29061377.

Unveiling the Chemical Composition, Bioactive Profile and Antioxidant Capacity

Ali MR(1), Ibrahim HH(2), Salah-Eldin AA(2).

Phytochemicals from waste materials generated by agricultural and industrial

Conflict of interest statement: The authors declare no conflict of interest.

5. Fitoterapia. 2024 Mar 24;175:105920. doi: 10.1016/j.fitote.2024.105920. Online

Biological effects and phytochemical study of the underground part of Iris

Omarova BA(1), Shults EE(2), Zhakipbekov KS(3), Abekova АО(4), Ishmuratova

The expected toxicity and resistance of chemotherapeutic agents necessitate and

Copyright © 2024 Elsevier B.V. All rights reserved.

Conflict of interest statement: Declaration of competing interest The authors

6. Br J Pharmacol. 2024 Mar 25. doi: 10.1111/bph.16353. Online ahead of print.

Soy-derived isoflavones as chemo-preventive agents targeting multiple signalling

Kaufman-Szymczyk A(1), Jalmuzna J(1), Lubecka-Gajewska K(1).

The chemopreventive and chemotherapeutic properties of soy and soy-derived

© 2024 British Pharmacological Society.

7. Molecules. 2024 Feb 28;29(5):1044. doi: 10.3390/molecules29051044.

Chickpea Sprouts as a Potential Dietary Support in Different Prostate

Galanty A(1), Prochownik E(2), Grudzińska M(2)(3), Paśko P(2).

Conflict of interest statement: The authors declare no conflicts of interest.

8. Heliyon. 2024 Feb 20;10(5):e26562. doi: 10.1016/j.heliyon.2024.e26562.

Protective effects of hepatic diseases by bioactive phytochemicals in Fusarium

Shalapy NM(1)(2), Liu M(1), Kang W(1)(3).

© 2024 The Authors.

Conflict of interest statement: The authors declare the following financial

9. Mini Rev Med Chem. 2024 Feb 21. doi: 10.2174/0113895575283895240207065454.

Dietary Plant Metabolites Induced Epigenetic Modification as a Novel Strategy

Prostate cancer is a widespread malignancy among men, with a substantial global

Copyright© Bentham Science Publishers; For any queries, please email at

10. Carcinogenesis. 2024 Feb 20:bgae015. doi: 10.1093/carcin/bgae015. Online ahead

Estrogen plays crucial roles in ovarian tumorigenesis. Phytoestrogens (PEs) are

© The Author(s) 2024. Published by Oxford University Press.

11. Curr Med Chem. 2024 Feb 1. doi: 10.2174/0109298673278897231229121524. Online

The Use of Isoflavones as Lung Cancer Chemoprevention Agents and their

Athanasiou E(1), Papageorgiou S(2)(3), Dafni MF(4)(3), Kelesis I(5)(3),

Copyright© Bentham Science Publishers; For any queries, please email at

12. Phytochemistry. 2024 Apr;220:114005. doi: 10.1016/j.phytochem.2024.114005. Epub

Chemical and biological investigation of Indigofera ammoxylum (DC.) Polhill. red

Chemical investigation of ethyl acetate bark extracts of Indigofera ammoxylum

Conflict of interest statement: Declaration of competing interest The authors

13. Curr Drug Targets. 2024 Jan 12. doi: 10.2174/0113894501277556231221072938.

An Updated Insight into Phytomolecules and Novel Approaches used in the

Nooreen Z(1), Tandon S(2), Wal A(1), Rai AK(1).

Breast cancer is a widespread condition that kills more women from

Copyright© Bentham Science Publishers; For any queries, please email at

14. Iran J Basic Med Sci. 2024;27(1):57-65. doi: 10.22038/IJBMS.2023.70554.15353.

Moraea sisyrinchium inhibits proliferation, cell cycle, and migration of

OBJECTIVES: Experimental studies reported that some plants in the genus of

Conflict of interest statement: The authors report no conflicts of interest.

15. J Enzyme Inhib Med Chem. 2024 Dec;39(1):2288806. doi:

Anti-cancer activity and cellular uptake of 7,3',4'- and

Transarterial chemoembolisation (TACE) is used for unresectable hepatocellular