Moringin As TNF Alpha Inhibition

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Scopolamine alkaloid as novel green inhibitor of malleable Fe corrosion studied by EIS, DFT, PDP and
SEM techniques
0 Substances • 0 Reactions • 0 Citations
By: Ugi, B. U.; Boekom, J. E.; Ashishie, P. B.; Ubua, P. U.

Portugaliae Electrochimica Acta (2025), 43(1), 23-35 | Language: English, Database: CAplus
SAA as novel green inhibitor of M Fe corrosion studied by E IS, DFT, PDP and SEM was investigated. It was observed that the increase
in SAA various Ct triggered the rise in corrosion I E(%) up to 90.6, 97.6, 98.3 and 98.7%, as shown by E IS, PDP, WL and geometric
techniques, resp. This was due to high Rct during electr ochem. processes, which reduced Icorr, and to S AA mols. strong adsorption
onto the MFe surface. DFT results revealed short Δ E between S AA and M Fe bands, which gave rise to faster inhibitor mol. transfer,
stronger adsorption and increased inhibition . Thermodn. assessment showed that S AA caused an exothermic reaction, creating a
stable and spontaneous adsorption reaction. A phys. adsorption mechanism was proposed from Langmuir's isotherm results.
Substances (0) Reactions (0) Citing (0)
15-Lipoxygenase promotes resolution of inflammation in lymphedema by controlling Treg cell function

through IFN-beta
By: Zamora, A. ; Nougue, M.; Verdu, L.; Balzan, E.; Draia-Nicolau, T.; Benuzzi, E.; Pujol, F.; Baillif, V.; Lacazette, E.; Morfoisse, F. ;
et al
Nature Communications (2024), 15(1), 221 | Language: English, Database: CAplus and MEDLINE
Lymphedema (LD) is characterized by the accumulation of interstitial fluid, lipids and inflammatory cell infiltrate in the limb. Here,
we find that LD tissues from women who developed L D after breast cancer exhibit an inflamed gene expression profile. Lipidomic
anal. reveals decrease in specialized pro-resolving mediators (S PM) generated by the 15- lipoxygenase (15-LO) in LD. In mice, the loss
of SPM is associated with an increase in apoptotic regulatory T (Treg) cell number In addition, the selective depletion of 15- LO in the
lymphatic endothelium induces an aggravation of LD that can be rescued by Treg cell adoptive transfer or A LOX15-expressing lentiv
ector injections. Mechanistically, exogenous injections of the pro-resolving cytokine IFN-β restores both 15- LO expression and Treg
cell number in a mouse model of LD. These results provide evidence that lymphatic 15- LO may represent a therap eutic target for L D
by serving as a mediator of Treg cell populations to resolve inflammation.
Keywords: human lymphedema breast cancer inflammation 15 lipoxygenase Treg IFNbeta

Human-specific epigenomic states in spermatogenesis
By: Liao, Caiyun ; Walters, Benjamin William; DiStasio, Marcello ; Lesch, Bluma J.
Computational and Structural Biotechnology Journal (2024), 23, 577-588 | Language: English, Database: CAplus and MEDLINE
Infertility is becoming increasingly common, affecting one in six people globally. Half of these cases can be attributed to male
factors, many driven by abnormalities in the process of sperm develo pment. Emerging evidence from genome- wide association
studies, genetic screening of patient cohorts, and animal models highlights an important genetic contribution to spermatogenic
defects, but comprehensive identification and characterization of the genes critical for male fertility remain lacking. High divergence
of gene regulation in spermatogenic cells across species poses challenges for deline ating the genetic pathways required for human
spermatogenesis using common model organisms. In this study, we leveraged posttranslational histone modifi cation and gene
transcription data for 15,491 genes in four mammalian species (human, rhesus macaque, mouse, and opossum) , to identify human-
specific patterns of gene regulation during spermato genesis. We combined H3K27me3 ChIP-seq, H3K4me3 ChIP-seq, and R NA-seq
data to define epigenetic states for each gene at two stages of spermatogenesis, pachytene spermatocytes and round sperma tids,
in each species. We identified 239 genes that are uniquely active, poised, or dynamically regulated in human spermat ogenic cells
distinct from the other three species. While some of these genes have been implicated in reproductive functions, many more have
not yet been associated with human infertility and may be candidates for further mol. and epidemiol. studies. Our anal. offers an
example of the opportunities provided by evolutionary and epigenomic data for broadly screening candidate genes implicated in
reproduction, which might lead to discov eries of novel genetic targets for diagnosis and management of male infert ility and male
contraception.
Keywords: human infertility epigenomics data spermatogenesis; Evolution; Expres sion; Fertility; Genomics; Histone modific ation;
Spermatogenesis
M2 macrophages-derived exosomes regulate osteoclast differentiation by the CSF2/ TNF-α axis
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By: Zhou, Yue; Hu, Guangyao

BMC Oral Health (2024), 24(1), 107 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Osteoclast-mediated bone resorption cause bone loss in several bone diseases. Exosomes have been
reported to regulate osteoclast differentiation. M2-polarized macrophages exhibit anti-inflammatory activity. This study aimed to
explore the effect of exosomes from M2 polarized macrophages (M2-exos) on osteoclastogenesis and mol. mechanisms. Methods:
M2-exos were isolated from IL-4-induced Raw264.7 cells (M2 macrophages) and used to treat osteoc lasts (RANKL-induced
Raw264.7 cells). Osteoclast differentiation was visualized using tartrate resistant acid phosph atase staining. Quant. real-time PCR (q
PCR) was conducted to measure the levels of osteoclastogenesis-related genes. The underlying mechanisms of M2-exos were
evaluated using qPCR and western blotting. Results: M2- exos suppressed osteoclast differen tiation induced by R ANKL. Addnl., CSF2
was highly expressed in M2 macrophages, and knockdown of C SF2 further enhanced the effects of M2-exos on osteoclast differen
tiation. Moreover, CSF2 pos. regulated TN F-α signaling, which inhibition promoted differen tiation of M2-exo-treated osteoclasts.
Conclusion: M2-exos inhibited RANKL-induced osteoclast differentiation by downreg ulating the CSF2 expression through inacti
vating the TN F-α signaling, suggesting the potential applic ation of exosomes in bone disease therapy.
Keywords: CSF2; Exosomes; M2 macrop hages; Osteoclast differentiation; TN F-α

Evaluation of the association between TNF-α -1031 T/C polymorphism with oral lichen planus disease
By: Marabi, Mohammad Hesam; Mozaffari, Hamid Reza; Ghasemi, Haniyeh; Hatami, Masoud; Yari, Kheirollah
Abstract: Background: Oral lichen planus (O LP) is a T-cell-mediated autoimmune disease that affects the epithelial cells of the oral
cavity. This study was performed to investigate any possible relationship between - 1031 (T/C) polymorphism (rs1799964) of the
tumor necrosis factor α ( TN F-α) gene with the risk and severity of oral lichen planus (O LP) disease among an Iranian popula tion.
Method: Saliva samples were collected from 100 patients with OLP and a similar number of healthy controls (age and sex- matched)
. Then, DNA was extracted from the collected samples for genotyping TN F-α -1031 T/C polymorphism using the PCR-CTPP method.
The results were assessed using SPSS software. Results: The findings revealed a signifi cantly higher prevalence of the C allele in O LP
patients (53%) compared to healthy controls (36%), suggesting an association between TN F-alpha gene polymorphism and OLP. A
multivariate logistic regression anal. supported this finding, as the presence of the C allele was signifi cantly associated with an
increased risk of OLP [χ2 = 4.17, p = 0.04, 95% C I = 1.01-2.65, OR = 1.64]. However, our data indicated no signif icant association
between TN F-alpha -1031 T/C gene polymo rphism and OLP severity. Conclusions: These findings provide the first evidence
supporting a possible role of TN F-α -1031 T/C gene polymo rphism in OLP susceptibility in the Iranian popula tion. The findings of
this study demonstrate a pos. association between TN F-α -1031 C/T allele distri bution and the risk of O LP disease in the Iranian
population. Therefore, carrying the C allele may increase the suscept ibility to OLP disease.
Keywords: Genetic polymorphism; Oral lichen planus; PCR-CTPP; SNP; Tumor necrosis factor - α
Longitudinal assessment of sweat-based TNF-alpha in inflammatory bowel disease using a wearable

device
By: Hirten, Robert P.; Lin, Kai-Chun; Whang, Jessica; Shahub, Sarah; Helmus, Drew; Muthukumar, Sriram; Sands, Bruce E.; Prasad,
Shalini
Scientific Reports (2024), 14(1), 2833 | Language: English, Database: CAplus and MEDLINE
Abstract: Wearable devices can non-invasively monitor patients with chronic diseases. Sweat is an easily accessible biofluid for
continuous sampling of analytes, including inflammatory markers and cytokines. We evaluated a sweat sensing wearable device in
subjects with and without inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal tract. Partic
ipants with an IBD related hospital admission and a C- reactive protein level above 5 mg/L wore a sweat sensing wearable device for
up to 5 days. Tumor necrosis factor - alpha ( TN F-α) levels were continually assessed in the sweat via the sensor, and daily in the
blood. A second cohort of healthy subjects without chronic diseases wore the device for up to 48 h. Twenty-eight subjects were
enrolled. In the 16 subjects with IBD, a moderate linear relati onship between serum and sweat TN F-α levels was observed (R 2 =
0.72). Subjects with IBD were found to have a mean sweat TN F-α level of 2.11 pg/m L, compared to a mean value of 0.19 pg/m L in
12 healthy controls (p < 0.0001). Sweat TN F-α measurements differentiated subjects with active IBD from healthy subjects with an
AUC of 0.962 (95% C I 0.894-1.000). A sweat sensing wearable device can longitu dinally measure key sweat-based markers of IBD. T
N F-α levels in the sweat of subjects with I BD correlate with serum values, suggesting feasib ility in non-invasive disease monitoring.

PLOD3 facilitated T cell activation in the colorectal tumor microenvironment and liver metastasis by
the TNF-α/ NF-κB pathway
By: Ding, Min; Wang, Cheng; Hu, Junhong; She, Junjun; Shi, Ruoyu; Liu, Yixuan; Sun, Qi; Xu, Haojun; Zhou, Guoren; Wu, Wenlan; et al
Journal of Translational Medicine (2024), 22(1), 30 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Colorectal cancer (CRC) has been the third most prevalent cancer worldwide. Liver metastasis is the critical
factor for the poor prognosis of CRC. Here, we invest igated the expression and role of PLOD3 in CRC. Methods: Different liver
metastasis models were established by injecting PLOD3 stable knockdown or overexpression CT26 or MC38 mouse C RC cells into
the spleen of mice to verify the tumorigenicity and metastasis ability in vivo. Results: We identified P LOD3 is significantly overexp
ressed in liver metastasis samples of C RC. High expression of PLOD3 was significantly associated with poor survival of C RC patients.
The knockdown of PLOD3 exhibited remarkable inhibition of proliferation, migration, and invasion in C RC cells, while the opposite
results could be found in different PLOD3-overexpressed CRC cells. Stable knockdown of PLOD3 also significantly inhibited liver
metastasis of CRC cells in different xenografts models, while stable overexp ression of PLOD3 promotes liver metastasis and tumor
progression. Further studies showed that P LOD3 facilitated the T cell activation in the tumor microenv ironment and affected the TN
F-α/ NF-κB pathway. Conclusions: This study revealed the essential biol. functions of P LOD3 in colon cancer progre ssion and metast
asis, suggesting that PLOD3 is a promising transla tional medicine target and bioengi neering targeting PLOD3 overcomes CRC liver
metastasis. Graphical Abstract: [graphic not available: see fulltext]
Keywords: Colorectal cancer; Liver metastasis; NF-κB; PLOD3; Proliferation
Manganese nutrient mitigates ammonia, arsenic toxicity and high temperature stress using gene
regulation via NFkB mechanism in fish
By: Kumar, Neeraj; Thorat, Supriya Tukaram; Kochewad, Sanjivkumar Angadrao; Reddy, Kotha Sammi
The ongoing challenges of climate change and pollution are major factors disturbing ecosystems, including aquatic systems. They
also have an impact on gene regulation and biochem. changes in aquatic animals, including fish. Understanding the mechanisms of
gene regulation and biochem. changes due to climate change and pollution in aquatic animals is a challenging task. However, with
this backdrop, the present investigation was conducted to explore the effects of arsenic (As) and ammonia (N H3) toxicity and high-
temperature (T) stress on gene regulation and biochem. profiles, mitigated by dietary manganese (Mn) in Pangasi anodon hypopht
halmus. The fish were exposed to different combin ations of As, N H3, and T, and fed with dietary Mn at 4, 8, and 12 mg kg- 1 to
evaluate the gene expression of immunity, antioxidative status, cytokine, and Nf KB signaling pathway genes. H SP 70, cytochrome P
450 (CYP 450), metallothionein (MT), DNA damage-inducible protein (DDIP), caspase (CAS), tumor necrosis factor (TNFα), toll-like
receptor (TLR), interleukin (IL), inducible nitric oxide synthase (i NOS), catalase (CAT), superoxide dismutase (SOD), and glutathione
peroxidase (GPx) were noticeably highly upregu lated by As + N H3 + T stress, whereas Mn diet at 8 mg kg- 1 downregulated these
genes. Further, total Ig (Ig), myostatin (MYST), somatostatin (SMT), growth hormone (GH), growth hormone regulator 1 and β,
insulin-like growth factors (IGF1X1 and IGF1X2) were significantly upregulated by Mn diets. The biochem. profiles were highly
affected by stressors (As + NH3 + T). The bioaccumulation of arsenic in different tissues was also notably reduced by Mn diets.
Furthermore, the infectivity of the fish was reduced, and survival against pathogenic bacteria was enhanced by Mn diet at 8 mg kg-
1. The results of the present investi gation revealed that dietary Mn at 8 mg kg- 1 controls gene regulation against multiple stressors
(As, NH3, As + N H3, NH3 + T, As + N H3 + T) in fish.
Keywords: Pangasianodon manganese ammonia arsenic toxicity temper ature stress N FkB

Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death
By: Ma, Fengxia ; Ghimire, Laxman ; Ren, Qian ; Fan, Yuping; Chen, Tong ; Balasubramanian, Arumugam ; Hsu, Alan ;
Liu, Fei; Yu, Hongbo; Xie, Xuemei; et al
Both lytic and apoptotic cell death remove senescent and damaged cells in living organisms. However, they elicit contrasting pro-
and anti-inflammatory responses, resp. The precise cellular mechanism that governs the choice between these two modes of death
remains incompletely understood. Here we identify Gasdermin E (G SDME) as a master switch for neutrophil lytic pyroptotic death.
The tightly regulated GSDME cleavage and activation in aging neutro phils are mediated by protei nase-3 and caspase-3, leading to
pyroptosis. GSDME deficiency does not alter neutrophil overall survival rate; instead, it specif ically precludes pyroptosis and skews
neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferoc ytosis of apoptotic
neutrophils by macrophages. In a clin. relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME
reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, by contro lling the mode of
neutrophil death, GSDME dictates host inflam matory outcomes, providing a potential therap eutic target for infectious and inflam
matory diseases.
Keywords: lung injury inflammation gasderminE neutrophil cell death apoptosis
10
The p53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-
induced gastrointestinal syndrome
By: Wang, Jianming; Chang, Chun-Yuan ; Yang, Xue; Zhou, Fan; Liu, Juan; Bargonetti, Jill ; Zhang, Lanjing ; Xie, Ping ; Feng,
Zhaohui ; Hu, Wenwei
Radiation-induced gastrointestinal syndrome is a major compli cation and limiting factor for radioth erapy. Tumor suppressor p53
has a protective role in radiation-induced gastrointestinal toxicity. However, its underlying mechanism remains unclear. Here we
report that regulating the IL12-p40/MHC class II signaling pathway is a critical mechanism by which p53 protects against radiation-
induced gastrointestinal syndrome. p53 inhibits the expression of inflam matory cytokine IL12-p40, which in turn suppresses the
expression of MHC class II on intestinal epithelial cells to suppress T cell activation and inflam mation post-irradiation that causes
intestinal stem cell damage. Anti-IL12-p40 neutralizing antibody inhibits inflammation and rescues the defects in intestinal epithelial
regeneration post-irradiation in p53-deficient mice and prolongs mouse survival. These results uncover that the I L12-p40/MHC class
II signaling mediates the essential role of p53 in ensuring intestinal stem cell function and proper immune reaction in response to
radiation to protect mucosal epithelium, and suggest a potential therap eutic strategy to protect against radiation- induced gastroin
testinal syndrome.
Keywords: p53 MHC class II intestinal stem cell gastrointestinal syndrome

11
Microglial inhibition alleviates alpha -synuclein propagation and neurodegeneration in Parkinson′s

disease mouse model
By: Thi Lai, Thuy ; Kim, Young Eun; Nguyen, Linh Thi Nhat; Thi Nguyen, Tinh; Kwak, In Hee; Richter, Franziska ; Kim, Yun Joong;
Ma, Hyeo-il
npj Parkinson's Disease (2024), 10(1), 32 | Language: English, Database: CAplus and MEDLINE
Abstract: The accumulation of alpha -synuclein (αSyn) is widely recognized as the main pathol. process in Parkin son′s disease (PD).
Addnl., neuroinflammation is considered to be one of the contributing mechanisms in the development of PD. In light of this, it is
hypothesized that the reactive microglia exacerbate the propag ation of αSyn and neurodegeneration, while the inhibition of
microglial activity may mitigate these effects. To test this hypothesis, αSyn preformed fibrils (PFF)-injected PD mouse model was
employed. Co-injection of lipopolysaccharide (LPS) and PFF was performed to investigate if microglial reactivity intensified αSyn
propagation and neurodegeneration. Addnl., oral administration of PLX5622, a microglial inhibitor that targets the colony- stimul
ating factor 1 receptor, was given for two weeks before and after P FF injection each to explore if microglial inhibition could prevent
or reduce αSyn pathol. Intrast riatal co-injection of LPS and PFF resulted in increased microglial reactivity, αSyn accumulation, and
neurodegeneration compared to PFF injection alone. However, treatment with P LX5622 significantly suppressed microglial reacti
vity, reduced α Syn pathol., and alleviated dopaminergic neuron degeneration in the PD mouse model injected with P FF. Based on
these findings, it is evident that microglial reactivity plays a crucial role in the progression of αSyn pathol. and neurodegeneration in
PD. Furthermore, the results suggest that microglial inhibition may hold promise as a therap eutic strategy to delay the progre ssion
of αSyn pathol. in PD.
12
Oculomotor inhibition markers of working memory load
By: Kadosh, Oren; Inbal, Kfir; Snir, Hadar; Bonneh, Yoram S.

Abstract: Involuntary eye movements occur constantly even during fixation and were shown to convey inform ation about cognitive
processes. They are inhibited momentarily in response to external stimuli (oculomotor inhibition , OMI), with a time and magnitude
that depend on stimulus saliency, attention, and expectations. It was recently shown that the working memory load for numbers
modulates the microsaccade rate; however, the generality of the effect and its temporal properties remain unclear. Our goal was to
investigate the relationship between OMI and the working memory load for simple colored shapes. Partic ipants (N = 26)
maintained their fixation while their eyes were tracked; they viewed briefly flashed colored shapes accompanied by small arrows
indicating the shapes to be memorized (1/2/3). After a retention period, a probe shape appeared for matching. The micros accade
rate modulation and temporal properties were analyzed for the memory encoding, maintenance, and retrieval phases. Micros
accade inhibition was stronger when more shapes were memorized, and perfor mance improved when microsa ccades were
suppressed during maintenance and retrieval. This occurred even though the phys. stimuli were identical in number under all
conditions. Thus, oculomotor inhibition may play a role in silencing the visual input while processing current stimuli and is
generally related to processing time and load.

13
A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/β-catenin and
modulates the immune cells
By: Feng, Chunyan; Yu, Albert; Wang, Zhongfu; Wang, Kun; Chen, Jiawei; Wu, Yaojiong; Deng, Ting; Chen, Huaqing; Hou, Yibo; Ma,
Shaohua; et al
Journal of Experimental & Clinical Cancer Research (2024), 43(1), 9 | Language: English, Database: CAplus and MEDLINE
Podoplanin (PDPN) is a highly conserved, mucin- type protein specific to the lymphatic system. Overexp ression of PDPN is associated
with the progression of various solid tumors, and plays an important roles in the tumor microenv ironment by regulating the
immune system. However, the role of PDPN-mediated signal activation in the progre ssion of melanoma is still unknown. P DPN
expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experi ments
including proliferation, clone formation, migration, and metastasis were utilized to identify the suppre ssive effects of PDPN. The Ph.
D. TM-12 Phage Display Peptide Library was used to obtain a P DPN antagonist peptide, named C Y12-RP2. The immunofluorescence,
SPR assay, and flow cytometry were used to identify the binding specif icity of CY12-RP2 with PDPN in melanoma cells. Functional
and mechanistic assays in vivo and in vitro were performed for discrim inating the antitumor and immune activation effects of C Y12-
RP2. PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells prolife ration, migration, and metastasis
by blocking the EMT and Wnt/β-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppre
ssing melanoma various functions inducing apoptosis in both melanoma cells and 3 D spheroids. CY12-RP2 also enhanced the anti-
tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, C Y12-RP2
could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of C
D3 + CD4 + T cells, C D3 + CD8 + T cells, C D49b + Granzyme B + N K cells, and C D11b + CD86 + M1-like macrophages and the levels of
IL-1β, TN F-α , and IFN-γ. This study has demons trated the important role of P DPN in the progression of melanoma and formation
of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel C Y12-RP2 peptide. In
melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the
Wnt/β-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and
metastasis both in vitro and in vivo through Wnt/β-catenin pathway blockade, but also abrogate the immunosup pressive effects of
PDPN through modulating immune cells.
Keywords: sequence immune cell PDPN antagonist C Y12RP2 Wnt catenin signaling; CY12-RP2 peptide; EMT; Immune activation;
Melanoma; PDPN; Wnt/β-catenin pathway
14
Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion
neurons by cannabinol
By: Ghovanloo, Mohammad-Reza; Effraim, Philip R.; Tyagi, Sidharth; Zhao, Peng; Dib-Hajj, Sulayman D.; Waxman, Stephen G.
Communications Biology (2024), 7(1), 120 | Language: English, Database: CAplus and MEDLINE
Abstract: Cannabinol (CBN), an incompletely understood metabolite for Δ9- tetrahydrocannabinol, has been suggested as an
analgesic. CBN interacts with endocann abinoid (CB) receptors, but is also reported to interact with non- CB targets, including various
ion channels. We assessed CBN effects on voltage- dependent sodium (Nav) channels expressed heterol ogously and in native dorsal
root ganglion (DRG) neurons. Our results indicate that CBN is a functionally-selective, but structurally-non-selective Nav current
inhibitor. CBN′s main effect is on slow inactiv ation. CBN slows recovery from slow- inactivated states, and hyperpolarizes steady-
state inactivation, as channels enter deeper and slower inacti vated states. Multiel ectrode array recordings indicate that CBN
attenuates DRG neuron excitability. Voltage- and current-clamp anal. of freshly isolated DRG neurons via our automated patch-
clamp platform confirmed these findings. The inhibitory effects of C BN on Nav currents and on D RG neuron excitability add a new
dimension to its actions and suggest that this cannabinoid may be useful for neurop athic pain.

15
Diosmin ameliorates renal fibrosis through inhibition of inflammation by regulating SIRT3-mediated

NF-κB p65 nuclear translocation
1 Substance • 0 Reactions • 1 Citation
By: Zhao, Wen-Man; Li, Xun-Liang; Zhu, Yuyu; Shi, Rui; Wang, Zhi-Juan; Xiao, Jian-Ping; Wang, De-Guang
BMC Complementary Medicine and Therapies (2024), 24(1), 29 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Renal fibrosis is considered an irreve rsible pathol. process and the ultimate common pathway for the develo
pment of all types of chronic kidney diseases and renal failure. Diosmin is a natural flavonoid glycoside that has antiox idant, anti-
inflammatory, and antifibrotic activities. However, whether Diosmin protects kidneys by inhibiting renal fibrosis is unknown. We
aimed to investigate the role of Diosmin in renal inters titial fibrosis and to explore the underlying mechan isms. Methods: The UUO
mouse model was established and gavaged with Diosmin (50 mg/kg·d and 100 mg/kg·d) for 14 days. H E staining, Masson staining,
immunohistochem., western blotting and PCR were used to assess renal tissue injury and fibrosis. Elisa kits were used to detect the
expression levels of IL-1β, IL-6, and TN F-α and the activity of SIRT3 in renal tissues. In addition, enrichment maps of R NA
sequencing analyzed changes in signaling pathways. In vitro, human renal tubular epithelial cells (HK-2) were stimulated with TGF-
β1 and then treated with diosmin (75 μ M). The protein and m RNA expression levels of SIRT3 were detected in the cells. In addition,
3-TYP (selective inhibitor of SIRT3) and SIRT3 small interfering RNA (siRNA) were used to reduce S IRT3 levels in HK-2. Results:
Diosmin attenuated UUO-induced renal fibrosis and TGF-β1-induced HK-2 fibrosis. In addition, Diosmin reduced I L-1β, IL-6, and TN
F-α levels in kidney tissues and supern atants of HK-2 medium. Interestingly, Diosmin adminis tration increased the enzymic activity
of SIRT3 in UUO kidneys. In addition, Diosmin significantly increased mRNA and protein expression of S IRT3 in vitro and in vivo.
Inhibition of SIRT3 expression using 3- TYP or SIRT3 siRNA abolished the anti-inflammatory effects of diosmin in HK-2 cells.
Enrichment map anal. by RNA sequencing indicates that the nuclear factor- kappa B (NF-κB) signaling pathway was inhibited in the
Diosmin intervention group. Furthermore, we found that T GF-β1 increased the nuclear expression of nuclear N F-κB p65 but had
little significant effect on the total intrace llular expression of N F-κB p65. Addnl., Diosmin reduced T GF-β1-caused NF-κB p65 nuclear
translocation. Knockdown of S IRT3 expression by S IRT3 siRNA increased the nuclear expression of N F-κB p65 and abolished the
inhibition effect of Diosmin in N F-κB p65 expression. Conclusions: Diosmin reduces renal inflam mation and fibrosis, which is contri
buted by inhibiting nuclear translo cation of NF-κB P65 through activating SIRT3.
Keywords: Diosmin; Fibrosis; Inflammation; NF-κB p65; SIRT3; UUO
Substance (1) Reactions (0) Citing (1)

16
Cryo- EM structure of the mycobacterial 70S ribosome in complex with ribosome hibernation
promotion factor RafH
By: Kumar, Niraj ; Sharma, Shivani; Kaushal, Prem S.

Ribosome hibernation is a key survival strategy bacteria adopt under environ mental stress, where a protein, hibern ation promotion
factor (HPF), transitorily inactivates the ribosome. Mycobacterium tuberculosis encounters hypoxia (low oxygen) as a major stress in
the host macrophages, and upregulates the expression of RafH protein, which is crucial for its survival. The Raf H, a dual domain HP
F, an orthologue of bacterial long HPF (HPFlong), hibernates ribosome in 70S monosome form, whereas in other bacteria, the H PFlong
induces 70S ribosome dimerization and hibernates its ribosome in 100 S disome form. Here, we report the cryo- E M structure of M.
smegmatis, a close homolog of M. tuberculosis, 70S ribosome in complex with the Raf H factor at an overall 2.8 Å resolution The N-
terminus domain (NTD) of RafH binds to the decoding center, similarly to HPFlong NTD. In contrast, the C- terminus domain (C TD) of
RafH, which is larger than the HPFlong CTD, binds to a distinct site at the platform binding center of the ribosomal small subunit. The
two domain-connecting linker regions, which remain mostly disordered in earlier reported H PFlong structures, interact mainly with
the anti-Shine Dalgarno sequence of the 16 S rRNA.
Keywords: mycobacterial ribosome hibernation promotion factor RafH

17
All-trans retinoic acid alleviates transmissible gastroenteritis virus-induced intestinal inflammation and
barrier dysfunction in weaned piglets
By: Pu, Junning; Chen, Daiwen; Tian, Gang; He, Jun; Zheng, Ping; Huang, Zhiqing; Mao, Xiangbing; Yu, Jie; Luo, Yuheng; Luo, Junqiu; et
al
Journal of Animal Science and Biotechnology (2024), 15(1), 22 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Transmissible gastroenteritis virus (TGEV) is one of the main pathogens causing severe diarrhea of piglets.
The pathogenesis of TGEV is closely related to intestinal inflammation. All-trans retinoic acid (A TRA) is the main active metabolite of
vitamin A, which has immunomodulatory and anti-inflammatory properties. However, it is unclear whether A TRA can alleviate T GEV-
induced intestinal inflammation and barrier dysfunction in piglets. This study aimed to invest igate the effects of ATRA on growth
performance, diarrhea, intestinal inflammation and intestinal barrier integrity of T GEV-challenged piglets. Methods: In a 19- d study,
32 weaned piglets were randomly divided into 4 treatments: Control group (basal diet), TGEV group (basal diet + T GEV challenge), TG
EV + ATRA5 group (basal diet + 5 mg/d A TRA + TGEV challenge) and TGEV + ATRA15 group (basal diet + 15 mg/d A TRA + TGEV
challenge). On d 14, piglets were orally admini stered TGEV or the sterile medium. Results: Feeding piglets with 5 and 15 mg/d A TRA
alleviated the growth inhibition and diarrhea induced by T GEV (P < 0.05). Feeding piglets with 5 and 15 mg/d A TRA also inhibited
the increase of serum diamine oxidase (DAO) activity and the decrease of occludin and claudin- 1 protein levels in jejunal mucosa
induced by TGEV, and maintained intestinal barrier integrity (P < 0.05) . Meanwhile, 5 mg/d A TRA feeding increased the sucrase
activity and the expressions of nutrient transporter related genes (G LUT2 and S LC7A1) in jejunal mucosa of TGEV-challenged piglets
(P < 0.05). Furthermore, 5 mg/d ATRA feeding attenuated T GEV-induced intestinal inflammatory response by inhibiting the release
of interleukin (IL)-1β, IL-8 and tumor necrosis factor - α ( TN F-α) , and promoting the secretion of IL-10 and secretory Ig A (sIgA) (P <
0.05). Feeding 5 mg/d ATRA also down-regulated the expressions of Toll-like receptors and RIG-I like receptors signaling pathway
related genes (TLR3, TLR4, RIG-I, MyD88, TRIF and MAVS) and the phosphor ylation level of nuclear factor- κB-p65 (NF-κB p65), and
up-regulated the inhibitor kappa B alpha (IκBα) protein level in jejunal mucosa of T GEV-challenged piglets (P < 0.05) . Conclusions: A
TRA alleviated TGEV-induced intestinal barrier damage by inhibiting inflam matory response, thus improving the growth perfor
mance and inhibiting diarrhea of piglets. The mechanism was associated with the inhibition of NF-κB signaling pathway mediated
by TLR3, TLR4 and R IG-I. Graphical Abstract: [graphic not available: see fulltext]
Keywords: All-trans retinoic acid; Inflamm ation; Intestinal barrier; Piglets; Transmissible gastroenteritis virus

18
Comparison of the inhibition effects of naringenin and its glycosides on LPS-induced inflammation in
RAW 264.7 macrophages
1 Substance • 0 Reactions • 0 Citations
By: Cho, Shu-Chi; Shaw, Shyh-Yu

Molecular Biology Reports (2024), 51(1), 56 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Inflammation is intricately linked to the development of various diseases, such as diabetes, cardiov ascular
diseases, and cancer. Flavonoids, commonly found in plants, are known for their diverse health benefits, including antiox idant and
anti-inflammatory properties. These compounds are catego rized into different classes based on their chem. structure. struct ures.
However, limited research has compared the effects of flavonoid aglycons and flavonoid glycosides. This study aims to assess the
anti-inflammatory effects of naringenin and its glycosides (naringin and narirutin) in R AW264.7 macrophages. Methods and Results:
RAW264.7 cells were treated with naring enin, naringin, and narirutin, followed by stimul ation with lipopolysaccharide. The levels of
inflammatory mediators, including tumor necrosis factor α ( TN F-α) , interleukin-1β (IL-1β), nitric oxide (N O), inducible NO
synthase (iNOS), and cyclooxygenase-2 (COX-2), were assessed. Addnl., the study examined nuclear factor- κB (NF-κB) and mitogen-
activated protein kinase (M APK) activation using western blot anal. Among the compounds tested, narirutin exhibited the most
potent anti-inflammatory effect against TN F-α , NO, and iNOS. Naringin and narirutin showed comparable inhibitory effects on I L-
1β and COX-2. Both naringin and narirutin suppressed the expression of proinflammatory mediators by targeting different levels
of the NF-κB and MAPK pathways. Naringenin demonstrated the weakest anti-inflammatory effect, primarily inhibiting N F-κB and
reducing the phosphorylation levels of p38. Conclusions: This study suggests that the presence of glycosides on naringenin and the
varied binding forms of sugars in naringenin glycosides significantly influence the anti-inflammatory effects compared with
naringenin in RAW 264.7 macrophages.
Keywords: Anti-inflammation; Mitogen-activated protein kinases (MAPK); Naringenin; Naringin; Narirutin; Nuclear factor- κB (NF-κB)

19
Melissa officinalis extract palliates redox imbalance and inflammation associated with
hyperthyroidism-induced liver damage by regulating Nrf-2/ Keap-1 gene expression in γ-irradiated rats
By: Kawara, Ragaa SM; Moawed, Fatma SM ; Elsenosi, Yakout; Elmaksoud, Hussein Abd; Ahmed, Esraa S. A. ; Abo-Zaid, Omayma
AR
Abstract: Background: Melissa offici nalis (MO) is a well-known medicinal plant species used in the treatment of several diseases; it is
widely used as a vegetable, adding flavor to dishes. This study was designed to evaluate the therapeutic effect of M O Extract against
hyperthyroidism induced by Eltroxin and γ- radiation. Methods: Hyperthyroidism was induced by injecting rats with Eltroxin (100
μg/kg/ day) for 14 days and exposure to γ-radiation (IR) (5 Gy single dose) . The hyperthyroid rats were orally treated with M O
extract (75 mg/kg/day) at the beginning of the second week of the Eltroxin injection and continued for another week. The levels of
thyroid hormones, liver enzymes and proteins besides the impaired hepatic redox status and antioxidant parameters were
measured using com. kits. The hepatic gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its inhibitor Kelch-
like ECH-associated protein-1(Keap-1) in addition to hepatic inflammatory mediators including tumor necrosis factor - α ( TN F- α) ,
Monocyte chemoattractant protein-1 (MCP-1) and fibrogenic markers such as transforming growth factor-beta1 (TGF-β1) were
determined Results: MO Extract reversed the effect of Eltroxin + I R on rats and attenuated the thyroid hormones. Moreover, it
alleviated hyperthyroidism-induced hepatic damage by inhibiting the hepatic enzymes′ activities as well as enhancing the
production of proteins concomitant with improving cellular redox homeos tasis by attenu ating the deranged redox balance and
modulating the Nrf2/Keap-1 pathway. Addnl., MO Extract alleviated the inflammatory response by suppressing the TN F- α and MC
P-1 and prevented hepatic fibrosis via Nrf2- mediated inhibition of the TGF-β1/Smad pathway. Conclusion: Accordingly, these
results might strengthen the hepatoprotective effect of M O Extract in a rat model of hyperthy roidism by regulating the Nrf-2/ Keap-
1 pathway.
Keywords: Hyperthyroidism; Inflammation; Liver damage; Melissa offici nalis; Nrf2/Keap1

20
Unveiling the potent effect of vitamin D: harnessing Nrf2/HO-1 signaling pathways as molecular
targets to alleviate urban particulate matter-induced asthma inflammation
By: Ge, Dandan; Chen, Qihong; Xie, Xiaohua; Li, Qiyuan; Yang, Yungang
BMC Pulmonary Medicine (2024), 24(1), 55 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Asthma is the most common allergic disease charact erized by an inflammatory response in the airways.
Mechanismly, urban particulate matter (PM) is the most widely air pollutant associated with increased asthma morbidity and airway
inflammation. Current research found that vitamin D is an essential vitamin with anti- inflammatory, antioxidant and other medical
efficacy. Inadequate or deficient vitamin D often leads to the pathogenesis and stability of asthma. N GF exacerbates airway inflam
mation in asthma by promoting smooth muscle cell prolife ration and inducing the Th2 immune response. Activation of the Nrf2/H
O-1 signaling pathway can exert a protective effect on the inflam matory response in bronchial asthma. However, the specific
mechanism of this pathway in PM-involved asthmatic airway smooth muscle cells remains unclear. Methods: Mice were sensitized
and challenged with Ovalbumin (OVA) to establish an asthma model. They were then exposed to either P M, vitamin D or a combin
ation of both, and inflammatory responses were observed Including, acetylc holine stimulation at different concentrations
measured airway hyperresponsiveness in mice. Bronchoalveolar lavage fluid (B ALF) and serum were collected for TN F-α , IL-1β, IL-6,
and Nerve growth factor (NGF) anal. Addnl., lung tissues underwent histop athol. examination to observe alveolar structure and
inflammatory cell infiltr ation. Specific ELISA kits were utilized to determine the levels of the inflammatory factors TN F-α , IL-1β, IL-6,
and Nerve growth factor (NGF). Nrf2/HO-1 signaling pathways were examined by western blot anal. Meanwhile, we constr ucted a
cell system with low HO-1 expression by lentiviral transfection of airway smooth muscle cells. The changes of Nrf2, H O-1, and NGF
were observed after the treatment of OVA, PM, and Vit D were given. Results: The in vivo results showed that vitamin D signifi cantly
alleviated pathol. changes in lung tissue of PM-exposed mice models. Mechanismly, vitamin D decreased substantial inflammatory
cell infiltration in lung tissue, as well as the number of inflam matory cells in BALF. Furthermore, vitamin D reduced the heightened
inflammatory factors including of TN F-α , IL-1β, IL-6, and NGF caused by PM exposure, and triggered the activity of nucleus Nrf2
and HO-1 in PM-exposed asthmatic mice. Notably, knockdown H O-1 weakens the Vitamin D- mediated inhibition to pollution
toxicity in asthma. Importantly, in vitro experiments on OVA-stimulated mice airway smooth muscle cells, the results showed that O
VA and PM, resp., reduced Nrf2/HO-1 and increased N GF′s expression, while vitamin D reversed the process. And in the H O-1
knockdown cell line of Lenti-si-HO-1 ASMCs, OVA and PM reduced Nrf2′s expres sion, while HO-1 and NGF′s expression were
unchanged. Conclusions: The above results demastrate that vitamin D downreg ulated the inflammatory response and the
expression of NGF by regulating the Nrf2/HO-1 signaling pathways in airway smooth muscle cells, thereby showing potent anti-
inflammatory activity in asthma.
Keywords: Asthma; HO-1; Nerve growth factor; Partic ulate matters; Vitamin D

21
Porous Se@SiO 2 nanospheres alleviate diabetic retinopathy by inhibiting excess lipid peroxidation and
inflammation
By: Niu, Tian; Shi, Xin; Liu, Xijian; Wang, Haiyan; Liu, Kun; Xu, Yupeng
Molecular Medicine (London, United Kingdom) (2024), 30(1), 24 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Lipid peroxidation is a characteristic metabolic manifestation of diabetic retinopathy (DR) that causes
inflammation, eventually leading to severe retinal vascular abnorma lities. Selenium (Se) can directly or indirectly scavenge intrace
llular free radicals. Due to the narrow distin ction between Se′s effective and toxic doses, porous Se@Si O2 nanospheres have been
developed to control the release of Se. They exert strong antioxidant and anti-inflammatory effects. Methods: The effect of anti-lipid
peroxidation and anti-inflammatory effects of porous Se@SiO2 nanospheres on diabetic mice were assessed by detecting the level
of Malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), decreased reduced/oxidized glutathione (GSH/GSSG) ratio, tumor
necrosis factor ( TN F)- α , interferon (IFN)-γ, and interleukin (IL) -1β of the retina. To further examine the protective effect of porous
Se@SiO2 nanospheres on the retinal vasculopathy of diabetic mice, retinal acellular capillary, the expression of tight junction
proteins, and blood-retinal barrier destruction was observed Finally, we validated the G PX4 as the target of porous Se@SiO2 nanosp
heres via decreased expression of G PX4 and detected the level of M DA, GSH/GSSG, TN F-α , IFN-γ, IL -1β, wound healing assay, and
tube formation in high glucose (HG) cultured Human retinal microvascular endothelial cells (HRMECs). Results: The porous Se@SiO2
nanospheres reduced the level of M DA, TN F-α , IFN-γ, and IL -1β, while increasing the level of G PX4 and GSH/GSSG in diabetic mice.
Therefore, porous Se@SiO2 nanospheres reduced the number of retinal acellular capill aries, depletion of tight junction proteins,
and vascular leakage in diabetic mice. Further, we identified GPX4 as the target of porous Se@SiO2 nanospheres as GPX4 inhibition
reduced the repression effect of anti-lipid peroxidation, anti-inflammatory, and protective effects of endothelial cell dysfunction of
porous Se@SiO2 nanospheres in HG-cultured HRMECs. Conclusion: Porous Se@SiO2 nanospheres effectively attenuated retinal
vasculopathy in diabetic mice via inhibiting excess lipid peroxi dation and inflammation by target GPX4, suggesting their potential as
therapeutic agents for DR.
Keywords: Diabetic retinopathy; Inflammation; Lipid peroxidation; Porous Se@SiO2 nanospheres

22
Libertellenone C attenuates oxidative stress and neuroinflammation with the capacity of NLRP3
inhibition
By: Cao, Jie; Li, Lanqin; Zhang, Runge; Shu, Zhou; Zhang, Yaxin; Sun, Weiguang; Zhang, Yonghui; Hu, Zhengxi
Natural Products and Bioprospecting (2024), 14(1), 17 | Language: English, Database: CAplus and MEDLINE
Abstract: Neurodegenerative diseases (NDs) are common chronic diseases arising from progre ssive damage to the nervous system.
Here, inhouse natural product database screening revealed that libertellenone C (LC) obtained from the fermentation products of
Arthrinium arundinis separated from the gut of a centipede collected in our Tongji campus, showed a remarkable neuroprotective
effect. Further investigation was conducted to clarify the specific mechanism. LC dose-dependently reversed glutamate-induced
decreased viability, accumulated reactive oxygen species, mitocho ndrial membrane potential loss, and apoptosis in S H-SY5Y cells.
Network pharmacol. anal. predicted that the targets of LC were most likely directly related to oxidative stress and the regulation of
inflammatory factor-associated signaling pathways. Further study demons trated that LC attenuated nitrite, TN F-α , and IL-1β
production and decreased inducible nitric oxide synthase and cyclooxygenase expression in lipopolysaccharide-induced BV-2 cells.
LC could directly inhibit N LRP3 inflammasome activation by decreasing the expression levels of N LRP3, ASC, cleaved Caspase-1, and
NF-κB p65. Our results provide a new underst anding of how LC inhibits the N LRP3 inflammasome in microglia, providing neuropro
tection. These findings might guide the develo pment of effective LC-based therapeutic strategies for N Ds.
Keywords: Libertellenone C; NLRP3 inflammasome; Narural products; Neurodegenerative diseases
23
Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by

downregulation of ACE2 protein level
By: Wan, Lina; Li, Yuchen; Liao, Wenhao; Lei, Lizhen; Zhao, Maoyuan; Zeng, Jinhao; Zhao, Ziyi; Tang, Jianyuan
Abstract: The SARS-CoV-2 virus, belonging to the Coronavirus genus, which poses a threat to human health worldwide. Current
therapies focus on inhibiting viral replication or using anti-inflammatory/immunomodulatory compounds to enhance host
immunity. This makes the active ingredients of traditional Chinese medicine compounds ideal therapies due to their proven safety
and minimal toxicity. Previous research suggests that andrographolide and baicalin inhibit coronav iruses; however, their synerg istic
effects remain unclear. Here, we studied the antiviral mechanisms of their synergistic use in vitro and in vivo. We selected the S ARS-
CoV-2 pseudovirus for viral studies and found that synerg istic andrographolide and baicalein significantly reduced angiot ensin-
converting enzyme 2 protein level and viral entry of S ARS-CoV-2 into cells compared to singal compound indivi dually and inhibited
the major protease activity of SARS-CoV-2. This mechanism is essential to reduce the pathog enesis of SARS-CoV-2. In addition, their
synergistic use in vivo also inhibited the elevation of proinflammatory cytokines, including IL-6 and TN F-α -the primary cytokines in
the development of acute respiratory distress syndrome (the main cause of C OVID-19 deaths). In conclusion, this study shows that
synergistic andrographolide and baicalein treatment acts as potent inhibitors of corona virus mechanisms in vitro and in vivo-and is
more effective together than in isolation.

24
Protective effect of Luffa cylindrica fermentation liquid on cyclophosphamide-induced premature

ovarian failure in female mice by attenuating oxidative stress, inflammation and apoptosis
By: Feng, Yueying; Zhang, Wei; Xu, Xiaowei; Wang, Wanzhen; Xu, Yuanyuan; Wang, Mengqi; Zhang, Jinfeng; Xu, Hengyi; Fu, Fen
Journal of Ovarian Research (2024), 17(1), 24 | Language: English, Database: CAplus and MEDLINE
Abstract: Premature ovarian failure (POF) is a leading cause of women′s infert ility without effective treatment. The purpose of this
study was to investigate the protective effects of Luffa cylindrica fermen tation liquid (LF) on cyclophosphamide (CTX) -induced POF
in mice and to preliminarily investigate the underlying mechanisms. Thirty-two Balb/c mice were divided into four groups randomly.
One group served as the control, while the other three received CTX injections to establish POF models. A 14- day gavage of either 5
or 10 μL/g LF was administered to two LF pretreatment groups. To analyze the effects of LF, the ovarian index, follicle number, the
levels of serum sex hormones, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), inflammatory factors, and
apoptosis of the ovarian cells were measured. The effects of LF pretreatment on the expression of TLR4/NF-κB and apoptosis
pathways were also evaluated. We found that LF pretreatment increased the ovarian index and the number of primordial and antral
follicles while decreasing those of atretic follicles. LF pretreatment also increased the serum levels of estradiol (E2) and anti-
Mullerian hormone (A MH), while decreasing those of LH (LH) and FSH (FSH). Furthermore, LF pretreatment increased the levels of S
OD and GSH in the ovaries, while decreasing those of MDA, tumor necrosis factor - α ( TN F-α) and interleukin-1β (IL-1β). LF
administration reduced the amount of T UNEL+ ovarian cells and the levels of T LR4 and N F-κB P65 protein expression. In conclusion,
LF has antioxidant, anti-inflammatory as well as anti-apoptotic effects against CTX-induced POF, and the inhibition of TLR4/NF-κB
and apoptosis pathways may be involved in its mechanisms. Graphical Abstract: [graphic not available: see fulltext]
Keywords: Apoptosis; Cyclophosphamide; Inflammation; Luffa cylindrica fermen tation liquid; Oxidative stress; Premature ovarian
failure
25
Synthesis, in vitro potency of inhibition , enzyme kinetics and in silico studies of quinoline-based α -
glucosidase inhibitors
By: Ghomi, Minoo Khalili; Dastyafteh, Navid; Montazer, Mohammad Nazari; Noori, Milad; Mojtabavi, Somayeh; Faramarzi,
Mohammad Ali; Hashemi, Seyedeh Mahdieh; Mahdavi, Mohammad
Diabetes mellitus is a multifactorial global health disorder that is rising at an alarming rate. One effective therap eutic approach for
controlling hyperglycemia associated with type- 2 diabetes is to target α -glucosidase, which catalyzes starch hydrolysis in the
intestine. In an attempt to find potential α -glucosidase inhibitors, a series of twenty new quinoline linked benzoth iazole hybrids
were synthesized in good yields from suitable reaction proced ures. The synthe sized derivatives further screened for their activity
against α -glucosidase. Among them, some compounds exhibited remarkable α -glucosidase inhibitory activity with IC50 values
ranging from 38.2 ± 0.3 to 79.9 ± 1.2 μM compared with standard drug acarbose (I C50 = 750.0 ± 2.0 μ M). Enzyme kinetic studies of
the most active para-fuorophenyl substituted compound indicated a non- competitive inhibition with Ki value of 38.2 μ M.
Moreover, the homol. modeling, mol. docking and mol. dynamics simulation studies were conducted to reveal key interactions
between the most active para-fuorophenyl substituted compound and the targeted enzyme. These results are complem entary to
the exptl. observations. In order to predict the druggability of the novel derivatives, the pharmacokinetic properties were also
applied. These findings could be useful for the design and development of new α -glucosidase inhibitors.
Keywords: benzothiazolyl quinolinyl thio benzylac etamide preparation glucosidase inhibitor SAR; homol modeling mol dynamics
simulation ADMET

26
Fungal polysaccharides from Inonotus obliquus are agonists for Toll-like receptors and induce
macrophage anti-cancer activity
By: Wold, Christian Winther ; Christopoulos, Panagiotis F.; Arias, Maykel A.; Dzovor, Deborah Elikplim; Oeynebraaten, Inger;
Corthay, Alexandre ; Inngjerdingen, Kari Tvete
Abstract: Fungal polysaccharides can exert immunomo dulating activity by triggering pattern recogn ition receptors (PRRs) on innate
immune cells such as macrophages. Here, we evaluate six polysacc harides isolated from the medicinal fungus Inonotus obliquus
for their ability to activate mouse and human macrophages. We identify two water- soluble polysaccharides, AcF1 and AcF3, being
able to trigger several critical antitumor functions of macrophages. AcF1 and AcF3 activate macrophages to secrete nitric oxide and
the pro-inflammatory cytokines tumor necrosis factor - α ( TN F-α) and interleukin-6 (IL-6). Combined with interferon-γ, the fungal
polysaccharides trigger high production of I L-12p70, a central cytokine for antitumor immunity, and induce macrop hage-mediated
inhibition of cancer cell growth in vitro and in vivo. Ac F1 and AcF3 are strong agonists of the PRRs Toll-like receptor 2 (TLR2) and TL
R4, and weak agonists of Dectin-1. In comparison, two prototypical particulate β-glucans, one isolated from I. obliquus and one
from Saccharomyces cerevisiae (zymosan), are agonists for Dectin-1 but not TLR2 or TLR4, and are unable to trigger anti-cancer
functions of macrophages. We conclude that the water- soluble polysaccharides AcF1 and AcF3 from I. obliquus have a strong
potential for cancer immunotherapy by triggering multiple P RRs and by inducing potent anticancer activity of macrophages.
27
Process analysis of the anaerobe Phocaeicola vulgatus in a shake flasks and fermenter reveals pH and
product inhibition
By: Keitel, Laura; Miebach, Katharina; Rummel, Lea; Yordanov, Stanislav; Buechs, Jochen
Annals of Microbiology (London, United Kingdom) (2024), 74(1), 7 | Language: English, Database: CAplus
The anaerobic gut bacterium Phocaeicola vulgatus (formerly Bacteroides vulgatus) has a signif icant role in the human gut microb
iome. It can produce bioactive compounds with antimic robial properties and indust rially relevant organic acids like succinate.
However, there is a knowledge gap in understanding the metabolism of P. vulgatus, as cultivation of anaerobic gut bacteria is challe
nging and usually conducted with enriched microbiota cultures. We aim to close this gap by charact erizing this anaerobe bacterium
in different cultivation conditions and scales. In this work, axenic cultures were studied in a shake flask and 2 L fermenter scale to
characterize the influence of initial pH, buffer concentration, osmolality, and product inhibition on growth and organic acid
production by P. vulgatus. Both cultivation systems had online gas measur ements for total gas and C O2 production HPLC anal.
generated closed carbon balances, accounting for all produced acids. Total gas transfer rates and CO2 transfer rates revealed that
65% of produced gas was attributed to H2, while just 35% was connected to CO2 production A min. buffer concent ration of 50 mM
MOPS and an initial p H of 7.3 were identified to mitigate p H inhibition in P. vulgatus cultivations with a defined minimal medium
and glucose as substrate. The initial addition of lactate showed an inhibitory effect, starting at a concentration of 1 g L- 1. On the
contrary, initial acetate addition was beneficial for organic acid production A comparison of a pH-buffered and a p H-controlled 2 L
fermentation demonstrated a switch in acid production toward succinate under p H control. The study provides insight into
improved cultivation conditions for the gut bacterium P. vulgatus and demons trates a successful scale- up from the shake flask to
the 2 L bioreactor. By applying pH control in the bioreactor, growth was increased, and the organic acid production was switched
from lactate to succinate. Even though P. vulgatus could serve as a production organism for interesting bioactive compounds and
organic acids, further characterization and improvement are necessary to improve titers.
Keywords: Phocaeicola anaerobe shake flask fermenter p H osmolality bioactive compound

28
Diuresis and α -glucosidase inhibition by erythritol in Aedes aegypti (Diptera: Culicidae) and viability
for efficacy against mosquitoes
By: Nelson, Irvane E.; Baker, Kobi A.; Faraji, Ary; White, Gregory S.; Bibbs, Christopher S.
Parasites & Vectors (2024), 17(1), 76 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Sugar alcs., such as erythritol, are low-impact candidates for attractive toxic sugar baits (A TSB) to kill mosqui
toes. To determine whether erythritol has a viable future in A TSB formulations, a suite of assays was conducted to diagnose toxicity
mechanisms and starvation effects on mortality in Aedes aegypti (L.) as a model system. Methods: We measured general carboh
ydrate load, glucos idase levels, and free glucose in intoxicated adult mosquitoes to observe whether sugar digestion was impaired.
We assayed the effects of sugar combinations with erythritol on larvae and adults. To measure erythritol effects when mosquitoes
were not resource-deprived, addnl. assays manipu lated the prior starvation status. Results: Up to 50, 000 ppm of erythritol in water
had no effect on larvae within 72 h, but an ammonia spike indicated diuresis in larvae as early as 4 h (F8,44 = 22.50, P < 0.0001) after
sucrose/erythritol combinations were added. Adult consumption of erythritol was diuretic regardless of the sugar pairing, while
sucrose and erythritol together generated above 80% mortality (F2,273 = 33.30, P < 0.0001) alongside triple the normal excretion (
F5,78 = 26.80, P < 0.0004) . Glucose and fructose paired indivi dually with erythritol had less mortality, but still double the fecal
excretion. When ingesting erythritol-laced meals, less sugar was detected in mosquitoes as compared to after sucrose meals (χ 2 =
12.54, df = 1, P = 0.0004). Conclusions: Data showed that erythritol is a linear compet itive inhibitor of α -glucosidase, marking it as a
novel class of insecticide in the current research climate. However, the efficacy on larvae was null and not persistent in adult
mosquitoes when compared across various starvation levels. Despite significant diuresis, the combined effects from erythritol are
not acute enough for vector control programs considering ATSB against mosquitoes. Graphical Abstract: [graphic not available: see
fulltext]
Keywords: Excretion; Starvation; Sugar alcohol; Sugar meals; Toxicity
29
Angiotensin type 1 receptor activation promotes neuronal and glial alpha -synuclein aggregation and
transmission
By: Lage, Lucia; Rodriguez-Perez, Ana I. ; Villar-Cheda, Begona ; Labandeira-Garcia, Jose L. ; Dominguez-Meijide, Antonio
Abstract: The brain renin-angiotensin system (RAS) has been related to dopami nergic degeneration, and high expression of the
angiotensin II (AngII) type 1 receptor (A T1) gene is a marker of the most vulnerable neurons in humans. However, it is unknown
whether AngII/AT1 overactivation affects α -synuclein aggregation and transmission. In vitro, AngII/AT1 activation increased α -
synuclein aggregation in dopaminergic neurons and microglial cells, which was related to Ang II-induced NADPH-oxidase activation
and intracellular calcium raising. In mice, AngII/AT1 activation was involved in M PTP-induced increase in α -synuclein expression
and aggregation, as they significantly decreased in mice treated with the A T1 blocker telmis artan and AT1 knockout mice. Cell co-
cultures (transwells) revealed strong transm ission of α -synuclein from dopaminergic neurons to astrocytes and microglia. Ang II
induced a higher α -synuclein uptake by microglial cells and an increase in the transfer of α -synuclein among astroglial cells.
However, AngII did not increase the release of α -synuclein by neurons. The results further support brain R AS dysregulation as a
major mechanism for the progression of Parkinson′s disease, and AT1 inhibition and RAS modulation as therapeutic targets.

30
Involvement of TNFα, IL-1β, COX-2 and NO in the anti-inflammatory activity of Tamarix aphylla in
Wistar albino rats: an in-vivo and in-vitro study
By: Fayez, Nada; Khalil, Waleed; Abdel-Sattar, Essam; Abdel-Fattah, Abdel-Fattah Mohamed
Abstract: Background: With the emergence of many side effects from synthetic drugs, there is an urgent need to find a natural
alternative to these products. Therefore, our primary aim was to evaluate the anti- inflammatory activity of Tamarix aphylla (T A) and
investigate the potential mechanism underlying this action. Methods: Initially, to ensure the safety of the extract and for dose
selection, we performed an acute oral toxicity Assay through the oral administration of graded doses up to 4 g\kg in Wistar rats.
then, we used the carrageenan-induced edema model to elucidate the anti-inflammatory activity. Using specific E LISA kits, we
measured the levels of TN F-α , IL-1β, COX-2 and NO inside the inflamed paw tissue. Finally, for the in- vitro anti-inflammatory experi
ment, we used the erythr ocyte membrane stability test. Results: Based on the acute oral toxicity assay, T. aphylla was considered
generally safe and three different doses of 100, 200, and 400 mg/kg were chosen for further experiments Addnl., TA expressed a
significant (P < 0.05) anti-inflammatory activity, showing the maximum inhibition percentage at the fifth hour of measur ement at
53.47% and 70.06%, at doses of 200 and 400 mg/kg resp., compared to 63.81% for the standard drug. Similarly, we found that TA
effectively reduced the levels of TN F-α and IL-1β at all tested doses (100- 200-400 mg/kg) to a greater extent than the standard
drug. Moreover, at 400 mg/kg, TA was able to significantly lower the levels of COX-2 and NO inside the inflamed tissue to a level
comparable (P < 0.05) with that measured inside the paw tissue of normal rats. Finally, Tamarix aphylla at 100, 200 and 400 mg/kg
doses significantly (P < 0.05) inhibited the heat- induced hemolysis of RBCs membrane by 67.78, 74.82 and 82.08%, resp., compared
to 83.89% produced by Aspirin. Conclusion: T. aphylla produced a signif icant (P < 0.05) anti-inflammatory activity compared to the
standard drugs either through the reduction of pro-inflammatory mediators or the protection of the lysosomal membrane.
Keywords: Anti-inflammatory; Carrageenan; Diclofenac; Paw edema; Tamarix aphylla

31
Redirecting antibody responses from egg-adapted epitopes following repeat vaccination with
recombinant or cell culture-based versus egg-based influenza vaccines
By: Liu, Feng ; Gross, F. Liaini; Joshi, Sneha; Gaglani, Manjusha ; Naleway, Allison L.; Murthy, Kempapura; Groom, Holly C.;
Wesley, Meredith G.; Edwards, Laura J.; Grant, Lauren; et al
Repeat vaccination with egg-based influenza vaccines could prefere ntially boost antibodies targeting the egg- adapted epitopes and
reduce immunogenicity to circulating viruses. In this randomized trial (Clinicaltr ials.gov: NCT03722589), sera pre- and post- vaccin
ation with quadrivalent inactivated egg-based (IIV4), cell culture-based (ccIIV4), and recombinant (RIV4) influenza vaccines were
collected from healthcare personnel (18-64 years) in 2018-19 (N = 723) and 2019- 20 (N = 684) influenza seasons. We performed an
exploratory anal. Vaccine egg-adapted changes had the most impact on A (H3N2) immunogenicity. In year 1, RIV4 induced higher
neutralizing and total HA head binding antibodies to cell- A (H3N2) virus than ccIIV4 and IIV4. In year 2, among the 7 repeat vaccin
ation arms (IIV4-IIV4, IIV4-ccIIV4, IIV4-RIV4, RIV4-ccIIV4, RIV4-RIV4, ccIIV4-ccIIV4 and ccIIV4-RIV4), repeat vaccination with either RIV4
or ccIIV4 further improved antibody responses to circul ating viruses with decreased neutralizing antibody egg/cell ratio. RIV4 also
had higher post-vaccination A(H1N1)pdm09 and A(H3N2) HA stalk antibodies in year 1, but there was no signif icant difference in HA
stalk antibody fold rise among vaccine groups in either year 1 or year 2. Multiple seasons of non-egg-based vaccination may be
needed to redirect antibody responses from immune memory to egg-adapted epitopes and re-focus the immune responses
towards epitopes on the circulating viruses to improve vaccine effectiveness.
Keywords: influenza vaccine vaccination epitope H3N2 immune response

32
Synergistic effect of potential alpha -amylase inhibitors from Egyptian propolis with acarbose using in
silico and in vitro combination analysis
By: Nada, Ahmed A.; Metwally, Aly M.; Asaad, Aya M.; Celik, Ismail; Ibrahim, Reham S.; Eldin, Safa M. Shams
Abstract: Background: Type 2 Diabetes mellitus (D M) is an affliction impacting the quality of life of millions of people worldwide. An
approach used in the management of Type 2 DM involves the use of the carbohy drate-hydrolyzing enzyme inhibitor, acarbose.
Although acarbose has long been the go-to drug in this key approach, it has become apparent that its side effects neg. impact
patient adherence and subsequently, therapeutic outcomes. Similar to acarbose in its mechanism of action, bee propolis, a unique
natural adhesive biomass consisting of biol. active metabolites, has been found to have antidi abetic potential through its inhibition
of α -amylase. To minimize the need for ultimately novel agents while simulta neously aiming to decrease the side effects of
acarbose and enhance its efficacy, combination drug therapy has become a promising pharmacoth erapeutic strategy and a focal
point of this study. Methods: Computer-aided mol. docking and mol. dynamics (M D) simulations accompanied by in vitro testing
were used to mine novel, pharmacol. active chem. entities from Egyptian propolis to combat Type 2 DM. Glide docking was utilized
for a structure-based virtual screening of the largest inhouse library of Egyptian propolis metabo lites gathered from litera ture, in
addition to GC-MS anal. of the propolis sample under investi gation. Thereafter, combination anal. by means of fixed- ratio combin
ations of acarbose with propolis and the top chosen propolis- derived phytoligand was implemented. Results: Aucubin, identified for
the first time in propolis worldwide and kaempferol were the most promising virtual hits. Subsequent in vitro α -amylase inhibitory
assay demonstrated the ability of these hits to signifi cantly inhibit the enzyme in a dose- dependent manner with an I C50 of 2.37 ±
0.02 mM and 4.84 ± 0.14 m M, resp. The binary combin ation of acarbose with each of propolis and kaempferol displayed maximal
synergy at lower effect levels. Mol. docking and MD simulations revealed a cooperative binding mode between kaempferol and
acarbose within the active site. Conclusion: The suggested strategy seems imperative to ensure a steady supply of new therap eutic
entities sourced from Egyptian propolis to regress the development of DM. Further pharmacol. in vivo investi gations are required
to confirm the potent antidiabetic potential of the studied combination.
Keywords: Alpha -amylase; Combination analysis; Cooperative binding; Egyptian propolis; G C–MS

33
Quercetin inhibits caspase-1-dependent macrophage pyroptosis in experimental folic acid

nephropathy
By: Gao, Xianli; Guo, Caiyun; Li, Wenjun; Deng, Yingdong; Ning, Wenjun; Xie, Jiaqi; Zhan, Xiaoying; Fan, Youling; Chen, Hongtao;
Huang, Zengping; et al
Chinese Medicine (London, United Kingdom) (2024), 19(1), 11 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The role of pyroptosis in kidney disease is limited and incomp lete. Quercetin, a flavonoid compound present
in a variety of fruits, vegetables, and plants, has shown antiox idant and anti-inflammatory properties. This study was designed to
validate the importance of pyroptosis in an exptl. model of folic acid nephropathy and to explore the effect of quercetin in
protecting against pyroptosis. Methods: Gene set enrichment anal. (GSEA) and weighted gene co- expression network anal. (WGCN
A) were used to establish the correl ation between pyroptosis and folic acid nephro pathy. Immune cell infiltr ation, network
pharmacol. and single-cell RNA sequencing anal. were utilized to ascertain the specific target of quercetin in relation to pyropt osis.
Finally, quercetin′s role was verified in vivo and in vitro. Results: The G SEA anal. revealed a signif icant correlation between
pyroptosis and folic acid nephropathy (NES = 1.764, P = 0.004) . The hub genes identified through W GCNA were closely associated
with inflammation. Mol. docking demonstrated a strong binding affinity between quercetin and caspase- 1, a protein known to be
involved in macrophage function, as confirmed by immune cell infiltration and single-cell anal. Quercetin demons trated a signif icant
amelioration of kidney injury and reduction in macrophage infilt ration in the animal model. Furthermore, quercetin exhibited a
significant inhibition of caspase-1 expression, subsequently leading to the inhibition of pro-inflammatory cytokines expression,
such as IL-1β, IL-18, TN F-α , and IL-6. The inhibitory effect of quercetin on macrophage pyroptosis was also confirmed in R AW264.7
cells. Conclusion: This study contri butes substantial evidence to support the signif icant role of pyroptosis in the develo pment of folic
acid nephropathy, and highlights the ability of quercetin to downregulate caspase-1 in macrophages as a protective mechanism
against pyroptosis.
Keywords: Caspase-1; Folic acid; Macrophage; Pyroptosis; Quercetin

34
Propolis from different Brazilian stingless bee species: phenolic composition and antimicrobial activity
By: Rocha, Vitor Moreira; Portela, Ricardo Wagner; Lacerda, Luiz Eduardo; Sokolonski, Ana Rita; de Souza, Carolina Oliveira; dos
Anjos, Jeancarlo Pereira; Nascimento, Renata Quartieri; Umsza-Guez, Marcelo Andres
Food Production, Processing and Nutrition (2024), 6(1), 12 | Language: English, Database: CAplus
Stingless bees (SLB) are insects bread many centuries ago by indigenous people and more than 500 species have already been
described. Interest in SLB′s propolis has grown as a way to value and preserve native bees, in addition to investiga ting/prospecting
compounds with biol. functionality (antimicrobial activity, antiox idant, etc.). The natural active compounds found in propolis come
from different plant sources, and consequently, each propolis may show unique biol./ph armacol. activity. There is still an important
gap about the profile of chem. compounds, biol. and pharmacol. potential of propolis produced by SLBs. This work aimed to invest
igate the presence of phenolic and coumaric compounds (H PLC-DAD-FLD) and the antimicrobial activity (microdilution method) of
propolis extracts from five different species of SLB reared in different places. The samples from Melipona quadrif asciata (82.05 mgG
AEg-1) and one from, Frieseomelitta doederleini (56.22 mgGAEg-1) showed the highest concent rations of phenolic compounds It
was possible to identify in the propolis samples formononetin, kaempferol, gallic acid and coumarin. Resver atrol was detected in all
samples, an unprecedent fact for S LB propolis. Candida albicans was suscep tible to all tested extracts, while Escherichia coli was
inhibited only by propolis from Melipona quadrifasciata; Enterococcus faecalis was inhibited by propolis from Plebeiadr oryana.,
Melipona quadrifasciata and Frieseomelitta doederleini. It was verified that S LB propolis constitutes a source of different biocomp
ounds, which varies according to the location where the bees are raised, and has mainly antifungal activity, generating possibi lities
of its use in different biotechnol. products.
Keywords: Apis propolis extract phenol antimicrobial

35
Efficient inhibition of amyloid fibrillation and cytotoxicity of α -synuclein and human insulin using
biosynthesized silver nanoparticles decorated by green tea polyphenols
By: Mirzaei-Behbahani, Behnaz; Meratan, Ali Akbar; Moosakhani, Beitollah; Mohammad-Zaheri, Mahya; Mousavi-Jarrahi, Zahra;
Nikfarjam, Nasser; Shahsavani, Mohammad Bagher; Saboury, Ali Akbar
Abstract: Green tea polyphenols (GTPs), particularly epigallocatechin-3-gallate, stand out among natural small mols. screened for
their ability to target protein aggregates due to their potent anti-amyloidogenic and neuroprotective activities against various
disease-related peptides and proteins. However, the clin. applic ations of GTPs in amyloid-related diseases have been greatly limited
by drawbacks such as poor chem. stability and low bioavailability. To address these limita tions, this study utilized an Iranian green
tea polyphenolic extract as a reducing agent to neutralize silver ions and facilitate the formation of silver nanopa rticle capped by GT
Ps (GTPs-capped AgNPs). The results obtained from this study demons trate that GTPs-capped AgNPs are more effective than free G
TPs at inhibiting amyloid fibril lation and reducing cytotoxicity induced by amyloid fibrils of human insulin and α -synuclein ( α -syn).
This improved efficacy is attributed to the increased surface/volume ratio of GTPs-capped AgNPs, which can enhance their binding
affinity to amyloidogenic species and boosts their antiox idant activity. The mechanism by which G TPs-capped AgNPs inhibit amyloid
fibrillation appears to vary depending on the target protein. For structured protein human insulin, G TPs-capped AgNPs hinder fibril
lation by constraining the protein in its native- like state. In contrast, GTPs-capped AgNPs modulate fibrillation of intrinsically
disordered proteins like α -syn by redirecting the aggregation pathway towards the formation of non- toxic off-pathway oligomers or
amorphous aggregates. These findings highlight polyph enol-functionalized nanoparticles as a promising strategy for targeting
protein aggregates associated with neurodegenerative diseases.
Keywords: Amyloid fibril; Cytotoxicity; GTPs; GTPs-capped AgNPs; Human insulin; α -Synuclein

36
Trichoderma afroharzianum TRI07 metabolites inhibit Alternaria alternata growth and induce tomato
defense-related enzymes
By: Philip, Bassant; Behiry, Said I.; Salem, Mohamed Z. M.; Amer, Mostafa A.; El-Samra, Ibrahim A.; Abdelkhalek, Ahmed; Heflish,
Ahmed
Identifying a viable substitute for the limited array of current antifungal agents stands as a crucial objective in modern agricu lture.
Consequently, extensive worldwide research has been undertaken to unveil eco- friendly and effective agents capable of contro lling
pathogens resistant to the presently employed fungicides. This study explores the efficacy of Tricho derma isolates in combating
tomato leaf spot disease, primarily caused by Alternaria alternata. The identified pathogen, A. alternata Alt3, was isolated and
confirmed through the ITS region (OQ888806). Six Tricho derma isolates were assessed for their ability to inhibit Alt3 hyphal growth
using dual culture, Et acetate extract, and volatile organic compounds (VOCs) techniques. The most promising biocontrol isolate was
identified as T. afroharzianum isolate TRI07 based on three markers: I TS region (OQ820171), translation elongation factor alpha 1
gene (OR125580), and RNA polymerase II subunit gene (OR125581). The Et acetate extract of T RI07 isolate was subjected to GC-MS
anal., revealing spathulenol, triacetin, and aspartame as the main compounds, with percen tages of 28.90, 14.03, and 12.97%, resp.
Anal. of TRI07-VOCs by solid-phase microextraction technique indicated that the most abundant compounds included ethanol,
hydroperoxide, 1-methylhexyl, and 1- octen-3-one. When T RI07 interacted with Alt3, 34 compounds were identi fied, with major
components including 1-octen-3-one, ethanol, and hexanedioic acid, bis(2-ethylhexyl) ester. In greenhouse experiment, the
treatment of TRI07 48 h before inocul ation with A. alternata (A3 treatment) resulted in a reduction in disease severity (16.66%) and
incidence (44.44%). Furthermore, A3 treatment led to improved tomato growth perfor mance parameters and increased chlorophyll
content. After 21 days post-inoculation, A3 treatment was associated with increased production of antiox idant enzymes (CAT, POD,
SOD, and PPO), while infected tomato plants exhibited elevated levels of oxidative stress markers M DA and H2O2. HPLC anal. of
tomato leaf extracts from A3 treatment revealed higher levels of phenolic acids such as gallic, chlorogenic, caffeic, syringic, and
coumaric acids, as well as flavonoid compounds including catechin, rutin, and vanillin. The novelty lies in bridging the gap between
strain-specific attributes and practical applic ation, enhancing the underst anding of TRI07′s potential for integrated pest manage
ment. This study concludes that T RI07 isolate presents potential natural compounds with biol. activity, effect ively controlling tomato
leaf spot disease and promoting tomato plant growth. The findings have practical implications for agriculture, suggesting a sustai
nable biocontrol strategy that can enhance crop resilience and contribute to integrated pest management practices. The raw
sequence data for the ITS region, the translation elongation factor alpha 1 gene, and the R NA polymerase II subunit gene for all
specimens were submitted to the NCBI GenBank database under the accession numbers (O Q888806, OQ820171, OR125580 and O
R125581).
Keywords: sequence Trichoderma Alternaria tomato leaf spot disease phytochem metabo lite; volatile organic compound biocontrol

37
Optimization, characterization, and cytotoxicity studies of novel anti-tubercular agent-loaded

liposomal vesicles
6 Substances • 1 Reaction • 0 Citations
By: Obiedallah, Manar M.; Mironov, Maxim A.; Belyaev, Danila V.; Ene, Antoaneta; Vakhrusheva, Diana V.; Krasnoborova, Svetlana
Yu.; Bershitsky, Sergey Y.; Shchepkin, Daniil V.; Minin, Artem S.; Ishmetova, Rashida I.; et al
The treatment of tuberculosis is still a challenging process due to the widespread of pathogen strains resistant to antibac terial
drugs, as well as the undesirable effects of anti-tuberculosis therapy. Hence, the development of safe and effective new anti- antitub
ercular agents, in addition to suitable nanoca rrier systems, has become of utmost importance and necessity. Our research aims to
develop liposomal vesicles that contain newly synthesized compounds with antimycob acterial action. The compound being studied
is a derivative of imidazo-tetrazine named 3- (3,5-dimethylpyrazole-1-yl)-6-(isopropylthio) imidazo [1,2-b] [1,2,4,5] tetrazine
compound Several factors that affect liposomal characteristics were studied. The maximum encapsu lation efficiency was 53.62 ±
0.09. The selected liposomal formulation T8* possessed a mean particle size of about 205.3 ± 3.94 nm with P DI 0.282, and zeta
potential was + 36.37 ± 0.49 mv. The results of the in vitro release study indicated that the solubility of compound I was increased
by its incorporation in liposomes. The free compound and liposomal prepar ation showed antimycobacterial activity against
Mycobacterium tuberculosis H37Rv (ATCC 27294) at M IC value 0.94-1.88 μg/mL. We predict that the liposomes may be a good
candidate for delivering new antitubercular drugs.
Keywords: Mycobacterium liposomal vesicle drug nanoca rrier formulation anti tubercular agent
Substances (6) Reaction (1) Citing (0)
38
Splenectomy ameliorates liver cirrhosis by restoring the gut microbiota balance
By: Jin, Ye; Shi, Meixin; Feng, Jing; Zhang, Zhengwei; Zhao, Bingbing; Li, Qingyu; Yu, Ligen; Lu, Zhaoyang
Cellular and Molecular Life Sciences (2024), 81(1), 32 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Dysbiosis of gut microbiota is frequent in liver cirrhosis (L C) patients, and splenectomy (SP) has been
reported to improve LC. Herein, we report the effects of S P on gut microbiota, especially on Veillonella parvula, a Gram-neg. coccus
of the gastrointestinal tract, in LC mice, and the underlying mechanism. Methods: LC mice models were induced by tail vein
injection of Con A (ConA), followed by S P. 16 s r RNA sequencing was conducted to analyze the effects of Con A induction and SP on
mouse gut microbiota and the gene expression affected by gut microbiota. LC mice receiving SP were gavaged with Veillonella
parvula. Likewise, hepatic stellate cells (HSC) and hepatocytes (HC) were induced with conditioned medium (CM) of Veillonella
parvula. Results: SP alleviated LC in mice by restoring gut barrier function and mainta ining gut microbiota balance, with Veillo nella
as the key genus. The Veillonella parvula gavage on LC mice reversed the ameliorative effect of S P. The CM of Veillonella parvula
promoted the activation of HSC and the release of I L-6, IL-1β, and TN F-α . Also, the CM of Veillonella parvula induced HC pyroptosis
and the release of ALT and AST. Veillonella parvula represented an imbalance in the gut microbiota, thus enhancing gut- derived
endotoxins in the liver with the main target being Tlr4/Nlrp3. Inhibition of Tlr4 blocked Veillonella parvula-induced HC damage, HS
C activation, and subsequent LC progression. Conclusion: SP-mediated gut microbiota regulation amelio rates ConA-related LC
progression by inhibiting Tlr4/Nlrp3 in the liver.
Keywords: C57BL/6JGpt; Collagen deposition; Inflammatory signaling; Liver injury; Spleen

39
Biogenic zinc selenide nanoparticles fabricated using Rosmarinus officinalis leaf extract with potential
biological activity
By: Somaghian, Shahram Ahmadi; Mirzaei, Seyedeh Zahra; Shakib, Mohammad Ebrahim Khosravi; Marzban, Abdolrazagh;
Alsallameh, Sarah; Lashgarian, Hamed Esmaeil
Zinc selenide nanoparticles (ZnSe) are semiconductor metals of zinc and selenium. Zn Se NPs are advantageous for biomedical and
bio-imaging applications due to their low toxicity. Zn Se NPs can be used as a therap eutic agent by synthe sizing those using biol. safe
methods. As a novel facet of these NPs, plant-based ZnSe NPs were fabricated from an aqueous extract of Rosmarinus offici nalis L.
(RO extract). Physiochem. analyses such as UV-visible and FTIR spectroscopy, SEM-EDX and TEM Imaging, X RD and DLS-Zeta
potential analyses confirmed the biol. fabrication of RO-ZnSe NPs. Addnl., Ro-ZnSe NPs were investigated for their bioact ivity. There
was an apparent peak in the UV-visible spectrum at 398 nm to confirm the presence of Zn Se NPs. FTIR anal. confirmed R O-extract
participation in ZnSe NPs synthesis by identi fying putative functional groups associated with biomols. T EM and S EM analyses
revealed that RO-ZnSe NPs have spherical shapes in the range of 90- 100 nm. According to XRD and EDX anal., RO-ZnSe NPs had a
crystallite size of 42.13 nm and contain Se and Zn (1: 2 ratio). These N Ps demonstrated approx. 90.6% antiox idant and antibacterial
activity against a range of bacterial strains at 100 μg/mL. Antibiofilm activity was greatest against Candida glabrata and Pseudo
monas aeruginosa at 100 g/m L. Accordingly, the IC50 values for anticancer activity against H TB-9, SW742, and HF cell lines were
14.16, 8.03, and 35.35 g/mL, resp. In light of the multiple applic ations for ZnSe NPs, our research indicates they may be an excellent
option for biol. and therapeutic purposes in treating cancers and infect ions. Therefore, addnl. research is required to determine
their efficacy.
Keywords: Rosmarinus leaf extract antioxidant antibacterial zinc selenide nanoparticle; Biological activity; Green synthesis;
Rosmarinus officinalis L; Zinc selenide nanoparticles
40
Machine learning assisted rational design of antimicrobial peptides based on human endogenous
proteins and their applications for cosmetic preservative system optimization
By: Yue, Lizhi; Song, Liya; Zhu, Siyu; Fu, Xiaolei; Li, Xuhui; He, Congfen ; Li, Junxiang
Preservatives are essential components in cosmetic products, but their safety issues have attracted widespread attention. There is
an urgent need for safe and effective alternatives. Antimicrobial peptides (A MPs) are part of the innate immune system and have
potent antimicrobial properties. Using machine learning- assisted rational design, we obtained a novel antibac terial peptide, IK-16-1,
with significant antibacterial activity and maintaining safety based on β-defensins. IK-16-1 has broad-spectrum antimicrobial
properties against Escherichia coli, Staphylococcus aureus, Pseudo monas aeruginosa, and Candida albicans, and has no haemolytic
activity. The use of IK-16-1 holds promise in the cosmetics industry, since it can serve as a preser vative synergist to reduce the
amount of other preservatives in cosmetics. This study verified the feasib ility of combining computa tional design with artificial intell
igence prediction to design AMPs, achieving rapid screening and reducing develo pment costs.
Keywords: cosmetics human endogenous protein preservative antimicrobial peptides machine learning

41
Silver nanoparticles improve the fungicidal properties of Rhazya stricta decne aqueous extract against
plant pathogens
By: Al-Sahli, Sarah A.; Al-Otibi, Fatimah ; Alharbi, Raedah I.; Amina, Musarat; Al Musayeib, Nawal M.
One of the most promising, non-toxic, and biocompatible developments for many biol. activities is the green synthesis of nanopar
ticles from plants. In this work, we invest igated the antifungal activity of silver nanoparticles (AgNPs) biosynthesized from Rhazya
stricta aqueous extract against several plant pathogenic fungi. UV-visible spectroscopy, Zeta potential anal., Fourier- transform IR
spectroscopy (FTIR), and transmitted electron microscopy (T EM) were used to analyze the biosynt hesized AgNPs. Drechslera
halodes, Drechslera tetramera, Macrophomina phaseolina, Alternaria alternata, and Curvularia austral iensis were tested for their
potential antifungal activity. Surface Plasmon Resonance (SPR) of Aqueous Ag NPs and Alk. Aqueous Ag NPs was observed at 405 nm
and 415 nm, resp. FTIR anal. indicated hydroxyl, nitrile, amine, and ketone functional groups. Aqueous Ag NPs and Alka-line
Aqueous AgNPs had velocities of - 27.7 m V and - 37.9 m V and sizes of 21-90 nm and 7.2- 25.3 nm, resp., according to zeta potential
studies and TEM. The antifungal examination revealed that all species mycelial develo pment was significantly inhibited, accomp
anied by severe ultra-structural alterations. Among all treatm ents, Aqueous AgNPs were the most effective fungicide. M. phaseolina
was statistically the most resistant, whereas A. alternata was the most vulner able. To the best of our knowledge, this is the first
report on R. stricta's antifungal activity against these species.
Keywords: Rhazya aqueous extract plant pathogen silver nanoparticle fungicidal

42
Decoction regulating phytochemicals′ micromorphology changes and anti-inflammation activity

enhancements originated from herb medicine supermolecules
By: Yang, Luping; Zhang, Xiang; Wang, Zhijia; Lin, Xiaoyu; Zhang, Yaozhi; Lu, Jihui; Wu, Linying; Yao, Shuchang; Jing, Wenguang;
Huang, Xuemei; et al
Abstract: Background: Mahuang Fuzi decoction (M GF) is composed of three herb medicines that has been clin. used to treat inflam
matory diseases for a long history. At present, more and more active phytoc hems.′ aggregations have been found during the
thermodn. process of herb medicine decoction, and revealing the clin. efficacy of herb medicine through supramol. strategies is the
focus of current research. However, it is not clear whether decoction induced supermols.′ morphol. changes to modify activity.
Methods: Dynamic light scattering (DLS) and field emission S EM (FESEM) were used to analyze the micromo rphol. of M GF, MGF SA
(MGF supermols.), and MIX (phys. mixture of M GF single decoction). The interaction and thermodn. parameters of single herbs in a
decoction were investigated by Isothermal titration calorimetry (ITC). The phytochems. were systematically analyzed by ultra high
performance liquid chromatog.-Q Exactive hybrid quadru pole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-
Orbitrap HRMS). Under the safe dose on R AW264.7 cells, N O, IL-6 and TN F-α were determined by E LISA (ELISA) method. NF-κB p65
translocation from the cytoplasm into the nucleus was examined using the immunoflu orescence assay and the western blot, resp.
Furthermore, Metabolomics was used to discover potential biomarkers and the associated metabolic pathways of M GF SA
treatment. Results: There were nanoscale aggregations in MGF, and the micromo rphol. of the extracted M GF SA consisted of
uniform particles; while the MIX micromorphol. had no unifor mity. ITC showed that the interaction MH-GC and FZ-GC were a
spontaneous exothermic reaction, indicating that their phytoc hems. had the property of self- assembly. Though the micromo rphol.
between MGF, MGF SA, and MIX was obviously different, UHPLC-Q-Orbitrap HRMS results displayed that the main phytoc hems. of
MGF and MIX had nearly the same components. Interestingly, MGF and MGF SA could significantly inhibit the production of N O, and
had better inhibition effect on the expression of nuclear protein N F-κB p65 than M IX, among which MGF SA had the best effect.
Further investigation indicated that the perturbance of metabolic profiling in RAW264.7 inflammatory cells was obviously reversed
by MGF SA. Conclusions: The decoction enriched the key active phytoc hems. and regulated the formation of homogeneous nanopar
ticles in MGF SA. The supermols. in M GF SA significantly enhanced its anti-inflammatory activity, primarily affecting the NF-κB
signaling pathway and the biosynthesis and metabolism of arginine in R AW264.7 inflammatory cells. Current study displayed that
co-decocting herbal medicine were beneficial to the treatment of diseases than the mixture of the single herbs′ extraction Graphical
Abstract: [graphic not available: see fulltext]
Keywords: Decoction; Inflammation; Mahuang Fuzi decoction; Metabol omics; Supermolecules

43
WNTA5-mediated miR-374a-5p regulates vascular smooth muscle cell phenotype transformation and
M1 macrophage polarization impacting intracranial aneurysm progression
By: Li, Zengshi; Huang, Junqiang; Yang, Lijian; Li, Xi; Li, Wei
Abstract: miR-374a-5p expression and localization in intracranial aneurysm (IA) tissues were detected, and its correl ation with
vascular smooth muscle cells (VSMCs) and macrophage markers was analyzed. Using platelet- derived growth factor-BB (PDGF-BB)
induced VSMC model, elastase- induced IA rat model. Subsequently, miR-374a-5p was knocked down or overexp ressed. We invest
igated the effects of miR-374a-5p on phenotypic conver sion, and in vivo experi ments were also carried out to verify the findings.
The targeted relationship between miR-374a-5p and WNTA5 was analyzed. The effect of W NT5A inhibition on VSMC phenotypic
transformation and THP-1-derived macrophage polarization was explored. Clin. studies have shown that mi R-374a-5p was upregu
lated in IA patients. mi R-374a-5p was neg. correlated with S M22α, α -SMA, CD206, and pos. correlated with C D86. In vitro experi
ments showed that knocking down mi R-374a-5p reversed the promotion of S M22α and α -SMA expression by PDGF-BB, while
overexpression of miR-374a-5p had the opposite effect. In addition, knocking down mi R-374a-5p also reversed the decrease in
Calponin, TIMP3, TIMP4, and IL-10 levels caused by PDGF-BB, and further reduced the levels of M MP1, MMP3, MMP9, IL-1β, IL-6,
and TN F-α . These findings were further validated in vivo. In I A rats, there were notable increases in both systolic and diastolic blood
pressure, along with an elevated M1/M2 ratio and the occurrence of vascular lesions. However, these symptoms were improved
after knocking down miR-374a-5p. Furthermore, miR-374a-5p could target the W NT signals (WNT2B, WNT3, and WNT5A). miR-374a-
5p regulated the VSMC phenotypic conversion and M1 macrophage polari zation by targeting W NT5A, thereby impacting the progre
ssion of IA.
44
Anti-psoriatic characteristics of ROCEN (topical Arthrocen) in comparison with Cyclosporine A in a

murine model
By: Goudarzi, Ramin; Min-Ho Kim; Partoazar, Alireza

Abstract: Topical ROCEN (Roc), liposomal arthrocen hydrogel, is a robust anti- inflammatory formulation which has been developed
for skin diseases such as eczema. Therefore, we aimed to evaluate the efficacy of Roc 2% on the healing of imiquimod (Imiq)-
induced psoriasis in a mouse model. Psoriasis was induced by applying Imiq topically to the mice′s back skin once daily for five
consecutive days. Moreover, a group of animal experi ments was treated with Cyclos porine A (Cs A), as a standard drug, for
comparison with Roc treated group. The efficacy of Roc on skin lesions was evaluated by employing Psoriasis Area and Severity
Index (PASI) scores. Subsequ ently, the skin samples were assessed using Baker′s scoring system and Masson′s trichrome staining,
immunohistochem., and real-time PCR anal. The observational and histopathol. results indicated that topical applic ation of Roc
significantly reduced the PASI and Baker′s scores in the plaque- type psoriasis model. Moreover, biochem. assessments showed that
Roc suppressed significantly the increase of I L-17, IL-23, and TN F-α cytokines gene expression in the lesion site of psoriatic
animals. In conclusion topical Roc 2% could significantly alleviate major pathol. aspects of Imiq- induced psoriasis through inflam
mation inhibition which was comparable to the Cs A drug. The beneficial outcomes of Roc applic ation in the psoriasis model
suggest its potential usage in complementary medicine.
Keywords: Animal; Arthrocen; Inflammation; Liposome; Psoriasis

45
Genetic and pharmacologic p32- inhibition rescue CHCHD2-linked Parkinson′s disease phenotypes in
vivo and in cell models
By: Tio, Murni ; Wen, Rujing; Choo, Cai Ning; Tan, Jian Bin; Chua, Aaron; Xiao, Bin; Sundaram, Jeyapriya Rajameenakshi; Chan,
Christine Hui Shan; Tan, Eng-King
Journal of Biomedical Science (London, United Kingdom) (2024), 31(1), 24 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Mutations in CHCHD2 have been linked to Parkinson′s disease, however, their exact pathoph ysiol. roles are
unclear. The p32 protein has been suggested to interact with CHCHD2, however, the physiol. functions of such intera ction in the
context of PD have not been clarified. Methods: Intera ction between CHCHD2 and p32 was confirmed by coimmunoprecipitation
experiments We studied the effect of p32- knockdown in the transgenic Drosophila and Hela cells expressing the wild type and the
pathogenic variants of hCHCHD2. We further invest igated the rescue ability of a custom generated p32- inhibitor in these models as
well as in the human fibroblast derived neural precursor cells and the dopaminergic neurons harboring h CHCHD2-Arg145Gln.
Results: Our results showed that wildtype and mutant hCHCHD2 could bind to p32 in vitro, supported by in vivo intera ction
between human CHCHD2 and Drosophila p32. Knockdown of p32 reduced mutant h CHCHD2 levels in Drosophila and in vitro. In
Drosophila hCHCHD2 models, inhibition of p32 through genetic knockdown and pharmacol. treatment using a customized p32-
inhibitor restored dopaminergic neuron numbers and improved mitocho ndrial morphol. These were correlated with improved
locomotor function, reduced oxidative stress and decreased mortality. Consistently, Hela cells expressing mutant hCHCHD2 showed
improved mitochondrial morphol. and function after treatment with the p32- inhibitor. As compared to the isogenic control cells,
large percentage of the mutant neural precursor cells and dopaminergic neurons harboring h CHCHD2-Arg145Gln contained
fragmented mitochondria which was accompanied by lower ATP production and cell viability. The N PCs harboring h CHCHD2-Arg145
Gln also had a marked increase in α -synuclein expression. The p32-inhibitor was able to ameliorate the mitochondrial fragmen
tation, restored A TP levels, increased cell viability and reduced α -synuclein level in these cells. Conclu sions: Our study identified p32
as a modulator of CHCHD2, possibly exerting its effects by reducing the toxic mutant h CHCHD2 expression and/or mitigating the
downstream effects. Inhibition of the p32 pathway can be a potential therap eutic intervention for CHCHD2-linked PD and diseases
involving mitochondrial dysfunction.
Keywords: CHCHD2; Drosophila; Isogenic line; Mitochondria; Parkinson’s disease; p32; p32- inhibition

46
PRMT2 silencing regulates macrophage polarization through activation of STAT1 or inhibition of

STAT6
By: Liu, Ting; Li, Yinjiao; Xu, Muqiu; Huang, Hongjun; Luo, Yan
BMC Immunology (2024), 25(1), 1 | Language: English, Database: CAplus and MEDLINE
Macrophages play signif icant roles in innate immune responses and are heterog eneous cells that can be polarized into M1 or M2
phenotypes. PRMT2 is one of the type I protein arginine methyltra nsferases involved in inflamm ation. However, the role of PRMT2
in M1/M2 macrophage polarization remains unclear. Our study revealed the effect and mechanism of P RMT2 in macrophage
polarization. Bone marrow-derived macrophages (BMDMs) were polarized to M1 or M2 state by L PS plus murine recombinant interf
eron-γ (IFN-γ) or interleukin-4 (IL-4). Quant. polymerase chain reaction (qPCR), western blot and flow cytometry (F CM) assay were
performed and analyzed markers and signaling pathways of macrophage polarization. We found that PRMT2 was obviously upregu
lated in LPS/IFN-γ-induced M1 macrophages, but it was little changed in I L-4-induced M2 macrophages. Furthermore, PRMT2
konckdown increased the expression of M1 macrophages markers through activation of S TAT1 and decreased the expression of
M2 macrophages markers through inhibition of STAT6. PRMT2 silencing modulates macrophage polari zation by activating S TAT1 to
promote M1 and inhibiting STAT6 to attenuate the M2 state.
Keywords: PRMT2 silencing regulate macrophage polari zation activation STAT1; M1/M2; Macrophage polarization; PRMT2; STAT1/S
TAT6

47
LRP10 and α -synuclein transmission in Lewy body diseases
By: Carreras Mascaro, Ana; Grochowska, Martyna M.; Boumeester, Valerie; Dits, Natasja F. J.; Bilgic, Ece Naz; Breedveld, Guido J.;
Vergouw, Leonie; de Jong, Frank Jan; van Royen, Martin E.; Bonifati, Vincenzo; et al
Abstract: Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (L BDs), including Parkin
son′s disease (PD), Parkinson′s disease-dementia (PDD), and dementia with Lewy bodies (D LB). Nevertheless, there is little mechan
istic insight into the role of L RP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-
neuronal cells like astrocytes and neurovasc ulature, but in idiopathic and genetic cases of P D, PDD, and DLB, it is also present in α -
synuclein-pos. neuronal Lewy bodies. These observations raise the questions of what leads to the accumu lation of LRP10 in Lewy
bodies and whether a possible interaction between LRP10 and α -synuclein plays a role in disease pathoge nesis. Here, we demons
trate that wild-type LRP10 is secreted via extracellular vesicles (E Vs) and can be internalised via clathrin-dependent endocytosis.
Addnl., we show that LRP10 secretion is highly sensitive to autophagy inhibition , which induces the formation of atypical LRP10
vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that
LRP10 overexpression leads to a strong induction of monomeric α -synuclein secretion, together with time- dependent, stress-
sensitive changes in intrace llular α -synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5 G > A LRP10
variant secrete aberrant high-mol.-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-
derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonizes the effect of L
RP10 on α -synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of L RP10 in L
BDs by modulating intra- and extrace llular α -synuclein levels, and pathogenic mechanisms linked to the disease- associated c.1424
+ 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs. Graphical abstract: [graphic not
available: see fulltext]
Keywords: Astrocytes; Brain organoids; Dementia with Lewy bodies (D LB); Extracellular vesicles (E Vs); Induced plurip otent stem cells
(iPSC); Lewy body diseases (L BDs); Low-density lipoprotein receptor-related protein 10 (LRP10); Parkinson’s disease (P D); α -
Synuclein
48
Transcriptomics identifies blunted immunomodulatory effects of vitamin D in people with multiple

sclerosis
By: Yeh, Wei Z.; Lea, Rodney; Stankovich, Jim; Sampangi, Sandeep; Laverick, Louise; Van der Walt, Anneke; Jokubaitis, Vilija; Gresle,
Melissa; Butzkueven, Helmut
Abstract: Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). However, the immune effects of vitamin D in
people with MS are not well unders tood. We analyzed transcr iptomic datasets generated by R NA sequencing of immune cell
subsets (CD4+, CD8+ T cells, B cells, monocytes) from 33 healthy controls and 33 untreated M S cases. We utilized a tradit ional bioinfo
rmatic pipeline and weighted gene co- expression network anal. (WGCNA) to determine genes and pathways correlated with
endogenous vitamin D. In controls, CD4+ and CD8+ T cells had 1079 and 1188 genes, resp., whose expres sions were correlated with
plasma 25-hydroxyvitamin D level (P < 0.05) . Functional enrichment anal. identified associ ation with TN F-alpha and MAPK signaling.
In CD4+ T cells of controls, vitamin D level was associated with expression levels of several genes proximal to multiple sclerosis risk
loci (P = 0.01). Genes differentially associated with endogenous vitamin D by case- control status were enriched in TN F-alpha
signaling via NF-κB. WGCNA suggested a blunted response to vitamin D in cases relative to controls. Collect ively, our findings
provide further evidence for the immune effects of vitamin D, and demonstrate a differential immune response to vitamin D in
cases relative to controls, highlighting a possible mechanism contri buting to MS pathophysiol.

49
Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
By: Luo, Zhangyi; Huang, Yixian; Batra, Neelu; Chen, Yuang ; Huang, Haozhe; Wang, Yifei; Zhang, Ziqian ; Li, Shichen; Chen,
Chien-Yu; Wang, Zehua ; et al
The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identi fying a target that is
critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. i Rhom1 plays a role
in cancer cell proliferation and its expression is neg. correlated with immune cell infiltr ation. Here we show that i Rhom1 decreases
chemotherapy sensitivity by regulating the M APK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by
reducing the stability of ERAP1 protein and the E RAP1-mediated antigen processing and presentation. To facilitate the therapeutic
translation of these findings, we develop a biodegr adable nanocarrier that is effective in codelivery of i Rhom pre-siRNA (pre-sii
Rhom) and chemotherapeutic drugs. This nanoca rrier is effective in tumor targeting and penetr ation through both enhanced
permeability and retention effect and C D44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of i
Rhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a
chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenv ironment in multiple cancer
models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo- immune
resistance in cancer treatment.
Keywords: inhibition iRhom CD nanocarrier cancer immunochemotherapy
50
Flavonoids as dual-target inhibitors against α -glucosidase and α -amylase: a systematic review of in

vitro studies
By: Lam, Thua-Phong ; Tran, Ngoc-Vi Nguyen; Pham, Long-Hung Dinh ; Lai, Nghia Vo-Trong ; Dang, Bao-Tran Ngoc ;
Truong, Ngoc-Lam Nguyen; Nguyen-Vo, Song-Ky; Hoang, Thuy-Linh ; Mai, Tan Thanh ; Tran, Thanh-Dao
Abstract: Diabetes mellitus remains a major global health issue, and great attention is directed at natural therapeutics. This
systematic review aimed to assess the potential of flavonoids as antidiabetic agents by investigating their inhibitory effects on α -
glucosidase and α -amylase, two key enzymes involved in starch digestion. Six scientific databases (Pub Med, Virtual Health Library, E
MBASE, SCOPUS, Web of Science, and WHO Global Index Medicus) were searched until August 21, 2022, for in vitro studies
reporting IC50 values of purified flavonoids on α -amylase and α -glucosidase, along with corresp onding data for acarbose as a pos.
control. A total of 339 eligible articles were analyzed, resulting in the retrieval of 1643 flavonoid structures. These structures were
rigorously standardized and curated, yielding 974 unique compounds, among which 177 flavonoids exhibited inhibition of both α -
glucosidase and α -amylase are presented. Quality assessment utilizing a modified C ONSORT checklist and structure- activity relati
onship (SAR) anal. were performed, revealing crucial features for the simult aneous inhibition of flavonoids against both enzymes.
Moreover, the review also addressed several limitations in the current research landscape and proposed potential solutions The
curated datasets are available online at https://github.com/MedChemUMP/FDIGA. Graphical Abstract: [graphic not available: see
fulltext]
Keywords: Amylase; Dual-target; Flavonoids; Glucosidase; PRISMA; SAR; Systematic review

51
Adhesion, metastasis, and inhibition of cancer cells: a comprehensive review
By: Yayan, Josef; Franke, Karl-Josef; Berger, Melanie; Windisch, Wolfram; Rasche, Kurt
Abstract: This comprehensive review delves into cancer′s comple xity, focusing on adhesion, metastasis, and inhibition . It explores
the pivotal role of these factors in disease progression and therapeutic strategies. This review covers cancer cell migration, invasion,
and colonization of distant organs, emphasizing the significance of cell adhesion and the intricate metastasis process. Inhibition
approaches targeting adhesion mols., such as integrins and cadherins, are discussed. Overall, this review contributes significantly to
advancing cancer research and developing targeted therapies, holding promise for improving patient outcomes worldwide.
Exploring different inhibition strategies revealed promising therap eutic targets to alleviate adhesion and metastasis of cancer cells.
The effectiveness of integrin-blocking antibodies, small mol. inhibitors targeting Focal adhesion kinase (F AK) and the Transforming
Growth Factor β (TGF-β) pathway, and combin ation therapies underscores their potential to disrupt focal adhesions and control
epithelial-mesenchymal transition processes. The identif ication of as FAK, Src, β-catenin and SMAD4 offers valuable starting points
for further research and the development of targeted therapies. The complex interrelationships between adhesion and metastatic
signaling networks will be relevant to the development of new treatment approa ches.
Keywords: Adhesion; Cancer; Inhibition ; Metastasis; Targeted therapies; Therapeutic approaches
52
A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition
By: Biswal, Mahamaya; Yao, Wangyuan; Lu, Jiuwei ; Chen, Jianbin; Morrison, Juliet; Hai, Rong ; Song, Jikui
Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (N S5) for both replic ation of
viral genome and suppression of host I FN signaling. DENV and ZIKV NS5s were shown to facilitate proteosome-mediated protein
degradation of human S TAT2 (hSTAT2). However, how flavivirus N S5s have evolved for species-specific IFN-suppression remains
unclear. Here we report structure-function characterization of the DENV serotype 2 (DENV2) NS5-hSTAT2 complex. The M Tase and
RdRP domains of DENV2 NS5 form an extended confor mation to interact with the coiled-coil and N-terminal domains of h STAT2,
thereby promoting hSTAT2 degradation in cells. Disruption of the extended confor mation of DENV2/ZIKV NS5, but not the altern
ative compact state, impaired their h STAT2 binding. Our comparative structural anal. of flavivirus N S5s further reveals a conserved
protein-interaction platform with subtle amino- acid variations likely underp inning diverse IFN-suppression mechanisms. Together,
this study uncovers a conformational selection mechanism underlying species- specific hSTAT2 inhibition by flavivirus N S5.
Keywords: flavivirus ZIKV DENV STAT2 inhibition NS5 RdRP MTase interferon

53
Inhibition of mitochondrial cyclophilin D, a downstream target of glycogen synthase kinase 3α,

improves sperm motility
By: Park, Seung Hyun; Gye, Myung Chan

Reproductive Biology and Endocrinology (2024), 22(1), 15 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Cyclophilin D (CypD) neg. regulates A TP production by opening of the mitocho ndrial permeability transition
pore. This study aimed to understand the role of CypD in sperm motility regulation. Methods: Changes in CypD during sperm capaci
tation and its interaction with glycogen synthase kinase 3α (G SK3α), a key kinase regulating sperm motility, were examined in mouse
spermatozoa. The effects of CypD inhibitor cyclosporin A (Cs A) and GSK3 inhibitor 6-bromo-indirubin-3′-oxime (BIO) on sperm
motility, p-GSK3α(Ser21), mitochondrial permeability transition pore (m PTP), mitochondrial membrane potential (MMP), and ATP
production were examined The effect of proteasome inhibitor MG115 on the cellular levels of CypD was examined Results: In cauda
epididymal spermatozoa, GSK3α was found in both cytosolic and mitocho ndrial fractions whereas CypD was primarily found in the
mitochondrial fraction together with A TP synthase F1 subunit alpha (ATP5A), a mitochondrial marker. GSK3α and CypD were co-
localized in the sperm midpiece. Interaction between GSK3α and CypD was identified in coimmunoprecipitation CsA, a CypD
inhibitor, significantly increased sperm motility, tyrosine phosphor ylation, mPTP closing, MMP, and ATP levels in spermatozoa,
suggesting that CypD acts as a neg. regulator of sperm function. Under capaci tation condition, both G SK3α and CypD were
decreased in spermatozoa but ATP5A was not. The GSK3 inhibitor BIO markedly increased p-GSK3α(Ser21) and decreased Cyp D but
significantly increased mPTP closing, MMP, ATP production, and motility of sperma tozoa. This suggests that inhibitory phosphor
ylation of GSK3α is coupled with degradation of CypD, potentiating the mitochondrial function. Degrad ation of CypD was
attenuated by MG115, indicative of involvement of the ubiquitin proteasome system. Conclusions: During sperm capacit ation, CypD
act as a downstream target of GSK3α can be degraded via the ubiquitin proteasome system, stimul ating mitochondrial function and
sperm motility.
Keywords: Cyclophilin D; GSK3; Motility regulation; Mouse; Spermatozoa
54
The recombinant L-lysine α -oxidase from the fungus Trichoderma harzianum promotes apoptosis
and necrosis of leukemia CD34 + hematopoietic cells
By: Costa, Mariana do Nascimento; Silva, Thiago Aparecido; Guimaraes, Dimitrius Santiago Passos Simoes Froes; Ricci-Azevedo,
Rafael; Teixeira, Felipe Roberti; Silveira, Leonardo Reis; Gomes, Marcelo Damario; Faca, Vitor Marcel; de Oliveira, Eduardo Brandt;
Calado, Rodrigo T.; et al
Microbial Cell Factories (2024), 23(1), 51 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: In hematol. cancers, including leukemia, cells depend on amino acids for rapid growth. Anti- metabolites that
prevent their synthesis or promote their degradation are considered potential cancer treatment agents. Amino acid depriv ation
triggers proliferation inhibition , autophagy, and programmed cell death. L-lysine, an essential amino acid, is required for tumor
growth and has been investigated for its potential as a target for cancer treatment. L-lysine α -oxidase, a flavoenzyme that degrades
L-lysine, has been studied for its ability to induce apoptosis and prevent cancer cell prolife ration. In this study, we describe the use
of L-lysine α -oxidase (LO) from the filamentous fungus Trichoderma harzianum for cancer treatment. Results: The study identified
and characterized a novel LO from T. harzianum and demons trated that the recombinant protein (rLO) has potent and selective
cytotoxic effects on leukemic cells by triggering the apoptotic cascade through mitochondrial dysfunction. Conclusions: The results
support future translational studies using the recombinant LO as a potential drug for the treatment of leukemia.
Keywords: Cancer treatment; L-lysine α -oxidase; Leukemia; Trichoderma harzianum

55
Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice
By: Ni, Hai ; Wang, Yinuo; Yao, Kai; Wang, Ling; Huang, Jiancheng; Xiao, Yongfang; Chen, Hongyao; Liu, Bo ; Yang, Cliff Y. ;
Zhao, Jijun
Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythem atosus (SLE). However, the mol.
mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl- protein thioes
terase 1 (P PT1) regulates systemic autoimmunity by removing S- palmitoylation from TLR9 in lysosomes. PPT1 promotes the
secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TN F by macrophages. Genetic deficiency in or chem. inhibition of PP
T1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with S LE,
the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochem. and mass spectrometry analyses demons
trated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltran sferase, DHHC3, palmitoylates TLR9 in the
Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmit oylation by PPT1 facilitates the release of TLR9 from UN
C93B1. Our results reveal a posttrans lational modification cycle that controls T LR9 response and autoimmunity.
Keywords: palmitoylation TLR9 signalling autoimmunity systemic lupus erythematosus
56
Isatin-tethered halogen-containing acylhydrazone derivatives as monoamine oxidase inhibitor with

neuroprotective effect
By: Kumar, Sunil; Oh, Jong Min; Prabhakaran, Prabitha; Awasti, Abhimanyu; Kim, Hoon; Mathew, Bijo
Abstract: Sixteen isatin-based hydrazone derivatives (IS1-IS16) were synthesized and assessed for their ability to inhibit monoamine
oxidases (MAOs). All the mols. showed improved inhibitory M AO-B activity compared to M AO-A. Compound IS7 most potently
inhibited MAO-B with an IC50 value of 0.082 μ M, followed by I S13 and IS6 (IC50 = 0.104 and 0.124 μ M, resp.). Compound IS15 most
potently inhibited MAO-A with an IC50 value of 1.852 μ M, followed by I S3 (IC50 = 2.385 μ M). Compound IS6 had the highest select
ivity index (SI) value of 263.80, followed by I S7 and IS13 (233.85 and 212.57, resp.) . In the kinetic study, the K i values of IS6, IS7, and I
S13 for M AO-B were 0.068 ± 0.022, 0.044 ± 0.002, and 0.061 ± 0.001 μ M, resp., and that of I S15 for M AO-A was 1.004 ± 0.171 μ M,
and the compounds were reversible-type inhibitors. The lead compounds were central nervous system (C NS) permeable, as per
parallel artificial membrane permeability assay (PAMPA) test results. The lead compounds were examined for their cytoto xicity and
potential neuroprotective benefits in hazardous lipopolys accharide (LPS)-exposed SH-SY5Y neuroblastoma cells. Pre-treatment with
lead compounds enhanced anti-oxidant levels (SOD, CAT, GSH, and GPx) and decreased R OS and pro-inflammatory cytokine (IL-6, T
N F-alpha , and NF-kB) production in LPS-intoxicated SH-SY5Y cells. To confirm the promising effects of the compound, mol. docking,
dynamics, and MM-GBSA binding energy were used to examine the mol. basis of the I S7-MAO-B interaction. Our findings indicate
that lead compounds are potential therapeutic agents to treat neurol. illnesses, such as Parkinson′s disease.

57
Study on synergistic inhibition and mechanism of flotation separation of fluorite and calcite by tannin
and sodium humate
By: Zhu, Zhi-xiong; Nie, Guang-Hua; Tang, Yun; Jiang, Ying; Tuo, Biyang; Li, Jiaxin
At present, the separation technol. of fluorite and calcite is still immature, and the research in this paper can promote the improv
ement of the separation technol. of fluorite and calcite. The selective inhibition mechanism of tannin and humate sodium on calcite
was studied by means of actual ore flotation test, single mineral flotation test, Zeta potential measurement and FT-IR spectroscopy.
The results show that the mixture of tannin and sodium humate inhibitor has a good inhibitory effect on carbonate under weak alk.
condition. The reaction products of sodium humate, tannin and calcium ions in solution interact with organic compounds adsorbed
on the surface of calcite, forming multilayer adsorption on the surface of calcite, making calcite more hydrophilic. Based on d.
functional theory, Materials Studio (MS) was used to calculate the relevant adsorption energy, and the result was as follows: (a)
compared with fluorite, tannin and humate sodium mols. are more easily adsorbed on the surface of calcite. (b) Compared with
calcite alone adsorption of tannin mols. or sodium humate mols., the adsorption state will be more stable, and the effect of tannin
and sodium humate synergistic inhibition of calcite is better than the effect of inhibition alone. Therefore, using tannin and
sodium humate as a combination inhibitor can effectively sep. fluorite and calcite, which will promote the develo pment and utiliz
ation of fluorite ore in industry.
Keywords: fluorite calcite tannin sodium humate flotation separation synergistic inhibition

58
RUNX1 targeting AKT3 promotes alveolar hypercoagulation and fibrinolytic inhibition in LPS induced
ARDS
By: Xiao, Chuan; Liu, Jiaoyangzi; Cheng, Yumei; Wu, Yingxia; Li, Qing; Chen, Xianjun; Yuan, Jia; Dong, Qi; Li, Lu; liu, Ying; et al
Respiratory Research (2024), 25(1), 54 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Alveolar hypercoa gulation and fibrinolytic inhibition are mainly responsible for massive alveolar fibrin deposi
tion, which are closely related with refractory hypoxemia in acute respir atory distress syndrome (A RDS). Our previous study
testified runt-related transcription factor (RUNX1) participated in the regulation of this pathoph ysiol. in this syndrome, but the
mechanism is unknown. We speculate that screening the downstream genes associated with RUNX1 will presumably help uncover
the mechanism of RUNX1. Methods: Genes associated with R UNX1 were screened by C HIP-seq, among which the target gene was
verified by Dual Luciferase experiment Then the efficacy of the target gene on alveolar hypercoagulation and fibrinolytic inhibition
in LPS-induced ARDS was explored in vivo as well as in vitro. Finally, whether the regulatory effects of R UNX1 on alveolar hypercoa
gulation and fibrinolytic in ARDS would be related with the screened target gene was also suffic iently explored. Results: Among
these screened genes, AKT3 was verified to be the direct target gene of R UNX1. Results showed that A KT3 was highly expressed
either in lung tissues of LPS-induced rat ARDS or in LPS-treated alveolar epithelia cell type I I (AECII). Tissue factor (TF) and plasmi
nogen activator inhibitor 1 (P AI-1) were increasingly expressed both in lung tissues of A RDS and in LPS-induced AECII, which were all
significantly attenuated by downregulation of AKT3. Inhibition of AKT3 gene obviously amelio rated the LPS-induced lung injury as
well as the collagen I expression in ARDS. RUNX1 overexpression not only promoted the expres sions of TF, PAI-1, but also boosted A
KT3 expression in vitro. More import antly, the efficacy of RUNX1 on TF, PAI-1 were all effectively reversed by downregulation of AK
T3 gene. Conclu sion: AKT3 is an important target gene of R UNX1, through which RUNX1 exerted its regulatory role on alveolar
hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS. RUNX1/ATK3 signaling axis is expected to be a new target for the
exploration of ARDS genesis and treatment.
Keywords: AKT3; Acute respiratory distress syndrome; Alveolar hypercoag ulation; Fibrinolytic inhibition ; Runt-related transcription
factor 1
59
ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
By: Maas-Bauer, Kristina ; Stell, Anna-Verena ; Yan, Kai-Li; de Vega, Enrique; Vinnakota, Janaki Manoja; Unger, Susanne; Nunez,
Nicolas; Norona, Johana ; Talvard-Balland, Nana; Kossmann, Stefanie; et al
Abstract: Patients with corticosteroid-refractory acute graft-vs.-host disease (aGVHD) have a low one-year survival rate. Identif
ication and validation of novel targetable kinases in patients who experience corticos teroid-refractory-aGVHD may help improve
outcomes. Kinase-specific proteomics of leukocytes from patients with corticos teroid-refractory-GVHD identified rho kinase type 1
(ROCK1) as the most significantly upregulated kinase. ROCK1/2 inhibition improved survival and histol. G VHD severity in mice and
was synergistic with JAK1/2 inhibition , without compromising graft-vs.-leukemia-effects. ROCK1/2- inhibition in macrophages or
dendritic cells prior to transfer reduced GVHD severity. Mechanistically, ROCK1/2 inhibition or ROCK1 knockdown interfered with C
D80, CD86, MHC-II expression and IL-6, IL-1β, iNOS and TN F production in myeloid cells. This was accomp anied by impaired T cell
activation by dendritic cells and inhibition of cytoskeletal rearrangements, thereby reducing macrophage and D C migration. N F-κB
signaling was reduced in myeloid cells following ROCK1/2 inhibition . In conclusion, ROCK1/2 inhibition interferes with immune
activation at multiple levels and reduces acute GVHD while maintaining GVL-effects, including in corticosteroid-refractory settings.

60
Synergistic potential of α -Phellandrene combined with conventional antifungal agents and its
mechanism against antibiotic resistant Candida albicans
By: Bhattacharya, Riya; Sharma, Prashant; Bose, Debajyoti ; Singh, Manish

CABI Agriculture and Bioscience (2024), 5(1), 17 | Language: English, Database: CAplus
Abstract: Candida albicans is resistant to various antifungal drugs, this presents a significant problem on a global scale. This study
investigates a novel approach on the potential fungicidal effects of α -Phellandrene combinations with fluconazole and amphot
ericin B against antibiotic resistant C. albicans. The agar well diffusion experiment was used to measure the anti- candida activity of
α -Phellandrene which exhibited a zone of inhibition of 24 ± 0.5 mm and 22 ± 0.5 mm against the C. albicans cells (M TCC277 and A
TCC90028), resp. Addnl., the fungicidal min. inhibitory concent ration (MIC) ranged 0.0312-0.0156 mg/mL (w/v) against C. albicans
strains. It was determined to have powerful and efficient antifungal action against Candida cells. Further, the synergistic potential
was evaluated by employing a time kill assay and a checkerboard technique, resp., which revealed after 16 h, the colony count of C.
albicans cells ATCC90028 (2.56 ± 0.33) and M TCC277 (2.53 ± 0.33) dropped by a log10 when treated with a combin ation of α -Phella
ndrene and Fluconazole and α -Phellandrene and amphotericin B exhibited synergy against both C. albicans strains A TCC90028
and MTCC277 (2.42 ± 0.28 and 2.00 ± 0.21) l og10 reduction in colony count, resp., Addnl., 16- 624-fold increase in the antifungal
efficacy of clin. medicines, with total cell death occurring after 16 h. α -Phellandrene and antifungal drugs were tested in combin
ation with the osmoprotectant test, ergosterol test and F ESEM observations to determine their modes of action. In the era of
multidrug-resistant diseases antibiotic resistance can be curtailed in its tracks with the help of combin ation treatments that allow
for lower drug doses.
61
Aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamides as potent α -

glucosidase inhibitors; molecular dynamics, kinetic and structure-activity relationship studies
By: Hamedifar, Haleh; Mirfattahi, Mahroo; Khalili Ghomi, Minoo; Azizian, Homa; Iraji, Aida; Noori, Milad; Moazzam, Ali; Dastyafteh,
Navid; Nokhbehzaim, Ali; Mehrpour, Katayoun; et al
Abstract: Regarding the important role of α -glucosidase enzyme in the management of type 2 diabetes mellitus, the current study
was established to design and synthesize aryl- quinoline-4-carbonyl hydrazone bearing different 2- methoxyphenoxyacetamide (11a-
o) and the structure of all deriva tives was confirmed through various techniques including I R, 1H-NMR, 13 C-NMR and elemental
anal. Next, the α -glucosidase inhibitory potentials of all derivatives were evaluated, and all compounds displayed potent inhibition
with IC50 values in the range of 26.0 ± 0.8- 459.8 ± 1.5 μ M as compared to acarbose used as control, except 11f and 11l. Addnl., in
silico-induced fit docking and mol. dynamics studies were performed to further invest igate the interaction, orientation, and confor
mation of the newly synthesized compounds over the active site of α -glucosidase.

62
Crosstalk with renal proximal tubule cells drives acidosis-induced inflammatory response and
dedifferentiation of fibroblasts via p38-singaling
By: Schulz, Marie-Christin; Kopf, Michael; Gekle, Michael

Cell Communication and Signaling (2024), 22(1), 148 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Tubulointerstitial kidney disease associated microenvironmental dysregulation, like acidification, inflam
mation and fibrosis, affects tubule cells and fibrob lasts. Micromilieu homeostasis influences intrace llular signaling and interce llular
crosstalk. Cell-cell communication in turn modulates the interstitial microenvironment. We assessed the impact of acidosis on
inflammatory and fibrotic responses in proximal tubule cells and fibrob lasts as a function of cellular crosstalk. Furthe rmore, cellular
signaling pathways involved were identified. Methods: HK-2 (human proximal tubule) and C CD-1092Sk (human fibrob lasts), in mono
and coculture, were exposed to acidic or control media for 3 or 48 h. Protein expression of inflammation markers ( TN F , TGF-ss and
COX-2), dedifferentiation markers (N-cadherin, vinculin, ss-catenin and vimentin), fibrosis markers (collagen III and fibronectin) and
phospho- as well as total MAPK levels were determined by western blot. Secreted collagen I II and fibronectin were measured by E LI
SA. The impact of M APK activation was assessed by pharmacol. interve ntion. In addition, necrosis, apoptosis and epithelial permea
bility were determined Results: Independent of culture condit ions, acidosis caused a decrease of C OX-2, vimentin and fibronectin
expression in proximal tubule cells. Only in monoculture, ss-Catenin expression decreased and collagen I II expression increased in
tubule cells during acidosis. By contrast, in coculture collagen III protein expression of tubule cells was reduced. In fibrob lasts
acidosis led to an increase of TN F , COX-2, vimentin, vinculin, N-cadherin protein expression and a decrease of T GF-ss expression
exclusively in coculture. In monocu lture, expression of COX-2 and fibronectin was reduced. Collagen I II expression of fibroblasts
was reduced by acidosis independent of culture condit ions. In coculture, acidosis enhanced phosphorylation of ERK1/2, JNK1/2 and
p38 transiently in proximal tubule cells. In fibrob lasts, acidosis enhanced phosphorylation of p38 in a sustained and very strong
manner. ERK1/2 and JNK1/2 were not affected in fibrob lasts. Inhibition of JNK1/2 and p38 under coculture conditions reduced
acidosis-induced changes in fibroblasts significantly. Conclusions: Our data show that the crosstalk between proximal tubule cells
and fibroblasts is crucial for acidosis-induced dedifferentiation of fibroblasts into an inflam matory phenotype. This dedifferentiation
is at least in part mediated by p38 and JNK1/2. Thus, cell-cell communication is essential for the pathophysiol. impact of tubuloint
erstitial acidosis.
Keywords: Cellular crosstalk; Chronic kidney diseases; Dedifferentiation; Extracellular acidosis; Inflamm ation; JNK1/2; MAPK-
Signaling; p38

63
Targeting an inflammation-amplifying cell population can attenuate osteoarthritis-associated pain
By: Pandey, Akshay; Singla, Mamta; Geller, Ana; Goodman, Stuart B.; Bhutani, Nidhi
Arthritis Research & Therapy (2024), 26(1), 53 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Understanding of pain in osteoarthritis, its genesis, and perception is still in its early stages. Identif ication of
precise ligand-receptor pairs that transduce pain and the cells and tissues in which they reside will elucidate new therap eutic
approaches for pain management. Our recent studies had identified an inflamm ation-amplifying (Inf-A) cell population that is
expanded in human OA cartilage and is distinctive in the expression of both I L1R1 and TN F -R2 receptors and active Jnk signaling
cascade. Methods: In this study, we have tested the function of the cartilage-resident IL1R1 +TN F -R2 + Inf-A cells in OA. We have
identified that the IL1R1 +TN F -R2 + Inf-A cells expand in aged mice as well as after anterior cruciate ligament tear upon tibia loading
and OA initiation in mice. We targeted and modulated the Jnk signaling cascade in Inf A through competitive inhibition of Jnk
signaling in mice and human OA explants and tested the effects on joint structure and gait in mice. Results: Modulation of Jnk
signaling led to attenuation of inflammatory cytokines CCL2 and CCL7 without showing any structural improvements in the joint
architecture. Interestingly, Jnk inhibition and lowered C CL2 and 7 are sufficient to significantly improve the gait parameters in
treated PTOA mice demonstrating reduced OA-associated pain. Consistent with the mice data, treatment with J NK inhibitor did not
improve human OA cartilage explants. Conclusion: These studies demons trate that Inf-A, an articular-cartilage resident cell popula
tion, contributes to pain in OA via secretion of CCL2 and 7 and can be targeted via inhibition of Jnk signaling.
Keywords: Inflammation; Osteoarthritis; Pain; Senescence
64
Reduced progranulin increases tau and α -synuclein inclusions and alters mouse tauopathy
phenotypes via glucocerebrosidase
By: Takahashi, Hideyuki ; Bhagwagar, Sanaea ; Nies, Sarah H. ; Ye, Hongping; Han, Xianlin ; Chiasseu, Marius T.; Wang,
Guilin; Mackenzie, Ian R.; Strittmatter, Stephen M.
Abstract: Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer′s disease (AD),
increase with age, and influence clin. outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progra
nulin (PGRN), a lysosomal protein associated with T DP-43 proteinopathy, also increases tau inclusions, causes concomitant accumu
lation of α -synuclein and worsens mortality and disinh ibited behaviors in tauopathy mice. The increased inclusions paradox ically
protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity
of β-glucocerebrosidase (GCase), a protein previously associated with synuclei nopathy, while increasing glucosylceramide (GlcCer)-
pos. tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified Glc
Cer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopa thies are also GlcCer-immunoreactive. Thus,
in addition to TDP-43, PGRN regulates tau- and synuclein opathies via GCase and GlcCer. A lysosomal PGRN-GCase pathway may be
a common therapeutic target for age- related comorbid proteinopathies.

65
Phosphorylated α -synuclein deposited in Schwann cells interacting with TLR2 mediates cell damage
and induces Parkinson′s disease autonomic dysfunction
By: Li, Yangxia; Tong, Qing; Wang, Ye; Cheng, Yue; Geng, Yao; Tian, Tian; Yuan, Yongsheng; Fan, Yi; Lu, Ming; Zhang, Kezhong
Cell Death Discovery (2024), 10(1), 52 | Language: English, Database: CAplus and MEDLINE
Abstract: Despite the significant frequency of autonomic dysfunction (AutD) in Parkinson′s disease (PD) patients, its pathogenesis
and diagnosis are challenging. Here, we aimed to further explore the mechanism of phospho rylated α -synuclein (p- α -syn)
deposited in vagus nerve Schwann cells (SCs) causing SCs damage and P D AutD. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPT
P, 20 mg/kg) was adminis trated to C57BL/6 mice twice a week for 35 days. Following the final injection, locomotor functions,
gastrointestinal symptoms, urine functions, and cardiov ascular system functions were evaluated. Meanwhile, we examined p- α -syn
deposited in vagus nerve SCs, Toll-like receptor 2 (TLR2) activation, and SCs loss using immunofluorescence, western blot, and Luxol
fast blue staining. In vitro, the rat SCs line RSC96 cells were exposed to α -synuclein preformed fibril ( α -syn PFF), and cell viability
was detected by CCK8. Co-IP was used to identify the interaction between p- α -syn and TLR2. Furthermore, the role of T LR2 in p- α -
syn-mediated SCs damage was confirmed by the adminis tration of CU-CPT22, a specific blocker of T LR2. In vivo, apart from dyskin
esia, MPTP mice exhibited constipation, urinary dysfunction, and cardiov ascular failure, which were associated with the deposition
of p- α -syn in vagus nerve S Cs, TLR2 activation, and vagus nerve demyeli nation. In vitro, stimulation of α -syn PFF induced a time-
dependent loss of viability, and p- α -syn deposited in RSC96 cells induced a cellular inflam matory response by interacting with TLR2,
resulting in cell dysfunction and apoptosis. However, both S Cs inflammatory response and cell viability were alleviated after
inhibition of TLR2. Furthermore, 1 h fecal pellets and water content, the frequency of 1 h urine, blood pressure, heart rate, and
heart rate variability of mice in the M PTP + CU-CPT22 group were also improved. Our results support the perspe ctive that p- α -syn
interacts with TLR2 induced SCs damage and is involved in P D AutD, which sheds fresh light on the mechanism of P D AutD and
indicates a promising treatment for PD AutD targeting SCs p- α -syn/ TLR2 signaling pathway.
66
α -Ketoglutarate supplementation and NAD+ modulation enhance metabolic rewiring and

radiosensitization in SLC25A1 inhibited cancer cells
By: Xiang, Kexu; Kunin, Mikhail; Larafa, Safa ; Busch, Maike; Duenker, Nicole; Jendrossek, Verena ; Matschke, Johann
Abstract: Metabolic rewiring is the result of the increasing demands and proliferation of cancer cells, leading to changes in the biol.
activities and responses to treatment of cancer cells. The mitochondrial citrate transport protein S LC25A1 is involved in metabolic
reprogramming offering a strategy to induce metabolic bottle necks relevant to radiosensitization through the accumulation of the
oncometabolite D-2-hydroxyglutarate (D-2HG) upon SLC25A1 inhibition (SLC25A1i). Previous studies have revealed the compar
ative effects of SLC25A1i or cell-permeable D-2HG (octyl-D-2HG) treatments on DNA damage induction and repair, as well as on
energy metabolism and cellular function, which are crucial for the long-term survival of irradiated cells. Here, α -ketoglutarate (αKG)
, the precursor of D-2HG, potentiated the effects observed upon S LC25A1i on DNA damage repair, cell function and long- term
survival in vitro and in vivo, rendering NCI-H460 cancer cells more vulnerable to ionizing radiation. However, α KG treatment alone
had little effect on these phenotypes. In addition, supplementation with nicotinamide (NAM), a precursor of N AD (including NAD+
and NADH), counteracted the effects of S LC25A1i or the combination of SLC25A1i with αKG, highlighting a potential importance of
the NAD+/NADH balance on cellular activities relevant to the survival of irradiated cancer cells upon S LC25A1i. Furthermore,
inhibition of histone lysine demeth ylases (KDMs), as a major factor affected upon SLC25A1i, by J IB04 treatment alone or in combin
ation with αKG supplementation phenocopied the broad effects on mitocho ndrial and cellular function induced by S LC25A1i. Taken
together, αKG supplementation potentiated the effects on cellular processes observed upon S LC25A1i and increased the cellular
demand for NAD to rebalance the cellular state and ensure survival after irradi ation Future studies will elucidate the underlying
metabolic reprogramming induced by S LC25A1i and provide novel therapeutic strategies for cancer treatment.

67
Catalyst-free late-stage functionalization to assemble α -acyloxyenamide electrophiles for selectively

profiling conserved lysine residues
By: Zhao, Yuanyuan ; Duan, Kang; Fan, Youlong; Li, Shengrong; Huang, Liyan; Tu, Zhengchao; Sun, Hongyan; Cook, Gregory M.;
Yang, Jing; Sun, Pinghua ; et al
Communications Chemistry (2024), 7(1), 31 | Language: English, Database: CAplus and MEDLINE
Abstract: Covalent probes coupled with chem. proteomics represent a powerful method for investigating small mol. and protein
interactions. However, the creation of a reactive warhead within various ligands to form covalent probes has been a major obstacle.
Herein, we report a convenient and robust process to assemble a unique electrophile, an α -acyloxyenamide, through a one-step
late-stage coupling reaction. This procedure demons trates remarkable tolerance towards other functional groups and facili tates
ligand-directed labeling in proteins of interest. The reactive group has been succes sfully incorporated into a clin. drug targeting the
EGFR L858R mutant, erlotinib, and a pan- kinase inhibitor. The resulting probes have been shown to be able to covalently engage a
lysine residue proximal to the ATP-binding pocket of the EGFR L858R mutant. A series of active sites, and Mg 2+ , ATP-binding sites of
kinases, such as K33 of CDK1, CDK2, CDK5 were detected. This is the first report of engaging these conserved catalytic lysine
residues in kinases with covalent inhibition . Further applic ation of this methodol. to natural products has demons trated its success
in profiling ligandable conserved lysine residues in whole proteome. These findings offer insights for the development of new
targeted covalent inhibitors (TCIs).
68
Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer
By: Jones, Vivian Truong; Graves-Deal, Ramona; Cao, Zheng; Bogatcheva, Galina; Ramirez, Marisol A.; Harmych, Sarah J.;
Higginbotham, James N.; Sharma, Vineeta; Damalanka, Vishnu C.; Wahoski, Claudia C.; et al
Abstract: Although amplifications and mutations in receptor tyrosine kinases (R TKs) act as bona fide oncogenes, in most cancers, R T
Ks maintain moderate expression and remain wild- type. Consequently, cognate ligands control many facets of tumorig enesis,
including resistance to anti-RTK therapies. Herein, we show that the ligands for the R TKs MET and R ON, HGF and HGFL, resp., are
synthesized as inactive precursors that are activated by cellular proteases. Our newly generated H GF/HGFL protease inhibitors
could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was
necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be
overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibi tors. Addnl., HAI-1, an endogenous inhibitor of
HGF proteases, (i) was downreg ulated in CRC, (ii) exhibited increased genomic methyl ation that correlated with poor prognosis, (iii)
HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recomb inant HA
I-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a target able, autocrine HAI-1/Protease/HGF/MET axis in
cetuximab resistance in CRC.
Keywords: 3D culture; Cetuximab; Colorectal cancer; Crizot inib; Drug resistance; EGFR; HAI-1; HGF; MET; Protease inhibition

69
RUNX3 pathway signature predicts clinical benefits of immune checkpoint inhibition plus tyrosine
kinase inhibition in advanced renal cell carcinoma
By: Wang, Jiajun; Zhang, Sihong; Wang, Ying; Zhu, Yanjun; Xu, Xianglai; Guo, Jianming
BMC Urology (2024), 24(1), 8 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (I O/TKI) have been recently recomm
ended as standard first-line therapy for advanced renal cell carcinoma, while no clin.- available biomarker has been applied. This
study aimed to investigate the associations between R UNX3 pathway signature and I O/TKI benefits in renal cell carcinoma (R CC).
Methods: Two IO/TKI cohorts (ZS-MRCC, JAVELIN-101) and one high-risk localized RCC cohort (ZS-HRRCC) were included. All samples
were evaluated by RNA-sequencing, and RUNX Family Transcription Factor 3 (R UNX3) pathway were determined by single sample
gene set enrichment anal. Flow cytometry were applied for immune cell infiltration and function. Results: R UNX3 signature was
elevated in RCC samples, compared non- tumor tissues (P < 0.001) . High-RUNX3 signature was associated with shorter progre ssion-
free survival (PFS) in both I O/TKI cohorts (ZS-MRCC cohort, P = 0.025; JAVELIN-101 cohort, P = 0.019). RUNX3 signature also
predicted IO/TKI benefit in advanced R CC, compared with T KI monotherapy (interaction p = 0.027) . RUNX3 signature was associated
with decreased number of GZMB + CD8 + T cells (Spearman′s ρ=- 0.42, P = 0.006), and increased number of PD1 + CD8 + T cells
(Spearman′s ρ = 0.29, P = 0.072). Moreover, the integration of RUNX3 signature and GZMB expression showed predictive potential
for TKI/IO (log-rank P < 0.001). In addition, the predictive value of R UNX3 signature for IO/TKI benefit was restricted in S ETD2-wild
type patients (log-rank P < 0.001). Finally, a risk score was establ ished by random forest for I O/TKI benefit, showing remarkable
predictive potency (Log-rank P < 0.001). Conclusions: RUNX3 pathway signature could be a potential predictive biomarker for I O/TKI
treatment in advanced RCC, for both prognosis and treatment selection between I O/TKI and TKI monotherapy.
Keywords: Immune checkpoint inhibition plus tyrosine kinase inhibition ; Immune evasion; Renal cell carcinoma; Runt- related
transcription factor 3
70
Impaired motor inhibition during perceptual inhibition in older, but not younger adults: a
psychophysiological study
By: Healey, Rebecca; Goldsworthy, Megan; Salomoni, Sauro; Weber, Simon; Kemp, Sarah; Hinder, Mark R.; St George, Rebecca J.
Abstract: The prefrontal cortex (PFC) governs the ability to rapidly cancel planned movements when no longer approp riate (motor
inhibition ) and ignore distracting stimuli (perceptual inhibition ). It is unclear to what extent these processes interact, and how they
are impacted by age. The interplay between perceptual and motor inhibition was investigated using a Flanker Task, a Stop Signal
Task and a combined Stop Signal Flanker Task in healthy young (n = 33, Mean = 24 years) and older adults (n = 32, Mean = 71 years).
PFC activity was measured with functional near-IR spectroscopy (fNIRS), while electromyog. (EMG) measured muscle activity in the
fingers used to respond to the visual cues. Perceptual inhibition (the degree to which incongruent flankers slowed response time
to a central cue) and motor inhibition (the speed of cancel lation of EMG activation following stop cues) indepen dently declined with
age. When both processes were engaged together, PFC activity increased for both age groups, however only older adults exhibited
slower motor inhibition . The results indicate that cortical upregu lation was sufficient to compensate for the increased task
demands in younger but not older adults, suggesting potential resource sharing and neural limitations particularly in older adults.

71
IKKE and TBK1 prevent RIPK1 dependent and independent inflammation
By: Eren, Remzi Onur; Kaya, Goeksu Goekberk ; Schwarzer, Robin; Pasparakis, Manolis
TBK1 and IKKε regulate multiple cellular processes including antiviral type-I interferon responses, metabolism and TN F receptor
signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflam mation and
tissue homeostasis remain poorly unders tood. Here we show that I KKε compensates for the loss of T BK1 kinase activity to prevent
RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused
embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive
versions of IKKε and TBK1 developed systemic inflammation that was induced by both R IPK1-dependent and -independent mechan
isms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced R IPK1-dependent cell death and systemic
inflammation mediated by IL-1 family cytokines. Tissue- specific studies showed that IKKε and TBK1 were required to prevent cell
death and inflammation in the intestine but were dispensable for liver and skin homeos tasis. Together, these findings revealed that
IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflam mation and maintain tissue
homeostasis.
Keywords: MRT67307 Nec1s BX795 IKBKE TBK1 RIPK1 ALT inflammation
72
Splicing inhibition mediated by reduced splicing factors and helicases is associated with the cellular
response of lung cancer cells to cisplatin
By: Wang, Lujuan; Yin, Na; Shi, Wenhua; Xie, Yaohuan; Yi, Junqi; Tang, Ziying; Tang, Jingqun; Xiang, Juanjuan
Lung cancer′s mortality is predominantly linked to post-chemotherapy recurrence, driven by the reactivation of dormant cancer
cells. Despite the critical role of these reactivated cells in cancer recurrence and metastasis, the mol. mechanisms governing their
therapeutic selection remain poorly unders tood. In this study, we conducted an integr ative anal. by combining Pac Bio single mol.
real-time (SMRT) sequencing with short reads Illumina R NA-seq. Our study revealed that cisplatin- induced dormant and reactivated
cancer cells exhibited a noteworthy reduction in gene transcripts and alternative splicing events. Particu larly, the differential altern
ative splicing events were found to be overla pping with the differentially expression genes and enriched in genes related to cell
cycle and cell division. Utilizing ENCORI database and correl ation anal., we identified key splicing factors, including S RSF7, SRSF3, PR
PF8, and HNRNPC, as well as RNA helicase such as EIF4A3, DDX39A, DDX11, and BRIP1, which were associated with the observed
reduction in alternative splicing and subsequent decrease in gene expres sion. Our study demonstrated that lung cancer cells
reduce gene transcripts through diminished alternative splicing events mediated by specific splicing factors and R NA helicase in
response to the chemotherapeutic stress. These findings provide insights into the mol. mechanisms underlying the therap eutic
selection and reactivation of dormant cancer cells. This discovery opens a potential avenue for the develo pment of therapeutic
strategies aimed at preventing cancer recurrence following chemotherapy.
Keywords: Cell dormancy; Chemotherapy; Lung adenocarcinoma cells; Splicing inhibition

73
Regulatory T and B cells in pediatric Henoch-Schonlein purpura: friends or foes?
By: Filleron, Anne; Cezar, Renaud; Fila, Marc; Protsenko, Nastassja; Van Den Hende, Kathleen; Jeziorski, Eric; Occean, Bob; Chevallier,
Thierry; Corbeau, Pierre; Tran, Tu Anh
Arthritis Research & Therapy (2024), 26(1), 52 | Language: English, Database: CAplus and MEDLINE
Abstract: Background and objectives: Henoch-Schonlein purpura (HSP) is the most common Ig A-mediated systemic vasculitis in
childhood. We studied immune dysregulation in HSP by analyzing regulatory T (Treg) , T helper 3 (Th3) , and regulatory B cell (Breg)
subpopulations that might intervene in immune activa tion, IgA production, and HSP clin. manifestations. Methods: This prospe ctive
study included 3 groups of children: 30 HSP on acute phase, 30 H SP on remission, and 40 healthy controls (HCs) matched on age.
Treg, Breg, and Th3 were analyzed by flow cytometry. Serum Ig and cytokine levels were quantified by ELISA and Luminex. Results:
Treg frequencies were higher in acute HSP than in remitting HSP and HCs (6.53% [4.24; 9.21] vs. 4.33% [3.6; 5.66] , p = 0.002, and vs.
4.45% [3.01; 6.6], p = 0.003, resp.) . Activated Th3 cells (FoxP3 + Th3 cells) tend to be more abundant in HSP than in HCs (78.43%
[50.62; 80.84] vs. 43.30% [40.20; 49.32], p = 0.135). Serum Ig A, IL-17, and latency-associated peptide (a marker of the anti-inflam
matory cytokine TGF-beta production) were significantly and inflammatory cytokines TN F-alpha , IL-1-beta, and IL-6 were non-
significantly higher in HSP than HCs. Bregs were identical between the groups, but, in patients with renal impair ment, Breg
percentage was lower compared to those without. Treg removal in PBMC culture resulted in an increase in Ig A production in HSP
proving a neg. regulatory role of Tregs on IgA production Conclusions: In pediatric HSP, immune activation persists in spite of an
increase in Th3 and Tregs. Th3 could be involved in IgA hyperprodn., inefficiently downregulated by Tregs. Lack of Bregs appears
linked to renal impairment.
Keywords: Cytokines; IgA vasculitis; Kidney disease; Regulatory B cells; Regulatory T cells; T helper 3 cell
74
Total flavonoids of Astragalus protects glomerular filtration barrier in diabetic kidney disease
By: Liu, Pei-Yu; Hong, Kin-Fong; Liu, Ya-Di; Sun, Zhong-Yan; Zhao, Ting-Ting; Li, Xu-Ling; Lao, Chi-Chou; Tan, Shu-Feng; Zhang, Hai-
Ying; Zhao, Yong-Hua; et al
Abstract: Background: Diabetic kidney disease (D KD) is a prevalent compli cation of diabetes and the leading cause of end- stage
renal disease. Recent evidence suggests that total flavonoids of Astragalus (TFA) has promising effects on diabetes; however, its
influence on DKD and the underlying mechanism remains unclear. Methods: In this study, we induced the D KD model using strepto
zotocin (STZ) in male C57BL/6J mice and utilized glomerular endoth elial cell (GEC) lines for in vitro investig ations. We constructed a
network pharmacol. anal. to understand the mechanism of TFA in DKD. The mechanism of T FA action on DKD was investigated
through Western blot anal. and multi-immunol. methods. Results: Our findings revealed that T FA significantly reduced levels of
urinary albumin (ALB). Network pharmacol. and intrace llular pathway experi ments indicated the crucial involvement of the PI3K/AK
T signaling pathway in mediating these effects. In vitro experi ments showed that TFA can preserve the integrity of the glomerular
filtration barrier by inhibiting the expression of inflammatory factors TN F-alpha and IL-8, reducing oxidative stress. Conclusion:
Our findings demonstrated that TFA can ameliorates the progression of DKD by ameliorating renal fibrosis and preserving the
integrity of the kidney filtration barrier. These results provide pharmacol. evidence supporting the use of TFA in the treatment of
kidney diseases.
Keywords: Astragalus; Diabetic kidney disease; Flavon oids; Proteinuria

75
A developmental increase of inhibition promotes the emergence of hippocampal ripples
By: Pochinok, Irina ; Stoeber, Tristan M.; Triesch, Jochen ; Chini, Mattia ; Hanganu-Opatz, Ileana L.
Sharp wave-ripples (SPW-Rs) are a hippocampal network phenomenon critical for memory consoli dation and planning. S PW-Rs have
been extensively studied in the adult brain, yet their develop mental trajectory is poorly unders tood. While SPWs have been
recorded in rodents shortly after birth, the time point and mechanisms of ripple emergence are still unclear. Here, we combine in
vivo electrophysiol. with optoge netics and chemogenetics in 4 to 12-day-old mice to address this knowledge gap. We show that
ripples are robustly detected and induced by light stimulation of channelrhodopsin-2-transfected CA1 pyramidal neurons only from
postnatal day 10 onwards. Leveraging a spiking neural network model, we mechanistically link the maturation of inhibition and
ripple emergence. We corroborate these findings by reducing ripple rate upon chemog enetic silencing of CA1 interneurons. Finally,
we show that early SPW-Rs elicit a more robust prefrontal cortex response than S PWs lacking ripples. Thus, develo pment of
inhibition promotes ripples emergence.
Keywords: channelrhodopsin2 pyramidal neuron prefrontal cortex brain
76
Mechanism of anion exchange and small-molecule inhibition of pendrin
By: Wang, Lie ; Hoang, Anthony ; Gil-Iturbe, Eva ; Laganowsky, Arthur ; Quick, Matthias ; Zhou, Ming
Pendrin (SLC26A4) is an anion exchanger that mediates bicarb onate (HCO3-) exchange for chloride (Cl-) and is crucial for mainta
ining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I- ) in the thyroid gland. Pendrin
mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for
attenuating airway hyperresponsiveness in asthma and for treating hyperte nsion. However, the mechanism of anion exchange and
its inhibition by drugs remains poorly unders tood. We applied cryo-electron microscopy to determine structures of pendrin from
Sus scrofa in the presence of either Cl-, I-, HCO3- or in the apo-state. The structures reveal two anion-binding sites in each protomer,
and functional analyses show both sites are involved in anion exchange. The structures also show interactions between the Sulfate
Transporter and Anti-Sigma factor antagonist (S TAS) and transme mbrane domains, and mutational studies suggest a regulatory
role. We also determine the structure of pendrin in a complex with niflumic acid (NFA), which uncovers a mechanism of inhibition
by competing with anion binding and impeding the structural changes necessary for anion exchange. These results reveal
directions for understanding the mechanisms of anion selectivity and exchange and their regula tions by the STAS domain. This
work also establishes a foundation for analyzing the pathophysiol. of mutations associated with Pendred syndrome.
Keywords: pendrin STAS mutation homeostasis mutagenesis Pendred syndrome

77
Activation of mucosal insulin receptor exacerbates intestinal inflammation by promoting tissue

resident memory T cells differentiation through EZH2
By: Li, Teming; Han, Ben; Wang, Liucan; Sun, Lihua; Cai, Yujiao; Yu, Min; Xiao, Weidong; Yang, Hua
Abstract: Background: Inflammatory Bowel Diseases (IBD), an autoimmune disease characterised by abnormal intestinal immunity,
are related to vital morbidity around the world. However, therapeutic agents for IBD have not achieved desired benefit. Exploring
new therapeutic targets for I BD, especially based on its abnormally intestinal immunity, could alleviate the flare- up and worsening
of IBD. Tissue resident memory T cells (T RM) are core of multiple autoimmune diseases, including I BD. However, the mechanism of
TRM differentiation remains to be investigated. Methods: The altera tions in mRNA and lncRNA profile of intestinal intraepithelial
lymphocytes (IELs), the largest component of intestinal T RM, were analyzed in DSS-induced chronic colitis. Based on it, we
examined the function of rectal insulin instillation in a dextran sodium sulfate (D SS) induced chronic colitis. Furthermore, we invest
igated the downstream-target of the insulin pathway-EZH2 and the crucial role of E ZH2 in intestinal tissue resident memory T cell
differentiation by utilizing E ZH2fl/flCD4cre mice. Results: Insulin receptor (I NSR) expression was found to be significantly reduced.
Activation of mucosal insulin pathway by rectal insulin instillation exacerbated colitis by disrupting I ELs subgroups and up-
regulating TN F - and I L-17 expression. Rectal insulin instillation promoted E ZH2 expression and EZH2 inhibition alleviated chronic
colitis. EZH2fl/flCD4cre mice restored the normal I EL subgroups and suppressed TN F - and I L-17 expression, exhibiting alleviated
colitis. IELs from EZH2fl/flCD4cre mice exhibit significant changes in TRM related phenotype. CD4+TRM was significantly increased in
chronic colitis and decreased in EZH2fl/flCD4cre mice. Conclu sion: Insulin receptor of intestinal mucosal T- cells could promote
intestinal TRM differentiation via EZH2. Our discoveries suggest that therapies targeting colonic I NSR and E ZH2 could be potential
treatment for IBD based on its regulatory effects on T RM. Insulin receptor inhibitors rather than insulin should be applied during
colitis-active phase. In addition, EZH2 shows to be a downstream signal of the insulin pathway and E ZH2 inhibitor could alleviating
intestinal inflammation. However, the critical role of E ZH2 in TRM differentiation restricts the anti-tumor effects of EZH2 inhibitor in
vivo.
Keywords: Inflammatory bowel disease; Insulin receptor; Intestinal intraepithelial lymphocytes; Tissue resident memory T cells

78
Inhibition of mitochondrial calcium transporters alters adp-induced platelet responses
By: Shehwar, Durre; Barki, Saima; Aliotta, Alessandro; Veuthey, Lucas; Bertaggia Calderara, Debora; Alberio, Lorenzo; Alam,
Muhammad Rizwan
Abstract: Introduction: ADP-stimulated elevation of cytosolic Ca 2+ is an important effector mechanism for platelet activa tion. The
rapidly elevating cytosolic Ca2+ is also transported to mitochondrial matrix via Mitochondrial Ca 2+ Uniporter (M CU) and extruded via
Na+/Ca2+ /Li+ Exchanger (NCLX). However, the exact contri bution of MCU and NCLX in ADP-mediated platelet responses remains
incompletely understood. Methods and results: The present study aimed to elucidate the role of mitocho ndrial Ca 2+ transport in AD
P-stimulated platelet responses by inhibition of MCU and NCLX with mitoxantrone (MTX) and CGP37157 (CGP), resp. As these
inhibitory strategies are reported to cause distinct effects on matrix Ca2+ concentration, we hypothesized to observe opposite
impact of MTX and CGP on ADP-induced platelet responses. Platelet aggregation profiling was performed by microplate-based
spectrophotometery while p-selectin externalization and integrin αIIbβ3 activation were analyzed by fluore scent immunolabeling
using flow cytometery. Our results confirmed the expression of both M CU and NCLX mRNAs with relatively low abundance of N CLX
in human platelets. In line with our hypothesis, MTX caused a dose-dependent inhibition of ADP-induced platelet aggregation
without displaying any cytotoxicity. Likewise, ADP-induced p-selectin externalization and integrin αIIbβ3 activation was also signifi
cantly attenuated in M TX-treated platelets. Concordantly, inhibition of NCLX with CGP yielded an accelerated ADP-stimulated
platelet aggregation which was associated with an elevation of p- selectin surface expression and α IIbβ3 activation. Conclusion:
Together, these findings uncover a vital and hitherto poorly characterized role of mitocho ndrial Ca 2+ transporters in ADP-induced
platelet activation. Graphical Abstract: [graphic not available: see fulltext]
Keywords: CGP37157; Mitochondrial Calcium Uniporter; Mitoxantrone; Platelet Aggregation; Sodium/Calcium/Lithium Exchanger
79
Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition
and platinum chemotherapy
By: Walmsley, Charlotte S.; Jonsson, Philip; Cheng, Michael L.; McBride, Sean; Kaeser, Christopher; Vargas, Herbert Alberto; Laudone,
Vincent; Taylor, Barry S.; Kappagantula, Rajya; Baez, Priscilla ; et al
npj Precision Oncology (2024), 8(1), 34 | Language: English, Database: CAplus and MEDLINE
Abstract: Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of
resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient
with metastatic castration-resistant prostate cancer (mCRPC) with a germline B RCA2 mutation who developed acquired resistance
to PARP inhibition . Extensive genomic interro gation of cell-free DNA (cfDNA) and tissue at baseline, post- progression, and
postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were
private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for
reversion mutations in the presence of therapeutic pressure by P ARP inhibition . Variable cfDNA shed was seen across tumor sites,
emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the
temporal and spatial heterogeneity of prostate cancer under the selective pressure of a P ARP inhibition and exposes limitations in
the current strategies for detection of reversion mutations.

80
Camptothecin bioprocessing from Aspergillus terreus, an endophyte of Catharanthus roseus:

antiproliferative activity, topoisomerase inhibition and cell cycle analysis
By: El-Sayed, Ashraf S. A.; ElSayed, Abdelaleim I.; Wadan, Khalid M.; El-Saadany, Sayed S.; Abd El-Hady, Nouran A. A.
Attenuation of camptothecin (CPT) productivity by fungi with preser vation and subculturing is the challenge that halts fungi to be an
industrial platform of CPT production Thus, screening for novel endophytic fungal isolates with metabolic stability for C PT
production was the objective. Catharanthus roseus is one of the medicinal plants with diverse bioactive metabo lites that could have
a plethora of novel endophytes with unique metabolites. Among the endophytes of C. roseus, Asperg illus terreus EFBL-NV O
R131583.1 had the most CPT producing potency (90.2μg/l), the chem. identity of the putative C PT was verified by H PLC, FT-IR, NMR
and LC-MS/MS. The putative A. terreus C PT had the same mol. mass (349 m/z) , and mol. fragmentation patterns of the authentic
one, as revealed from the MS/MS analyses. The purified C PT had a strong activity against M CF7 (5.27μM) and UO-31 (2.2μM), with a
potential inhibition to Topo II (IC50 value 0.52 n M) than Topo 1 (I C50 value 6.9 n M). The CPT displayed a high wound healing activity
to UO-31 cells, stopping their metast asis, matrix formation and cell immigration. The purified CPT had a potential inducing activity
to the cellular apoptosis of UO-31 by ∼ 17 folds, as well as, arresting their cellular division at the S- phase, compared to the control
cells. Upon Plackett-Burman design, the yield of C PT by A. terreus was increased by ∼ 2.6 folds, compared to control. The yield of C P
T by A. terreus was sequen tially suppressed with the fungal storage and subcult uring, losing ∼ 50% of their C PT productivity by 3rd
month and 5th generation. However, the productivity of the attenuated A. terreus culture was completely restored by adding 1%
surface sterilized leaves of C. roseus, and the CPT yield was increased over- the-first culture by ∼ 3.2 folds (315.2μg/l) . The restoring
of CPT productivity of A. terreus in response to indigenous microbiome of C. roseus, ensures the A. terreus- microbiome interac
tions, releasing a chem. signal that triggers the C PT productivity of A. terreus. This is the first reports exploring the potency of A.
terreus, endophyte of C. roseus" to be a platform for industrial production of CPT, with an affordable sustain ability with addition of
C. roseus microbiome.
Keywords: Aspergillus Catharanthus topoisomerase inhibition cell cycle antiproli ferative; Anticancer activity; Apoptosis; Aspergillus
terreus; Camptothecin; Catharanthus roseus; Cell cycle; Topoiso merase inhibitors; Wound healing
81
In-silico testing of new pharmacology for restoring inhibition and human cortical function in
depression
By: Guet-McCreight, Alexandre ; Chameh, Homeira Moradi; Mazza, Frank; Prevot, Thomas D.; Valiante, Taufik A. ; Sibille, Etienne
; Hay, Etay
Abstract: Reduced inhibition by somatostatin-expressing interneurons is associated with depres sion. Administration of pos.
allosteric modulators of α5 subunit-containing GABAA receptor (α5-PAM) that selectively target this lost inhibition exhibit antidep
ressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of α5- PAM on the human brain
in vivo are unknown, and currently cannot be assessed exptl. We modeled the effects of α5-PAM on tonic inhibition as measured in
human neurons, and tested in silico α5-PAM effects on detailed models of human cortical microci rcuits in health and depression.
We found that α5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also
recovered the power spectral d. profile of the microcircuit EEG signals. We performed an α5-PAM dose-response and identified
simulated EEG biomarker candidates. Our results serve to de- risk and facilitate α5-PAM translation and provide biomarkers in non-
invasive brain signals for monitoring target engagement and drug efficacy.

82
Endothelial lipase variant T111I does not alter inhibition by angiopoietin-like proteins
By: Sylvers-Davie, Kelli L.; Bierstedt, Kaleb C.; Schnieders, Michael J.; Davies, Brandon S. J.
Abstract: High levels of HDL-C are correlated with a decreased risk of cardiov ascular disease. HDL-C levels are modulated in part by
the secreted phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL and decreases circul ating HDL-C
concentrations A 584C/T polymorphism in LIPG, the gene which encodes E L, was first identified in indivi duals with increased HDL
levels. This polymorphism results in a T111 I point mutation the E L protein. The association between this variant, H DL levels, and the
risk of coronary artery disease (CAD) in humans has been extensively studied, but the findings have been inconsi stent. In this study,
we took a biochem. approach, investigating how the T111I variant affected EL activity, structure, and stability. Moreover, we tested
whether the T111I variant altered the inhibition of phospholipase activity by angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4
(ANGPTL4), two known EL inhibitors. We found that neither the stability nor enzymic activity of E L was altered by the T111 I variant.
Moreover, we found no difference between wild-type and T111I EL in their ability to be inhibited by A NGPTL proteins. These data
suggest that any effect this variant may have on HDL-C levels or cardiovascular disease are not mediated through altera tions in
these functions.
83
Resistance of HNSCC cell models to pan-FGFR inhibition depends on the EMT phenotype associating
with clinical outcome
By: Broghammer, Felix; Korovina, Irina; Gouda, Mahesh; Celotti, Martina; van Es, Johan; Lange, Inga; Brunner, Cornelia; Mircetic,
Jovan; Coppes, Robert P.; Gires, Olivier; et al
Molecular Cancer (2024), 23(1), 39 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Focal adhesion signaling involving receptor tyrosine kinases (R TK) and integrins co- controls cancer cell
survival and therapy resistance. However, co-dependencies between these receptors and therapeu tically exploitable vulnerabilities
remain largely elusive in HPV-neg. head and neck squamous cell carcinoma (H NSCC). Methods: The cytotoxic and radioch emosens
itizing potential of targeting 10 R TK and β1 integrin was determined in up to 20 3 D matrix-grown HNSCC cell models followed by
drug screening and patient-derived organoid validation. RNA sequencing and protein- based biochem. assays were performed for
mol. characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. Results: Fibroblast
growth factor receptor (FGFR 1-4) targeting exhibited the strongest cytotoxic and radiosen sitizing effects as monotherapy and
combined with β1 integrin inhibition , exceeding the efficacy of the other R TK studied. Pharmacol. pan-FGFR inhibition elicited
responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence anal. revealed a
mesenchymal-to-epithelial transition (M ET) in sensitive cell models, whereas resistant cell models exhibited a partial epithe lial-to-
mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance
and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid- dependently. Transferring the EMT-associated
transcriptomic profiles to HNSCC patient cohorts not only demons trated their prognostic value but also provided a conclusive
validation of the presence of EGFR-related vulnerabilities that can be strateg ically exploited for therapeutic interventions. Conclu
sions: This study demons trates that pan-FGFR inhibition elicits a beneficial radioch emosensitizing and a detrim ental radioprotective
potential in HNSCC cell models. Adaptive E MT-associated resistance appears to be of clin. importance, and we provide effective
mol. approaches to exploit this therapeutically.
Keywords: Adaptive resistance; Epidermal growth factor receptor; Epithelial-to-mesenchymal transition; Fibroblast growth factor
receptor; HNSCC; Radioprotection; Radiosensitization; β1 integrin

84
Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
By: Xie, Stanley C. ; Wang, Yinuo ; Morton, Craig J. ; Metcalfe, Riley D. ; Dogovski, Con; Pasaje, Charisse Flerida A. ; Dunn,
Elyse ; Luth, Madeline R.; Kumpornsin, Krittikorn; Istvan, Eva S. ; et al
Abstract: Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakt
hrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimi dine-based sulfonamides as a
new low mol. weight inhibitor class with drug-like phys. parameters and a synthet ically accessible scaffold. We show that the
exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance
development. In vitro evolution of resistance using a slow ramp- up approach pointed to the Plasmodium falciparum cytopl asmic
asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that O SM-S-106 inhibits protein translation and
activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that
inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less suscep tible
to this reaction hijacking mechanism. X-ray crystallog. studies of human Asn RS in complex with inhibitor adducts and docking of
pro-inhibitors into a model of Asn- tRNA-bound PfAsnRS provide insights into the structure- activity relationship and the selectivity
mechanism.
85
RANKL inhibition reduces lesional cellularity and Gα s variant expression and enables osteogenic
maturation in fibrous dysplasia
By: de Castro, Luis F. ; Whitlock, Jarred M.; Michel, Zachary ; Pan, Kristen; Taylor, Jocelyn; Szymczuk, Vivian; Boyce, Brendan ;
Martin, Daniel; Kram, Vardit; Galisteo, Rebeca; et al
Bone Research (2024), 12(1), 10 | Language: English, Database: CAplus and MEDLINE
Abstract: Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no establ ished treatments. Growing
evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa- B ligand (RANKL) as a potential
treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect
effects on osteoprogenitors by evaluating human F D tissue pre- and post-treatment in a phase 2 clin. trial of denosumab (N C
T03571191) and in murine in vivo and ex vivo preclin. models. Histol. anal. of human and mouse tissue demons trated increased
osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gα s variant in FD lesions after RANKL
inhibition . RNA sequencing of human and mouse tissue supported these findings. The intera ction between osteoclasts and mutant
osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the prolife ration of abnormal FD osteopro
genitors was dependent on osteoclasts. The results from this study demons trated that, in addition to its expected antioste oclastic
effect, denosumab reduces FD lesion activity by decreasing F D cell proliferation and increasing osteogenic matura tion, leading to
increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoc lasts
and preosteoblasts/osteoblasts as a driver of FD pathol. and demonstrate a novel mechanism of action of denosumab in the
treatment of bone disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191

86
Mammalian target of rapamycin inhibition protects glioma cells from temozolomide-induced cell
death
By: Sauer, Benedikt; Lorenz, Nadja I.; Dive, Iris; Klann, Kevin; Luger, Anna-Luisa; Urban, Hans; Schroeder, Jan-Hendrik; Steinbach,
Joachim P.; Muench, Christian; Ronellenfitsch, Michael W.
Abstract: Glioblastoma is an incurable brain tumor with a median survival below two years. Trials investi gating targeted therapy
with inhibitors of the kinase mTOR have produced ambiguous results. Especially combin ation of mTOR inhibition with standard
temozolomide radiochemotherapy has resulted in reduced survival in a phase I I clin. trial. To date, this phenomenon is only poorly
understood. To recreate the therapeutic setting in vitro, we exposed gliobl astoma cell lines to co- treatment with rapamycin and
temozolomide and assessed cell viability, D NA damage and reactive oxygen species. Addnl., we employed a novel translat. based
mass spectrometry approach ("mePROD") to analyze acute changes in translated proteins. m TOR inhibition with rapamycin
protected glioblastoma cells from temozolomide toxicity. Following co- treatment of temozolomide with rapamycin, an increased
translation of reactive oxygen species (R OS)-detoxifying proteins was detected by mass spectro metry. This was accompanied by
improved ROS-homeostasis and reduced D NA damage. Addnl., rapamycin induced the expression of the D NA repair enzyme O-6-
methylguanine-DNA methyltransferase (MGMT) in glioblastoma cells with an unmeth ylated MGMT gene promotor. Inhibition of m
TOR antagonized the cytotoxic effects of temozolomide in vitro. The induction of antiox idant defences and M GMT are two
underlying candidate mechanisms. Further functional experi ments in vitro and in vivo are warranted to charac terize this effect that
appears relevant for combinatorial therapeutic strategies.

87
Pancreatic cancer acquires resistance to MAPK pathway inhibition by clonal expansion and adaptive
DNA hypermethylation
By: Godfrey, Laura K.; Forster, Jan; Liffers, Sven-Thorsten; Schroeder, Christopher; Koester, Johannes; Henschel, Leonie; Ludwig,
Kerstin U.; Laehnemann, David; Trajkovic-Arsic, Marija; Behrens, Diana; et al
Clinical Epigenetics (2024), 16(1), 13 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Pancreatic ductal adenoca rcinoma (PDAC) is an aggressive cancer with poor prognosis. It is marked by
extraordinary resistance to conventional therapies including chemotherapy and radiation, as well as to essent ially all targeted
therapies evaluated so far. More than 90% of PDAC cases harbor an activating K RAS mutation. As the most common K RAS variants
in PDAC remain undruggable so far, it seemed promising to inhibit a downstream target in the M APK pathway such as M EK1/2, but
up to now preclin. and clin. evaluation of MEK inhibitors (MEK i) failed due to inherent and acquired resistance mechan isms. To gain
insights into mol. changes during the formation of resistance to oncogenic MAPK pathway inhibition , we utilized short-term
passaged primary tumor cells from ten PDACs of genetically engineered mice. We followed gain and loss of resistance upon M EK i
exposure and withdrawal by longitudinal integrative anal. of whole genome sequencing, whole genome bisulfite sequencing, RNA-
sequencing and mass spectrometry data. Results: We found that resistant cell popula tions under increasing M EK i treatment evolved
by the expansion of a single clone but were not a direct consequence of known resistance-conferring mutations. Rather, resistant
cells showed adaptive DNA hypermethylation of 209 and hypomethylation of 8 genomic sites, most of which overlap with
regulatory elements known to be active in murine PDAC cells. Both DNA methylation changes and M EK i resistance were transient
and reversible upon drug withdrawal. Furthermore, MEK i resistance could be reversed by D NA methyltransferase inhibition with
remarkable sensitivity exclusively in the resistant cells. Conclu sion: Overall, the concept of acquired therapy resistance as a result of
the expansion of a single cell clone with epigenetic plasticity sheds light on genetic, epigenetic and phenotypic patterns during
evolvement of treatment resistance in a tumor with high adaptive capabilities and provides potential for reversion through
epigenetic targeting.
Keywords: Cancer; Clonal expansion; DNA methylation; Epigenetic plasticity; PDAC; Therapy resistance; WGBS
88
A destabilizing Y891D mutation in activated EGFR impairs sensitivity to kinase inhibition
By: Lenchner, Daniel S.; Petrova, Zaritza O.; Hunihan, Lisa; Ashtekar, Kumar D.; Walther, Zenta; Wilson, Frederick H.
Abstract: EGFR tyrosine kinase inhibitors (T KIs) have transformed the treatment of E GFR-mutated non-small cell lung carcinoma (N S
CLC); however, therapeutic resistance remains a clin. challenge. Acquired secondary E GFR mutations that increase A TP affinity
and/or impair inhibitor binding are well-described mediators of resistance. Here we identify a de novo E GFR Y891D secondary
alteration in a NSCLC with EGFR L858R. Acquired EGFR Y891D alterations were previously reported in associ ation with resistance to
first generation EGFR TKIs. Functional studies in Ba/F3 cells demons trate reduced TKI sensitivity of EGFR L858R + Y891D, with the
greatest reduction observed for first and second generation TKIs. Unlike other E GFR mutations associated with T KI resistance, Y891
D does not significantly alter A TP affinity or promote steric hindrance to inhibitor binding. Our data suggest that the Y891 D
mutation destabilizes EGFR L858R, potentially generating a population of misfolded receptor with preserved signaling capacity but
reduced sensitivity to EGFR inhibitors. These findings raise the possib ility of protein misfolding as a mechanism of resistance to E GF
R inhibition in EGFR-mutated NSCLC.

89
Autophagy inhibition improves the targeted radionuclide therapy efficacy of 131I-FAP-2286 in

pancreatic cancer xenografts
By: Liu, Xingyu; Li, Danni; Ma, Tianbao; Luo, Xiu; Peng, Ye; Wang, Tao; Zuo, Changjing ; Cai, Jianming
Abstract: Purposes: Radiotherapy can induce tumor cell autophagy, which might impair the antitu moral effect. This study aims to
investigate the effect of autophagy inhibition on the targeted radionuclide therapy (TRT) efficacy of 131I-FAP-2286 in pancreatic
cancer. Methods: Human pancreatic cancer PANC-1 cells were exposed to 131I-FAP-2286 radiotherapy alone or with the autophagy
inhibitor 3-MA. The autophagy level and prolife rative activity of PANC-1 cells were analyzed. The pancreatic cancer xenograft-
bearing nude mice were establ ished by the co-injection of PANC-1 cells and pancreatic cancer- associated fibroblasts (CAFs), and
then were randomly divided into four groups and treated with saline (control group), 3-MA, 131I-FAP-2286 and 131I-FAP-2286 + 3-MA,
resp. SPECT/CT imaging was performed to evaluate the bio-distribution of 131I-FAP-2286 in pancreatic cancer-bearing mice. The
therapeutic effect of tumor was evaluated by 18 F-FDG PET/CT imaging, tumor volume measurements, and the hematoxylin and
eosin (H&E) staining, and immunohistochem. staining assay of tumor tissues. Results: 131I-FAP-2286 inhibited proliferation and
increased the autophagy level of PANC-1 cells in a dose-dependent manner. 3-MA promoted 131I-FAP-2286-induced apoptosis of PA
NC-1 cells via suppressing autophagy. SPECT/CT imaging of pancreatic cancer xenograft- bearing nude mice showed that 131I-FAP-
2286 can target the tumor effect ively. According to 18 F-FDG PET/CT imaging, the tumor growth curves and immunohi stochem. anal.,
131I-FAP-2286 TRT was capable of suppre ssing the growth of pancreatic tumor accomp anying with autophagy induction, but the
addition of 3-MA enabled 131I-FAP-2286 to achieve a better therapeutic effect along with the autophagy inhibition . In addition, 3-M
A alone did not inhibit tumor growth. Conclu sions: 131I-FAP-2286 exposure induces the protective autophagy of pancreatic cancer
cells, and the application of autophagy inhibitor is capable of enhancing the T RT therapeutic effect.
Keywords: Autophagy; FAP-2286; Pancreatic cancer; Targeted radion uclide therapy

90
ZSWIM4 inhibition improves chemosensitivity in epithelial ovarian cancer cells by suppressing

intracellular glycine biosynthesis
By: Gong, Kunxiang; Huang, Yinger; Zheng, Yanqin; Hao, Wenbo; Shi, Kun
Abstract: Background: Zinc finger S WIM-type containing 4 (ZSWIM4) induces drug resistance in breast cancer cells. However, its role
in epithelial ovarian cancer (EOC) remains unknown. In this study, we aimed to invest igate the clin. significance of ZSWIM4
expression in EOC and develop new clin. therap eutic strategies for E OC. Methods: ZSWIM4 expression in control and E OC tumor
tissues was examined using immunohistochem. Lentiviral transduction, Cell Counting Kit- 8 assay, tumorsphere formation assay,
flow cytometry, western blotting, and animal xenograft model were used to assess the role of ZSWIM4 in chemotherapy. Cleavage
Under Targets and Tagmentation (CUT&Tag) assays, chromatin immunoprecipitation assays, and luciferase reporter assays were
used to confirm FOXK1-mediated upregulation of ZSWIM4 expression. The mechanism by which Z SWIM4 inhibition improves
chemosensitivity was evaluated using R NA-sequencing. A ZSWIM4-targeting inhibitor was explored by virtual screening and surface
plasmon resonance anal. Patient-derived organoid (P DO) models were constructed from E OC tumor tissues with Z SWIM4 expres
sion. Results: ZSWIM4 was overexpressed in EOC tumor tissues and impaired patient prognoses. Its expression correlated pos. with
EOC recurrence. ZSWIM4 expression was upregulated following carboplatin treatment, which, in turn, contri buted to chemores
istance. Silencing Z SWIM4 expression sensitized E OC cells to carboplatin treatment in vitro and in vivo. F OXK1 could bind to the GTA
AACA sequence of the Z SWIM4 promoter region to upregulate Z SWIM4 transcriptional activity and FOXK1 expression increased
following carboplatin treatment, leading to an increase in Z SWIM4 expression. Mechanistically, ZSWIM4 knockdown downreg ulated
the expression of several rate-limiting enzymes involved in glycine synthesis, causing a decrease in intrace llular glycine levels, thus
enhancing intracellular reactive oxygen species production induced by carbop latin treatment. Compound IPN60090 directly bound
to ZSWIM4 protein and exerted a signif icant chemosensitizing effect in both E OC cells and PDO models. Conclu sions: ZSWIM4
inhibition enhanced EOC cell chemosen sitivity by ameliorating intracellular glycine metabolism reprogr amming, thus providing a
new potential therapeutic strategy for E OC.
Keywords: Carboplatin; Chemosensitivity; Epithelial ovarian cancer; F OXK1; Glycine biosynthesis; ZSWIM4

91
Inhibition of ferroptosis reverses heart failure with preserved ejection fraction in mice
By: Xiong, Yixiao; Liu, Xin; Jiang, Ling; Hao, Tao; Wang, Yanyan; Li, Tao
Abstract: Background: Heart failure with preserved ejection fraction (H FpEF) accounts for approx. 50% of heart failure cases. The
mol. mechanisms by which HFpEF leads to impaired diastolic function of the heart have not been clarified, nor have the drugs that
target the clin. symptoms of HFpEF patients. Methods: HFpEF chip data (GSE180065) was downloaded from the National Center for
Biotechnol. Information (NCBI) database. Differe ntially expressed genes (DEGs) were filtered by the limma package in R and
processed for GO and KEGG pathway analyses. Then, ferrop tosis-related genes in HFpEF were identified by taking the inters ection
between DEGs and ferroptosis-related genes. CytoHubba and M CODE were used to screen ferrop tosis-related hub DEGs in the
protein-protein interaction (PPI) network. Establishment of a mouse H FpEF model to validate the transcript levels of ferroptosis-
related hub DEGs and ferroptosis-related phenotypes. Transcript levels of ferroptosis-related hub DEGs and HFpEF phenotypic
changes in the hearts of HFpEF mice were further examined after the use of ferrop tosis inhibitors. Results: GO and KEGG
enrichment analyses suggested that the DEGs in HFpEF were significantly enriched in ferroptosis-related pathways. A total of 24
ferroptosis-related DEGs were identified between the ferrop tosis gene dataset and the D EGs. The established PPI network was
further analyzed by CytoHubba and M CODE modules, and 11 ferrop tosis-related hub DEGs in HFpEF were obtained. In animal
experiments, HFpEF mice showed significant abnormal activation of ferroptosis. The expression trends of the 11 hub D EGs
associated with ferroptosis, except for Cdh1, were consistent with the results of the bioinfo rmatics anal. Inhibition of ferroptosis
alters the transcript levels of 11 ferroptosis-related hub DEGs and ameliorates HFpEF phenotypes. Conclusions: The present study
contributes to a deeper underst anding of the specific mechanisms by which ferrop tosis is involved in the development of HFpEF
and suggests that inhibition of ferroptosis may mitigate the progression of HFpEF. In addition, eleven hub genes were recognized
as potential drug binding targets.
Keywords: Bioinformatics analysis; Deferiprone; Ferroptosis; Ferrostatin-1; Heart failure with preserved ejection fraction

92
DNA methylases for site-selective inhibition of type IIS restriction enzyme activity
By: Flores-Fernandez, Carol N.; Lin, Da; Robins, Katherine; O′Callaghan, Chris A.
Applied Microbiology and Biotechnology (2024), 108(1), 174 | Language: English, Database: CAplus and MEDLINE
Abstract: DNA methylases of the restriction-modifications (R-M) systems are promising enzymes for the develo pment of novel mol.
and synthetic biol. tools. Their use in vitro enables the deployment of independent and controlled catalytic reactions. This work
aimed to produce recombinant DNA methylases belonging to the R-M systems, capable of in vitro inhibition of the type IIS restri
ction enzymes Bsa I, BpiI, or LguI. Non-switchable methylases are those whose recognition sequences fully overlap the recognition
sequences of their associated endonuclease. In switch methylases, the methylase and endonuclease recognition sequences only
partially overlap, allowing sequence engineering to alter methylation without altering restriction. In this work, ten methylases from
type I and II R-M systems were selected for cloning and expression in E. coli strains tolerant to methyl ation. Iso-Pr β-D-1-thiogal
actopyranoside (IPTG) concentrations and post-induction temperatures were tested to optimize the soluble methylases expres sion,
which was achieved with 0.5 mM IPTG at 20 °C. The C- terminal His6-Tag versions showed better expression than the N- terminal
tagged versions. DNA methylation was analyzed using purified methylases and custom test plasmids which, after the methyl ation
reactions, were digested using the corresponding associated type IIS endonuclease. The non-switchable methylases M2.Eco31I,
M2.BsaI, M2.HpyAII, and M1. MboII along with the switch methylases M.Osp807 II and M2. NmeMC58II showed the best activity for
site-selective inhibition of type IIS restriction enzyme activity. This work demons trates that our recombinant methylases were able
to block the activity of type IIS endonucleases in vitro, allowing them to be developed as valuable tools in synthetic biol. and D NA
assembly techniques. Key points: • Non-switchable methylases always inhibit the relevant type I IS endonuclease activity • Switch
methylases inhibit the relevant type IIS endonuclease activity depending on the sequence engine ering of their recognition site •
Recombinant non-switchable and switch methylases were active in vitro and can be deployed as tools in synthetic biol. and D NA
assembly Graphical Abstract: [graphic not available: see fulltext]
Keywords: Blocking endonuclease activity; DNA methylation; Non-switchable methylases; Recombinant methylases; Switch methyl
ases; Type IIS restriction enzymes
93
Neuromorphic electro-stimulation based on atomically thin semiconductor for damage-free

inflammation inhibition
By: Bao, Rong; Wang, Shuiyuan ; Liu, Xiaoxian; Tu, Kejun ; Liu, Jingquan; Huang, Xiaohe; Liu, Chunsen ; Zhou, Peng ; Liu,
Shen
Abstract: Inflammation, caused by accumu lation of inflammatory cytokines from immunocytes, is prevalent in a variety of diseases.
Electro-stimulation emerges as a promising candidate for inflam matory inhibition . Although electroacupuncture is free from
surgical injury, it faces the challenges of imprecise pathways/current spikes, and insufficiently defined mechanisms, while non-
optimal pathway or spike would require high current amplitude, which makes electro- stimulation usually accompanied by damage
and complications. Here, we propose a neurom orphic electro-stimulation based on atomically thin semicon ductor floating-gate
memory interdigital circuit. Direct stimulation is achieved by wrapping sympat hetic chain with flexible electrodes and floating- gate
memory are programmable to fire bionic spikes, thus minimizing nerve damage. A substa ntial decrease (73.5%) in inflam matory
cytokine IL-6 occurred, which also enabled better efficacy than com. stimulator at record- low currents with damage- free to sympat
hetic neurons. Addnl., using transgenic mice, the anti- inflammation effect is determined by β2 adrenergic signaling from myeloid
cell lineage (monocytes/macrophages and granul ocytes).

94
Paclitaxel-induced inhibition of NSCLC invasion and migration via RBFOX3-mediated circIGF1R

biogenesis
By: Xu, Zhanyu; Zheng, Liping; Li, Shikang

Abstract: We previously reported that circIGF1R is significantly downregulated in non-small cell lung cancer (N SCLC) cells and
tissues. It inhibits cancer cell invasion and migration, although the underlying mol. mechanisms remain elusive. The invasion and
migration of NSCLC cells was analyzed by routine in vivo and in vitro functional assays. Fluore scent in situ hybridi zation, luciferase
reporter assay, RNA pull-down assay and RNA immunoprecipitation (RIP) assay were performed to explore the mol. mechan isms.
Mechanism of action of paclitaxel-induced RBFOX3-mediated inhibition of NSCLC invasion and migration was invest igated through
in vitro and in vivo experiments Our study reveals that circ IGF1R acts as a Competing Endogenous R NA (ceRNA) for miR-1270,
thereby regulating Van-Gogh-like 2 (VANGL2) expression and subsequently inhibiting N SCLC cell invasion and migration via the Wnt
pathway. We also found that RNA binding protein fox- 1 homolog 3 (RBFOX3) enhances circ IGF1R biogenesis by binding to I GF1R
pre-mRNA, which in turn suppresses migration and invasion in N SCLC cells. Addnl., the chemotherapeutic drug paclitaxel was
shown to impede NSCLC invasion and migration by inducing R BFOX3-mediated circIGF1R biogenesis. RBFOX3 inhibits the invasion
and migration of NSCLC cells through the circIGF1R/ miR-1270/VANGL2 axis, circIGF1R has the potential to serve as a biomarker and
therapeutic target for N SCLC.
95
Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
By: Thambyrajah, Roshana ; Maqueda, Maria ; Neo, Wen Hao ; Imbach, Kathleen; Guillen, Yolanda; Grases, Daniela;
Fadlullah, Zaki; Gambera, Stefano ; Matteini, Francesca ; Wang, Xiaonan ; et al
Abstract: Hematopoietic stem cells (HSCs) develop from the hemogenic endoth elium (HE) in the aorta- gonads-and mesonephros (A
GM) region and reside within Intra- aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling
mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specifi cation, IAHC formation
and HSC activity, but current studies on how Notch segregates these different fates are inconsi stent. We now demons trate that
Notch activity is highest in a subset of, GFI1 + , HSC-primed HE cells, and is gradually lost with H SC maturation. We uncover that the
HSC phenotype is maintained due to increasing levels of N OTCH1 and JAG1 interactions on the surface of the same cell (cis) that
renders the NOTCH1 receptor from being activated. Forced activation of the N OTCH1 receptor in IAHC activates a hematopoietic
differentiation program. Our results indicate that N OTCH1-JAG1 cis- inhibition preserves the HSC phenotype in the hematopoietic
clusters of the embryonic aorta.

96
Inhibition of the ILK-AKT pathway by upregulation of PARVB contributes to the cochlear cell death in
Fascin2 gene knockout mice
By: Liu, Rongrong; Shang, Wenjing ; Liu, Yingying; Xie, Yi; Luan, Jun; Zhang, Ting; Ma, Ying; Wang, Zengxian; Sun, Yan ; Song,
Xicheng ; et al
Abstract: The Fscn2 (Fascin2) gene encodes an actin crosslinking protein that is involved in the formation of hair cell stereo cilia and
retina structure. Mutations in Fscn2 gene have been linked to hearing impairment and retinal degeneration in humans and mice. To
understand the function of the Fscn2 gene, we generated the Fscn2 knockout mice, which showed progressive loss of hearing and
hair cells. Our goal of the present study was to investigate the mechanism underlying cochlear cell death in the Fscn2 knockout
mice. Microarray anal. revealed upregulation of expression of PARVB, a local adhesion protein, in the inner ears of Fscn2 knockout
mice at 8 wk of age. Further studies showed increased levels of PARVB together with cleaved- Caspase9 and decreased levels of I LK,
p-ILK, p-AKT, and Bcl-2 in the inner ears of Fscn2 knockout mice of the same age. Knockdown of Fscn2 in H EI-OCI cells led to
decreased cell proliferation ability and migration rate, along with increased levels of P ARVB and decreased levels of I LK, p-ILK, p-AK
T, Bcl-2 and activated Rac1 and Cdc42. Overexp ression of Fscn2 or inhibition of Parvb expression in HEI-OC1 cells promoted cell
proliferation and migration, with increased levels of I LK, p-ILK, p-AKT, and Bcl-2. Finally, FSCN2 binds with PPAR-γ to reduce its
nuclear translocation in HEI-OC1 cells, and inhibition of PPAR-γ by GW9662 decreased the level of P ARVB and increased the levels
of p-AKT, p-ILK, and Bcl-2. Our results suggest that F SCN2 neg. regulates P ARVB expression by inhibiting the entry of P PAR-γ into
the cell nucleus, resulting in inhibition of ILK-AKT related pathways and of cochlear cell survival in Fscn2 knockout mice. Our
findings provide new insights and ideas for the prevention and treatment of genetic hearing loss.
97
Transcriptomic and proteomic analysis of tumor suppressive effects of GZ17-6.02 against mycosis
fungoides
By: Bordeaux, Zachary A.; Reddy, Sriya V.; Choi, Justin; Braun, Gabriella; McKeel, Jaimie; Lu, Weiying; Yossef, Selina M.; Ma, Emily Z.;
West, Cameron E.; Kwatra, Shawn G.; et al
Abstract: Mycosis fungoides (MF) is the most common form of cutaneous T- cell lymphoma (CTCL). Despite having a wide variety of
therapeutic agents available for the treatment of M F, patients often suffer from a signif icant decrease in quality of life and rarely
achieve long-term remission or complete cure, highli ghting a need to develop novel therap eutic agents for this disease. The present
study was undertaken to evaluate the efficacy of a novel anti-tumor agent, GZ17-6.02, which is composed of curcumin, harmine,
and isovanillin, against MF in vitro and in murine models. Treatment of H H and MyLa cells with GZ17-6.02 inhibited the growth of
both cell lines with IC50 ± standard errors for growth inhibition of 14.37 ± 1.19 μg/m L and 14.56 ± 1.35 μg/m L, resp., and increased
the percentage of cells in late apoptosis (p = .0304 for HH; p = .0301 for My La). Transcriptomic and proteomic analyses revealed
that GZ17-6.02 suppressed several pathways, including tumor necrosis factor ( TN F )- signaling via nuclear factor (N F)-kB,
mammalian target of rapamycin complex (mTORC)1, and Pi3K/Akt/mTOR signaling. In a s.c. tumor model, G Z17-6.02 decreased
tumor volume (p = .002) and weight (p = .009) compared to control conditions. Proteomic anal. of tumor samples showed that G
Z17-6.02 suppressed the expression of several proteins that may promote C TCL growth, including mitogen- activated protein kinase
(MAPK)1, MAPK3, Growth factor receptor bound protein (G RB)2, and Mediator of RAP80 interactions and targeting subunit of 40 k Da
(MERIT)40.

98
Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control
assessed in mice
By: Nguyen, Quynh-Anh ; Klein, Peter M. ; Xie, Cheng; Benthall, Katelyn N.; Iafrati, Jillian; Homidan, Jesslyn; Bendor, Jacob T.;
Dudok, Barna ; Farrell, Jordan S. ; Gschwind, Tilo; et al
Abstract: Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail
to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas
and specifically activated by selective agonists, are appealing methods to constrain overactive neuronal activity. We developed B AR
NI (Bradanicline- and Acetylc holine-activated Receptor for Neuronal Inhibition ), an engineered channel comprised of the α7
nicotinic acetylcholine receptor ligand-binding domain coupled to an α1 glycine receptor anion pore domain. Here we demons trate
that BARNI activation by the clin. stage α7 nicotinic acetylc holine receptor-selective agonist bradanicline effectively suppressed
targeted neuronal activity, and controlled both acute and chronic seizures in male mice. Our results provide evidence for the use of
an inhibitory acetylcholine-based engineered channel activa table by both exogenous and endogenous agonists as a potential
therapeutic approach to treating epilepsy.
99
Re-expression of epigenetically silenced PTPRR by histone acetylation sensitizes RAS-mutant lung

adenocarcinoma to SHP2 inhibition
By: Du, Tingting; Hu, Xiaowen; Hou, Zhenyan; Wang, Weida; You, Shen; Wang, Mingjin; Ji, Ming; Xue, Nina; Chen, Xiaoguang
Abstract: Silenced protein tyrosine phosphatase receptor type R (P TPRR) participates in mitogen-activated protein kinase (M APK)
signaling cascades during the genesis and development of tumors. Rat sarcoma virus (Ras) genes are frequently mutated in lung
adenocarcinoma, thereby resulting in hyperactivation of downstream MAPK signaling. However, the mol. mechanism manipu lating
the regulation and function of PTPRR in R AS-mutant lung adenocarcinoma is not known. Patient records collected from the Cancer
Genome Atlas and Gene Expression Omnibus showed that silenced PTPRR was pos. correlated with the prognosis. Exogenous
expression of PTPRR suppressed the proliferation and migration of lung cancer cells. P TPRR expression and Src homol. 2 containing
protein tyrosine phosphatase 2 (SHP2) inhibition acted synergistically to control ERK1/2 phosphorylation in RAS-driven lung cancer
cells. Chromatin immunoprecipitation assay revealed that HDAC inhibition induced enriched histone acetyl ation in the promoter
region of PTPRR and recovered P TPRR transcription. The combination of the HDAC inhibitor SAHA and SHP2 inhibitor SHP099
suppressed the progression of lung cancer markedly in vitro and in vivo. Therefore, we revealed the epigenetic silencing mechanism
of PTPRR and demonstrated that combination therapy targeting HDAC and SHP2 might represent a novel strategy to treat R AS-
mutant lung cancer.
Keywords: Anti-cancer drugs; Drug combination; Epigenetics; Signaling pathway; Targeted therapy

100
Transfer RNA-derived small RNA tRF-Glu-CTC attenuates neointimal formation via inhibition of
fibromodulin
By: Jiang, Qi-Lan; Xu, Jia-Ying; Yao, Qing-Ping; Jiang, Rui; Xu, Qin; Zhang, Bo-Tao; Li, Tao; Jiang, Jun
Cellular & Molecular Biology Letters (2024), 29(1), 2 | Language: English, Database: CAplus and MEDLINE
Abstract: Neointimal hyperplasia is a pathol. vascular remodeling caused by abnormal prolife ration and migration of subintimal
vascular smooth muscle cells (VSMCs) following intimal injury. There is increasing evidence that t RNA-derived small R NA (tsRNA)
plays an important role in vascular remodeling. The purpose of this study is to search for ts RNAs signature of neointima formation
and to explore their potential functions. The balloon injury model of rat common carotid artery was replicated to induce intimal
hyperplasia, and the differentially expressed tsRNAs (DE-tsRNAs) in arteries with intimal hyperp lasia were screened by small R NA
sequencing and tsRNA library. A total of 24 D E-tsRNAs were found in the vessels with intimal hyperp lasia by small R NA sequencing.
In vitro, tRF-Glu-CTC inhibited the expression of fibrom odulin (FMOD) in VSMCs, which is a neg. modulator of T GF-β1 activity. tRF-
Glu-CTC also increased VSMC proliferation and migration. In vivo experi ments showed that inhibition of tRF-Glu-CTC expression
after balloon injury of rat carotid artery can reduce the neointimal area. In conclusion, tRF-Glu-CTC expression is increased after
vascular injury and inhibits FMOD expression in VSMCs, which influences neointima formation. On the other hand, reducing the
expression of tRF-Glu-CTC after vascular injury may be a potential approach to prevent vascular stenosis.
Keywords: Migration; Neointimal hyperplasia (NIH); Proliferation; Transfer R NA (tRNA)-derived small R NAs (tsRNAs); Vascular
remodeling; Vascular smooth muscle cell
101
Inhibition of NRF2 enhances the acute myeloid leukemia cell death induced by venetoclax via the
ferroptosis pathway
By: Yu, Xibao ; Wang, Yan; Tan, Jiaxiong; Li, Yuchen; Yang, Pengyue; Liu, Xuan; Lai, Jing; Zhang, Yue; Cai, Letong; Gu, Yinfeng; et al
Abstract: Venetoclax, an inhibitor that selectively targets B cell lymphoma- 2 (BCL-2) that has been approved for treating adult acute
myeloid leukemia (AML) in combination with hypomethylating agents. However, its short duration of response and emergence of
resistance are significant issues. In this study, we found that the sensit ivity of AML cells to venetoclax was considerably enhanced by
ML385, an inhibitor of the ferroptosis factor nuclear transcription factor erythroid 2- related factor 2 (NRF2). Using A ML samples, we
verified that NRF2 and its target gene ferritin heavy chain 1 (F TH1) were highly expressed in patients with A ML and correlated with
poor prognosis. Downregulation of NRF2 could inhibit FTH1 expression and significantly enhance the veneto clax-induced labile iron
pool and lipid peroxidation By contrast, N RF2 overexpression or administration of the reactive oxygen species inhibitor N- acetylc
ysteine and vitamin E could effect ively suppress the anti-AML effects of ML385+venetoclax. Furthermore, the ferroptosis inducer
erastin increased the anti-AML effects of venetoclax. Our study demonstrated that NRF2 inhibition could enhance the A ML cell
death induced by venetoclax via the ferroptosis pathway. Thus, the combination of ML385 with venetoclax may offer a favorable
strategy for AML treatment.

102
Inhibition of valve mesenchymal stromal cell calcium deposition by bFGF through alternative
polyadenylation regulation of the CAT gene
By: Zhang, Jiajun; Wu, Jun; Gao, Yuan; Fan, Xingli; Liu, Xiaohong; Zhang, Guanxin; Tang, Yangfeng; Han, Lin
BMC Cardiovascular Disorders (2024), 24(1), 128 | Language: English, Database: CAplus and MEDLINE
Abstract: Objective: Calcific aortic valve disease (CAVD) is the leading cause of angina, heart failure, and death from aortic stenosis.
However, the mol. mechanisms of its progression, especially the complex disease-related transcriptional regulatory mechanisms,
remain to be further elucidated. Methods: This study used porcine valvular inters titial cells (PVIC) as a model. We used osteogenic
induced medium (OIM) to induce calcium deposition in P VICs to calcify them, followed by basic fibroblast growth factor (b FGF)
treatment to inhibit calcium deposition. Transcriptome sequencing was used to study the m RNA expression profile of PVICs and its
related transcriptional regulation. We used Da Pars to further examine alternative polyadenylation (APA) between different
treatment groups. Results: We successfully induced calcium deposition of PVICs through OIM. Subsequently, mRNA-seq was used to
identify differentially expressed mRNAs for three different treatm ents: control, O IM-induced and OIM-induced bFGF treatment.
Global APA events were identified in the O IM and b FGF treatment groups by bioinfo rmatics anal. Finally, it was discovered and
proven that catalase (CAT) is one of the potential targets of b FGF-induced APA regulation. Conclusion: We described a global A PA
change in a calcium deposition model related to CAVD. We revealed that transcri ptional regulation of the CAT gene may contribute
to bFGF-induced calcium deposition inhibition .
Keywords: Alternative polyadenylation; Calcific aortic valve disease; Catalase; b FGF

103
Inhibition of myocardial remodeling through miR-150/TET3 axis after AMI
By: Lu, Wenbin; Liu, Zhuyuan; Chiara Villamil Orion, I. R.; Qu, Yangyang; Ma, Genshan
Abstract: Background: Current studies have suggested that mi RNA is beneficial in inhibiting myocardial remodeling after myocardial
infarction (AMI), however, its underlying mechanism is unclear. Object ives: We aimed to invest igate whether miR-150 can inhibit
myocardial remodeling after myocardial infarction and whether this process is regulated by the miR-150/TET3 pathway. Methods:
On the first day, C57BL/6 AMI mice(n = 15) were adminis trated with mi R-150, and another 15 A MI mice were administrated with the
same volume of control Agomir. Left ventricular ejection fraction (LVEF%) and myocardial remodeling were compared after one
week; TET3 (ten-eleven translocation 3) and VEGF- α (vascular endothelial growth factor- α) were also determined in the infracted
heart simultaneously. The neovascularization in the infarcted area at day 21 was compared through C D31 using fluorescence
microscopy; Activated monocytes stimulated with LPS were transfected with mi R-150. Laser scanning confocal microscopy was used
to detect the intracytoplasmic imaging of mi R-150 in Ly6Chigh monocytes. Expression of the miR-150 in the monocytes was
measured using Q-PCR. After 48 h, the proportion of Ly6 Chigh/low monocytes was determined using flow cytometry. Expression of T
ET3 in Ly6Chigh/low monocytes was measured using Q- PCR and Western blot. After the downreg ulation of TET3 specifically, the levels
of Ly6Chigh/low monocytes were further determined Results: We first observed an increased trend of mice survival rate in the mi R-
150 injection group, but it didn′t reach a statis tical difference (66.7% vs. 40.0%, p = 0.272) . However, AMI mice administrated with mi
R-150 displayed better LVEF% (51.78%±2.90% vs. 40.28%±4.20%, p<0.001) and decreased infarct size% (25.47 ± 7.75 vs. 50.39 ±
16.91, p = 0.002). After mi R-150 was transfected into monocytes, the percentage of Ly6 Clow monocytes increased significantly after
48 h (48.5%±10.1% vs. 42.5%±8.3%, p < 0.001) . Finally, Western blot anal. (0.56 ± 0.10/β- actin vs. 0.99 ± 0.12/β-actin, p < 0.001) and
real-time PCR (1.09 ± 0.09/G APDH vs. 2.53 ± 0.15/GAPDH, p < 0.001, p < 0.001) both confirmed decreased expression of T ET3 in
monocytes after transfection with miR-150. After the downregulation of TET3 specifically, Ly6Clow monocytes showed a signif icant
increase (16.73%±6.45% vs. 6.94%±2.99%, p<0.001, p < 0.001) . Conclusions: miR-150 alleviated myocardial remodeling after A MI.
Possible mechanisms are ascribed to the regulating of TET3 and VEGF- α in inflammatory monocytes.
Keywords: AMI; Inflammation; Monocytes; TET3; miR-150

104
Combined inhibition of HER2 and VEGFR synergistically improves therapeutic efficacy via PI3K-AKT
pathway in advanced ovarian cancer
By: Li, Weisong; Zhang, Kai; Wang, Wenjun; Liu, Yuanyuan; Huang, Jianming; Zheng, Meihong; Li, Ling; Zhang, Xinyu; Xu, Minjuan;
Chen, Guofang; et al
Abstract: Background: Ovarian cancer (OC) is a prevalent malignancy in the female reprod uctive system, and developing effective
targeted therapies for this disease remains challenging. The aim of this study was to use clin.- relevant OC models to evaluate the
therapeutic effectiveness of RC48, an antibody-drug conjugate (ADC) targeting HER2, either alone or in combination with the VEGFR
inhibitor Cediranib Maleate (CM), for the treatment of advanced O C. Methods: OC tumor specimens and cell lines were analyzed to
determine HER2 and VEGFR expression by Western blot, immunocy tochem. and immunofluorescence. Moreover, the OC cell lines,
cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were treated with R C48 and/or CM and then subjected to
cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasib ility of combination therapy for OC both in
vitro and in vivo. Addnl., RNA-Seq was performed to investigate the critical mechanism underlying the combin ation therapy of RC48
and CM. Results: Our results demonstrated that RC48 alone effectively targeted and inhibited the growth of H ER2-pos. OC tumors
in both cell lines and PDX models. Furthermore, the combination of RC48 and CM synergistically induced tumor regression in
human OC cell lines, as well as C DX and PDX models. Mechanistically, we observed that the combin ation treatment inhibited the
growth of OC cells involved inducing apoptosis and suppre ssing cell motility. R NA-seq anal. provided further mechanistic insights
and revealed that co-administration of RC48 and CM downregulated multiple cancer-related pathways, including the AKT/mTOR
pathway, cell cycle, and cell proliferation. Notably, our data further confirmed that the P I3K-AKT pathway played a key role in the
inhibition of proliferation triggered by combina tional treatment of R C48 and CM in OC cells. Conclusions: These findings provide a
preclin. framework supporting the potential of dual targeting HER2 and VEGFR as a promising therap eutic strategy to improve
outcomes in patients with OC.
Keywords: Antibody drug conjugate; Cediranib Maleate; HER2; Ovarian cancer; RC48; Synergetic effect; VEGFR
105
A miniaturized mode-of-action profiling platform enables high throughput characterization of the

molecular and cellular dynamics of EZH2 inhibition
By: Falkenstern, Lilia; Georgi, Victoria; Bunse, Stefanie; Badock, Volker; Husemann, Manfred; Roehn, Ulrike; Stellfeld, Timo; Fitzgerald,
Mark; Ferrara, Steven; Stoeckigt, Detlef; et al
Abstract: The market approval of Tazemetostat (TAZVERIK) for the treatment of follicular lymphoma and epithe lioid sarcoma has
established "enhancer of zeste homolog 2" (E ZH2) as therapeutic target in oncol. Despite their structural simila rities and common
mode of inhibition , Tazemetostat and other E ZH2 inhibitors display differentiated pharmacol. profiles based on their target
residence time. Here we established high throughput screening methods based on time- resolved fluorescence energy transfer,
scintillation proximity and high content anal. microscopy to quantify the biochem. and cellular binding of a chem. diverse collection
of EZH2 inhibitors. These assays allowed to further charac terize the interplay between E ZH2 allosteric modulation by methylated
histone tails (H3K27me3) and inhibitor binding, and to evaluate the impact of E ZH2′s clin. relevant mutant Y641 N on drug target
residence times. While all compounds in this study exhibited slower off-rates, those with clin. candidate status display signifi cantly
slower target residence times in wild type EZH2 and disease-related mutants. These inhibitors interact in a more entropy- driven
fashion and show the most persistent effects in cellular washout and antiproliferative efficacy experiments Our work provides
mechanistic insights for the largest cohort of E ZH2 inhibitors reported to date, demonst rating that-among several other binding
parameters-target residence time is the best predictor of cellular efficacy.

106
Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition

rescues neurodegenerative phenotypes in Pink1/parkin models
By: Martinez, Aitor; Sanchez-Martinez, Alvaro; Pickering, Jake T.; Twyning, Madeleine J.; Terriente-Felix, Ana; Chen, Po-Lin; Chen,
Chun-Hong; Whitworth, Alexander J.
Molecular Neurodegeneration (2024), 19(1), 12 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathog
enesis of neurodegenerative diseases, such as Parkinson′s disease (PD). Functional anal. of genes linked to P D have revealed that
the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitocho ndrial quality control. PINK1 phospho
rylates and activates Parkin, which in turn ubiquit inates mitochondrial proteins priming them and the mitocho ndrion itself for
degradation However, it is unclear whether dysregulated mitochondrial degradation or the toxic build-up of certain Parkin ubiquitin
substrates is the driving pathophysiol. mechanism leading to P D. The iron-sulfur cluster containing proteins C ISD1 and CISD2 have
been identified as major targets of Parkin in various proteomic studies. Methods: We employed in vivo Drosophila and human cell
culture models to study the role of CISD proteins in cell and tissue viability as well as aged- related neurodegeneration, specifically
analyzing aspects of mitophagy and autophagy using orthogonal assays. Results: We show that the Drosophila homolog Cisd
accumulates in Pink1 and parkin mutant flies, as well as during ageing. We observed that build- up of Cisd is particularly toxic in
neurons, resulting in mitochondrial defects and Ser65- phospho-Ubiquitin accumulation. Age-related increase of Cisd blocks
mitophagy and impairs autophagy flux. Importantly, reduction of Cisd levels upregu lates mitophagy in vitro and in vivo, and amelio
rates pathol. phenotypes in locomo tion, lifespan and neurodegeneration in Pink1/parkin mutant flies. In addition, we show that
pharmacol. inhibition of CISD1/2 by rosiglitazone and NL-1 induces mitophagy in human cells and amelio rates the defective
phenotypes of Pink1/parkin mutants. Conclu sion: Altogether, our studies indicate that Cisd accumu lation during ageing and in
Pink1/parkin mutants is a key driver of pathol. by blocking mitophagy, and geneti cally and pharmacol. inhibiting C ISD proteins may
offer a potential target for therapeutic intervention. Graphical Abstract: [graphic not available: see fulltext]
Keywords: Ageing; Autophagy; CISD1; CISD2; Cisd; Mitochondria; Mitophagy; Neurodegeneration; PINK1; Parkin; Parkinson’s
disease

107
5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and

metastasis for lung cancer cells
By: Chen, Huang-Chi; Kuo, Chia-Yu; Chang, Yu; Tsai, Dong-Lin; Lee, Mei-Hsuan; Lee, Jui-Ying; Lee, Hui-Ming; Su, Yu-Chieh
BMC Cancer (2024), 24(1), 248 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Lung cancer is a leading cause of cancer- related mortality worldwide, and effective therapies are limited.
Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi- tyrosine
kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib
showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clin. application.
This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5- methoxytryptophan (5-MTP) on
cell growth and metastasis of Lewis lung carcinoma (LLC) cells. Method: The anticancer effect of the combin ation treatment of
sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using
flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combin
ation treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combin ation
treatment on the tumorigenic ability of LLC cells. Result: Our results demons trated that the sorafenib and 5- MTP combination
synergistically reduced viability and proliferation compared to sorafenib or 5- MTP treatment alone. Reduction of cyclin D1
expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthe rmore, the sorafenib-
5-MTP combination significantly increased the inhibitory effect on migration and invasion of L LC cells compared to the single treatm
ents. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The
reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on prolife ration and metast
asis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of
sorafenib alone. Conclusions: In conclusion, our data indicate that 5- MTP sensitizes the antitumor activity of sorafenib in L LC cells in
vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.
Keywords: 5-methoxytryptophan; Lung cancer; Lung metastasis; Oncogenesis; Sorafenib
108
In situ monolayer patch clamp of acutely stimulated human iPSC-derived cardiomyocytes promotes
consistent electrophysiological responses to SK channel inhibition
By: Butler, Andrew S.; Ascione, Raimondo; Marrion, Neil V.; Harmer, Stephen C.; Hancox, Jules C.
Abstract: Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) represent an in vitro model of cardiac function.
Isolated iPSC-CMs, however, exhibit electrop hysiol. heterogeneity which hinders their utility in the study of certain cardiac currents.
In the healthy adult heart, the current mediated by small conductance, calcium-activated potassium (SK) channels (ISK) is atrial-
selective. Functional expression of ISK within atrial-like iPSC-CMs has not been explored thorou ghly. The present study therefore
aimed to investigate atrial-like iPSC-CMs as a model system for the study of ISK. iPSCs were differentiated using retinoic acid (R A) to
produce iPSC-CMs which exhibited an atrial-like phenotype (RA-iPSC-CMs). Only 18% of isolated R A-iPSC-CMs responded to SK
channel inhibition by UCL1684 and isolated iPSC-CMs exhibited substantial cell-to-cell electrophysiol. heterogeneity. This variab ility
was significantly reduced by patch clamp of R A-iPSC-CMs in situ as a monolayer (i PSC-ML). A novel method of elec. stimul ation was
developed to facilitate recording from iPSC-MLs via In situ Monolayer Patch clamp of Acutely Stimulated i PSC-CMs (IMPASC). Using I
MPASC, > 95% of i PSC-MLs could be paced at a 1 Hz. In contrast to isolated R A-iPSC-CMs, 100% of R A-iPSC-MLs responded to UC
L1684, with APD50 being prolonged by 16.0 ± 2.0 ms (p < 0.0001; n = 12) . These data demons trate that in conjunction with IMPASC,
RA-iPSC-MLs represent an improved model for the study of ISK. IMPASC may be of wider value in the study of other ion channels
that are inconsistently expressed in isolated i PSC-CMs and in pharmacol. studies.

109
Metabolomic analysis of hydroxycinnamic acid inhibition on Saccharomyces cerevisiae
By: Ge, Xiaoli; Chen, Junxiao; Gu, Jie; Yi, Wenbo; Xu, Shujie; Tan, Liping; Liu, Tongjun
Abstract: Ferulic acid (FA) and p-coumaric acid (p-CA) are hydroxycinnamic acid inhibitors that are mainly produced during the
pretreatment of lignocellulose. To date, the inhibitory mechanism of hydroxyc innamic acid compounds on Sacchar omyces
cerevisiae has not been fully elucidated. In this study, liquid chromatog.-mass spectrometry (LC-MS) and SEM (SEM) were used to
investigate the changes in S. cerevisiae cells treated with F A and p-CA. In this experi ment, the control group was denoted as group C
K, the FA-treated group was denoted as group F, and the p- CA-treated group was denoted as group P. One hundred different
metabolites in group F and group C K and 92 different metabo lites in group P and group C K were selected and introduced to
metaboanalyst, resp. A total of 38 metabolic pathways were enriched in S. cerevisiae under F A stress, and 27 metabolic pathways
were enriched in S. cerevisiae under p-CA stress as identified through Kyoto Encyclo paedia of Genes and Genomes (K EGG) anal. The
differential metabolites involved included S- adenosine methionine, -arginine, and cysteine, which were signifi cantly downregulated,
and acetyl-CoA, -glutamic acid, and - threonine, which were significantly upregulated. Anal. of differential metabolic pathways
showed that the differentially expressed metabolites were mainly related to amino acid metabo lism, nucleotide metabo lism, fatty
acid degradation, and the tricarboxylic acid cycle (T CA). Under the stress of F A and p-CA, the metabolism of some amino acids was
blocked, which disturbed the redox balance in the cells and destroyed the synthesis of most proteins, which was the main reason
for the inhibition of yeast cell growth. This study provided a strong scientific reference to improve the durability of S. cerevisiae
against hydroxycinnamic acid inhibitors. Key points: • Morphol. changes of S. cerevisiae cells under inhibitors stress were observed •
Changes of the metabolites in S. cerevisiae cells were explored by metabol omics. • One of the inhibitory effects on yeast is due to
changes in the metabolic network.
Keywords: Ferulic acid; Inhibitor; P-coumaric acid; Saccharomyces cerevisiae; Untargeted metabo lomics
110
Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines reveals that
onametostat reduces proliferation and viability in both normoxic and hypoxic conditions
By: Lavogina, Darja; Krolov, Mattias Kaspar; Vellama, Hans; Modhukur, Vijayachitra; Di Nisio, Valentina; Lust, Helen; Eskla, Kattri-Liis;
Salumets, Andres; Jaal, Jana
Abstract: The choice of targeted therapies for treatment of glioblastoma patients is currently limited, and most gliobl astoma
patients die from the disease recurrence. Thus, systematic studies in simplified model systems are required to pinpoint the choice
of targets for further exploration in clin. settings. Here, we report screening of 5 compounds targeting epigenetic writers or erasers
and 6 compounds targeting cell cycle-regulating protein kinases against 3 gliobl astoma cell lines following incubation under
normoxic or hypoxic conditions. The viability/proliferation assay indicated that PRMT5 inhibitor onametostat was endowed with
high potency under both normoxic and hypoxic conditions in cell lines that are strongly MGMT-pos. (T98-G), weakly MGMT-pos. (U-
251 MG), or MGMT-neg. (U-87 MG). In U-251 MG and U-87 MG cells, onametostat also affected the spheroid formation at concent
rations lower than the currently used chemothe rapeutic drug lomustine. In T98- G cell line, treatment with onamet ostat led to
dramatic changes in the transcriptome profile by inducing the cell cycle arrest, suppre ssing RNA splicing, and down-regulating
several major glioblastoma cell survival pathways. Further validation by immunos taining in three cell lines confirmed that onamet
ostat affects cell cycle and causes reduction in nucleolar protein levels. In this way, inhibition of epigenetic targets might represent
a viable strategy for glioblastoma treatment even in the case of decreased chemo- and radiation sensit ivity, although further
studies in clin. more relevant models are required.

111
A single intranasal dose of essential oil spray confers modulation of the nasopharyngeal microbiota
and short-term inhibition of Mannheimia in feedlot cattle: a pilot study
By: Magossi, Gabriela; Schmidt, Kaycie N.; Winders, Thomas M.; Carlson, Zachary E.; Holman, Devin B.; Underdahl, Sarah R.;
Swanson, Kendall C.; Amat, Samat
Abstract: Five essential oils (EOs) were previously characterized in vitro and identified as candidate E Os for the development of an
intranasal EO spray to mitigate bovine respir atory disease (BRD) pathogens. In the present study, these E Os were evaluated for
their potential to (i) reduce BRD pathogens, (ii) modulate nasopharyngeal microbiota, and (iii) influence animal perfor mance,
feeding behavior and immune response when a single dose administered intranasally to feedlot cattle. Forty beef steer calves (7- 8
mo old, Initial body weight = 284 ± 5 kg [SE]) received either an intranasal E O spray (ajowan, thyme, fennel, cinnamon leaf, and
citronella) or PBS (Control; n = 20/group) on day 0. Deep nasopha ryngeal swabs were collected on days (d) - 1, 1, 2, 7, 14, 28, and 42
and processed for 16S rRNA gene sequencing, qPCR, and culturing. Significant effects of EO on community structure (d1) , microbial
richness and diversity, relative abundance of some dominant phyla (d1, d2, and d14), and the overall interaction network structure
of the nasopharyngeal microbiota were detected. The relative abundance of Mannheimia was lower in the E O calves (4.34%) than in
Control calves (10.4%) on d2, and M. haemolytica prevalence on d7 as compared to control calves. Feed intake, average daily gain,
feeding behavior, and blood cell counts were not affected by EO treatment. Overall, a single intranasal dose of E O spray resulted in
moderate modulation of nasopharyngeal microbiota and short- term inhibition of Mannheimia while not influe ncing animal perfor
mance, feeding behavior or immune response. Our study, for the first time, shows the potential use of intranasal E O to mitigate BR
D in feedlot cattle.
112
Long-term inhibition of ODC1 in APP/PS1 mice rescues amyloid pathology and switches astrocytes
from a reactive to active state
By: Bhalla, Mridula; Lee, C. Justin

Molecular Brain (2024), 17(1), 3 | Language: English, Database: CAplus and MEDLINE
Abstract: Alzheimer′s disease (AD) is characterized by the loss of memory due to aggreg ation of misphosphorylated tau and
amyloid beta (Aβ) plaques in the brain, elevated release of inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and
reactive oxygen species from astrocytes, and subsequent neurodegeneration. Recently, it was found that enzyme Ornithine
Decarboxylase 1 (ODC1) acts as a bridge between the astrocytic urea cycle and the putres cine-to-GABA conversion pathway in the
brain of AD mouse models as well as human patients. In this study, we show that the long- term knockdown of astrocytic Odc1 in A P
P/PS1 animals was sufficient to completely clear Aβ plaques in the hippoc ampus while simultaneously switching the astrocytes
from a detrimental reactive state to a regenerative active state, charact erized by pro BDNF expression. Our experiments also reveal
an effect of astrocytic ODC1 inhibition on the expression of genes involved in synapse pruning and organiz ation, histone modific
ation, apoptotic signaling and protein proces sing. These genes are previously known to be associated with astrocytic activation and
together create a neuroregeneration-supportive environment in the brain. By inhibiting O DC1 for a long period of 3 mo in A D mice,
we demonstrate that the beneficial amyloid-clearing process of astrocytes can be completely segregated from the system ically
harmful astrocytic response to insult. Our study reports an almost complete clearance of Aβ plaques by controlling an endogenous
degradation process, which also modifies the astrocytic state to create a regener ation-supportive environment in the brain. These
findings present the potential of modulating astrocytic clearance of Aβ as a powerful therapeutic strategy against A D.
Keywords: Alzheimer’s disease; Ornithine decarbo xylase 1; Reactive astrocytes

113
Effect of zinc oxide nanocomposite and ginger extract on lipid profile, glucose, pancreatic tissue and
expression of Gpx1 and Tnf-α genes in diabetic rat model
By: Hassanpour, Shahram; Naghsh, Nooshin; Yazdanpanahi, Nasrin; Talebian, Nasrin

Diabetes is a life-threatening health condition that requires expensive treatment and places a signif icant financial burden on society.
Consequently, this study aimed to explore the potential of low and high concent rations of ginger extract, Zn O-NPs, and a combin
ation of both to help manage diabetes and reduce high levels of lipids in diabetic rats. The research focused on agglom erated
nanoparticles under 100 nm, specifically ZnO nanoparticles. The size of the nanoparticles was determined using X-ray diffraction
anal. and SEM anal., with a monodi sperse particle size distri bution of 20 to 48 nm and an average size of 38 nm, as shown by
dynamic light scattering. Fourier transform I R spectroscopy revealed the presence of typical peaks of ginger extract and Zn O-NPs in
the nanocomposite structure. The pancreatic tissue histop athol. study indicated that a concent ration of 10 mg/kg of the composite
had the most significant antidiabetic effect compared to other treatm ents. Lower concentrations could significantly reduce and
balance fasting blood sugar and triglycerides levels while also increasing the high-d. lipoproteins levels. However, all treatments
induced a significant decrease in total choles terol and low-d. lipoproteins levels. Only metformin and Zn O-NPs in lower concent
rations could decrease very low- d. lipoproteins levels. The mol. technique showed that a low concent ration of the composite led to
the most significant decrease in Tnf- α gene expression compared to the diabetic group. The expression of the glutat hione
peroxidase 1 (Gpx1) gene in treated groups had no significant difference with the level of Gpx1 expression in the control rats.
Conclusions: In general, this study demons trated that lower concentrations of the treatments, especially composite, were more
effective for treating diabetic rats due to reduced pancreatic tissue damage.
Keywords: Zingiber diabetes ZnO NP lipid glucose pancreas Gpx1 T NFA; Antioxidants; Ginger; Pancreatic tissue; Type 2 diabetes
mellitus; ZnO-NPs

114
MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition -mediated
RONΔ160/PI3K/AKT signaling pathway activation
By: Yu, Shanshan; Chen, Cheng; Chen, Ming; Liang, Jinxiao; Jiang, Kecheng; Lou, Bin; Lu, Jun; Zhu, Xiaohua; Zhou, Donghui
Abstract: Background: Gastric cancer (GC) is associated with high mortality and heterog eneity and poses a great threat to humans.
Gene therapies for the receptor tyrosine kinase RON and its splice osomes are attracting increasing amounts of attention due to
their unique characteristics. However, little is known about the mechanism involved in the formation of the R ON mRNA alternative
spliceosome RONΔ160. Methods: Fourteen human GC tissue samples and six normal gastric tissue samples were subjected to label-
free relative quant. proteomics anal., and M AGOH was identified as a candidate protein for subsequent studies. The expression of
MAGOH in clin. specimens was verified by quant. real- time PCR and western blotting. We then determined the biol. function of M AG
OH in GC through in vitro and in vivo experi ments RNA pulldown, RNA sequencing and R NA immunoprecipitation (RIP) were subseq
uently conducted to uncover the underlying mechanism by which M AGOH regulated the formation of RONΔ160. Results: Proteomic
anal. revealed that MAGOH, which is located at key nodes and partic ipates in RNA processing and mRNA splicing, was upregulated
in GC tissue and GC cell lines and was associated with poor prognosis. Functional anal. showed that M AGOH promoted the prolife
ration, migration and invasion of GC cells in vitro and in vivo. Mechanis tically, MAGOH inhibited the expression of hnRNPA1 and
reduced the binding of hnRNPA1 to RON mRNA, thereby promoting the formation of R ONΔ160 to activate the PI3K/AKT signaling
pathway and consequently facilitating GC progression. Conclusions: Our study revealed that M AGOH could promote the formation
of RONΔ160 and activate the PI3K/AKT signaling pathway through the inhibition of hnRNPA1 expression. We elucidate a novel
mechanism and potential therapeutic targets for the growth and metastasis of G C based on the MAGOH-RONΔ160 axis, and these
findings have important guiding significance and clin. value for the future develo pment of effective therapeutic strategies for G C.
Keywords: Alternative splicing; Gastric cancer; MAGOH; PI3K/AKT signaling pathway; R ONΔ160; hnRNPA1

115
S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer
mouse models
By: Begg, Lauren R.; Orriols, Adrienne M. ; Zannikou, Markella; Yeh, Chen; Vadlamani, Pranathi ; Kanojia, Deepak; Bolin,
Rosemary; Dunne, Sara F.; Balakrishnan, Sanjeev; Camarda, Roman; et al
Communications Medicine (2024), 4(1), 22 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Understanding why some triple- neg. breast cancer (T NBC) patients respond poorly to existing therapies
while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing
early-stage TNBC tumors that respond to clin. interv ention from non-responders, as well as to identify clin. viable therapeutic strate
gies, specifically for TNBC patients who may not benefit from existing therapies. Methods: We conducted retrosp ective bioinfo
rmatics anal. of historical gene expression datasets to identify a group of genes whose expression levels in early- stage tumors
predict poor clin. outcomes in TNBC. In vitro small- mol. screening, genetic manipulation, and drug treatment in syngeneic mouse
models of TNBC were utilized to invest igate potential therapeutic strategies and elucidate mechanisms of drug action. Results: Our
bioinformatics anal. reveals a robust association between increased expression of immunosup pressive cytokine S100A8/A9 in early-
stage tumors and subsequent disease progre ssion in TNBC. A targeted small- mol. screen identifies PIM kinase inhibitors as capable
of decreasing S100A8/A9 expression in multiple cell types, including T NBC and immunosuppressive myeloid cells. Combining P IM
inhibition and immune checkpoint blockade induces signif icant antitumor responses, especially in otherwise resistant S100 A8/A9-
high PD-1/PD-L1-pos. tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100 A8/A9 in a syngeneic mouse model of T
NBC. Conclusions: Our data propose S100 A8/A9 as a potential predictive and pharmaco dynamic biomarker in clin. trials evaluating
combination therapy targeting PIM and immune checkp oints in TNBC. This work encourages the develo pment of S100A8/A9-based
liquid biopsy tests for treatment guidance.

116
Inhibition of STAT3 alleviates LPS-induced apoptosis and inflammation in renal tubular epithelial cells
by transcriptionally down-regulating TASL
By: Xu, Jin-Wen; Wang, Ming-Yan; Mao, Yan; Hu, Zheng-Yun; Miao, Xiao-Lin; Jiang, Feng; Zhou, Guo-Ping
European Journal of Medical Research (2024), 29(1), 34 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Systemic lupus erythematosus (SLE) is a common autoimmune disease that impacts various organs. Lupus
nephritis (LN) significantly contributes to death in children with S LE. Toll-like receptor (TLR) adaptor interacting with SLC15A4 on the
lysosome (TASL) acts as an innate immune adaptor for T LR and is implicated in the pathog enesis of SLE. A transcription factor
known as signal transducer and activator of transcription 3 (STAT3), which is known to be linked to autoimmune diseases, is also
involved in the development of SLE. Methods: Bioinformatics and real-time quant. PCR (qRT-PCR) was used to detect the expression
of STAT3 and TASL in peripheral blood of S LE patients and their correl ation. Bioinformatics anal., qRT-PCR, luciferase assay and
chromatin immunoprecipitation (ChIP) were used to verify the regulation of transcr iption factor STAT3 on TASL. The expression
levels of STAT3, TASL and apoptosis-related genes in LPS-induced HK2 cells were detected by q RT-PCR and Western blot. T UNEL
staining were used to detect the apoptosis of HK2 cells after LPS stimulation. ELISA and q RT-PCR were used to detect the levels of
inflammatory cytokines in the cell culture supern atant. TASL knockdown in HK2 cells was used to detect the changes in apoptosis-
related genes and inflammatory factors. The expression level of T ASL in LPS-stimulated HK2 cells and its effect on cell apoptosis and
inflammatory factors were observed by knocking down and overexp ressing STAT3, resp. It was also verified in a rescue experiment
Results: The expressions of STAT3 and TASL were higher in SLE than in healthy children, and the expression of S TAT3 was pos.
correlated with TASL. Transcription factor STAT3 can directly and pos. regulate the expression of T ASL through the promoter region
binding site. The expression of STAT3, TASL and inflammatory cytokines was elevated, and the change of apoptosis was up-
regulated in LPS-stimulated HK2 cells. Inhibition of STAT3 alleviates LPS-stimulated apoptosis and inflammatory response in HK2
cells through transcriptional regulation of TASL. Conclusions: These findings provide new insights into the transcri ptional regulation
of TASL and provide new evidence of a direct regulatory relati onship between signaling nodes in the lupus signaling network.
Graphical Abstract: [graphic not available: see fulltext]
Keywords: Promoter; SLE; STAT3; TASL

117
Flubendazole carbonyl reduction in drug-susceptible and drug-resistant strains of the parasitic

nematode Haemonchus contortus: changes during the life cycle and possible inhibition
By: Rychla, Nikola; Navratilova, Martina; Kohoutova, Eliska; Raisova Stuchlikova, Lucie; Sterbova, Karolina; Kratky, Josef; Matouskova,
Petra; Szotakova, Barbora; Skalova, Lenka
Veterinary Research (2024), 55(1), 7 | Language: English, Database: CAplus and MEDLINE
Abstract: Carbonyl-reducing enzymes (CREs) catalyze the reduction of carbonyl groups in many eobiotic and xenobiotic compounds
in all organisms, including helminths. Previous studies have shown the important roles of CREs in the deactivation of several anthel
mintic drugs (e.g., flubendazole and mebendazole) in adults infected with the parasitic nematode Haemonchus contortus, in which
the activity of a CRE is increased in drug-resistant strains. The aim of the present study was to compare the abilities of nematodes
of both a drug-susceptible strain (ISE) and a drug- resistant strain (IRE) to reduce the carbonyl group of fluben dazole (FLU) in
different developmental stages (eggs, L1/2 larvae, L3 larvae, and adults) . In addition, the effects of selected C RE inhibitors (e.g.,
glycyrrhetinic acid, naringenin, silybin, luteolin, glyceraldehyde, and menadione) on the reduction of F LU were evaluated in vitro and
ex vivo in H. contortus adults. The results showed that FLU was reduced by H. contortus in all develop mental stages, with adult I RE
females being the most metabolically active. Larvae (L1/2 and L3) and adult females of the I RE strain reduced FLU more effectively
than those of the ISE strain. Data from the in vitro inhibition study (performed with cytosolic- like fractions of H. contortus adult
homogenate) revealed that glycyrrhetinic acid, naringenin, mebendazole and menadione are effective inhibitors of F LU reduction Ex
vivo study data showed that menadione inhibited FLU reduction and also decreased the viability of H. contortus adults to a similar
extent. Naringenin and mebendazole were not toxic at the concent rations tested, but they did not inhibit the reduction of F LU in
adult worms ex vivo.
Keywords: Anthelmintics; Strongyloides; drug biotransformation; helminths; inhibitors

118
Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals

a new metabolic vulnerability as possible target for treatment
By: Krug, Adrien; Tosolini, Marie; Madji Hounoum, Blandine; Fournie, Jean-Jacques; Geiger, Roger; Pecoraro, Matteo; Emond, Patrick;
Gaulard, Philippe; Lemonnier, Francois; Ricci, Jean-Ehrland; et al
Abstract: Background: Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in urgent need
of more specific therapeutic strategies. The drivers of malignancy in this disease are C D4+ follicular helper T cells (Tfh) . The
metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requir ements with
the objective to propose a novel therapeutic option. Methods: To reveal the prominent metabolic pathways used by the A ITL
lymphoma cells, we relied on metabolomic and proteomic anal. of murine AITL (mAITL) T cells isolated from our establ ished mAITL
model. We confirmed these results using AITL patient and healthy T cell expression data. Results: Striki ngly, the mAITL Tfh cells
were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of
the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from A ITL patient
tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase,
catalyzing the first step in the phosphatidylcholine pathway, are upregulated in multiple tumors other than A ITL. Here we showed
that treatment of our mAITL preclin. mouse model with a fatty acid oxydation inhibitor, signifi cantly increased their survival and
even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti- tumor cells. Specific inhibition of Chokα confirmed
the importance of the phosphatidylcholine production pathway in neoplastic C D4 + T cells, nearly eradic ating mAITL Tfh cells from
the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the h AITL PD-1high
neoplastic cells. Conclusion: Our results suggest that interfering with choline metabolism in AITL reveals a specific metabolic
vulnerability and might represent a new therap eutic strategy for these patients.
Keywords: AITL; CDP-choline pathway; CDP-ethanolamine pathway; Cancer therapy; Choline; Choline kinase; Lipid metabolism; T-
cell lymphoma

119
Integrated compact regulators of protein activity enable control of signaling pathways and genome-
editing in vivo
By: Franko, Nik; da Silva Santinha, Antonio Jose; Xue, Shuai; Zhao, Haijie; Charpin-El Hamri, Ghislaine; Platt, Randall Jeffrey; Teixeira,
Ana Palma; Fussenegger, Martin
Cell Discovery (2024), 10(1), 9 | Language: English, Database: CAplus and MEDLINE
Viral proteases and clin. safe inhibitors were employed to build integrated compact regulators of protein activity (iCROP) for post-
translational regulation of functional proteins by tunable proteo lytic activity. In the absence of inhibitor, the colocalized/fused
protease cleaves a target peptide sequence introduced in an exposed loop of the protein of interest, irreversibly fragmenting the
protein structure and destroying its functionality. We selected three proteases and demons trated the versatility of the i CROP
framework by validating it to regulate the functional activity of ten different proteins. ICROP switches can be delivered either as mR
NA or DNA, and provide rapid actuation kinetics with large induction ratios, while remaining strongly suppressed in the off state
without inhibitor. ICROPs for effectors of the N F-κB and NFAT signaling pathways were assembled and confirmed to enable precise
activation/ inhibition of downstream events in response to protease inhibi tors. In lipopolysaccharide-treated mice, iCROP-sr-IκBα
suppressed cytokine release ("cytokine storm") by rescuing the activity of IκBα, which suppresses N F-κB signaling. We also constr
ucted compact inducible CRISPR-(d)Cas9 variants and showed that i CROP-Cas9-mediated knockout of the PCSK9 gene in the liver
lowered blood LDL-cholesterol levels in mice. ICROP-based protein switches will facilitate protein-level regulation in basic research
and translational applications.
Keywords: genome editing signal transduction viral protease C RISPR Cas system
120
Synthesis, structural characterizations, in vitro biological evaluation and computational investigations

of pyrazole derivatives as potential antidiabetic and antioxidant agents
By: Mortada, Salma; Karrouchi, Khalid; Hamza, El Hadki; Oulmidi, Afaf; Bhat, Mashooq Ahamd; Mamad, Hassane; Aalilou, Youssra;
Radi, Smaail; Ansar, M′hammed; Masrar, Azlarab; et al
Abstract: In this study, a two pyrazole derivatives; 2-(5-methyl-1H-pyrazole-3-carbonyl)-N-phenylhydrazine-1-carboxamide (Pyz-1)

and 4-amino-5-(5-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiol (Pyz-2) were synthesized and characterized by 13 C-NMR, 1H-NMR,
FT-IR, and mass spectrometry. A complete mol. structures optimiz ation, electronic and thermodn. properties of Pyz- 1 and Pyz-2 in
gas phase and aqueous solution were predicted by using hybrid B3LYP method with the 6-311++G** basis sets. Pyz- 1 and Pyz-2
were evaluated in vitro for their anti-diabetic, antioxidant and xanthine oxidase inhibition activities. For anti-diabetic activity, Pyz-1
and Pyz-2 showed a potent α -glucosidase and α -amylase inhibition with IC50 values of 75.62 ± 0.56, 95.85 ± 0.92 and 119.3 ± 0.75,
120.2 ± 0.68 μM, resp., compared to Acarbose (IC50 (α -glucosidase) = 72.58 ± 0.68 μ M, IC50 (α -amylase) = 115.6 ± 0.574 μ M). In
xanthine oxidase assay, Pyz-1 and Pyz-2 exhibited remarkable inhibitory ability with I C50 values 24.32 ± 0.78 and 10.75 ± 0.54 μ M,
resp. The result of antioxidant activities showed that the title compounds have consid erable antioxidant and radical scavenger
abilities. In addition, mol. docking simulation was used to determine the binding modes and energies between the title compounds
and α -glucosidase and α -amylase enzymes.

121
Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent
microvascular complications in diabetes
By: Gamez, Monica; Elhegni, Hesham E.; Fawaz, Sarah; Ho, Kwan Ho; Campbell, Neill W.; Copland, David A.; Onions, Karen L.; Butler,
Matthew J.; Wasson, Elizabeth J.; Crompton, Michael; et al
Cardiovascular Diabetology (2024), 23(1), 50 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Diabetes mellitus is a chronic disease which is detrim ental to cardiovascular health, often leading to
secondary microvascular complications, with huge global health implica tions. Therapeutic interventions that can be applied to
multiple vascular beds are urgently needed. Diabetic retinopathy (DR) and diabetic kidney disease (D KD) are characterised by early
microvascular permeability changes which, if left untreated, lead to visual impairment and renal failure, resp. The heparan sulfate
cleaving enzyme, heparanase, has previously been shown to contribute to diabetic microva scular complications, but the common
underlying mechanism which results in microvascular dysfunction in conditions such as DR and DKD has not been determined
Methods: In this study, two mouse models of heparan sulfate depletion (enzymic removal and genetic ablation by endothelial
specific Exotosin-1 knock down) were utilized to invest igate the impact of endoth elial cell surface (i.e., endoth elial glycocalyx)
heparan sulfate loss on microvascular barrier function. Endoth elial glycocalyx changes were measured using fluore scence
microscopy or transmission electron microscopy. To measure the impact on barrier function, we used sodium fluore scein angiog. in
the eye and a glomerular albumin permeability assay in the kidney. A type 2 diabetic (T2 D, db/db) mouse model was used to
determine the therapeutic potential of preventing heparan sulfate damage using treatment with a novel heparanase inhibitor, O V
Z/HS-1638. Endothelial glycocalyx changes were measured as above, and microva scular barrier function assessed by albumin
extravasation in the eye and a glomerular permea bility assay in the kidney. Results: In both models of heparan sulfate depletion,
endothelial glycocalyx depth was reduced and retinal solute flux and glomerular albumin permea bility was increased. T2D mice
treated with OVZ/HS-1638 had improved endoth elial glycocalyx measurements compared to vehicle treated T2 D mice and were
simultaneously protected from microva scular permeability changes associated with D R and DKD. Conclusion: We demonstrate that
endothelial glycocalyx heparan sulfate plays a common mechan istic role in microvascular barrier function in the eye and kidney.
Protecting the endothelial glycocalyx damage in diabetes, using the novel heparanase inhibitor O VZ/HS-1638, effectively prevents
microvascular permeability changes associated with D R and DKD, demonstrating a novel systemic approach to address diabetic
microvascular complications.

122
Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by
palbociclib-heptamethine cyanine dye conjugate
By: Cooper, Elizabeth; Oyagawa, Caitlin R. M.; Johnson, Rebecca; Choi, Peter J.; Foliaki, Jena Macapagal; Correia, Jason; Schweder,
Patrick; Heppner, Peter; Mee, Edward; Turner, Clinton; et al
Abstract: Glioblastoma is the most common and aggressive primary brain tumor in adults. The develo pment of anti-brain cancer
agents are challenged by the blood-brain barrier and the resistance conferred by the local tumor microenvi ronment. Heptamethine
cyanine dyes (HMCDs) are a class of near-IR fluorescence compounds that have recently emerged as promising agents for drug
delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug
activity anal. on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies
revealed that palbociclib-MHI-148 conjugate resulted in an almost 100- fold increase in cytotoxicity compared to palboc iclib alone.
This shift of palbociclib from cytostatic to cytotoxic when conjugated to M HI-148 was due to increased DNA damage, as indicated by
an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including T P53, TNFR1, TRAIL, FADD
and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of T NFR1, consistent with an
observed increase in the secretion TNFα, followed by T NFR1 endocytosis at 48 h. The treatment of patient G BM cells with the
palbociclib-MHI-148 conjugate prevented T NFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favored
the TNFR1-mediated apoptotic response rather than the proinflammatory response pathway. Notably, pharmacol. inhibition of
endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palboc iclib-MHI-148-induced cell death. These results show a
novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical N FκB signalling
using our previously reported palbociclib-HMCD conjugate. [media not available: see fulltext]
123
Effect of ginger supplementation on the fecal microbiome in subjects with prior colorectal adenoma
By: Prakash, Ajay; Rubin, Nathan; Staley, Christopher; Onyeaghala, Guillaume; Wen, Ya-Feng; Shaukat, Aasma; Milne, Ginger; Straka,
Robert J.; Church, Timothy R.; Prizment, Anna
Abstract: Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory
pathways and inhibition of tumor growth. Recent preclin. models have implicated changes in the gut microbiome as a possible
mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger
supplementation would alter the fecal microbiome in the direction consistent with its C RC-inhibitory effect. Sixty-eight adults were
randomized to take either ginger or placebo daily for 6 wk, with a 6-wk washout and longit udinal stool collection throug hout. We
performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of prespecified
CRC-associated taxa using mixed- effects logistic regression. Ginger suppleme ntation showed no signif icant effect on microbial
community structure through alpha or beta diversity. Of 10 prespecified CRC-associated taxa, there were signif icant decreases in
the relative abundances of the genera Akkermansia (p < 0.001), Bacteroides (p = 0.018) , and Ruminococcus (p = 0.013) after 6- wk
treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances of Akkerm ansia and Bacter
oides, which suggests that ginger may have an inhibitory effect on C RC-associated taxa. Overall, ginger suppleme ntation appears to
have a limited effect on gut microbiome in patients with colorectal adenomas.

124
Targeting the prefrontal-supplementary motor network in obsessive-compulsive disorder with

intensified electrical stimulation in two dosages: a randomized, controlled trial
By: Alizadehgoradel, Jaber ; Molaei, Behnam; Barzegar Jalali, Khandan; Pouresmali, Asghar; Sharifi, Kiomars; Hallajian, Amir-
Homayun ; Nejati, Vahid; Glinski, Benedikt ; Vicario, Carmelo M.; Nitsche, Michael A.; et al
Translational Psychiatry (2024), 14(1), 78 | Language: English, Database: CAplus and MEDLINE
Abstract: Obsessive-compulsive disorder (OCD) is associated with a high disease burden, and treatment options are limited. We
used intensified elec. stimulation in two dosages to target a main circuitry associated with the pathoph ysiol. of OCD, left dorsol
ateral prefrontal cortex (l- DLPFC), and pre-supplementary motor area (pre- SMA) and assessed clin. outcomes, neurops ychol. perfor
mance, and brain physiol. In a double- blind, randomized controlled trial, thirty-nine patients with O CD were randomly assigned to
three groups of sham, 2-mA, or 1-mA transcranial d.c. stimulation (tDCS) targeting the l-DLPFC (F3) and pre- SMA (FC2) with anodal
and cathodal stimulation resp. The treatment included 10 sessions of 20- min stimulation delivered twice per day with 20- min
between-session intervals. Outcome measures were reduction in OCD symptoms, anxiety, and depressive states, performance on a
neuropsychol. test battery (response inhibition , working memory, attention), oscillatory brain activities, and functional connectivity.
All outcome measures except EEG were examined at pre- intervention, post-intervention, and 1- mo follow-up times. The 2- mA
protocol significantly reduced O CD symptoms, anxiety, and depression states and improved quality of life after the interv ention up
to 1-mo follow-up compared to the sham group, while the 1- mA protocol reduced O CD symptoms only in the follow-up and
depressive state immediately after and 1- mo following the intervention. Both protocols partially improved response inhibition , and
the 2-mA protocol reduced attention bias to O CD-related stimuli and improved reaction time in working memory perfor mance.
Both protocols increased alpha oscillatory power, and the 2- mA protocol decreased delta power as well. Both protocols increased
connectivity in higher frequency bands at frontal- central areas compared to the sham. Modulation of the prefro ntal-supplementary
motor network with intensified tDCS ameliorates OCD clin. symptoms and results in beneficial cognitive effects. The 2- mA intens
ified stimulation resulted in larger symptom reduction and improved more converging outcome variables related to therap eutic
efficacy. These results support applying the intensified prefrontal-SMA tDCS in larger trials.

125
Red blood cell-derived arginase release in hemolytic uremic syndrome
By: Friberg, Niklas; Arvidsson, Ida; Tontanahal, Ashmita; Kristoffersson, Ann-Charlotte; Gram, Magnus; Kaplan, Bernard S.; Karpman,
Diana
Abstract: Background: Hemolysis is a cardinal feature of hemolytic uremic syndrome (H US) and during hemolysis excess arginase 1
is released from red blood cells. Increased arginase activity leads to reduced L-arginine, as it is converted to urea and L- ornithine,
and thereby reduced nitric oxide bioavailability, with secondary vascular injury. The objective of this study was to invest igate
arginase release in HUS patients and laboratory models and correlate arginase levels to hemolysis and kidney injury. Methods: Two
sep. cohorts of patients (n = 47 in total) with HUS associated with Shiga toxin- producing enterohemorrhagic E. coli (E HEC) and
pediatric controls (n = 35) were investigated. Two mouse models were used, in which mice were either challenged intragas trically
with E. coli O157:H7 or injected i.p. with Shiga toxin 2. An in vitro model of thrombotic microang iopathy was developed in which
Shiga toxin 2- and E. coli O157 lipopolysaccharide-stimulated human blood cells combined with A DAMTS13-deficient plasma were
perfused over glomerular endothelial cells. Two group statis tical comparisons were performed using the Mann-Whitney test,
multiple groups were compared using the Kruskal-Wallis test followed by Dunn′s procedure, the Wilcoxon signed rank test was used
for paired data, or linear regression for continuous variables. Results: HUS patients had excess ively high plasma arginase 1 levels
and activity (conversion of L-arginine to urea and L-ornithine) during the acute phase, compared to remission and controls. Arginase
1 levels correlated with lactate dehydrogenase activity, indicating hemolysis, as well as the need for dialysis treatment. Patients also
exhibited high levels of plasma alpha -1-microglobulin, a heme scavenger. Both mouse models exhibited signifi cantly elevated
plasma arginase 1 levels and activity. Plasma arginase 1 levels correlated with lactate dehydrogenase activity, alpha -1-microgl
obulin and urea levels, the latter indicative of kidney dysfun ction. In the in vitro model of thrombotic microang iopathy, bioactive
arginase 1 was released and levels correlated to the degree of hemolysis. Conclusions: Elevated red blood cell- derived arginase was
demonstrated in HUS patients and in relevant in vivo and in vitro models. The excess ively high arginase levels correlated to the
degree of hemolysis and kidney dysfunction. Thus, arginase inhibition should be investigated in HUS.
Keywords: Arginase; Hemolytic uremic syndrome; Nitric oxide; Shiga toxin; Thrombotic microangiopathy

126
Facile adipocyte uptake and liver/adipose tissue delivery of conjugated linoleic acid-loaded tocol
nanocarriers for a synergistic anti-adipogenesis effect
By: Hsu, Ching-Yun; Liao, Chia-Chih; Lin, Zih-Chan; Alalaiwe, Ahmed; Hwang, Erica; Lin, Tzu-Wei; Fang, Jia-You
Journal of Nanobiotechnology (2024), 22(1), 50 | Language: English, Database: CAplus and MEDLINE
Abstract: Obesity is a major risk to human health. Adipogenesis is blocked by α -tocopherol and conjugated linoleic acid (C LA).
However, their effect at preventing obesity is uncertain. The effectiveness of the bioactive agents is associated with their delivery
method. Herein, we designed CLA-loaded tocol nanostructured lipid carriers (N LCs) for enhancing the anti- adipogenic activity of α -
tocopherol and CLA. Adipogenesis inhibition by the nanocarriers was examined using an in vitro adipocyte model and an in vivo rat
model fed a high fat diet (HFD). The targeting of the tocol N LCs into adipocytes and adipose tissues were also investi gated. A synerg
istic anti-adipogenesis effect was observed for the combin ation of free α -tocopherol and CLA. Nanoparticles with different
amounts of solid lipid were developed with an average size of 121-151 nm. The NLCs with the smallest size (121 nm) showed
greater adipocyte internalization and differentiation prevention than the larger size. The small- sized NLCs promoted C LA delivery
into adipocytes by 5.5-fold as compared to free control. The nanoca rriers reduced fat accumulation in adipocytes by counter acting
the expression of the adipogenic transcription factors peroxisome prolif erator activated receptor (P PAR)γ and CCAAT/enhancer-
binding protein (C/EBP) α , and lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (F AS). Localized adminis
tration of CLA-loaded tocol N LCs significantly reduced body weight, total choles terol, and liver damage indicators in obese rats. The
biodistribution study demonstrated that the nanoparticles mainly accumulated in liver and adipose tissues. The N LCs decreased
adipocyte hypertrophy and cytokine overexpression in the groin and epididymis to a greater degree than the combin ation of free
α -tocopherol and CLA. In conclusion, the lipid-based nanocarriers were verified to inhibit adipog enesis in an efficient and safe way.
Keywords: Anti-adipogenesis; Conjugated linoleic acid; Nanostr uctured lipid carriers; Obesity; Passive targeting; α -tocopherol
127
Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple
negative breast cancer
By: Tan, Yan Qin ; Chiou, Yi-Shiou ; Guo, Hui; Zhang, Shuwei; Huang, Xiaoming; Dukanya, Dukanya; Kumar, Arun M. ;
Basappa, Shreeja; Liu, Suling; Zhu, Tao; et al
Abstract: Aberrant activation of the PI3K/AKT signaling axis along with the sustained phosphor ylation of downstream BAD is
associated with a poor outcome of TNBC. Herein, the phosphorylated to non-phosphorylated ratio of BAD, an effector of PI3K/AKT
promoting cell survival, was observed to be correlated with worse clinicopathol. indicators of outcome, including higher grade,
higher proliferative index and lymph node metast asis. The structural optimization of a previously reported inhibitor of B AD-Ser99
phosphorylation was therefore achieved to generate a small mol. inhibiting the phosphor ylation of BAD at Ser99 with enhanced
potency and improved oral bioavailability. The mol. 2- ((4-(2,3-dichlorophenyl)piperazin-1-yl)(pyridin-3-yl)methyl) phenol (N CK)
displayed no toxicity at supra-therapeutic doses and was therefore assessed for utility in T NBC. NCK promoted apoptosis and
G0/G1 cell cycle arrest of TNBC cell lines in vitro, concordant with gene expression analyses, and reduced in vivo xenograft growth
and metastatic burden, demonstrating efficacy as a single agent. Addnl., combina torial oncol. compound library screening demons
trated that NCK synergized with tyrosine kinase inhibitors (T KIs), specifically OSI-930 or Crizotinib in reducing cell viability and
promoting apoptosis of TNBC cells. The synerg istic effects of NCK and T KIs were also observed in vivo with complete regression of a
percentage of TNBC cell line derived xenografts and prevention of metastatic spread. In patient- derived TNBC xenograft models, N C
K prolonged survival times of host animals, and in combin ation with TKIs generated superior survival outcomes to single agent
treatment. Hence, this study provides proof of concept to further develop rational and mechanistic based therapeutic strategies to
ameliorate the outcome of TNBC.

128
High estrogen during ovarian stimulation induced loss of maternal imprinted methylation that is
essential for placental development via overexpression of TET2 in mouse oocytes
By: Lu, Xueyan; Mao, Jiaqin; Qian, Chenxi; Lei, Hui; Mu, Fei; Sun, Huijun; Yan, Song; Fang, Zheng; Lu, Jie; Xu, Qian; et al
Abstract: Background: Ovarian stimulation (OS) during assisted reprod uctive technol. (ART) appears to be an independent factor
influencing the risk of low birth weight (LBW). Previous studies identified the associ ation between LBW and placenta deterio ration,
potentially resulting from disturbed genomic D NA methylation in oocytes caused by O S. However, the mechanisms by which OS
leads to aberrant DNA methylation patterns in oocytes remains unclear. Methods: Mouse oocytes and mouse partheno genetic
embryonic stem cells (pESCs) were used to invest igate the roles of OS in oocyte DNA methylation. Global 5-methylcytosine (5mC)
and 5-hydroxymethylcytosine (5hmC) levels were evaluated using immunofluorescence or colorimetry. Genome-wide DNA methyl
ation was quantified using an Agilent Sure SelectXT mouse Methyl- Seq. The DNA methylation status of mesoderm- specific transcript
homolog (Mest) promoter region was analyzed using bisulfite sequencing polymerase chain reaction (BSP). The regulatory network
between estrogen receptor alpha (ERα, ESR1) and DNA methylation status of Mest promoter region was further detected following
the knockdown of ERα or ten-eleven translocation 2 (Tet2). Results: O S resulted in a signif icant decrease in global 5m C levels and an
increase in global 5hmC levels in oocytes. Further investi gation revealed that supraphysiol. β-estradiol (E2) during O S induced a
notable decrease in DNA 5mC and an increase in 5hm C in both oocytes and p ESCs of mice, whereas inhibition of estrogen
signaling abolished such induction. Moreover, Tet2 may be a direct transcriptional target gene of E Rα, and through the ERα-TET2
axis, supraphysiol. E2 resulted in the reduced global levels of D NA 5mC. Furthermore, we identified that M EST, a maternal imprinted
gene essential for placental development, lost its imprinted methylation in parthenogenetic placentas originating from OS, and ERα
and TET2 combined together to form a protein complex that may promote Mest demethy lation. Conclusions: In this study, a
possible mechanism of loss of DNA methylation in oocyte caused by O S was revealed, which may help increase safety and reduce
epigenetic abnormalities in ART procedures.
Keywords: DNA methylation; ERα; TET2; MEST; Ovarian stimulation; Parthenogenetic activation; Parthenogenetic embryonic stem
cells
129
Inhibition of mucus secretion by niclosamide and benzbromarone in airways and intestine
By: Ousingsawat, Jiraporn; Centeio, Raquel; Reyne, Nicole; McCarron, Alexandra; Cmielewski, Patricia; Schreiber, Rainer; diStefano,
Gabriella; Roemermann, Dorothee; Seidler, Ursula; Donnelley, Martin; et al
Abstract: The Ca2+ activated Cl- channel T MEM16A (anoctamin 1; ANO1) is expressed in secretory epithelial cells of airways and
intestine. Previous studies provided evidence for a role of ANO1 in mucus secretion. In the present study we invest igated the effects
of the two ANO1-inhibitors niclosamide (Niclo) and benzbromarone (Benz) in vitro and in vivo in mouse models for cystic fibrosis (C
F) and asthma. In human CF airway epithelial cells (C FBE), Ca2+ increase and activation of A NO1 by A TP (ATP) or ionomycin was
strongly inhibited by 200 nM Niclo and 1 μ M Benz. In asthmatic mice airway mucus secretion was inhibited by intratr acheal instil
lation of Niclo or Benz. In homozygous F508del- cftr mice, intestinal mucus secretion and infilt ration by CD45-pos. cells was inhibited
by i.p. injection of Niclo (13 mg/kg/day for 7 days). In homozygous F508del-cftr rats intestinal mucus secretion was inhibited by oral
application of Benz (5 mg/kg/day for 60 days) . Taken together, well tolerated therap eutic concentrations of niclosamide and
benzbromarone corresponding to plasma levels of treated patients, inhibit ANO1 and intracellular Ca 2+ signals and may therefore
be useful in inhibiting mucus hypersecretion and mucus obstru ction in airways and intestine of patients suffering from asthma and
CF, resp.

130
Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer′s

pathology
By: Gebril, Hoda M. ; Aryasomayajula, Aravind; de Lima, Mariana Reis Nogueira; Uhrich, Kathryn E.; Moghe, Prabhas V.
Translational Neurodegeneration (2024), 13(1), 2 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Alzheimer′s disease (AD) is considered to have a multifactorial etiol. The hallmark of A D is progressive
neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The
neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extrace llular amyloid beta (Aβ)
plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the
symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanote chnol.
based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (f Aβ)
burden, microglial modulation, and neuroprotection. Methods: We designed a nanote chnol. approach to regulate the S R-mediated
intracellular fAβ trafficking within microglia. We synthe sized SR-targeting sugar-based amphiphilic macromols. (AM) and used them
as a bioactive shell to fabricate serum-stable AM-NPs via flash nanopptn. Using electron micros copy, in vitro approa ches, ELISA, and
confocal microscopy, we investigated the effect of AM-NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neuroto
xicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines. Results: A M-NPs interrupted Aβ fibrili zation, attenuated fAβ microglial
internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response,
and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM-NPs counteracted the microglial-mediated neurotoxicity
after exposure to fAβ. Conclusions: The AM-NP nanotechnol. presents a multifa ctorial strategy to target pathol. Aβ aggreg ation and
arrest the fAβ-mediated pathol. progression in microglia and neurons. Graphical Abstract: [graphic not available: see fulltext]
Keywords: Alzheimer’s disease; Amphip hilic nanoparticle; Fibril amyloid beta; Microglia; Neuroinfl ammation; Scavenger receptor
131
The role of vasoactive intestinal peptide (VIP) in atropine-related inhibition of the progression of
myopia
By: Wang, Ying; Li, Lan; Tang, Xiaoli; Fan, Haobo; Song, Weiqi; Xie, Juan; Tang, Yangyu; Jiang, Yanqing; Zou, Yunchun
BMC Ophthalmology (2024), 24(1), 41 | Language: English, Database: CAplus and MEDLINE
Abstract: Objective: This study aimed to investigate the potential involvement of vasoactive intestinal polype ptide (VIP) in myopia
development and its contribution to the mechanism of action of the anti- myopia drug, atropine. Methods: Thirty-three-week-old
guinea pigs were randomly divided into normal control (NC, n = 10), monocularly form-deprived (FDM, n = 10), and FDM treated
with 1% atropine (FDM + AT, n = 10) groups. The diopter and axial length were measured at 0, 2, and 4 wk. Guinea pig eyeballs were
removed at week four, fixed, and stained for morphol. changes. Immunohistochem. (IHC) and in situ hybridi zation (ISH) were
performed to evaluate VIP protein and mRNA levels. Results: The F DM group showed an apparent myopic shift compared to the
control group. The results of the H&E staining were as follows: the cells of the inner/outer nuclear layers and retinal ganglion cells
were disorganized; the choroidal thickness (Ch T), blood vessel lumen, and area were decreased; the sclera was thinner, with
disordered fibers and increased interfibrillar space. IHC and ISH revealed that VIP′s mRNA and protein expres sions were signifi
cantly up-regulated in the retina of the FDM group. Atropine treatment attenuated F DM-induced myopic shift and fundus changes,
considerably reducing VIP′s mRNA and protein expres sions. Conclusions: The findings of elevated V IP mRNA and protein levels
observed in the FDM group indicate the potential involvement of VIP in the pathogenesis and progression of myopia. The ability of
atropine to reduce this phenomenon suggests that this may be one of the mol. mechanisms for atropine to control myopia.
Keywords: Atropine; Form-deprivation myopia; Guinea pig; Vasoactive intestinal polype ptide (VIP)

132
Effect of huankuile on colon injury in rats with ulcerative colitis by reducing TNF-α and MMP9
By: Wushouer, Xilinguli; Aximujiang, Kasimujiang; Kadeer, Nafeisha; Aihemaiti, Abulaiti; Zhong, Li; Yunusi, Kurexi
Abstract: Objective: To explore the mechanism of huankuile (HKL) in colon injury repair in rats with ulcerative colitis (U C). Methods:
Fifty SPF Wistar male rats were divided randomly into a normal group, a neg. control group, an H KL intervention group (′HKL group′)
and a 5-aminosalicylic acid intervention group (′5-ASA group′). After 14 days of interv ention with corresponding drugs, pathol.
scores were obtained using the results of immunohistochem. staining; morphol. changes were observed by hemato xylin-eosin
staining, and the mRNA expression levels of tumor necrosis factor - α ( TN F-α) , matrix metalloproteinase 9 (M MP9) and interl
eukin-13 (IL-13) were detected by real-time quant. PCR. Results: After the successful constr uction of the rat model, it was compared
with the rats in the normal group. In the neg. group, it was found that the expression of TN F-α and MMP9 was significantly
increased in the colonic mucosal epithelia of the rats, the pathol. score was significantly increased (P < 0.05) , and the mRNA
expression levels of TN F-α , MMP9 and IL-13 were increased (P < 0.05) . After treatment with H KL, the colonic morphol. of the rats
returned to normal, the expression of TN F-α and MMP9 in the colonic mucosal epithelium of the rats returned to normal, the
pathol. score grade was significantly reduced (P < 0.05) , and the mRNA expression levels of TN F-α , MMP9 and IL-13 were reduced;
these results were largely consistent with those of the normal group, with no statistically significant difference. Conclusion: HKL
effectively improved the general symptoms and tissue injury in U C rats, and the therap eutic effect was better than that of 5- ASA
group. Ulcerative colitis in rats increased the expression of TN F-α , MMP9 and IL-13. HKL repaired UC-induced colonic injury in rats
by decreasing the expression of TN F-α , MMP9 and IL-13.
Keywords: Huankuile; Inflammatory factor; MMP9; TN F-α ; Ulcerative colitis
133
p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck
cancer
By: Yassin-Kassab, Abdulkader; Chatterjee, Suman; Khan, Nayel; Wang, Nathaniel; Sandulache, Vlad C.; Huang, Eric H-B.; Burns,
Timothy F.; Duvvuri, Umamaheswar
Abstract: Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and
often metastasizes to lymph nodes. Platinum- based chemotherapeutic drugs are commonly used for treatment of a wide range of
cancers, including HNSCC. Its mode of action relies on its ability to impede D NA repair mechanisms, inducing apoptosis in cancer
cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combina
tional therapeutic strategies to overcome cisplatin resist ance. In the current study, we identified p90 RSK, an ERK1/2 downstream
target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90 RS
K in cisplatin resistance and identify the combin ation of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therap eutic strategy to
overcome cisplatin resistance. In addition, we have identified T MEM16A expression as a potential upstream regulator of p90 RSK
through the ERK pathway and a biomarker of response to p90 RSK targeted therapy in the context of cisplatin resist ance.
Keywords: BI-1870; Cisplatin; Resistance; TMEM16A; p90RSK

134
Inhibition of the membrane repair protein annexin-A2 prevents tumor invasion and metastasis
By: Gounou, C.; Rouyer, L.; Siegfried, G.; Harte, E.; Bouvet, F.; d′Agata, L.; Darbo, E.; Lefeuvre, M.; Derieppe, M. A.; Bouton, L.; et al
Abstract: Cancer cells are exposed to major compressive and shearing forces during invasion and metast asis, leading to extensive
plasma membrane damage. To survive this mech. stress, they need to repair membrane injury efficiently. Targeting the membrane
repair machinery is thus potentially a new way to prevent invasion and metast asis. We show here that annexin- A2 (ANXA2) is
required for membrane repair in invasive breast and pancreatic cancer cells. Mechanistically, we show by fluore scence and electron
microscopy that cells fail to reseal shear-stress damaged membrane when A NXA2 is silenced or the protein is inhibited with neutra
lizing antibody. Silencing of ANXA2 has no effect on prolife ration in vitro, and may even accelerate migration in wound healing
assays, but reduces tumor cell dissemination in both mice and zebrafish. We expect that inhibiting membrane repair will be partic
ularly effective in aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane
damage during tumor invasion and metastasis. This could be achieved either with anti- ANXA2 antibodies, which have been shown
to inhibit metastasis of breast and pancreatic cancer cells, or with small mol. drugs.
Keywords: Annexins; AsPC-1; Invasion; MDA-MB-231; Metastasis; S100 proteins; Tumor progression
135
Bacterial adhesion inhibition by microalgal EPSs from Cylindrotheca closterium and Tetraselmis
suecica biofilms
By: Mougin, Julia; Pavaux, Anne-Sophie; Fanesi, Andrea; Lopez, Julien; Pruvost, Eric; Guiheneuf, Freddy; Sciandra, Antoine; Briandet,
Romain; Lopes, Filipa
Abstract: In the food industry, successful bacterial pathogen colonization and persistence begin with their adhesion to a surface,
followed by the spatial development of mature biofilm of public health concerns. Compro mising bacterial settlement with natural
inhibitors is a promising alternative to conventional anti-fouling treatments typically based on chem. biocides that contribute to the
growing burden of antimicrobial resistance. In this study, three extrace llular polymeric substance (EPS) fractions extracted from
microalgae biofilms of Cylindrotheca closterium (fraction C) and Tetras elmis suecica (fraction Ta rich in insoluble scale structure and
fraction Tb rich in soluble EPS) were screened for their antiadhesive properties, against eight human food- borne pathogens
belonging to Escherichia coli, Staphylococcus aureus, Salmonella enterica subsp. enterica, and Listeria monocyt ogenes species. The
results showed that the fraction Ta was the most effective inducing statistically significant reduction for three strains of E. coli, S.
aureus, and L. monocytogenes. Overall, E PSs coating on polystyrene surfaces of the different fractions increased the hydrop hilic
character of the support. Differences in bacterial adhesion on the different coated surfaces could be explained by several dissimil
arities in the structural and physicochem. EPS compositions, according to HPLC and ATR-FTIR anal. Interestingly, while fractions Ta
and Tb were extracted from the same microalgal culture, distinct adhesion patterns were observed, highlighting the importance of
the extraction process. Overall, the findings showed that EPS extracted from microalgal photosy nthetic biofilms can exhibit anti-
adhesive effects against food-borne pathogens and could help develop sustai nable and non-toxic anti-adhesive surfaces for the
food industry. Key points: •EPSs from a biofilm-based culture of C. closter ium/T. suecica were characterized. •Microalgal EPS
extracted from T. suecica biofilms showed bacterial anti-adhesive effects. •The anti-adhesive effect is strain- specific and affects both
Gram - and Gram + bacteria.
Keywords: Anti-adhesive coatings; Bio-based marine coatings; Biofilm; Exopolysaccharides; Food-borne pathogens; Microalgae

136
Transient inhibition of 53BP1 increases the frequency of targeted integration in human

hematopoietic stem and progenitor cells
By: Baik, Ron ; Cromer, M. Kyle ; Glenn, Steve E.; Vakulskas, Christopher A. ; Chmielewski, Kay O.; Dudek, Amanda M.; Feist,
William N. ; Klermund, Julia ; Shipp, Suzette; Cathomen, Toni ; et al
Abstract: Genome editing by homol. directed repair (HDR) is leveraged to precisely modify the genome of therapeu tically relevant
hematopoietic stem and progenitor cells (HSPCs). Here, we present a new approach to increasing the frequency of H DR in human H
SPCs by the delivery of an inhibitor of 53 BP1 (named "i53") as a recombinant peptide. We show that the use of i53 peptide effect
ively increases the frequency of HDR-mediated genome editing at a variety of therapeu tically relevant loci in HSPCs as well as other
primary human cell types. We show that incorporating the use of i53 recombinant protein allows high frequencies of HDR while
lowering the amounts of AAV6 needed by 8- fold. HDR edited HSPCs were capable of long- term and bi- lineage hematopoietic
reconstitution in N SG mice, suggesting that i53 recomb inant protein might be safely integrated into the standard C RISPR/AAV6-
mediated genome editing protocol to gain greater numbers of edited cells for transpla ntation of clin. meaningful cell popula tions.
137
Inhibition of LATS kinases reduces tumorigenicity and increases the sensitivity of human chronic
myelogenous leukemia cells to imatinib
By: Klaihmon, Phatchanat; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Saisaard, Wannachai; Issaragrisil, Surapol
Abstract: Chronic myelogenous leukemia (CML) is a clonal hematol. malignancy of the myeloid lineage caused by the oncogenic B C
R/ABL fusion protein that promotes C ML cell proliferation and protects them against drug- induced apoptosis. In this study, we
determine LATS1 and LATS2 expression in CML cells derived from patients who are resistant to imatinib (I M) treatment. Significant
upregulation of LATS1 and LATS2 was found in these C ML patients compared to healthy donors. To further explore whether the
expression of LATS1/2 contributes to the IM-resistant phenotype, IM-resistant CML cell lines generated by culturing C ML-derived
erythroblastic K562 cells in increasing concent rations of IM were used as in vitro models. Up- regulation of LATS1 and LATS2 was
observed in IM-resistant K562 cells. Reduction of L ATS using either Lats-IN-1 (TRULI), a specific LATS inhibitor, or shRNA targeting LA
TS1/2 significantly reduced clonogenicity, increased apoptosis and induced differen tiation of K562 cells to late- stage erythroid cells.
Furthermore, depletion of LATS1 and LATS2 also increased the sensitivity of K562 cells to I M. Taken together, our results suggest
that LATS could be one of the key factors contri buting to the rapid proliferation, reduced apoptosis, and I M resistance of CML cells.
Targeting LATS could be a promising treatment to enhance the therap eutic effect of a conven tional BCR/ABL tyrosine kinase
inhibitor such as IM.
Keywords: Apoptosis; Chronic myelogenous leukemia; Hippo pathway; Imatinib; LATS kinase

138
Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront

against S. aureus
By: Guo, Xuerui ; Wang, Li; Zhang, Jinlong; Liu, Quan ; Wang, Bingmei; Liu, Da; Gao, Fei; Lanzi, Gongga ; Zhao, Yicheng ; Shi,
Yan
npj Biofilms and Microbiomes (2024), 10(1), 15 | Language: English, Database: CAplus and MEDLINE
Abstract: Limitations in the clin. treatment of Staphyl ococcus aureus (S. aureus) infections have arisen due to the advent of antibi
otic-resistant strains. Given the immense potential of therap eutic strategies targeting bacterial virulence, the role of Mgr A as a
pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets- becomes indispe
nsable. In this investigation, leveraging advanced virtual screening and fluore scence anisotropy assays, we discerned methylo
phiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the Mgr A-DNA interaction nexus. Subsequent anal.
revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its
adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the delete rious effects inflicted by
S. aureus USA300 on A549 cells. Furthe rmore, our data indicate that Mo- A downregulates the transcription of genes associated with
immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement
Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemot axis. Upon application in an in vivo setting,
Mo-A assumes a protective persona in a murine model of S. aureus U SA300-induced pneumonia and demonstrates efficacy in the
Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was
synergistically enhanced when used in combin ation with vancomycin. Our findings add substa ntive weight to the expanding field of
virulence-targeted therapeutic strategies and set the stage for more compreh ensive exploration of Mo-A potential in combating
antibiotic-resistant S. aureus.
139
Dual anti-HER2/EGFR inhibition synergistically increases therapeutic effects and alters tumor
oxygenation in HNSCC
By: Song, Patrick N.; Lynch, Shannon E.; DeMellier, Chloe T.; Mansur, Ameer; Gallegos, Carlos A.; Wright, Brian D.; Hartman, Yolanda
E.; Minton, Laura E.; Lapi, Suzanne E.; Warram, Jason M.; et al
Abstract: Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (H ER2), and hypoxia are associated
with radioresistance. The goal of this study is to study the synergy of anti- HER2, trastuzumab, and anti-EGFR, cetuximab, and charac
terize the tumor microenvironment components that may lead to increased radiation sensit ivity with dual anti-HER2/EGFR therapy
in head and neck squamous cell carcinoma (HNSCC). Positron emission tomog. (P ET) imaging ([89 Zr]-panitumumab and [ 89 Zr]-
pertuzumab) was used to characterize EGFR and HER2 in HNSCC cell line tumors. HNSCC cells were treated with trastu zumab,
cetuximab, or combination followed by radiation to assess for viability and radiosen sitivity (colony forming assay, immunofluo
rescence, and flow cytometry) . In vivo, [ 18 F]-FMISO-PET imaging was used to quantify changes in oxygen ation during treatment. Bliss
Test of Synergy was used to identify combination treatment synergy. Quantifying EGFR and HER2 receptor expression revealed a
50% increase in heterogeneity of HER2 relative to EGFR. In vitro, dual trastuzumab-cetuximab therapy shows significant decreases
in DNA damage response and increased response to radiation therapy (p < 0.05) . In vivo, tumors treated with dual anti-HER2/EGFR
demonstrated decreased tumor hypoxia, when compared to single agent therapies. Dual trastu zumab-cetuximab demonstrates
synergy and can affect tumor oxygenation in HNSCC. Combination trastuzumab-cetuximab modulates the tumor microenv
ironment through reductions in tumor hypoxia and induces sustained treatment synergy.

140
KCNA1 promotes the growth and invasion of glioblastoma cells through ferroptosis inhibition via
upregulating SLC7A11
By: Wang, Weichao; Zhang, Yang; Li, Xuetao; E, Qinzi; Jiang, Zuoyu; Shi, Qikun; Huang, Yu; Wang, Jian; Huang, Yulun
Cancer Cell International (2024), 24(1), 7 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The high invasiveness and infiltrative nature of Glioblastoma (GBM) pose signif icant challenges for surgical
removal. This study aimed to investigate the role of K CNA1 in GBM progression. Methods: CCK8, colony formation assay, scratch
assay, transwell assay, and 3D tumor spheroid invasion assays were to determine how K CNA1 affects the growth and invasion of G
BM cells. Subsequ ently, to confirm the impact of K CNA1 in ferroptosis, western blot, transm ission electron microscopy and flow
cytometry were conducted. To ascertain the impact of KCNA1 in vivo, patient-derived orthotopic xenograft models were establ
ished. Results: In functional assays, K CNA1 promotes the growth and invasion of G BM cells. Besides, K CNA1 can increase the
expression of SLC7A11 and protect cells from ferrop tosis. The vivo experiments demonstrated that knocking down KCNA1 inhibited
the growth and infiltration of primary tumors in mice and extended survival time. Conclu sion: Therefore, our research suggests that
KCNA1 may promote tumor growth and invasion by upregu lating the expression of SLC7A11 and inhibiting ferroptosis, making it a
promising therapeutic target for G BM.
Keywords: Ferroptosis; Glioblastoma; KCNA1; SLC7A11; Tumor invasion
141
The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated

FGFR2-driven cholangiocarcinoma
By: Spahn, Stephan ; Kleinhenz, Fabian; Shevchenko, Ekaterina ; Stahl, Aaron ; Rasen, Yvonne; Geisler, Christine; Ruhm,
Kristina; Klaumuenzer, Marion; Kronenberger, Thales ; Laufer, Stefan A. ; et al
Abstract: Fibroblast growth factor receptor (FGFR)-2 can be inhibited by F GFR-selective or non-selective tyrosine kinase inhibitors (T
KIs). Selective T KIs are approved for cholangio carcinoma (CCA) with FGFR2 fusions; however, their applic ation is limited by a charact
eristic pattern of adverse events or evocation of kinase domain mutations. A compreh ensive characterization of a patient cohort
treated with the non-selective TKI lenvatinib reveals promising efficacy in F GFR2-driven CCA. In a bed- to-bench approach, we invest
igate FGFR2 fusion proteins bearing critical tumor- relevant point mutations. These mutations confer growth advantage of tumor
cells and increased resistance to selective TKIs but remain intriguingly sensitive to lenvat inib. In line with clin. observations, in-silico
analyses reveal a more favorable interaction pattern of lenvatinib with FGFR2, including an increased flexibility and ligand efficacy,
compared to FGFR-selective TKIs. Finally, the treatment of a patient with progre ssive disease and a newly developed kinase
mutation during therapy with a selective inhibitor results in a striking response to lenvatinib. Our in vitro, in silico, and clin. data
suggest that lenvatinib is a promising treatment option for FGFR2-driven CCA, especially when insurmo untable adverse reactions of
selective TKIs or acquired kinase mutations occur.

142
Inhibition of DNMT3B expression in activated hepatic stellate cells overcomes chemoresistance in the
tumor microenvironment of hepatocellular carcinoma
By: Song, Yeonhwa; Kim, Namjeong; Heo, Jinyeong; Shum, David; Heo, Taemoo; Seo, Haeng Ran
Abstract: Hepatocellular carcinoma (HCC) is a complex disease associated with a plethora of environ mental and genetic/h ereditary
causative risk factors, more so than other oncol. indications. Addnl., patients with HCC exhibit fibrosis, cirrhosis, and liver- related
disease. This complicated etiol. can affect the disease course and likely contri butes to its poor prognosis. In this study, we aimed to
improve HCC therapy by evaluating combin ation treatment using anti-cancer and anti-fibrosis drugs via identification of novel anti-
fibrosis drugs. We performed high- throughput screening of 10,000 compounds to identify hepatic fibrosis inhibitors through
morphometry anal. of multicellular hepatic spheroid (M CHS) models and identified C HIR-99021 as a candidate anti-fibrotic drug.
Treatment with CHIR-99021 induced loss of cell-cell interactions and suppression of extracellular matrix-related protein expression
via reprogramming of hepatic stellate cell (H SC) activation in MCHSs. In particular, CHIR-99021 regulated DNMT3B expression only
in activated HSCs. Moreover, CHIR-99021 markedly improved the efficacy of sorafenib in H CC- multicellular tumor spheroids in vitro
and through induction of apoptosis by decreasing DNMT3B expression in vivo. In summary, these findings suggest that targeting H S
C reprogramming by attenu ation of DNMT3B expression in the tumor enviro nment might represent a promising therap eutic
strategy for liver fibrosis and HCC.
143
In silico anti-alzheimer study of phytochemicals from Lamiaceae family through GSK3-β inhibition
By: Zareei, Sara; Pourmand, Saeed; Eskandarzadeh, Marzieh; Massahi, Shokoufeh

Abstract: Glycogen synthase kinase 3-beta (GSK3-β) is a serine- threonine protease expressed in the brain, and its hyperac tivity is
considered the underlying cause of Alzheimer′s disease. This enzyme requires an A TP mol. in its N-terminal lobe to phosphorylate
its substrates, with the most important substrate being the Tau protein. This study focuses on the inhibitory mechanism of four
naturally occurring compounds-apigenin, luteolin, rosmarinic acid, and salvia nolic acid-from the Laminaceae family against G SK3-β.
The orientation of the ligands within the ATP-binding pocket of GSK3-β and their binding energy were determined through mol.
docking. Addnl., mol. dynamics simulations was conducted to study the conform ational changes induced by the ligands in the
protein structure. The results showed that apigenin and salvianolic acid achieved deeper parts of the cavity compared to luteolin
and rosmarinic acid and formed stable complexes with the enzyme. In the rosmarinic acid complex, the enzyme exhibited the most
exposed conformation. On the other hand, luteolin binding caused a small closure of the opening, suggesting a potent ially ATP-
competitive role. Our results suggest these compounds as lead candidates for the design of G SK3-β inhibitors.

144
New dienelactone hydrolase from microalgae bacterial community-Antibiofilm activity against fish
pathogens and potential applications for aquaculture
By: Bergmann, Lutgardis; Balzer Le, Simone; Hageskal, Gunhild; Preuss, Lena; Han, Yuchen; Astafyeva, Yekaterina; Loevenich, Simon;
Emmann, Sarah; Perez-Garcia, Pablo; Indenbirken, Daniela; et al
Abstract: Biofilms are resistant to many traditional antibiotics, which has led to search for new antimic robials from different and
unique sources. To harness the potential of aquatic microbial resources, we analyzed the meta-omics datasets of microalgae-
bacteria communities and mined them for potential antimic robial and quorum quenching enzymes. One of the most intere sting
candidates (Dlh3), a dienelactone hydrolase, is a α/β -protein with predicted eight α -helixes and eight β-sheets. When it was applied
to one of the major fish pathogens, Edwardsiella anguillarum, the biofilm development was reproducibly inhibited by up to 54.5%.
The transcriptome dataset in presence of Dlh3 showed an upregu lation in functions related to self-defense like active genes for
export mechanisms and transport systems. The most interesting point regarding the biotechnol. potential for aquaculture applic
ations of Dlh3 are clear evidence of biofilm inhibition and that health and division of a relevant fish cell model (C HSE-214) was not
impaired by the enzyme.
145
Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation
of frontostriatal networks
By: Magnard, Robin ; Fouyssac, Maxime; Vachez, Yvan M.; Cheng, Yifeng; Dufourd, Thibault; Carcenac, Carole; Boulet, Sabrina;
Janak, Patricia H.; Savasta, Marc; Belin, David ; et al
Abstract: Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathol. gambling, hyperse
xuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3
receptor agonists, such as pramipexole (PPX). Despite evidence showing that impuls ivity is associated with functional altera tions in
corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucid ated. Here we used a hotspot
anal. to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (H I),
moderately impulsive (MI) or with low levels of impuls ivity (LI) in the 5-choice serial reaction time task (5- CSRTT). PPX dramatically
reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C- fos and Zif268 by in situ
hybridization subsequently revealed that PPX resulted in a decrease in Zif268 m RNA levels in different striatal regions of both L I
and HI rats accompanied by a high impuls ivity specific reduction of Zif268 m RNA levels in prelimbic and cingulate cortices. P PX also
decreased C-fos mRNA levels in all striatal regions of L I rats, but only in the dorsol ateral striatum and nucleus accumbens core (N Ac
Core) of HI rats. Structural equation modeling further suggested that the anti- impulsive effect of PPX was mainly attributable to the
specific downregulation of Zif268 mRNA in the NAc Core. Altoge ther, our results show that P PX restores impulse control in highly
impulsive rats by modulation of limbic frontostriatal circuits.

146
Retraction Note: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D

and 3D glioblastoma cell cultures
By: Ivanov, Vladimir N. ; Grabham, Peter W.; Wu, Cheng-Chia; Hei, Tom K.
There is no abstract available for this document.
147
Variation of the essential oil components of Citrus aurantium leaves upon using different distillation
techniques and evaluation of their antioxidant, antidiabetic, and neuroprotective effect against
Alzheimer′s disease
By: Elhawary, Esraa A.; Nilofar, Nilofar; Zengin, Gokhan; Eldahshan, Omayma A.
Abstract: Citrus fruit essential oil is considered one of the widely studied essential oils while its leaves attract less attention although
being rich in nearly the same composition as the peel and flowers. The leaves of bitter orange or sour orange (Citrus aurantium L.)
were extracted using three different techniques namely; hydrodistillation (HD), steam distillation (SD), and microwave-assisted distil
lation (MV) to compare their chem. compos ition The three essential oil samples were analyzed through G C/FID and GC/MS analyses.
The samples were tested in vitro using different antioxidant techniques (DPPH, ABTS, CUPRAC, FRAP, PBD, and M CA), neuropro
tective enzyme inhibitory activities (acetylc holine and Bu choline enzymes) , and antidiabetic activities ( α -amylase and α -glucos
idase). The results showed that thirty- five volatile ingredients were detected and quanti fied. Monoterpenes represented the most
abundant class in the three essential oils followed by sesquiterpenes. C. aurantium essential oil carried potential antiox idant activity
where SD exhibited the highest antiox idant activity, with values arranged in the following order: F RAP (200.43 mg T E/g), CUPRAC
(138.69 mg TE/g), ABTS (129.49 mg T E/g), and DPPH (51.67 mg T E/g). SD essential oil also presented the most potent α -amylase
(0.32) inhibition while the MV essential oil showed the highest α -glucosidase inhibition (2.73 mmol A CAE/g), followed by HD (2.53
mmol ACAE/g), and SD (2.46 mmol ACAE/g). The SD essential oil exhibited the highest B ChE and AChE inhibitory activities (3.73 and
2.06 mg GALAE/g), resp.). Thus, bitter orange essential oil can act as a potential source of potent antiox idant, antidiabetic, and
neuroprotective activities for future drug leads.
Keywords: Alzheimer’s; Citrus aurantium; Distillation; Essential oil; Microwave

148
PRMT5 inhibition shows in vitro efficacy against H3K27M-altered diffuse midline glioma, but does not
extend survival in vivo
By: Brown, Elizabeth J.; Balaguer-Lluna, Leire; Cribbs, Adam P.; Philpott, Martin; Campo, Leticia; Browne, Molly; Wong, Jong Fu;
Oppermann, Udo; Carcaboso, Angel M.; Bullock, Alex N.; et al
Abstract: H3K27-altered Diffuse Midline Glioma (DMG) is a universally fatal paediatric brainstem tumor. The prevalent driver
mutation H3K27M creates a unique epigenetic landscape that may also establish therap eutic vulnerabilities to epigenetic inhibitors.
However, while HDAC, EZH2 and BET inhibitors have proven somewhat effective in preclin. models, none have translated into clin.
benefit due to either poor blood-brain barrier penetration, lack of efficacy or toxicity. Thus, there remains an urgent need for new D
MG treatments. Here, we performed wider screening of an epigenetic inhibitor library and identified inhibitors of protein arginine
methyltransferases (PRMTs) among the top hits reducing D MG cell viability. Two of the most effective inhibi tors, LLY-283 and GS
K591, were targeted against PRMT5 using distinct binding mechanisms and reduced the viability of a subset of D MG cells
expressing wild-type TP53 and mutant ACVR1. RNA-sequencing and phenotypic analyses revealed that L LY-283 could reduce the
viability, clonogenicity and invasion of DMG cells in vitro, representing three clin. important phenot ypes, but failed to prolong
survival in an orthotopic xenograft model. Together, these data show the challenges of DMG treatment and highlight P RMT5
inhibitors for consideration in future studies of combin ation treatments.
149
Tailoring of an anti-diabetic drug empagliflozin onto zinc oxide nanoparticles: characterization and in
vitro evaluation of anti-hyperglycemic potential
By: Shoaib, Abdullah; Shahid, Sammia; Mansoor, Sana; Javed, Mohsin; Iqbal, Shahid; Mahmood, Sajid; Bahadur, Ali; Jaber, Fadi;
Alshalwi, Matar
Abstract: Diabetes is a serious health issue that can be a great risk factor related to numerous phys. problems. A class of drugs "Glifl
ozin" especially Sodium Glucose Co. Transp orter 2 was inhibited by a novel drug, which is known as "empagli flozin". While ZnO
nanoparticles (NPs) had considerable promise for combating diabetes, it was employed in the treatment and management of type-
2 diabetes mellitus. The new drug empagli flozin was initially incorporated into Zinc Oxide N Ps in this study using the surface physio-
sorption technique, and the degree of drug adsorption was assessed using the H PLC method. The tailored product was charact
erized by using the FTIR, EDX, UV-Visible, XRD and SEM techniques. With an average particle size of 17 nm, S EM revealed mono-
dispersion of NPs and sphere-like form. The Freundlich isotherm model best fits and explains the data for the physio- sorption
investigation, which examined adsorption capabilities using adsorption isotherms. The enzymes α -amylase and α -glucosidase,
which are involved in the human metabolism of carbohydrates, were used in the in- vitro anti-diabetic assays. It was discovered that
the composite showed the highest levels of 81.72 and 92.77% inhibition of - α -amylase and - glucosidase at an absolute concent
ration of 1000 μg per mL with IC50 values of 30.6 μg per m L and 72 μg per mL.

150
The inhibition effects of Lentilactobacillus buchneri-derived membrane vesicles on AGS and HT-29
cancer cells by inducing cell apoptosis
By: Abedi, Adel; Tafvizi, Farzaneh ; Jafari, Parvaneh ; Akbari, Neda

Abstract: In recent years, probiotics and their derivatives have been recognized as important therap eutic agents in the fight against
cancer. Therefore, this study aimed to investigate the anticancer effects of membrane vesicles (M Vs) from Lentilactobacillus
buchneri strain HBUM07105 probiotic isolated from conventional and unproc essed yogurt in Arak province, Iran, against gastric
and colon cancer cell lines. The MVs were prepared from the cell- free supernatant (CFS) of L. buchneri and charact erized using
field-emission SEM (FE-SEM) and transm ission electron microscopy (T EM) and S PS-PAGE techniques. The anticancer activity of MVs
was evaluated using MTT, flow cytometry, q RT-PCR techniques, and a scratch assay. The study invest igated the anti-adenoca
rcinoma effect of M Vs isolated from L. buchneri on a human gastric adenoca rcinoma cell line (A GS) and a human colorectal
adenocarcinoma cell line (HT-29) at 24, 48, and 72- h time intervals. The results demons trated that all prepared concent rations (12.5,
25, 50, 100, and 200 μg/mL) of MVs reduced the viability of both types of human adenoca rcinoma cells after 24, 48, and 72 h of
treatment. The anal. of the apoptosis results revealed that the percentage of AGS and HT-29 cancer cells in the early and late stages
of apoptosis was significantly higher after 24, 48, and 72 h of treatment compared to the untreated cancer cells. After treating both
AGS and HT-29 cells with the M Vs, the cells were arrested in the G0/G1 phase. These microve sicles demonstrate apoptotic activity
by increasing the expression of pro-apoptotic genes (BAX, CASP3, and CASP9). According to the scratch test, M Vs can significantly
decrease the migration of HT-29 and AGS cancer cells after 24, 48, and 72 h of incubation compared to the control groups. The M Vs
of L. buchneri can also be considered a potential option for inhibiting cancer cell activities.
Keywords: Apoptosis; Colon cancer; Gastric cancer; Lentilactobacillus buchneri; Membrane vesicles; Scratch test
151
Gastroprotective effect of rhodanine and 2,4-thiazolidinediones scaffolds in rat stomachs by

contribution of anti-apoptotic (BCL-2) and tumor suppressor (P53) proteins
By: Ameen, Rozh Q.; Amin, Zahra A.; Ahmad, Hiwa O.; Ghafur, Diler D.; Toma, Melodya G.; Sabah, Nyan; Fakhir, Muhammad; Abdulla,
Gardoon
Abstract: In recent times, the methods used to evaluate gastric ulcer healing worldwide have been based on visual examinations
and estimating ulcer dimensions in exptl. animals. In this study, the protective effect of rhodanine and 2,4-thiazolidinediones
scaffolds compared to esomeprazole was investigated in an ethanol model of stomach ulcers in rats. Pretre atment with exptl.
treatments or esomeprazole prevented the development of ethanol-induced gastric ulcers. The severity of the lesions and injuries
was significantly lower than that of vehicle (10% Tween 80) treated rats. Signif icant and excellent results were obtained with the
compound 6 group, with inhibition percentage and ulcer area values of 97.8% and 12.8 ± 1.1 mm 2, resp. Synthesized compounds 2,
7 and 8 exhibited inhibition percentages and ulcer areas of 94.3% and 31.2 ± 1.1 mm 2, 91. 3% and 48.1 ± 0. 8 mm 2, 89. 5% and 57.
6 ± 1. 2 mm2, and 89. 1% and 60.3 ± 0. 8 mm 2, resp. These biol. outcomes are consistent with the docking studies in which
Compounds 7 and 8 showed remarkable binding site affinities toward human H+/K+-ATPase α protein (ID: P20648), rat H+/K+-AT
Pase α protein (ID: P09626), and Na+/K+-ATPase crystal structure (P DB ID:2ZXE) with binding site energies of - 10.7, - 9.0, and - 10.4
(kcal/mol) and - 8.7, - 8.5, and - 8.0 (kcal/mol), resp. These results indicate that these test samples were as effective as esomepr
azole. Likewise, immunohistochem. staining of antiapoptotic (BCL2) and tumor suppressor (P53) proteins showed strong pos. marks
in the10% Tween 80- treated group, opposing the mild staining results for the esomeprazole-treated group. Similarly, the staining
intensity of the group treated with Compounds 2-8 was variable for both proteins.

152
Targeting cancer-derived extracellular vesicles by combining CD147 inhibition with tissue factor
pathway inhibitor for the management of urothelial cancer cells
By: Boddu, Vijay Kumar; Zamzow, Piet; Kramer, Mario Wolfgang; Merseburger, Axel S.; Gorantla, Sivahari Prasad; Klinger, Matthias;
Cramer, Lena; Sauer, Thorben; Gemoll, Timo; von Bubnoff, Nikolas; et al
Abstract: Background: Extracellular vesicles (E Vs), including microvesicles, hold promise for the management of bladder urothelial
carcinoma (BLCA), particularly because of their utility in identi fying therapeutic targets and their diagnostic potential using easily
accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer- derived EVs, tissue factor (TF) and C
D147 have been implicated in promoting tumor progre ssion. In this in vitro study, we explored a novel approach to impede cancer
cell migration and metastasis by simultaneously targeting these mols. on urothelial cancer- derived EVs. Methods: Cell culture
supernatants from invasive and non- invasive bladder cancer cell lines and urine samples from patients with B LCA were collected.
Large, microvesicle-like EVs were isolated using sequential centrif ugation and characterized by electron micros copy, nanoparticle
tracking anal., and flow cytometry. The impact of urinary or cell supernatant-derived EVs on cellular phenotypes was evaluated
using cell-based assays following combined treatment with a specific C D147 inhibitor alone or in combination with a tissue factor
pathway inhibitor (TFPI), an endogenous anticoagulant protein that can be released by low- mol.-weight heparins. Results: We
observed that EVs obtained from the urine samples of patients with muscle- invasive BLCA and from the aggressive bladder cancer
cell line J82 exhibited higher TF activity and CD147 expression levels than did their non- invasive counterparts. The shedding of GFP-
tagged CD147 into isolated vesicles demons trated that the vesicles originated from plasma cell membranes. E Vs originating from
invasive cancer cells were found to trigger migration, secretion of matrix metalloproteinases (MMPs), and invasion. The same
induction of MMP activity was replicated using EVs obtained from urine samples of patients with invasive B LCA. EVs derived from
cancer cell clones overexpressing TF and CD147 were produced in higher quantities and exhibited a higher invasive potential than
those from control cancer cells. TFPI interfered with the effect when used in conjun ction with the CD147 inhibitor, further suppre
ssing homotypic EV-induced migration, MMP production, and invasion. Conclu sions: Our findings suggest that combining a C D147
inhibitor with low mol. weight heparins to induce TFPI release may be a promising therap eutic approach for urothelial cancer
management. This combination can potentially suppress the tumor-promoting actions of cancer- derived microvesicle-like EVs,
including collective matrix invasion. Graphical Abstract: [graphic not available: see fulltext]
Keywords: Bladder carcinoma; CD142; EMMPRIN; Microvesicles

153
Amlexanox attenuates LPS-induced neuroinflammatory responses in microglial cells via inhibition of

NF-κB and STAT3 signaling pathways
By: Phan Van, Thach; Huyen Ton Nu Bao, Tien; Leya, Mwense; Zhou, Zixiong; Jeong, Hyuneui; Lim, Chae-Woong; Kim, Bumseok
Abstract: Amlexanox is an anti-inflammatory and anti-allergic agent used clin. for the treatment of aphthous ulcers, allergic rhinitis,
and asthma. Recent studies have demonstrated that amlexanox, a selective inhibitor of Ik B kinase epsilon (IKKε) and TANK-binding
kinase 1 (TBK1), suppresses a range of diseases or inflam matory conditions, such as obesity-related metabolic dysfunction and type
2 diabetes. However, the effects of amlexanox on neuroinflammatory responses to amlexanox have not yet been comprehe nsively
studied. In this study, we investigated the novel therapeutic effect of amlexanox on L PS-induced neuroinflammation in vivo, and i.p.
injection of amlexanox markedly reduced LPS-induced IKKε levels, proinflammatory cytokines, and microglial activation, as
evidenced by ionized calcium-binding adapter mol. 1 (Iba1) immunost aining. Furthermore, amlexanox significantly reduced proinfla
mmatory cytokines and chemokines in L PS-induced bone marrow-derived macrophages (BMDM), murine BV2, and human H MC3
microglial cells. This data provided considerable evidence that amlexanox can be used as a preventive and curative therapy for
neuroinflammatory and neurodegenerative diseases. In terms of mechanism aspects, our results demons trated that the anti-inflam
matory action of amlexanox in B V2 microglial cells was through the downregulation of NF-κB and STAT3 signaling pathways. In
addition, the combination of amlexanox and S PI (a STAT3 selective inhibitor) showed high efficiency in inhibiting the production of
neurotoxic and pro-inflammatory mediators. Overall, our data provide rational insights into the mechanisms of amlexanox as a
potential therapeutic strategy for neuroinfl ammation-related diseases.
154
Favipiravir, an antiviral drug, in combination with tamoxifen exerts synergistic effect in tamoxifen-
resistant breast cancer cells via hTERT inhibition
By: Fahim, Sally A.; ElZohairy, Yehia A.; Moustafa, Rehab I.

Abstract: Tamoxifen (TAM) is one of the most successful treatments for breast cancer; however, T AM resistance continues to be a
significant barrier. TAM resistance has been reported to be associated with increased expression of human telomerase reverse
transcriptase (hTERT). This enzyme shares structural similarity with R NA-dependent RNA polymerase (RdRp) enzyme of RNA viruses,
suggesting that RdRp inhibitors may also inhibit h TERT. Favipiravir (FAV) is an antiviral drug that inhibits RdRp of RNA viruses. Thus,
we propose that FAV may also elicit an antitumor effect by suppre ssing hTERT. This study aimed to invest igate the effect of FAV and
TAM on T AM-resistant breast cancer (T AMR-1). The cell viabil ities were determined The levels of C DK1/ hTERT, in addition to
regulators of hTERT-targeted signaling pathways were measured. Apoptosis, migration, and cell cycle distri bution were also
determined Our data revealed that the combination of TAM and FAV suppressed cell proliferation synergistically (CI < 1) and
resulted in a significant change in cell migration and apoptosis. Indeed, this was associated with reduced levels of h TERT and CDK1
and shift in the cell cycle distribution. Our findings suggest that the T AM/FAV combination exhibits synergistic effects against TAMR-
1 human breast cancer cells by targeting h TERT.

155
Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte

proliferation
By: Li, Xinhang; Zhu, Yalin; Ruiz-Lozano, Pilar; Wei, Ke

Cell Regeneration (2024), 13(1), 2 | Language: English, Database: CAplus and MEDLINE
Abstract: The regenerative capacity of the adult mammalian heart remains a formidable challenge in biol. research. Despite
extensive investigations into the loss of regene rative potential during evolution and develo pment, unlocking the mechanisms
governing cardiomyocyte proliferation remains elusive. Two recent groundb reaking studies have provided fresh perspe ctives on
mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiom yocyte proliferation. The studies
identified two mitochondrial processes, fatty acid oxidation and protein transl ation, as key players in restricting cardiomyocyte
proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomy ocytes, mediated by reduction in H3k4me3
levels through accumulated α -ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (U PRmt), resp. In
this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the
broad implications in cardiomyocyte biol. and cardiov ascular diseases, as well as the intriguing scientific questions inspired by the
studies that may facilitate future investigations into the detailed mol. mechanisms of cardiom yocyte metabolism, proliferation, and
mitochondrial-to-nuclear communications.
Keywords: ATF4; Cardiomyocyte; Cpt1b; FAO; H3k4me3; Mitochondria; Mrps5; Proliferation; UPRmt; αKG
156
Synthesis, characterization, synergistic inhibition , and biological evaluation of novel Schiff base on 304
stainless steel in acid solution
By: Hosny, Shimaa; Abdelfatah, Aliaa; Gaber, Ghalia A.

Abstract: A novel Schiff base [4-(morpholin-4-yl) benzylidenyl]thiosemicarbazide (MBT) was created by reaction condensation. The
mols. of the products were verified by IR, 1HNMR, MS, and elemental techniques. The synergistic effect of KI with novel MBT on 304
stainless steel (SS) in acidic has been invest igated exptl. and theor. using DFT. The findings demonstrate that restriction efficacy on
304 SS improved with rising inhibitor concentr ations, and this benefit was attributed to synergy when K I was injected. From EIS
results, IE % increased with a higher concent ration of MBT only and M BT + K I (from 100 to 600 ppm). MBT maximum IE % was
84.98%, at 600 ppm. MBT + K I, due to the I- ions synergistic effect, showed an IE% of about 95.48%, at 600 ppm. The adsorp tions of
MBT and M BT + K I on the surfaces of 304 S S are strongly fitted Langmuir adsorption isotherms. Thermodn. parameters (Kads, Δ
G0ads) were utilized. According to polari zation findings, MBT behaves as a mixed- category antagonist. The Schiff base M BT was
screened for its in vitro antimicrobial activities against some strains of bacteria and fungi. The result revealed that M BT proved to
be an excellent candidate as a fungal agent being able to inhibit Aspergillus flavus.
Keywords: morpholinylbenzylidenyl thiosemicarbazide preparation steel antibacterial antifungal

157
Combined laser-activated SVF and PRP remodeled spinal sclerosis via activation of Olig-2, MBP, and
neurotrophic factors and inhibition of BAX and GFAP
By: Farid, Mariam F. ; Yasin, Noha A. E.; Al-Mokaddem, Asmaa K.; Ibrahim, Marwa A.; Abouelela, Yara S. ; rizk, Hamdy
Abstract: A single injection of platelet-rich plasma (PRP) or stromal vascular fraction (S VF) in treating neurol. ailments suggests
promise; however, there is limited evidence of the efficacy of combination therapy. This trial aimed to determine whether
combining SVF and PRP could provide further therapeutic effects in treating multiple sclerosis (M S). Fifteen Persian cats were
separated into three groups (n = 5): group I (control neg.) , and group II (control pos.); EB was injected intrathecally into the spinal
cord and then treated 14 days later with intrathecal phosphate buffered saline injection, and group I II (SVF + PRP), cats were
injected intrathecally with EB through the spinal cord, followed by a combin ation of SVF and PRP 14 days after induction. Therap
eutic effects were evaluated using the Basso- Beattie-Bresnahan scale throughout the treatment timeline and at the end. Together
with morphol., MRI scan, immunohistochem., transmission electron microscopy, and gene expression investig ations. The results
demonstrated that combining S VF and PRP successfully reduced lesion intensity on gross inspection and M RI. In addition to
increased immunoreactivity to Olig2 and M BP and decreased immunore activity to Bax and GFAP, there was a signif icant improv
ement in BBB scores and an increase in neurot rophic factor (BDNF, NGF, and S DF) expression when compared to the pos. control
group. Finally, intrathecal SVF + PRP is the most promising and safe therapy for multiple sclerosis, resulting in clin. advantages such
as functional recovery, MRI enhancement, and axonal remyeli nation.
158
Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors
By: Pesaresi, Alessandro

Activation-by- inhibition is a biochem. paradox seldom observed in exosite enzymes, wherein active site- bound inhibitors unexpe
ctedly lead to enzyme activa tion. This intriguing phenomenon occurs at low, undersat urating substrate concentrations, posing a
significant challenge in drug discovery, especially when targeting enzymes such as protein kinases, proteases, and other posttrans
lational modification enzymes. These enzymes often rely on accessory recogn ition sites known as exosites, which contribute to
complex substrate binding mechanisms and unique kinetic behaviors. This study aims to provide a theor. kinetic explanation for
nonallosteric mechanism-based activation-by- inhibition , shedding light on the complexities of inhibiting exosite enzymes solely
through active site targeting. Notably, the dual activator-inhibitor behavior of active site-bound inhibitors manifests in a nonmon
otonic biphasic dose-response, emphasizing the importance of understanding the role of the inhibitor concent ration at low
substrate levels. Our findings underscore the potential widespread occurrence of activation by inhibition , a phenomenon that may
have been overlooked in the past, and thus advocate for novel strategies in drug design that consider the impact of exosites on
enzyme behavior to effectively target exosite enzymes.
Keywords: Activation by inhibition ; Exosite; Hormesis; PTM enzymes; Proteases; Protein kinases

159
Inhibition of growth of hepatocellular carcinoma by co-delivery of anti-PD-1 antibody and sorafenib

using biomimetic nano-platelets
By: Da, Xuanbo; Cao, Bangping; Mo, Jiantao; Xiang, Yukai; Hu, Hai; Qiu, Chen; Zhang, Cheng; Lv, Beining; Zhang, Honglei; He,
Chuanqi; et al
Abstract: Background: Traditional nanodrug delivery systems have some limita tions, such as eliciting immune responses and
inaccuracy in targeting tumor microenvironments. Materials and methods: Targeted drugs (Sorafenib, Sora) nanometers (hollow
mesoporous silicon, HMSN) were designed, and then coated with platelet membranes to form a PD-1-PLTM-HMSNs@Sora to
enhance the precision of drug delivery systems to the tumor microenvironment, so that more effective immunot herapy was
achieved. Results: These biomimetic nanoparticles were validated to have the same abilities as platelet membranes (P LTM),
including evading the immune system. The successful coating of HMSNs@Sora with PLTM was corroborated by transmission
electron microscopy (TEM), western blot and confocal laser micros copy. The affinity of aPD-1-PLTM-HMSNs@Sora to tumor cells was
stronger than that of HMSNs@Sora. After drug-loaded particles were i.v. injected into hepatoc ellular carcinoma model mice, they
were demonstrated to not only directly activate toxic T cells, but also increase the triggering release of Sora. The combin ation of
targeted therapy and immunotherapy was found to be of gratifying antineo plastic function on inhibiting primary tumor growth.
Conclusions: The aPD-1-PLTM-HMSNs@Sora nanocarriers that co-delivery of aPD-1 and Sorafenib integrates unique biomimetic
properties and excellent targeting performance, and provides a neoteric idea for drug delivery of person alized therapy for primary
hepatocellular carcinoma (HCC).
Keywords: Immunotherapy; Nanoparticles; Platelet membrane; Sorafenib; Tumor microenv ironment

160
Mitochondrial-mediated apoptosis as a therapeutic target for FNC (2′-deoxy-2′-b-fluoro-4′-

azidocytidine)-induced inhibition of Dalton′s lymphoma growth and proliferation
By: Kumar, Naveen; Kumar, Sanjeev; Shukla, Alok; Kumar, Sanjay; Singh, Rishi Kant; Ulasov, Ilya; Kumar, Sandeep; Patel, Anand
Kumar; Yadav, Lokesh; Tiwari, Ruchi; et al
Discover Oncology (2024), 15(1), 16 | Language: English, Database: CAplus and MEDLINE
Abstract: Purpose: T-cell lymphomas, refer to a diverse set of lymphomas that originate from T- cells, a type of white blood cell, with
limited treatment options. This investigation aimed to assess the efficacy and mechanism of a novel fluori nated nucleoside analog
(FNA), 2′-deoxy-2′-β-fluoro-4′-azidocytidine (FNC), against T-cell lymphoma using Dalton′s lymphoma (D L)-bearing mice as a model.
Methods: Balb/c mice transplanted with the DL tumor model received FNC treatment to study therap eutic efficacy against T- cell
lymphoma. Behavioral monitoring, physiol. measurements, and various analyses were conducted to evaluate treatment effects for
mechanistic investigations. Results: The results of study indicated that F NC prevented DL-altered behavior parameters, weight gain
and alteration in organ structure, hematol. parameters, and liver enzyme levels. Moreover, F NC treatment restored organ struct
ures, attenuated angiogenesis, reduced DL cell viability and proliferation through apoptosis. The mechanism investigation revealed
FNC diminished MMP levels, induced apoptosis through R OS induction, and activated mitocho ndrial-mediated pathways leading to
increase in mean survival time of DL mice. These findings suggest that F NC has potential therapeutic effects in mitigating DL-
induced adverse effects. Conclusion: FNC represents an efficient and targeted treatment strategy against T- cell lymphoma. FNC′s
proficient ability to induce apoptosis through ROS generation and M MP reduction makes it a promising candidate for developing
newer and more effective anticancer therapies. Continued research could unveil FNC′s potential role in designing a better therap
eutic approach against N HL.
Keywords: Apoptosis; Fluorinated nucleoside analogues; Haemat ology; Histology; Viability
161
CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-
dependent B cell responses
By: Scherlinger, Marc ; Li, Hao ; Pan, Wenliang; Li, Wei; Karino, Kohei ; Vichos, Theodoros ; Boulougoura, Afroditi; Yoshida,
Nobuya; Tsokos, Maria G.; Tsokos, George C.
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysreg ulated B cell compartment respon
sible for the production of autoanti bodies. Here, we show that T cell- specific expression of calcium/calmodulin-dependent protein
kinase IV (CaMK4) leads to T follicular helper ( Tfh) cells expansion in models of T-dependent immunization and autoimmunity.
Mechanistically, CaMK4 controls the Tfh-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcri ptional level through the
cAMP responsive element modulator α (CREMα). In the absence of Ca MK4 in T cells, germinal center formation and humoral
immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titers, as well as Ig G and complement kidney deposition
in the lupus-prone B6.lpr mouse. In human Tfh cells, Ca MK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo,
resulting in impaired plasmablast formation and Ig G production In patients with S LE, CAMK4 mRNA levels in Tfh cells correlated
with those of BCL6. In conclusion, we identify Ca MK4/CREMα as a driver of T cell- dependent B cell dysregulation in autoimmunity.

162
Leptin receptor deficiency impedes metabolic surgery related-weight loss through inhibition of energy
expenditure in db/db mice
By: Tong, Dan; Xiang, Jie; Liu, Wei; Sun, Fang; Wang, Lijuan; Mou, Aidi; Cao, Tingbing; Zhou, Qing; You, Mei; Liao, Yingying; et al
Diabetology & Metabolic Syndrome (2024), 16(1), 33 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Roux-en-Y gastric bypass (RYGB) surgery is an effective metabolic surgery against diabetes and obesity. Clin.
evidence indicates that patients with severe obesity have a poor curative effect in losing weight if they suffer from leptin or its
receptor deficiency, but the underlying mechanism remains elusive. Here, we invest igated the effect of leptin receptor deficiency on
metabolic dysfunction in db/db mice treated by R YGB surgery. Methods: The db/db mice and their hetero zygote control db/m mice
were subjected to RYGB or sham surgery. Body weight, blood glucose, food intake and glucose tolerance were evaluated. Micro- PE
T/CT and histol. anal. were performed to examine the glucose uptake of tissues and the fat changes in mice. The key factors in
glucose and fatty acid metabolism were detected by western blot anal. Results: Compared with the sham group, the db/db mice in
the RYGB group showed more signif icant weight regain after surgical recovery and improvement in hyperinsulinemia and glucose
tolerance. However, the total body fat and multiple organ lipid deposition of RYGB-treated db/db mice was increased. The
underlying mechanism studies suggested that the activation of AMPK regulated GLUT4 to increase glucose uptake, but A MPK could
not promote fatty acid oxidation through the JAK2/STAT3 pathway under leptin receptor deficiency in db/db mice. Conclu sion: We
conclude that leptin receptor deficiency impedes the AMPK activation-mediated fat catabolism but does not affect A MPK-related
glucose utilization after metabolic surgery in db/db mice. This result helps select surgical indica tions for patients with obesity and
diabetes.
Keywords: AMPK; Leptin receptor; Roux-en-Y gastric bypass; Weight regain

163
CD147 induces asthmatic airway remodeling and activation of circulating fibrocytes in a mouse model
of asthma
By: Li, Zhao; Cheng, Tao; Guo, Yaning; Gao, Rong; Ma, Xuankun; Mao, Xuecong; Han, Xinpeng
Airway remodeling is a poorly reversible feature of asthma which lacks effective therapeutic interventions. CD147 can regulate
extracellular matrix (ECM) remodeling and tissue fibrosis, and partic ipate in the pathogenesis of asthma. In this study, the role of C
D147 in airway remodeling and activation of circul ating fibrocytes was investigated in asthmatic mice. Asthmatic mouse model was
established by sensitizing and challenging mice with ovalbumin (O VA), and treated with anti-CD147 or Isotype antibody. The
number of eosinophils in bronchoalveolar lavage fluid (B ALF) was examined by micros cope, and the levels of interleukin-4 (IL-4), IL-5
and IL-13 in BALF were detected by E LISA (ELISA). The number of CD45+ and collagen I (C OL-I)+ circulating fibrocytes in BALF was
detected by flow cytometry. Lung tissue sections were resp. stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS) or
Masson trichrome staining, or used for immunohistochem. of CD31 and immunohistofluorescence of α -smooth muscle actin ( α -S
MA), CD45 and COL-I. The protein expression of α -SMA, vascular endothelial growth factor (VEGF), transforming growth factor-β1 (T
GF-β1), Fibronectin, and COL-I was determined by western blotting. Anti-CD147 treatment significantly reduced the number of
eosinophils and the levels of IL-4, IL-13, and IL-5 in BALF, and repressed airway inflam matory infiltration and airway wall thickening
in asthmatic mice. Anti-CD147 treatment also reduced airway goblet cell metapl asia, collagen deposition, and angiogenesis in
asthmatic mice, accompanied by inhibition of VEGF and α -SMA expression. The number of CD45+COL-I+ circulating fibrocytes was
increased in BALF and lung tissues of O VA-induced asthmatic mice, but was decreased by anti- CD147 treatment. In addition, anti-C
D147 treatment also reduced the protein expression of C OL-I, fibronectin, and TGF-β1 in lung tissues of asthmatic mice. O VA-
triggered airway inflammation and airway remodeling in asthmatic mice can be repressed by anti- CD147 treatment, along with
inhibiting the accumulation and activation of circul ating fibrocytes.
Keywords: CD147 circulating fibrocyte airway remodeling asthma; Airway remodeling; Asthma; C D147; Circulating fibrocytes
164
Apoptosis dysfunction: unravelling the interplay between ZBP1 activation and viral invasion in innate
immune responses
By: Zhan, Jianhao; Wang, Jisheng; Liang, Yuqing; Wang, Lisha; Huang, Le; Liu, Shanshan; Zeng, Xiaoping; Zeng, Erming; Wang,
Hongmei
Abstract: Apoptosis plays a pivotal role in pathogen elimination and maintaining homeostasis. However, viruses have evolved
strategies to evade apoptosis, enabling their persistence within the host. Z-DNA binding protein 1 (Z BP1) is a potent innate immune
sensor that detects cytoplasmic nucleic acids and activates the innate immune response to clear pathogens. When apoptosis is
inhibited by viral invasion, ZBP1 can be activated to compensate for the effect of apoptosis by triggering an innate immune
response. This review examined the mechanisms of apoptosis inhibition and ZBP1 activation during viral invasion. The authors
outlined the mechanisms of ZBP1-induced type I interferon, pyroptosis and necrop tosis, as well as the crosstalk between Z BP1 and
the cGAS-STING signalling pathway. Furthermore, ZBP1 can reverse the suppression of apoptotic signals induced by viruses. Intrigu
ingly, a pos. feedback loop exists in the Z BP1 signalling pathway, which intensifies the innate immune response while triggering a
cytokine storm, leading to tissue and organ damage. The prudent use of ZBP1, which is a double- edged sword, has signif icant clin.
implications for treating infections and inflamm ation.
Keywords: Apoptosis inhibition ; Innate immunity; Viral invasion; Z BP1

165
Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4
degradation and Wnt/β-catenin pathway inhibition
By: Xiao, Guodong; Lu, Weiping; Yuan, Jing; Liu, Zuyue; Wang, Peili; Fan, Huijie
Abstract: Background: Cancer stem cells (CSCs) are a small population of cells in tumor tissues that can drive tumor initiation and
promote tumor progression. A small number of previous studies indirectly mentioned the role of F- box and WD repeat domain-
containing 7 (FBXW7) as a tumor suppressor in Triple-neg. breast cancer (T NBC). However, few studies have focused on the function
of FBXW7 in cancer stemness in T NBC and the related mechanism. Methods: We detected F BXW7 by immunohistochem. (IHC) in 80
TNBC patients. FBXW7 knockdown and overexp ression in MD-MBA-231 and HCC1937 cell models were constr ucted. The effect of FB
XW7 on malignant phenotype and stemness was assessed by colony assays, flow cytometry, transwell assays, western blot, and
sphere formation assays. Immunoprecipitation-Mass Spectrometry (IP-MS) and ubiquitination experiments were used to find and
verify potential downstream substrate proteins of FBXW7. Animal experiments were constructed to examine the effect of F BXW7 on
tumorigenic potential and cancer stemness of T NBC cells in vivo. Results: The results showed that F BXW7 was expressed at low
levels in TNBC tissues and pos. correlated with prognosis of T NBC patients. In vitro, F BXW7 significantly inhibited colony formation,
cell cycle progression, cell migration, E MT process, cancer stemness and promotes apoptosis. Further experi ments confirmed that
chromodomain-helicase-DNA-binding protein 4 (C HD4) is a novel downstream target of FBXW7 and is downregulated by FBXW7 via
proteasomal degradation Moreover, CHD4 could promote the nuclear translo cation of β-catenin and reverse the inhibitory effect of
FBXW7 on β-catenin, and ultimately activate the Wnt/β-catenin pathway. Rescue experiments confirmed that the FBXW7-CHD4-
Wnt/β-catenin axis was involved in regulating the mainte nance of CSC in TNBC cells. In animal experiments, FBXW7 reduced CSC
marker expression and suppressed TNBC cell tumorig enesis in vivo. Conclu sions: Taken together, these results highlight that F BX
W7 degrades CHD4 protein through ubiquitination, thereby blocking the activation of the Wnt/β- catenin pathway to inhibit the
stemness of TNBC cells. Thus, targeting F BXW7 may be a promising strategy for therap eutic intervention against TNBC.
Keywords: CHD4; Fbxw7; Stemness; Triple-negative breast cancer; Wnt/β- catenin

166
Inhibition of soluble epoxide hydrolase enhances the dentin-pulp complex regeneration mediated by
crosstalk between vascular endothelial cells and dental pulp stem cells
By: Kong, Lingwenyao; Li, Juanjuan; Bai, Yuwen; Xu, Shaoyang; Zhang, Lin; Chen, Weixian; Gao, Lu; Wang, Fu
Abstract: Background: Revascularization and restoration of normal pulp-dentin complex are important for tissue- engineered pulp
regeneration. Recently, a unique period ontal tip-like endothelial cells subtype (POTCs) specialized to dentinogenesis was identified.
We have confirmed that TPPU, a soluble epoxide hydrolase (s EH) inhibitor targeting epoxyeicosatrienoic acids (EETs) metabolism,
promotes bone growth and regeneration by angiog enesis and osteogenesis coupling. We hypothesized that TPPU could also
promote revascularization and induce POTCs to contribute to pulp- dentin complex regeneration. Here, we in vitro and in vivo
characterized the potential effect of T PPU on the coupling of angiog enesis and odontogenesis and investigated the relevant
mechanism, providing new ideas for pulp-dentin regeneration by targeting s EH. Methods: In vitro effects of T PPU on the prolife
ration, migration, and angiog enesis of dental pulp stem cells (DPSCs), human umbilical vein endoth elial cells (HUVECs) and
cocultured DPSCs and HUVECs were detected using cell counting kit 8 (C CK8) assay, wound healing, transwell, tube formation and
RT-qPCR. In vivo, Matrigel plug assay was performed to outline the roles of T PPU in revascularization and survival of grafts. Then we
characterized the VEGFR2 + POTCs around odontoblast layer in the molar of pups from C57 BL/6 female mice gavaged with T PPU.
Finally, the root segments with DPSCs mixed with Matrigel were implanted s.c. in B ALB/c nude mice treated with T PPU and the root
grafts were isolated for histol. staining. Results: In vitro, TPPU significantly promoted the migration and tube formation capability of
cocultured DPSCs and HUVECs. ALP and ARS staining and R T-qPCR showed that T PPU promoted the osteogenic and odonto genic
differentiation of cultured cells, treatment with an anti- TGF-β blocking antibody abrogated this effect. Knockdown of HIF-1α in HUVE
Cs significantly reversed the effect of T PPU on the expression of angioge nesis, osteogenesis and odontogenesis-related genes in
cocultured cells. Matrigel plug assay showed that TPPU increased VEGF/VEGFR2-expressed cells in transplanted grafts. TPPU contri
buted to angiogenic-odontogenic coupling featured by increased V EGFR2 + POTCs and odontoblast maturation during early dentino
genesis in molar of newborn pups from C57 BL/6 female mice gavaged with T PPU. TPPU induced more dental pulp-like tissue with
more vessels and collagen fibers in transplanted root segment. Conclu sions: TPPU promotes revascula rization of dental pulp
regeneration by enhancing migration and angiog enesis of HUVECs, and improves odontogenic differentiation of DPSCs by T GF-β. TP
PU boosts the angiogenic-odontogenic coupling by enhancing V EGFR2 + POTCs meditated odontoblast maturation partly via upregu
lating HIF-1α, which contributes to increasing pulp- dentin complex for tissue-engineered pulp regeneration.
Keywords: Angiogenic-odontogenic coupling; DPSCs; HIF-1α; Pulp regeneration; TGF-β; TPPU; VEGFR2; Vascularization

167
Combination antimicrobial therapy: in vitro synergistic effect of anti-staphylococcal drug oxacillin with
antimicrobial peptide nisin against Staphylococcus epidermidis clinical isolates and Staphylococcus
aureus biofilms
By: Sharafi, Toktam; Ghaemi, Ezzat Allah; Rafiee, Maryam; Ardebili, Abdollah
Annals of Clinical Microbiology and Antimicrobials (2024), 23(1), 7 | Language: English, Database: CAplus and MEDLINE
Abstract: The ability of Staphylococcus epidermidis and S. aureus to form strong biofilm on plastic devices makes them the major
pathogens associated with device-related infections (DRIs). Biofilm-embedded bacteria are more resistant to antibi otics, making
biofilm infections very difficult to effectively treat. Here, we evaluate the in vitro activities of anti- staphylococcal drug oxacillin and
antimicrobial peptide nisin, alone and in combin ation, against methic illin-resistant S. epidermidis (MRSE) clin. isolates and the
methicillin-resistant S. aureus ATCC 43,300. The min. inhibitory concent rations (MIC) and min. biofilm eradication concentrations (M
BEC) of oxacillin and nisin were determined using the microbroth dilution method. The antibiofilm activities of oxacillin and nisin,
alone or in combination, were evaluated. In addition, the effects of antimic robial agents on the expression of ica A gene were
examined by quant. real-time PCR. MIC values for oxacillin and nisin ranged 4- 8 μg/mL and 64-128 μg/mL, resp. Oxacillin and nisin
reduced biofilm biomass in all bacteria in a dose-dependent manner and this inhibitory effect was enhanced with combina torial
treatment. MBEC ranges for oxacillin and nisin were 2048- 8192 μg/mL and 2048-4096 μg/mL, resp. The addition of nisin signifi
cantly decreased the oxacillin M BECs from 8- to 32- fold in all bacteria. At the 1x M IC and 1/2x MIC, both oxacillin and nisin
decreased significantly the expression of icaA gene in comparison with untreated control. When two antimic robial agents were
combined at 1/2x MIC concentration, the expression of icaA were significantly lower than when were used alone. Nisin/con ventional
oxacillin combination showed considerable anti-biofilm effects, including inhibition of biofilm formation, eradication of mature
biofilm, and down-regulation of biofilm-related genes, proposing its applications for treating or preventing staphyl ococcal biofilm-
associated infections, including device-related infections.
Keywords: Antimicrobial peptide; Biofilm inhibition ; MRSA; MRSE; Nisin; ica A
168
hUC-MSCs-derived MFGE8 ameliorates locomotor dysfunction via inhibition of ITGB3/ NF-κB signaling
in an NMO mouse model
By: Xu, Huiming ; Jiang, Wei ; Li, Xuejia ; Jiang, Jiaohua ; Afridi, Shabbir Khan ; Deng, Longhui ; Li, Rui ; Luo, Ermei;
Zhang, Zhaoqing; Huang, Yu-Wen Alvin ; et al
npj Regenerative Medicine (2024), 9(1), 4 | Language: English, Database: CAplus and MEDLINE
Abstract: Neuromyelitis optica (NMO) is a severe autoimmune inflam matory disease of the central nervous system that affects
motor function and causes relapsing disability. Human umbilical cord- derived mesenchymal stem cells (hUC-MSCs) have been used
extensively in the treatment of various inflam matory diseases, due to their potent regulatory roles that can mitigate inflam mation
and repair damaged tissues. However, their use in NMO is currently limited, and the mechanism underlying the beneficial effects of
hUC-MSCs on motor function in N MO remains unclear. In this study, we invest igate the effects of hUC-MSCs on the recovery of
motor function in an NMO systemic model. Our findings demonstrate that milk fat globule epidermal growth 8 (MFGE8), a key
functional factor secreted by hUC-MSCs, plays a critical role in amelio rating motor impairments. We also elucidate that the M FG
E8/Integrin αvβ3/NF-κB signaling pathway is partially respon sible for structural and functional recovery, in addition to motor
functional enhancements induced by h UC-MSC exposure. Taken together, these findings strongly support the involv ement of MFG
E8 in mediating hUC-MSCs-induced improvements in motor functional recovery in an N MO mouse model. In addition, this provides
new insight on the therapeutic potential of h UC-MSCs and the mechanisms underlying their beneficial effects in N MO.

169
Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated
molecular dynamics simulations: a dynamic odyssey
By: Sk, Fulbabu Md ; Samanta, Sunanda ; Poddar, Sayan ; Kar, Parimal

Journal of Computer-Aided Molecular Design (2024), 38(1), 8 | Language: English, Database: CAplus and MEDLINE
Abstract: The Janus kinases (JAK) are crucial targets in drug develo pment for several diseases. However, accounting for the impact
of possible structural rearrangements on the binding of different kinase inhibitors is compli cated by the extensive conform ational
variability of their catalytic kinase domain (K D). The dynamic K D contains mainly four prominent mobile structural motifs: the
phosphate-binding loop (P-loop), the αC-helix within the N-lobe, the Asp-Phe-Gly (DFG) motif, and the activation loop (A- loop) within
the C-lobe. These distinct structural orientations imply a complex signal transm ission path for regulating the A-loop′s flexibility and
conformational preference for optimal J AK function. Nevertheless, the precise dynamical features of the J AK induced by different
types of inhibitors still remain elusive. We performed comparative, microsecond-long, Gaussian accelerated mol. dynamics simula
tions in triplicate of three phospho rylated JAK2 systems: the K D alone, type-I ATP-competitive inhibitor (CI) bound K D in the catalyt
ically active DFG-in conformation, and the type-II inhibitor (AI) bound K D in the catalytically inactive DFG-out conformation. Our
results indicate significant conformational variations observed in the A- loop and αC helix motions upon inhibitor binding. Our
studies also reveal that the DFG-out inactive conformation is characterized by the closed A- loop rearrangement, open catalytic cleft
of N and C-lobe, the outward movement of the α C helix, and open P-loop states. Moreover, the outward positi oning of the αC helix
impacts the hallmark salt bridge formation between Lys882 and Glu898 in an inactive conformation. Finally, we compared their
ligand binding poses and free energy by the MM/PBSA approach. The free energy calcul ations suggested that the AI′s binding
affinity is higher than CI against JAK2 due to an increased favorable contri bution from the total non- polar interactions and the
involvement of the αC helix. Overall, our study provides the structural and energetic insights crucial for developing more promising
type I/II JAK2 inhibitors for treating J AK-related diseases.
Keywords: Conformational dynamics; Free energy surface; Gaussian accele rated molecular dynamics; Janus kinase; M M/PBSA; Type
I/II kinase inhibitors

170
Good manufacturing practice production of human corneal limbus-derived stromal stem cells and in
vitro quality screening for therapeutic inhibition of corneal scarring
By: Santra, Mithun; Geary, Moira L.; Rubin, Elizabeth; Hsu, Michael Y. S.; Funderburgh, Martha L.; Chandran, Christine; Du, Yiqin;
Dhaliwal, Deepinder K.; Jhanji, Vishal; Yam, Gary Hin-Fai
Stem Cell Research & Therapy (2024), 15(1), 11 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Mesenchymal stem cells in the adult corneal stroma (named corneal stromal stem cells, C SSCs) inhibit
corneal inflammation and scarring and restore corneal clarity in preclin. corneal injury models. This cell therapy could alleviate the
heavy reliance on donor materials for corneal transplantation to treat corneal opacities. Herein, we establ ished Good Manufacturing
Practice (GMP) protocols for C SSC isolation, propagation, and cryostorage, and developed in vitro quality control (Q C) metric for in
vivo anti-scarring potency of CSSCs in treating corneal opacities. Methods: A total of 24 donor corneal rims with informed consent
were used-18 were processed for the GMP optimization of CSSC culture and Q C assay development, while CSSCs from the
remaining 6 were raised under GMP-optimized conditions and used for Q C validation. The cell viability, growth, substrate adhesion,
stem cell phenotypes, and differen tiation into stromal kerato cytes were assayed by monitoring the elec. impedance changes using x
CELLigence real-time cell analyzer, quant. PCR, and immunofluorescence. CSSC′s conditioned media were tested for the anti- inflam
matory activity using an osteoclastogenesis assay with mouse macrophage R AW264.7 cells. In vivo scar inhibitory outcomes were
verified using a mouse model of anterior stromal injury caused by mech. ablation using an Algerbrush burring. Results: By compara
tively assessing various GMP-compliant reagents with the corresp onding non-GMP research-grade chems. used in the labora tory-
based protocols, we finalized G MP protocols covering donor limbal stromal tissue proces sing, enzymic digestion, primary CSSC
culture, and cryopreservation. In establishing the in vitro Q C metric, two parameters-stemness stability of ABCG2 and nestin and
anti-inflammatory ability (rate of inflammation)-were factored into a novel formula to calculate a Scarring Index (S I) for each C SSC
batch. Correlating with the in vivo scar inhibitory outcomes, the C SSC batches with S I < 10 had a predicted 50% scar reduction
potency, whereas cells with SI > 10 were ineffective to inhibit scarring. Conclusions: We established a full GMP-compliant protocol
for donor CSSC cultivation, which is essential toward clin.- grade cell manufac turing A novel in vitro Q C-in vivo potency correlation
was developed to predict the anti-scarring efficacy of donor C SSCs in treating corneal opacities. This method is applicable to other
cell-based therapies and pharmacol. treatments.
Keywords: Cell therapy; Cornea scarring; Corneal stromal stem cells; Good manufacturing practice; Quality control

171
Chili pepper extracts, capsaicin, and dihydrocapsaicin as potential anticancer agents targeting
topoisomerases
By: Hudakova, Terezia; Semelakova, Martina; Ocenas, Peter; Kozurkova, Maria; Krochtova, Kristina; Sovova, Simona; Tothova,
Zuzana; Gulasova, Zuzana; Popelka, Peter; Solar, Peter
Abstract: DNA topoisomerases regulate conform ational changes in D NA topol. during normal cell growth, such as replic ation,
transcription, recombination, and repair, and may be targeted for anticancer drugs. A D NA topol. assay was used to invest igate DN
A-damaging/protective activities of extracts from Habanero Red (H R), Habanero Maya Red (HMR), Trinidad Moruga Scorpion (T MS),
Jalapeno (J), Serrano pepper (SP), Habanero Red Savina (HRS), Bhut Jolokia (BJ), and Jamaica Rosso (JR) peppers, demonstrating their
inhibitory effect on the relaxation of pBR by Topo I. D NA topoisomerase II (Topo II) is proven therapeutic target of anticancer drugs.
Complete inhibition of Topo II was observed for samples T MS, HR, and HMR. Extracts J and S P had the lowest capsaicin and
dihydrocapsaicin content compared to other peppers. H R, HMR, TMS, J, S, HRS, BJ, JR extracts showed the anticancer effect,
examined by MTS and xCell assay on the in vitro culture of human colon carcinoma cell line H CT116.
Keywords: Capsaicin; Chili pepper extract; Dihydrocapsaicin; Topoisomerases inhibition
172
Effects of Ramadan on cognitive functions in young boys.
By: Miladi, Amira ; Saafi, Mohamed Ali ; Latiri, Imed

The Libyan journal of medicine (2024), 19(1), 2301830 | Language: English, Database: MEDLINE
Fasting during Ramadan involves abstaining from food and drink from dawn to sunset, potentially influencing cognitive functions
essential for the intellectual development of the youth. Therefore, understanding the effects of fasting on these functions in
children/adolescents provides valuable perspectives to enhance education and promote mental well- being. However, studies on
children/adolescents in this context are still limited. To evaluate the impact of Ramadan fasting on cognitive functions, including
information processing speed, inhibition , decision-making, and auditory attention processes among children and adoles cents aged
11 to 15 years. This study was conducted with 24 healthy children/adolescents (aged 12.84 ± 0 .69 years). The experimental protocol
consisted of two sessions: Before-Ramadan (BR) and at the beginning of the second week of Ramadan (R2) . At each session, the
boys were randomly tested on simple reaction time (SRT), choice reaction time (CRT), negative priming reaction time (NPRT), and
auditory discrimination (P300). The tests were administered and scored by the same person in the different sessions. The study
found that Ramadan fasting did not have an effect on various reaction times or on electro-physiological data, including P300
amplitude and latency. The current study, conducted with healthy children/adolescents, indicates that Ramadan fasting had no
impact on various reaction times (SRT, CRT, NPRT), suggesting the preservation of information processing speed and decision-
making, even in the face of increased task comple xity. This is evident, on the one hand, through the mainte nance of the ability to
react to unexpected events, and, on the other hand, through the mastery of resistance to automatism, thus reflecting the preser
vation of inhibitory function (NPRT). Regarding P300 data, the absence of changes in latencies and amplitudes suggests that
Ramadan fasting did not alter either the evaluation time of auditory stimuli or auditory attention processes.
Keywords: Children/adolescents; P300; Ramadan; attention; inhibition ; reaction time

173
Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis
By: Guo, Xuanming ; Asthana, Pallavi; Zhai, Lixiang; Cheng, Ka Wing ; Gurung, Susma; Huang, Jiangang; Wu, Jiayan; Zhang, Yijing;
Mahato, Arun Kumar ; Saarma, Mart ; et al
Abstract: Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty
liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show
that treatment with artesunate, an artemisinin derivative approved by the F DA for the treatment of severe malaria, effect ively
reduces body weight and improves metabolic profiles in preclin. models of obesity, including male mice with overnutrition-induced
obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes
weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differen
tiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem- restricted receptor, the GDNF family receptor α -like (GF
RAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/E BP
homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of G FRA
L or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet- induced obesity,
suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight
the therapeutic benefits of artesunate in the treatment of obesity and related comorbi dities.
174
Antimicrobial resistance in aeromonads and new therapies targeting quorum sensing
By: Neil, Blake ; Cheney, Gabrielle L.; Rosenzweig, Jason A.; Sha, Jian; Chopra, Ashok K.
Abstract: Aeromonas species (spp.) are well-known fish pathogens, several of which have been recognized as emerging human
pathogens. The organism is capable of causing a wide spectrum of diseases in humans, ranging from gastroenteritis, wound infect
ions, and septicemia to devastating necrotizing fasciitis. The systemic form of infection is often fatal, partic ularly in patients with
underlying chronic diseases. Indeed, recent trends demonstrate rising numbers of hospital- acquired Aeromonas infections,
especially in immuno-compromised individuals. Addnl., Aeromonas-associated antibiotic resistance is an increasing challenge in
combating both fish and human infections. The acquisition of antibiotic resistance is related to Aeromonas′ innate transfo rmative
properties including its ability to share plasmids and integron-related gene cassettes between species and with the enviro nment. As
a result, alternatives to antibiotic treatments are desper ately needed. In that vein, many treatments have been proposed and
studied extensively in the fish-farming industry, including treatments that target Aeromonas quorum sensing. In this review, we
discuss current strategies targeting quorum sensing inhibition and propose that such studies empower the development of novel
chemotherapeutic approaches to combat drug- resistant Aeromonas spp. infections in humans. Key points: • Aeromonas notori
ously acquires and maintains antimicrobial resistance, making treatment options limited. • Quorum sensing is an essential virulence
mechanism in Aeromonas infections. • Inhibiting quorum sensing can be an effective strategy in combating Aeromonas infections
in animals and humans.
Keywords: Aeromonas; Antimicrobial resistance; Horizontal gene transfer; Quorum sensing; Quorum sensing inhibition

175
Inhibition of IL-17 signaling in macrophages underlies the anti-arthritic effects of halofuginone

hydrobromide: Network pharmacology, molecular docking, and experimental validation
By: Zhu, Junping; Wei, Jiaming; Lin, Ye; Tang, Yuanyuan; Su, Zhaoli; Li, Liqing; Liu, Bin; Cai, Xiong
Abstract: Background: Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by chronic synovitis as well as cartilage
and bone destruction. Halofuginone hydrobromide (HF), a bioactive compound derived from the Chinese herbal plant Dichroa
febrifuga Lour., has demonstrated substantial anti-arthritic effects in RA. Nevertheless, the mol. mechanisms responsible for the
anti-RA effects of HF remain unclear. Methods: This study employed a combin ation of network pharmacol., mol. docking, and exptl.
validation to investigate potential targets of H F in RA. Results: Network pharmacol. analyses identified 109 differe ntially expressed
genes (DEGs) resulting from HF treatment in R A. Gene Ontol. (GO) and Kyoto Encyclopedia of Genes and Genomes (K EGG) analyses
unveiled a robust association between these DEGs and the IL-17 signaling pathway. Subsequ ently, a protein-protein interaction (PPI)
network anal. revealed 10 core DEGs, i.e., EGFR, MMP9, TLR4, ESR1, MMP2, PPARG, MAPK1, JAK2, STAT1, and MAPK8. Among them,
MMP9 displayed the greatest binding energy for H F. In an in vitro assay, HF significantly inhibited the activity of inflam matory
macrophages, and regulated the IL-17 signaling pathway by decreasing the levels of I L-17 C, p-NF-κB, and MMP9. Conclusion: In
summary, these findings suggest that HF has the potential to inhibit the activation of inflammatory macrophages through its
regulation of the IL-17 signaling pathway, unders coring its potential in the suppre ssion of immune-mediated inflammation in RA.
Keywords: Experimental validation; Halofuginone hydrobromide; Molecular docking; Network pharmac ology; Rheumatoid arthritis
176
Analysis of the immunological markers BTLA, TIM-3, and PD-L1 at the invasion front and tumor center
in clear cell renal cell carcinoma
By: Stuehler, Viktoria; Alemi, Bilal; Rausch, Steffen; Stenzl, Arnulf; Schwab, Matthias; Schaeffeler, Elke; Bedke, Jens
World Journal of Urology (2024), 42(1), 53 | Language: English, Database: CAplus and MEDLINE
Abstract: Purpose: Immune checkpoint inhibitors (ICI) are then backbone in the therapy of metastatic renal cell carcinoma (R CC).
The aim of this anal. was to explore the different expression of the ICI PD-L1, BTLA, and TIM-3 at the different tumor locations of the
invasion front and the tumor center. Methods: Large-area sections of the tumor center and invasion front of 44 stage p T1-4 clear
cell RCCs were examined immunohi stochem. using antibodies against BTLA, TIM-3, and PD-L1 and subsequently correlated with
clinicopathol. data. Results: T IM-3 was most strongly expressed at the invasion front (mean ± S D: 84.1 ± 46.6, p = 0.094) . BTLA
expression was highest in normal tissue, with weak staining in the tumor center and at the invasion front [110.2 vs. 18.6 (p < 0.001)
vs. 32.2 (p = 0.248)]. PD-L1 was weakly expressed at the tumor center (n = 5/44) and at the invasion front (n = 5/44) . Correlation with
clinicopathol. parameters revealed significantly higher BTLA expression in ≥ T3 tumors compared to T1/2 tumors (tumor center p =
0.009; invasion front p = 0.005). BTLA-pos. tumors at the tumor center correlated with worse C SS (median 48.46 vs. 68.91 mo, H R
4.43, p = 0.061). PD-L1 expression was associated with worse C SS (median 1.66 vs. 4.5 years, H R 1.63, p = 0.652) . For TIM-3, there
were no significant associations with clinicopathol. parameters and survival. Conclu sion: The present results show heterog eneous
intratumoral and intertumoral expression of the investigated checkpoint receptors PD-L1, BTLA, and TIM-3. In the clin. practice
tumor sampling should include different tumor locations, and multiple inhibition of different checkpoint receptors seems
reasonable to increase the therapeutic success.
Keywords: BTLA; Checkpoint inhibition ; Heterogeneity; PD-L1; Renal cell carcinoma; T IM-3

177
The impact of environmentally friendly supramolecular coordination polymers as carbon steel

corrosion inhibitors in HCl solution: synthesis and characterization
By: Eissa, M.; Etaiw, S. H.; El-Waseef, E. E.; El-Hossiany, A.; Fouda, A. S.
Two 3D-supramol. coordination polymers (SCP1 & SCP2) have been synthe sized and characterized by physicochem. and spectro
scopic methods. In a solution of 1.0 M H Cl, SCPs were used to prevent corrosion of carbon steel (C S). The inhibition productivity
(%η) rises as the synthetic inhibitor dose rises, and the opposite is true as the temperature rises. The study was carried out using
chem. (mass loss, ML) and electrochem. ( potentiodynamic polarization, PDP and electrochem. impedance microscopy, EIS) techni
ques, which showed %η reached to 93.1% and 92.5% for S CP1 & SCP2, resp. at 21 x 10 -6 M, 25 °C. For the polari zation results, SCPs
behave as mixed-type inhibitors. With increasing doses of S CPs, the charge transfer resistance grew and the double layer′s capaci
tance lowered. The creation of a monolayer on the surface of C S was demonstrated by the finding that the adsorption of S CPs on
its surface followed the Henry adsorption isotherm. The parameters of thermodn. were computed and explained. The phys.
adsorption of SCPs on the surface of C S is shown by the lowering values of free energy (Δ Goads < - 20 k J mol -1) and increasing the
activation energy (E*a) values in presence of SCP1 & SCP2 than in their absence. Atomic force microscope (A FM) and S EM (SEM)
demonstrated the development of a protective thin film of S CPs precipitated on the surface of C S. There is a strong matching
between results obtained from exptl. and theor. studies. Result from each approach that was used were consistent.
Keywords: supramol coordination polymer numerical model corrosion inhibition activation energy
178
Dexamethasone exposure during pregnancy triggers metabolic syndrome in offspring via epigenetic
alteration of IGF1
By: Xiao, Hao; He, Bo; Liu, Heze; Chen, Yawen; Xiao, Di; Wang, Hui
Abstract: Background: Previous research has reported that prenatal exposure to dexamet hasone (PDE) results in organ dysplasia
and increased disease susceptibility in offspring. This study aimed to invest igate the epigenetic mechanism of metabolic syndrome
induced by PDE in offspring. Methods: Pregnant Wistar rats were admini stered dexamethasone, and their offspr ing′s serum and
liver tissues were analyzed. The hepatocyte differentiation model was established to unveil the mol. mechanism. Neonatal cord
blood samples were collected to validate the phenomenon and mechanism. Results: The findings demonstrated that PDE leads to
insulin resistance and typical metabolic syndrome traits in adult offspring rats, which originated from fetal liver dysplasia. Addnl., P
DE reduced serum cortico sterone level and inhibited hepatic insulin- like growth factor 1 (IGF1) signaling in fetal rats. It further
revealed that liver dysplasia and functional impairment induced by PDE persist after birth, driven by the continuous downreg ulation
of serum corticosterone and hepatic IGF1 signaling. Both in vitro and in vivo experi ments confirmed that low endogenous cortico
sterone reduces the histone 3 lysine 9 acetyl ation (H3K27ac) level of IGF1 and its expression by blocking glucoco rticoid receptor α ,
special protein 1, and P300 into the nucleus, resulting in hepatocyte differentiation inhibition and liver dysplasia. Intrigu ingly,
neonatal cord blood samples validated the link between reduced liver function in neonates induced by PDE and decreased serum
cortisol and IGF1 levels. Conclusions: This study demons trated that low endogenous glucoco rticoid level under PDE lead to liver
dysplasia by downregulating the H3K27ac level of IGF1 and its expression, ultimately contri buting to metabolic syndrome in adult
offspring.
Keywords: Endogenous glucocorticoids; Histone acetylation; Insulin-like growth factor 1; Metabolic syndrome; Prenatal dexamet
hasone exposure

179
Deciphering agr quorum sensing in Staphylococcus aureus: insights and therapeutic prospects
By: Vinodhini, V.; Kavitha, M.

Abstract: The emergence of superbugs like methicillin-resistant Staphylococcus aureus exposed the limitations of treating microbial
infections using antibiotics. At present, the discovery of novel and convincing therap eutic methods are being executed increa singly
as possible substitutes to conventional antibiotic therapies. The quorum sensing helps Staphyl ococcus aureus become more viable
through their signaling mechanisms. In recent years, targeting the prominent factors of quorum sensing has obtained remarkable
attention as a futuristic approach to dealing with bacterial pathogenicity. The standard antibiotic therapy intends to inhibit the
organism by targeting specific mols. and afford a chance for the evolution of antibiotic resistance. This prompts the develo pment of
novel therapeutic strategies like inhibiting quorum sensing that can limit bacterial virulence by decreasing the selective pressure,
thereby restricting antibiotic resistance evolution. This review furnishes new insights into the accessory gene regulator quorum
sensing in Staphylococcus aureus and its inhibition by targeting the genes that regulate the operon. Further, this review comprehe
nsively explores the inhibitors reported up to date and their specific targets and discusses their potent ially ineffective alternative
therapy against methicillin-resistant Staphylococcus aureus. Graphical abstract: [graphic not available: see fulltext]
Keywords: AIP signal molecule; Agr quorum sensing; Quorum sensing; Quorum sensing inhibition ; Staphylococcus aureus
180
Comparative assessment of phenolic composition profile and biological activities of green extract and
conventional extracts of Salvia sclarea
By: Quradha, Mohammed Mansour; Duru, Mehmet Emin; Kucukaydin, Selcuk; Tamfu, Alfred Ngenge; Iqbal, Mudassar; Bibi, Hamida;
Khan, Rasool; Ceylan, Ozgur
Abstract: In recent years, there have been an attempt to develop safe and environmental friendly solvents to replace conven tional
solvents, and use for extraction bioactive compounds from natural sources. A current investigation involved the preparation of
green, methanolic, and ultrasonic extracts of S. sclarea, and compared their phenolic profiling using H PLC-DAD, antibacterial, antiox
idant, and enzyme inhibition activities. The HPLC-DAD anal. revealed that Rosmarinic acid was the main content in all extracts, with
Ellagic acid only present in the green extract The green extract exhibited superior anti-biofilm activity against S. Aureus and E.
Faecalis compared to the other extracts at MIC concentration Furthermore, the green extract also displayed the highest inhibition
of swarming motility in P. Aeruginosa with inhibition range 68.0 ± 2.1 (M IC) to 19.5 ± 0.6 (M IC/4). and better enzyme inhibitory
activity against BChE (with IC50 = 131.6 ± 0.98 μg/m L) and AChE (with inhibition 47.00 ± 1.50%) compared to the other extracts;
while, the ultrasonic extract showed strong inhibition of violacein production by C. Violaceum with a inhibition range 05.5 ± 0.1 (M I
C/32) to 100 ± 0.00 (M IC), followed by the green extract with a inhibition range 15.0 ± 0.5 (M IC/8) to 100 ± 0.00 (M IC), addnl., the
ultrasonic and methanoic extracts showed significant activity against urease enzyme with (IC50 = 171.6 ± 0.95 μg/m L and IC5 0 =
187.5 ± 1.32 μg/mL) resp. Both the green and methanolic extracts showed consid erable antioxidant activities, as β-carotene-linoleic
acid (IC50 = 5.61 ± 0.47 μg/m L and 5.37 ± 0.27 μg/m L), DPPH· (IC50 = 19.20 ± 0.70 μg/m L and 16.31 ± 0.23 μg/m L), ABTS·+(IC50 = 8.64 ±
0.63 μg/mL and 6.50 ± 0.45 μg/m L) and CUPRAC (A0.5 = 17.22 ± 0.36 μg/m L and 12.28 ± 0.12 μg/m L) resp., likewise the green extract
performing better in metal chelating compared to the other extracts The green extraction is reported as a cost effective and solvent
free method for extracting natural products that produces compounds free of toxic chems. This could be the method to be used in
the industries as a renewable method.

181
Targeting cholesterol impairs cell invasion of all breast cancer types
By: Maja, Mauriane; Verfaillie, Marie; Van Der Smissen, Patrick; Henriet, Patrick; Pierreux, Christophe E.; Sounni, Nor Eddine; Tyteca,
Donatienne
Abstract: Background: Breast cancer clin. outcome relies on its intrinsic mol. subtype and mortality is almost exclus ively due to
metastasis, whose mechanism remains unclear. We recently revealed the specific contri bution of plasma membrane cholesterol to
the invasion of malignant MCF10CAIa but not premalignant MCF10AT and normal M CF10A cell lines in 2 D, through invadopodia
formation and extracellular matrix (ECM) degradation In the present study, we address the impact of breast cancer subtypes,
mutations and aggressiveness on cholesterol implication in breast cancer cell invasion and 3 D spheroid invasion and growth.
Methods: We used nine breast cancer cell lines grouped in four subtypes matching breast tumor classification. Four of these cell
lines were also used to generate 3D spheroids. These cell lines were compared for cell invasion in 2 D and 3D, spheroid growth in 3
D, gelatin degradation, cortactin expression, activation and subcel lular distribution as well as cell surface choles terol distribution
and lipid droplets. The effect of plasma membrane cholesterol depletion on all these parameters was determined in parallel and
systematically compared with the impact of global matrix metallopr oteinase (MMP) inhibition . Results: The six invasive cell lines in
2D were sensitive to partial choles terol depletion, independently of their subtype, aggress iveness or mutation. Nevertheless, the
effect was stronger in the three cell lines able to degrade gelatin. 3D spheroid invasion was also reduced after choles terol depletion
in all breast cancer subtypes tested. Notably, targeting cholesterol was more powerful than MMP inhibition in reducing invasion in
both 2D and 3D culture models. Moreover, choles terol depletion in the six invasive cell lines impaired cortactin distri bution in the
perinuclear region where invado podia localized. Breast cancer cell line aggress iveness relied on cholesterol-enriched domains at
the ECM-free side and intrace llular lipid droplets. Furthe rmore, the three gelatin-degrading cell lines were charact erized by
increased cholesterol-enriched submicrometric domains at their E CM-contact side. Conclusion: Together, our data suggest cell
surface cholesterol combined with lipid droplet labeling as a breast cancer cell aggress iveness marker. They also open the way to
test other cholesterol-targeting drugs in more complex models to further evaluate whether choles terol could represent a strategy in
breast cancer therapy.
Keywords: 3D spheroid growth; 3D spheroid invasion; Breast cancer cell lines; Choles terol submicrometric domains; Cortactin; Lipid
droplets; MMP inhibition ; Matrigel invasion

182
Experimental and theoretical studies of the efficiency of metal-organic frameworks (MOFs) in

preventing aluminum corrosion in hydrochloric acid solution
By: Fouda, Abd El-Aziz S.; Etaiw, Safaa Eldin H.; Abd El-Aziz, Dina M.; El-Hossiany, Ahmed A.; Elbaz, Usama A.
BMC Chemistry (2024), 18(1), 21 | Language: English, Database: CAplus and MEDLINE
Aluminum corrosion inhibitors ′′{[CuI (CN)2(phen) CuII (CN)2(phen)]5H2O},(MOF1) and {[CuI(CN)2(phen)CuII(CN)2(phen)]2H2O}@TiO5

(MOF1@TiO2) were studied in one molar H Cl solution′′. The ML results for three different temper atures (25-45 °C) were compared
with the results of PDP and EIS analyses. The adsorption of inhibitors on Al surfaces has been calculated and discussed by a
Langmuir isotherm. The inhibitors that were created showed great effectiveness, with a noticeable increase in their inhibitory
efficiency as the dosage was raised and the temperature was lowered. Inhibition efficiency each amounted to 88.6%, 84.5% at 400
ppm and 25 °C for MOF1@TiO2 and MOF1, resp. Analyzing the polari zation curves of synthesized inhibitors revealed that they were
mixed-type inhibitors. Al was found to be surface inhibited when coated with a thin film of inhibi tors, and ′′Al′s surface morphol.
was assessed by different techniques such as SEM (SEM), energy dispersive X- ray (EDX) and at. force microscope (AFM)′′. ′′Theor.
models like quantum chem. and mol. dynamics simulation authenticated the exptl. observation′′. The MOFs exhibit exceptional
corrosion resistance against Al when exposed to acidic environments, according to several tests.
Keywords: aluminum hydrochloric acid metal organic framework corrosion; Al; Corrosion inhibition ; HCl; Langmuir isotherm;
Metal–organic frameworks (MOFs)
183
Molecular docking as a tool for the discovery of novel insight about the role of acid sphingomyelinase
inhibitors in SARS- CoV-2 infectivity
By: Alkafaas, Samar Sami; Abdallah, Abanoub Mosaad; Hassan, Mai H.; Hussien, Aya Misbah; Elkafas, Sara Samy; Loutfy, Samah A.;
Mikhail, Abanoub; Murad, Omnia G.; Elsalahaty, Mohamed I.; Hessien, Mohamed; et al
BMC Public Health (2024), 24(1), 395 | Language: English, Database: CAplus and MEDLINE
Abstract: Recently, COVID-19, caused by severe acute respir atory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6
million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. S ARS-CoV-2 attaches to the
ACE-2 receptor of the host cell membrane to enter. Targeting the S ARS-CoV-2 entry may effect ively inhibit infection. Acid sphingom
yelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphing olipid (sphingomyelin) to ceramide. Ceramide mols.
aggregate/assemble on the plasma membrane to form "platforms" that facilitate the viral intake into the cell. Impairing the A SMase
activity will eventually disrupt viral entry into the cell. In this review, we identified the metabolism of sphingolipids, sphingolipids′
role in cell signal transduction cascades, and viral infection mechan isms. Also, we outlined A SMase structure and underlying
mechanisms inhibiting viral entry 40 with the aid of inhibitors of acid sphingomyelinase (FIASMAs). In silico mol. docking analyses of
FIASMAs with inhibitors revealed that dilazep (S = - 12.58 kcal/mol) , emetine (S = - 11.65 kcal/mol) , pimozide (S = - 11.29 kcal/mol) ,
carvedilol (S = - 11.28 kcal/mol), mebeverine (S = - 11.14 kcal/mol) , cepharanthine (S = - 11.06 kcal/mol) , hydroxyzin (S = - 10.96
kcal/mol), astemizole (S = - 10.81 kcal/mol) , sertindole (S = - 10.55 kcal/mol) , and bepridil (S = - 10.47 kcal/mol) have higher inhibition
activity than the candidate drug amiodarone (S = - 10.43 kcal/mol), making them better options for inhibition .
Keywords: ASMase; COVID-19; Ceramide; FIASMAs; Sphingomyelin

184
Inflammatory responses and barrier disruption in the trachea of chicks following Mycoplasma
gallisepticum infection: a focus on the TNF-α -NF-κB/MLCK pathway
By: Zhong, Lemiao; Wu, Chunlin; Zhao, Yan; Huang, Baoqin; Luo, Zhongbao; Wu, Yijian
Veterinary Research (2024), 55(1), 8 | Language: English, Database: CAplus and MEDLINE
Abstract: Mycoplasma gallisepticum (MG) can induce persistent inflammatory damage to the tracheal mucosa of poultry and cause
chronic respiratory diseases in chickens. To further invest igate the mechanism of M G-induced injury to the tracheal mucosa, we
used chick embryo tracheal organ culture (TOC) as a model to study the invasion and reprod uction of MG, the effect of M G on
tracheal morphol., and the potential factors that promote MG tissue invasion. The results showed that M G infection significantly
damaged the tracheal epithelial structure and weakened tracheal epithelial barrier function; MG also increased the occurrence of
bacterial displacement, with a signif icant (p < 0.05) increase in the bacterial load of the infected T OCs at 5 and 7 days post- infection.
In addition, MG significantly (p < 0.05) increased the expression levels of inflam matory cytokines, such as TN F-α , interleukin-1β (IL-
1β), and IL-6, and activated the NF-κB signalling pathway, leading to increased nuclear translo cation of NF-κB p65. Simultaneously,
the map kinase pathway (MAPK) was activated. This activation might be associated with increased myosin light chain (M LC)
phosphorylation, which could lead to actin- myosin contraction and disruption of tight junction (T J) protein function, potentially
compromising epithelial barrier integrity and further catalyzing M G migration into tissues. Overall, our results contribute to a better
understanding of the interaction between M G and the host, provide insight into the mechanisms of damage to the tracheal mucosa
induced by MG infection, and provide new insights into the possible pathways involved in Mycoplasma gallise pticum infection in
vivo.
Keywords: Mycoplasma gallisepticum; NF-κB/MLCK pathway; TJ protein; chicken embryo tracheal organ culture; inflam matory
cytokines; tracheal epithelial barrier

185
RORα inhibits gastric cancer proliferation through attenuating G6PD and PFKFB3 induced glycolytic
activity
By: Wang, Xiaoshan; Zhang, Junyi; Wu, Yuwei; Zhang, Yuqing; Zhang, Siyuan; Li, Angqing; Wang, Jian; Wang, Zhengguang
Abstract: Background: Glycolysis is critical for harvesting abundant energy to maintain the tumor microenv ironment in malignant
tumors. Retinoic acid-related orphan receptor α (RORα) has been identified as a circadian gene. However, the associ ation of
glycolysis with RORα in regulating gastric cancer (GC) proliferation remains poorly understood. Methods: Bioinformatic anal. and
retrospective study were utilized to explore the role of R ORα in cell cycle and glycolysis in G C. The mechanisms were performed in
vitro and in vivo including colony formation, Cell Counting Kit-8 (CCK-8), Epithelial- mesenchymal transition (EMT) and s.c. tumors of
mice model assays. The key drives between RORα and glycolysis were verified through western blot and chip assays. Moreover, we
constructed models of high proliferation and high glucose environments to verify a neg. feedback and chemores istance through a
series of functional experiments in vitro and in vivo. Results: R ORα was found to be involved in the cell cycle and glycolysis through a
gene set enrichment anal. (GSEA) algorithm. GC patients with low R ORα expression were not only associated with high circul ating
tumor cells (CTC) and high vascular endoth elial growth factor (VEGF) levels. However, it also presented a pos. correl ation with the
standard uptake value (SUV) level. Moreover, the SUVmax levels showed a pos. linear relation with C TC and VEGF levels. In addition,
RORα expression levels were associated with glucose 6 phosphate dehydro genase (G6PD) and phosphofructokinase-2/fructose-2,6-
bisphosphatase (PFKFB3) expression levels, and GC patients with low R ORα and high G6PD or low RORα and high PFKFB3
expression patterns had poorest disease-free survival (DFS). Functionally, RORα deletion promoted GC proliferation and drove
glycolysis in vitro and in vivo. These phenomena were reversed by the RORα activator SR1078. Moreover, RORα deletion promoted
GC proliferation through attenuating G6PD and PFKFB3 induced glycolytic activity in vitro and in vivo. Mechanis tically, RORα was
recruited to the G6PD and PFKFB3 promoters to modulate their transcr iption. Next, high proliferation and high glucose inhibited R O
Rα expression, which indicated that neg. feedback exists in G C. Moreover, R ORα deletion improved fluorouracil chemoresistance
through inhibition of glucose uptake. Conclu sion: RORα might be a novel biomarker and therap eutic target for G C through attenu
ating glycolysis.
Keywords: G6PD; Gastric cancer; Glycolysis; PFKFB3; Proliferation; RORα

186
The novel phosphatase NUDT5 is a critical regulator of triple-negative breast cancer growth
By: Qian, Jing; Ma, Yanxia; Tahaney, William M.; Moyer, Cassandra L.; Lanier, Amanda; Hill, Jamal; Coleman, Darian; Koupaei, Negar;
Hilsenbeck, Susan G.; Savage, Michelle I.; et al
Breast Cancer Research (2024), 26(1), 23 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The most aggressive form of breast cancer is triple- neg. breast cancer (T NBC), which lacks expression of the
estrogen receptor (ER) and progesterone receptor (PR), and does not have overexp ression of the human epidermal growth factor
receptor 2 (HER2). Treatment options for women with T NBC tumors are limited, unlike those with ER-pos. tumors that can be
treated with hormone therapy, or those with HER2-pos. tumors that can be treated with anti-HER2 therapy. Therefore, we have
sought to identify novel targeted therapies for TNBC. In this study, we invest igated the potential of a novel phosphatase, NUDT5, as
a potential therapeutic target for T NBC. Methods: The mRNA expression levels of NUDT5 in breast cancers were invest igated using
TCGA and M ETABRIC (Curtis) datasets. N UDT5 ablation was achieved through siRNA targeting and N UDT5 inhibition with the small
mol. inhibitor TH5427. Xenograft TNBC animal models were employed to assess the effect of N UDT5 inhibition on in vivo tumor
growth. Proliferation, death, and DNA replication assays were conducted to invest igate the cellular biol. effects of N UDT5 loss or
inhibition . The accumulation of 8-oxo-guanine (8-oxoG) and the induction of γH2AX after NUDT5 loss was determined by
immunofluorescence staining. The impact of N UDT5 loss on replication fork was assessed by measuring D NA fiber length. Results:
In this study, we demonstrated the significant role of an overexpressed phosphatase, NUDT5, in regulating oxidative DNA damage in
TNBCs. Our findings indicate that loss of N UDT5 results in suppressed growth of T NBC both in vitro and in vivo. This growth
inhibition is not attributed to cell death, but rather to the suppre ssion of proliferation. The loss or inhibition of NUDT5 led to an
increase in the oxidative DNA lesion 8- oxoG, and triggered the DNA damage response in the nucleus. The interf erence with DNA
replication ultimately inhibited proliferation. Conclusions: NUDT5 plays a crucial role in preventing oxidative D NA damage in T NBC
cells. The loss or inhibition of NUDT5 significantly suppresses the growth of T NBCs. These biol. and mechan istic studies provide the
groundwork for future research and the potential development of NUDT5 inhibitors as a promising therap eutic approach for T NBC
patients.
Keywords: Oxidative stress; Phosphatase; Triple-negative breast cancer

187
Early Leishmania infectivity depends on miR-372/373/520d family-mediated reprogramming of

polyamines metabolism in THP-1-derived macrophages
By: Fernandes, J. C. R.; Muxel, S. M.; Lopez-Gonzalvez, M. A.; Barbas, C.; Floeter-Winter, L. M.
Abstract: Leishmania amazonensis is a protozoan that primarily causes cutaneous leishmaniasis in humans. The parasite relies on
the amino acid arginine to survive within macrophages and establish infection, since it is a precursor for producing polyam ines. On
the other hand, arginine can be metabolized via nitric oxide synthase 2 (N OS2) to produce the microbicidal mol. nitric oxide (N O),
although this mechanism does not apply to human macrophages since they lack N OS2 activity. MicroRNAs (miRNAs) are small
noncoding RNAs that regulate gene expression at posttransc riptional levels. Our previous work showed that mmu- miR-294 targets
Nos2 favoring Leishmania survival in murine macrophages. Here, we demonstrate that human macrophages upregulate the hsa- mi
R-372, hsa-miR-373, and hsa-miR-520d, which present the same seed sequence as the murine mmu- miR-294. Inhibition of the miR-
372 impaired Leishmania survival in T HP-1 macrophages and the effect was further enhanced with combina torial inhibition of the
miR-372/373/520d family, pointing to a cooper ative mechanism. However, this reduction in survival is not caused by mi RNA-
targeting of N OS2, since the seed-binding motif found in mice is not conserved in the human 3′U TR. Instead, we showed the mi R-
372/373/520d family targeting the macrop hage′s main arginine transporter SLC7A2/CAT2 during infection. Arginine- related
metabolism was markedly altered in response to infection and miRNA inhibition , as measured by Mass Spectro metry-based
metabolomics. We found that Leishmania infection upregu lates polyamines production in macrop hages, as opposed to simult
aneous inhibition of miR-372/373/520d, which decreased putrescine and spermine levels compared to the neg. control. Overall, our
study demonstrates miRNA-dependent modulation of polyamines production, establishing permissive conditions for intrace llular
parasite survival. Although the effector mechanisms causing host cell immunometabolic adaptations involve various parasite and
host-derived signals, our findings suggest that the mi R-372/373/520d family may represent a potential target for the develo pment of
new therapeutic strategies against cutaneous leishma niasis.

188
High CD133 expression in proximal tubular cells in diabetic kidney disease: good or bad?
By: Zhang, Yuhan; Xu, Lusi; Guo, Congcong; Li, Xianzhi; Tian, Yutian; Liao, Lin; Dong, Jianjun
Abstract: Background: Proximal tubular cells (P TCs) play a critical role in the progre ssion of diabetic kidney disease (DKD). As one of
important progenitor markers, CD133 was reported to indicate the regeneration of dedifferentiated PTCs in acute kidney disease.
However, its role in chronic DKD is unclear. Therefore, we aimed to invest igate the expression patterns and elucidate its functional
significance of CD133 in DKD. Methods: Data mining was employed to illustrate the expression and mol. function of C D133 in PTCs
in human DKD. Subsequently, rat models representing various stages of D KD progression were established. The expression of C
D133 was confirmed in DKD rats, as well as in human P TCs (HK-2 cells) and rat PTCs (NRK-52E cells) exposed to high glucose. The
immunofluorescence and flow cytometry techniques were utilized to determine the expression patterns of C D133, utilizing prolife
rative and injury indica tors. After overexpression or knockdown of CD133 in HK-2 cells, the cell prolife ration and apoptosis were
detected by EdU assay, real-time cell anal. and flow anal. Addnl., the evaluation of epithe lial, progenitor cell, and apoptotic indexes
was performed through western blot and quant. RT-PCR analyses. Results: The expression of C D133 was notably elevated in both
human and rat PTCs in DKD, and this expression increased as D KD progressed. CD133 was found to be co-expressed with CD24, KI
M-1, SOX9, and PCNA, suggesting that CD133+ cells were damaged and associated with prolife ration. In terms of functionality, the
knockdown of CD133 resulted in a signif icant reduction in proliferation and an increase in apoptosis in H K-2 cells compared to the
high glucose stimulus group. Conversely, the overexpression of CD133 significantly mitigated high glucose- induced cell apoptosis,
but had no impact on cellular proliferation. Furthermore, the Nephroseq database provided addnl. evidence to support the correl
ation between CD133 expression and the progression of DKD. Anal. of single-cell RNA-sequencing data revealed that C D133+ PTCs
potentially play a role in the advanc ement of DKD through multiple mechanisms, including heat damage, cell microtubule stabili
zation, cell growth inhibition and tumor necrosis factor -mediated signaling pathway. Conclu sion: Our study demonstrates that
the upregulation of CD133 is linked to cellular proliferation and protects PTC from apoptosis in D KD and high glucose induced PTC
injury. We propose that heightened CD133 expression may facilitate cellular self-protective responses during the initial stages of
high glucose exposure. However, its sustained increase is associated with the pathol. progression of DKD. In conclusion, CD133
exhibits dual roles in the advancement of DKD, necessitating further investigation.
Keywords: Apoptosis; CD133; Data mining; Diabetic kidney disease; Proximal tubular cells

189
Doxorubicin and folic acid-loaded zinc oxide nanoparticles-based combined anti-tumor and anti-
inflammatory approach for enhanced anti-cancer therapy
By: Gomaa, Soha; Nassef, Mohamed; Tabl, Ghada; Zaki, Somia; Abdel-Ghany, Asmaa
Zinc oxide nanoparticles (ZnONPs) have impressively shown their efficacy in targeting and therapy of cancer. The present research
was designated to investigate the potential of Zn ONP nanocomposites as a cancer chemother apeutic-based drug delivery system
and to assess the anti-tumor and anti-inflammatory effectiveness of Zn ONP nanocomposites combination with systemic chemothe
rapeutic drugs doxorubicin (DOX) and folic acid (F A) in Ehrlich ascites carcinoma (EAC) tumor cell line both in vitro and in vivo. Anti-
tumor potential of Zn ONP nanocomposites: ZnONPs, ZnONPs/FA, ZnONPs/DOX and ZnONPs/DOX/FA against EAC tumor cell line
was evaluated in vitro by MTT assay. Anti-tumor and anti-inflammatory efficacy of Zn ONP nanocomposites were analyzed in vivo by
examination of the proliferation rate and apoptosis rate of E AC tumor cells by flow cytometry, spleno cytes count, level of inflam
matory markers interleukin 6 (IL-6) and tumor necrosis factor alpha ( TN F-α) , as well as liver and kidney function in E AC-
challenged mice. In vitro results showed that Zn ONP nanocomposites showed a high anti-proliferative potency against E AC tumor
cells. Furthermore, the in vivo study revealed that the treatment E AC-challenged mice with Zn ONPs, ZnONPs/DOX, ZnONPs/FA and
ZnONPs/DOX/FA hindered the proliferation rate of implanted EAC tumor cells through lowering their number and increasing their
apoptosis rate. Moreover, the treatment of EAC-challenged mice with Zn ONPs/DOX/FA markedly decreased the level of I L-6 and TN
F-α and remarkably ameliorated the liver and kidney damages that were elevated by implan tation of EAC tumor cells, restoring the
liver and kidney functions to be close to the naive mice control. ZnONP nanocomposites may be useful as a cancer chemother
apeutic-based drug delivery system. Zn ONP nanocomposites: ZnONPs/DOX, ZnONPs/FA and Zn ONPs/DOX/FA regimen may have
anti-inflammatory approaches and a great potential to increase anti- tumor effect of conven tional chemotherapy, overcoming
resistance to cancer systemic chemotherapeutics and reducing their side effects, offering a promising regimen for cancer therapy.
Keywords: cancer therapy doxorubicin folic acid zinc oxide nanopar ticle; Anti-inflammatory; Anti-proliferative; Anti-tumor;
Apoptosis; EAC; ZnONPs

190
Integrated transcriptome and DNA methylome analysis reveal the biological base of increased
resistance to gray leaf spot and growth inhibition in interspecific grafted tomato scions
By: Liu, Ce; Jia, Yanhong; He, Lixia; Li, Hui; Song, Jian; Ji, Lizhu; Wang, Chunguo
BMC Plant Biology (2024), 24(1), 130 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Grafting is widely used as an important agronomic approach to deal with environ mental stresses. However,
the mol. mechanism of grafted tomato scions in response to biotic stress and growth regulation has yet to be fully understood.
Results: This study investigated the resistance and growth performance of tomato scions grafted onto various rootst ocks. A scion
from a gray leaf spot-susceptible tomato cultivar was grafted onto tomato, eggplant, and pepper rootst ocks, creating three grafting
combinations: one self-grafting of tomato/tomato (TT), and two interspecific graftings, namely tomato/e ggplant (TE) and tomato/
pepper (TP). The study utilized transcr iptome and DNA methylome analyses to explore the regulatory mechanisms behind the
resistance and growth traits in the interspecific graftings. Results indicated that intersp ecific grafting significantly enhanced
resistance to gray leaf spot and improved fruit quality, though fruit yield was decreased compared to self-grafting. Transcriptome
anal. demonstrated that, compared to self- grafting, interspecific graftings triggered stronger wounding response and endogenous
immune pathways, while restricting genes related to cell cycle pathways, especially in the T P grafting. Methylome data revealed that
the TP grafting had more hypermet hylated regions at CHG (H = A, C, or T) and C HH sites than the T T grafting. Furthermore, the TP
grafting exhibited increased methylation levels in cell cycle related genes, such as D NA primase and ligase, while several genes
related to defense kinases showed decreased methylation levels. Notably, several kinase transcripts were also confirmed among
the rootstock-specific mobile transcripts. Conclusions: The study concludes that intersp ecific grafting alters gene methyl ation
patterns, thereby activating defense responses and inhibiting the cell cycle in tomato scions. This mechanism is crucial in enhancing
resistance to gray leaf spot and reducing growth in grafted tomato scions. These findings offer new insights into the genetic and
epigenetic contributions to agronomic trait improv ements through interspecific grafting.
Keywords: Grafting; Gray leaf spot; Growth-defense tradeoff; Tomato

191
PLK4 as a potential target to enhance radiosensitivity in triple-negative breast cancer
By: Pellizzari, Sierra; Bhat, Vasudeva; Athwal, Harjot; Cescon, David W.; Allan, Alison L.; Parsyan, Armen
Radiation Oncology (2024), 19(1), 24 | Language: English, Database: CAplus and MEDLINE
Abstract: Radioresistance is one of the barriers to developing more effective therapies against the most aggres sive, triple-neg.,
breast cancer (TNBC) subtype. In our previous studies, we showed that inhibition of Polo-like Kinase 4 (PLK4) by a novel drug, C FI-
400945 significantly enhances the anticancer effects of radiot herapy (RT) compared to single treatment alone. Here we further
investigate the role of PLK4 in enhancing radiation effects in T NBC and explore mechanisms of PLK4 inhibition and radiation
combinatorial antiproliferative effects. To assess cellular proliferation in response to treatments, we used colony formation assays
in TNBC cell lines and patient- derived organoids (PDOs). Downregulation of PLK4 expression was achieved using si RNA silencing in
TNBC cell lines. Immunoflu orescence against centrin was used to assess the alteration of centriole amplifi cation in response to
treatments. We observed that inhibition of PLK4 by C FI-400945 or Centrinone B or its downreg ulation by siRNA, when combined
with RT, resulted in a signif icant increase in antiproliferative effect in TNBC cells lines and PDOs compared to untreated or single-
treated cells. Anticancer synergy was observed using a response matrix in P DOs treated with C FI-400945 and RT. We show that the
overamplification of centrioles might be involved in the combined antiproli ferative action of RT and PLK4 inhibition . Our data
suggest that PLK4 is a promising target for enhancing the anticancer effects of R T in TNBC that, at least in part, is modulated by the
overamplification of centrioles. These results support further mechan istic and translational studies of anti-PLK4 agents and R T as an
anticancer combination treatment strategy.
Keywords: Breast Cancer; CFI-400945; Centrinone B; Centro some; Combination therapy; Organoids; PLK4; Radiotherapy; Triple-
192
Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-
3-cyano-4H-pyran derivatives as tyrosinase inhibitors
By: Najafi, Zahra; Zandi Haramabadi, Maryam; Chehardoli, Gholamabbas; Ebadi, Ahmad; Iraji, Aida
Abstract: A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction
involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the
compounds were characterized using FT-IR, 1H-, and 13 C-NMR spectroscopic analyses. The designed compounds fall into three
series: (1) 4-benzyloxy-Ph kojopyran 6a-e, (2) 3-benzyloxy- Ph kojopyran derivatives 6f-j, and (3) 4- benzyloxy-3-methoxy-Ph
kojopyran derivative 6 k-o. The assessment of tyrosinase inhibition activity was conducted using L- Dopa as the substrate. Among
synthesized compounds, 2-amino-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-
carbonitrile (6b) demonstrated the highest antityr osinase activity with a competitive inhibition pattern (IC50 = 7.69 ± 1.99 μ M) as
compared to the control agent kojic acid (IC50 = 23.64 ± 2.56 μ M). Since compound 6b was synthe sized as a racemic mixture, in
silico studies were performed for both R and S enantiomers. The R- enantiomer showed critical interactions compared with the S-
enantiomer. Specifically, it established hydrogen bonds and hydrophobic interactions with crucial and highly conserved amino acids
within the enzyme′s binding site in the target protein. Moreover, the mol. dynamics simulations revealed that compound 6b
demonstrated significant interactions with essential residues of the binding site, resulting in a stable complex throughout the entire
simulation run. The drug-like and ADMET properties predictions showed an acceptable profile for compound 6b. Thus, it can serve
as a drug candidate to develop more potent antityrosinase agents due to its low toxicity and its high inhibition activity.
Keywords: 2-Amino-3-cyano-4H-pyran; Benzyloxy benzylidene; Kojic acid; Molecular dynamics simula tion; Tyrosinase inhibitors

193
Enhanced systematic delivery of fluconazole-loaded biotin-glutathione functionalized chitosan-g-

proline carrier into the infected retinitis treatment
By: Guo, Qing; Li, Zheng; Cao, Fang

BMC Ophthalmology (2024), 24(1), 48 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The polymer-based facile and effective drug carrier approach was developed to treat superf icial fungal
infected retinopathy infections. Methods: Here, biotin-glutathione (B-GHS) functionalized with chitosan grafted proline (CS-g-P)
moieties were fabricated with the loading of fluconazole (FLZ) for the treatment of retino pathy. FT-IR and XRD techniques were
used to characterize chem. structural and phase changes of the prepared carriers The S EM results show that the sphere morphol.
with interconnection particle nature. Results: The particle diameter was found as ∼ 6.5 and ∼ 8.6 nm for C S-g-P/B-GHS and FLZ-
loaded CS-g-P/B-GHS carriers, resp. The neg. surface charge was found as the values of C S-g-P/B-GHS and FLZ-loaded CS-g-P/B-GHS,
such as -20.7 mV and - 32.2 m V, from zeta potential anal. The in- vitro FLZ releases from the C S-g-P/B-GHS were investigated at pH
7.4 (PBS) as the tear fluid environment, and it was observed at 85.02% of F LZ release in 8 h reaction time. The sustained release was
observed, leading to the necessity for prolonged therapeutic effects. The antifungal effect of the carrier was studied by the min.
inhibitory concentration (MIC) and the percentage inhibition of viable fungal count against Candida albicans, and it observed
81.02% of the zone of inhibition by the FLZ carrier. Conclu sion: FLZ-loaded CS-g-P/B-GHS carrier could inhibit the biofilm formation
in a concentration-dependent inhibition . Hence, A novel F LZ/B-GHS-CS-g-P carrier is a hopeful approach for effect ively treating
superficial fungal contaminations of the retina region.
Keywords: Biotin; Chitosan; Fluconazole; Fungal infections; Proline; Retinopathy

194
PPARG activation promotes the proliferation of colorectal cancer cell lines and enhances the
antiproliferative effect of 5-fluorouracil
By: Schoeckel, Leah; Woischke, Christine; Surendran, Sai Agash; Michl, Marlies; Schiergens, Tobias; Hoelscher, Andreas; Glass,
Florian; Kreissl, Peter; Klauschen, Frederick; Guenther, Michael; et al
Abstract: Background: Peroxisome proliferator-activated receptor gamma (P PARG) is a member of the nuclear receptor family. It is
involved in the regulation of adipogenesis, lipid metabo lism, insulin sensitivity, vascular homeostasis and inflammation. In addition,
PPARG agonists, known as thiazolidinediones, are well established in the treatment of type 2 diabetes mellitus. P PARGs role in
cancer is a matter of debate, as pro- and anti-tumor properties have been described in various tumor entities. Currently, the
specific role of PPARG in patients with colorectal cancer (C RC) is not fully understood. Material and methods: The prognostic impact
of PPARG expression was investigated by immunohistochem. in a case-control study using a matched pair selection of C RC tumors
(n = 246) with either distant metastases to the liver (n = 82), lung (n = 82) or without distant metastases (n = 82) . Its effect on prolife
ration as well as the sensitivity to the chemotherapeutic drug 5- fluorouracil (5-FU) was examined after activa tion, inhibition , and
transient gene knockdown of PPARG in the CRC cell lines S W403 and HT29. Results: High PPARG expression was significantly
associated with pulmonary metastasis (p = 0.019). Patients without distant metastases had a signifi cantly longer overall survival
with low PPARG expression in their tumors compared to patients with high P PARG expression (p = 0.045) . In the pulmonary
metastasis cohort instead, a trend towards longer survival was observed for patients with high PPARG expression in their tumor (p =
0.059). Activation of PPARG by pioglitazone and rosiglitazone resulted in a signif icant dose-dependent increase in proliferation of CR
C cell lines. Inhibition of PPARG by its specific inhibitor GW9662 and siRNA-mediated knockdown of PPARG significantly decreased
proliferation. Activating PPARG significantly increased the CRC cell lines sensitivity to 5-FU while its inhibition decreased it. Conclu
sion: The prognostic effect of PPARG expression depends on the metastasis locali zation in advanced C RC patients. Activation of PPA
RG increased malignancy associated traits such as proliferation in CRC cell lines but also increases sensit ivity towards the chemothe
rapeutic agent 5- FU. Based on this finding, a combin ation therapy of PPARG agonists and 5-FU-based chemotherapy constitutes a
promising strategy which should be further investigated.
Keywords: 5-fluorouracil; Colorectal cancer; metastasis; Diabetes mellitus; PPARG

195
Polymeric coating doped with nanomaterials for functional impact on different substrates
By: Shahzadi, Phool; Majeed, Muhammad Amjad; Ibrahim, Saba; Asif, Sabahat; Kalsoom, Razia; Hussain, Irshad
Microorganism contamination on substrate surfaces is arousing increa singly concern as a serious health issue. In this research
work, antimicrobial water-based acrylic paint containing silver nanoparticles (Ag N Ps) was prepared using the facile Ag+ in situ
reduction process, in which AgNO3 and reducing agent sodium acrylate were refluxed with acrylic polymeric solution to obtain an
antimicrobial and antifungal polymeric material for substrate coating. The Synthe sized antimicrobial and antifungal water- based
acrylic paint were characterized by different spectroscopic techniques. The FTIR and UV-Visible spectroscopic analyses were invest
igated to study the water-based acrylic paint structure as well as the signif icant impact of Ag N Ps on the paint matrix. The UV-Visible
and FTIR Spectra peak shows successful integr ation of Ag N Ps within the polymer matrix without altering the core functional groups
of the paint. The water based acrylic paint exhibited a strong antimicrobial activity, revealed substa ntial inhibition zones against all
four strains of Gram neg. represented by Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae and Gram- pos. repres
ented by Bacillus cereus. The coated film on substrate also shows great inhibition zone which exhibit a strong antimic robial
activity. Moreover, water based acrylic paint also exhibited a great antifungal activity, revealed substantial zone of inhibition against
the Aspergillus niger, Aspergillus terreus and Rhizopus arrhizus fungal strains. Also, the coated film showed the best adhesion at
50% and 80% solution of polymeric coating sample as compared to pure or very dilute sample coating. This innovative approach
has the potential to revolutionize varies industries from healthcare to constru ction.
Keywords: PSK silver nanoparticle water acrylic paint coating antimic robial activity

196
Punicalagin, a pomegranate polyphenol sensitizes the activity of antibiotics against three MDR
pathogens of the Enterobacteriaceae
By: Kiran, Saba; Tariq, Anam; Iqbal, Shoaib; Naseem, Zubera; Siddique, Waqar; Jabeen, Sobia; Bashir, Rizwan; Hussain, Ashfaq;
Rahman, Moazur; Habib, Fazal-e; et al
Abstract: Background: Multidrug resistance (M DR) in the family Enterobacteriaceae is a perniciously increasing threat to global
health security. The discovery of new antimicrobials having the reversing drug resistance potential may contribute to augment and
revive the antibiotic arsenal in hand. This study aimed to explore the anti-Enterobacteriaceae capability of bioactive polyph enols
from Punica granatum (P. granatum) and their co-action with antibiotics against clin. isolates of Enterobacteriaceae predominantly
prevalent in South Asian countries. Methods: The Kandhari P. granatum (Pakistani origin) extracts were tested for anti-Enterobac
teriaceae activity by agar well diffusion assay against M DR Salmonella enterica serovar Typhi, serovar Typhim urium and Escherichia
coli. Predominant compounds of active extract were determined by mass spectr ometry and screened for bioact ivity by agar well
diffusion and min. inhibitory concentration (MIC) assay. The active punica lagin was further evaluated at sub- inhibitory concent
rations (SICs) for coactivity with nine conven tional antimicrobials using a disk diffusion assay followed by time- kill experiments that
proceeded with SICs of punica lagin and antimicrobials. Results: Among all P. granatum crude extracts, pomegr anate peel methanol
extract showed the largest inhibition zones of 25, 22 and 19 mm, and the M ICs as 3.9, 7.8 and 7.8 mg/m L for S. typhi, S. typhim
urium and E. coli, resp. Punica lagin and ellagic acid were determined as predom inant compounds by mass spectro metry. In plate
assay, punicalagin (10 mg/mL) was active with hazy inhibition zones of 17, 14, and 13 mm against S. typhi, S. typhim urium and E.
coli, resp. However, in broth dilution assay punicalagin showed no M IC up to 10 mg/mL. The SICs 30 μg, 100 μg, and 500 μg of
punicalagin combined with antimicrobials i.e., aminoglycoside, β-lactam, and fluoroquinolone act in synergy against M DR strains
with % increase in inhibition zone values varying from 3.4 ± 2.7% to 73.8 ± 8.4%. In time- kill curves, a signif icant decrease in cell d.
was observed with the SICs of antimicrobials/punicalagin (0.03-60 μg/mL/30, 100, 500 μg/mL of punicalagin) combinations. Conclu
sions: The P. granatum peel methanol extract exhibited antimic robial activity against M DR Enterobacteriaceae pathogens. Punica
lagin, the bacteriostatic flavonoid act as a concent ration-dependent sensitizing agent for antimic robials against Enterobacteriaceae.
Our findings for the therapeutic punicalagin-antimicrobial combination prompt further evaluation of punicalagin as a potent
activator for drugs, which otherwise remain less or inactive against MDR strains.
Keywords: MDR Enterobacteriaceae, Kandhari P. granatum; Punica lagin-antimicrobial synergism

197
GPR68-ATF4 signaling is a novel prosurvival pathway in glioblastoma activated by acidic extracellular

microenvironment
By: Williams, Charles H.; Neitzel, Leif R.; Cornell, Jessica; Rea, Samantha; Mills, Ian; Silver, Maya S.; Ahmad, Jovanni D.; Birukov,
Konstantin G.; Birukova, Anna; Brem, Henry; et al
Experimental Hematology & Oncology (2024), 13(1), 13 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Glioblastoma multiforme (GBM) stands as a formidable challenge in oncol. because of its aggressive nature
and severely limited treatment options. Despite decades of research, the survival rates for GBM remain effectively stagnant. A
defining hallmark of GBM is a highly acidic tumor microenvi ronment, which is thought to activate pro- tumorigenic pathways. This
acidification is the result of altered tumor metabolism favoring aerobic glycol ysis, a phenomenon known as the Warburg effect. Low
extracellular pH confers radioresistant tumors to glial cells. Notably G PR68, an acid sensing G PCR, is upregulated in radiore sistant G
BM. Usage of Lorazepam, which has off target agonism of G PR68, is linked to worse clin. outcomes for a variety of cancers.
However, the role of tumor microenvironment acidification in GPR68 activation has not been assessed in cancer. Here we interr
ogate the role of G PR68 specifically in GBM cells using a novel highly specific small mol. inhibitor of G PR68 named Ogremo rphin (O
GM) to induce the iron mediated cell death pathway: ferrop tosis. Method: OGM was identified in a non- biased zebrafish embryonic
development screen and validated with Morpholino and C RISPR based approaches. Next, A GPI-anchored pH reporter, pHluorin2,
was stably expressed in U87 glioblastoma cells to probe extracellular acidification. Cell survival assays, via nuclei counting and cell
titer glo, were used to demonstrate sensitivity to GPR68 inhibition in twelve immortalized and PDX GBM lines. To determine G PR68
inhibition′s mechanism of cell death we use D AVID pathway anal. of R NAseq. Our major indication, ferroptosis, was then confirmed
by western blotting and qRT-PCR of reporter genes including T FRC. This finding was further validated by transm ission electron
microscopy and liperfluo staining to assess lipid peroxidation Lastly, we use si RNA and CRISPRi to demonstrate the critical role of A T
F4 suppression via GPR68 for GBM survival. Results: We used a p HLourin2 probe to demonstrate how glioblastoma cells acidify
their microenvironment to activate the commonly over expressed acid sensing G PCR, GPR68. Using our small mol. inhibitor O GM
and genetic means, we show that blocking GPR68 signaling results in robust cell death in all thirteen gliobl astoma cell lines tested,
irresp. of genetic and phenotypic heterogeneity, or resistance to the mainstay GBM chemotherapeutic temozolomide. We use U87
and U138 glioblastoma cell lines to show how selective induction of ferrop tosis occurs in an ATF4-dependent manner. Importantly,
OGM was not-acutely toxic to zebrafish and its inhibitory effects were found to spare non- malignant neural cells. Conclusion: These
results indicate GPR68 emerges as a critical sensor for an autocrine pro- tumorigenic signaling cascade triggered by extrace llular
acidification in glioblastoma cells. In this context, G PR68 suppresses A TF4, inhibition of GPR68 increases expression of ATF4 which
leads to ferroptotic cell death. These findings provide a promising therap eutic approach to selectively induce ferroptosis in gliobl
astoma cells while sparing healthy neural tissue.

198
Exploring the impact of nano-Se and nano-clay feed supplements on interleukin genes, immunity and
growth rate in European Sea Bass (Dicentrarchus labrax)
By: Khaled, Asmaa A.; Shabaan, Amany M.; Hammad, Saad M.; Hafez, Elsayed E.; Saleh, Ahmed A.
This study aimed to investigate the effects of adding Nano- Selenium (NSe) and Nano-clay (NC) as feed supplements on European
Sea Bass (Dicentrarchus labrax). Two sep. experi ments were conducted, one with N C and the other with N Se. Each experiment
consisted of four sub-groups with varying concent rations of N C or NSe. The expression levels of five immune-related genes ( TN F-α ,
TN F -β, IL-2, IL-6 and IL-12) were measured using Real-time Quant. PCR (Rt-PCR) Assay. The results showed an increase in the
expression of interleukins (IL-2, IL-6 and IL-12) and pro-inflammatory cytokines ( TN F-α and TN F -β) after exposure to N C and N Se.
TN F-α gene expression was significantly higher with both 1 mg and 10 mg concent rations of N C and N Se. TN F -β gene expression
was highest with the 5 mg concentration of NC. The concentrations of 1 mg and 10 mg for N C, and 1 mg, 5 mg, and 10 mg for N Se,
led to the highest (p < 0.05) levels of IL-2 expression compared to the control. Similar trends were observed for I L-6 and IL-12 gene
expression. Understanding the impact of these concent rations on gene expres sion, growth rate, biochem. indexes, and antiox idant
status can provide valuable insights into the potential applications of NC and N Se supplements on European Sea Bass.
Keywords: Dicentrarchus labrax nanoselenium nanoclay feed supplement immune related gene
199
Entomotherapy as an alternative treatment for diseases due to Gram-negative bacteria in Burkina

Faso
By: Ouango, Mamadou; Cisse, Hama; Romba, Rahim; Drabo, Samuel Fogne; Semde, Rasmane; Savadogo, Aly; Gnankine, Olivier
Abstract: Insects are known for their harmful effects. However, they also benefit humans, animals, plants, and ecosystems. Its
beneficial uses include entomophagy and entomotherapy. This study aimed to evaluate the antibac terial activity of insect extracts
against Gram-neg. bacteria. Antibac terial activities of thirteen crude extracts of medicinal insects were tested against twelve Gram-
neg. bacteria by diffusion on agar. Imipenem was used as an antibiotic for pos. control. The thirteen extracts acted differ ently
against certain Gram-neg. bacteria. The largest inhibition diameter was for extracts of Cirina butyro spermi and Mylabris variabilis
against Pseudomonas aeruginosa A TCC27853 and Salmonella enteritidis ATCC13076, resp. The diameters of inhibition obtained
using imipenem against these same bacterial strains were 13.0 ± 0.0 mm and 22 ± 1.0 mm, resp. The lowest inhibition diameter
(7.5 ± 0.0 mm) was obtained using Anopheles gambiae extract against Salmonella Typhimurium ATCC14028. Imipenem was active
on all strains tested. The highest values of the index multi-resistance to insect′s extracts were reported for Pseudo monas
aeruginosa ATCC9027 and Serratia odorifera 652411. Overall, the results of this study confirmed the antibac terial activities of
insects used by traditional health practitioners to treat different pathologies. Entomotherapy could be an alternative treatment for
certain infectious pathologies caused by gram- neg. bacteria.

200
Direct effects of adipocyte lipolysis on AMPK through intracellular long-chain acyl-CoA signaling
By: Rahman, Abir A.; Butcko, Andrew J.; Songyekutu, Emmanuel; Granneman, James G.; Mottillo, Emilio P.
Long-chain acyl-CoAs (LC-acyl-CoAs) are important interm ediary metabolites and are also thought to function as intrace llular
signaling mols.; however, the direct effects of LC-acyl-CoAs have been difficult to determine in real- time and dissociate from Protein
Kinase A (PKA) signaling. Here, we examined the direct role of lipolysis in generating intrace llular LC-acyl-CoAs and activating A MPK
in white adipocytes by pharmacol. activation of ABHD5 (also known as C GI-58), a lipase coactivator. Activation of lipolysis in 3 T3-L1
adipocytes independent of PKA with synthetic A BHD5 ligands, resulted in greater activation of A MPK compared to receptor-
mediated activation with isoproterenol, a β-adrenergic receptor agonist. Import antly, the effect of pharmacol. activation of A BHD5
on AMPK activation was blocked by inhibiting A TGL, the rate-limiting enzyme for triacylglycerol hydrolysis. Utilizing a novel F RET
sensor to detect intracellular LC-acyl-CoAs, we demonstrate that stimulation of lipolysis in 3 T3-L1 adipocytes increased the
production of LC-acyl-CoAs, an effect which was blocked by inhibition of ATGL. Moreover, ATGL inhibition blocked AMPKβ1 S108
phosphorylation, a site required for allosteric regula tion. Increasing intracellular LC-acyl-CoAs by removal of B SA in the media and
pharmacol. inhibition of DGAT1 and 2 resulted in greater activation of A MPK. Finally, inhibiting LC-acyl-CoA generation reduced
activation of AMPK; however, did not lower energy charge. Overall, results demons trate that lipolysis in white adipocytes directly
results in allosteric activation of AMPK through the generation of LC-acyl-CoAs.
Keywords: AMPK long chain acyl CoA signaling adipocyte lipolysis

201
Marine-derived κ-carrageenan-coated zinc oxide nanoparticles for targeted drug delivery and
apoptosis induction in oral cancer
By: Marunganathan, Vanitha; Kumar, Meenakshi Sundaram Kishore; Kari, Zulhisyam Abdul; Giri, Jayant; Shaik, Mohammed Rafi;
Shaik, Baji; Guru, Ajay
Abstract: Background: Kappaphycus alvarezii, a marine red algae species, has gained signif icant attention in recent years due to its
versatile bioactive compounds Among these, κ-carrageenan (CR), a sulfated polysaccharide, exhibits remarkable antimicrobial
properties. This study emphasizes the synergism attained by function alizing zinc oxide nanoparticles (ZnO NPs) with CR, thereby
enhancing its antimicrobial efficacy and target specif icity against dental pathogens. Methods: In this study, we synthe sized ZnO-CR
NPs and characterized them using SEM, FTIR, and XRD techniques to authenticate their compos ition and structural attributes.
Moreover, our investigation revealed that ZnO-CR NPs possess better free radical scavenging capabil ities, as evidenced by their
effective activity in the DPPH and ABTS assay. Results: The antimic robial properties of Zn O-CR NPs were systematically assessed
using a zone of inhibition assay against dental pathogens of S. aureus, S. mutans, E. faecalis, and C. albicans, demonst rating their
substantial inhibitory effects at a minimal concent ration of 50 μg/mL. We elucidated the interaction between CR and the receptors
of dental pathogens to further understand their mechanism of action. The ZnO-CR NPs demonstrated a dose-dependent anticancer
effect at concentrations of 5 μg/mL, 25 μg/mL, 50 μg/mL, and 100 μg/mL on KB cells, a type of Human Oral Epidermal Carcinoma.
The mechanism by which ZnO-CA NPs induced apoptosis in K B cells was determined by observing an increase in the expression of
the BCL-2, BAX, and P53 genes. Conclu sion: Our findings unveil the promising potential of Zn O-CR NPs as a candidate with signif
icant utility in dental applications. The demonstrated biocompatibility, potent antioxidant and antiapoptotic activity, along with
impressive antimicrobial efficacy position these N Ps as a valuable resource in the ongoing fight against dental pathogens and oral
cancer.
Keywords: Antimicrobial; Dental pathogen; Zinc oxide nanopar ticle; κ-carrageenan

202
The role of empagliflozin-induced metabolic changes for cardiac function in patients with type 2
diabetes. A randomized cross-over magnetic resonance imaging study with insulin as comparator
By: Thirumathyam, Roopameera; Richter, Erik Arne; van Hall, Gerrit; Holst, Jens Juul; Fenger, Mogens; Goetze, Jens P.; Dixen, Ulrik;
Vejlstrup, Niels; Madsbad, Sten; Madsen, Per Lav; et al
Cardiovascular Diabetology (2024), 23(1), 13 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Metabolic effects of empagliflozin treatment include lowered glucose and insulin concentr ations, elevated
free fatty acids and ketone bodies and have been suggested to contribute to the cardiovascular benefits of empagli flozin treatment,
possibly through an improved cardiac function. We aimed to evaluate the influence of these metabolic changes on cardiac function
in patients with T2D. Methods: In a randomized cross- over design, the SGLT2 inhibitor empagliflozin (E) was compared with insulin
(I) treatment titrated to the same level of glycemic control in 17 patients with type 2 diabetes, BMI of > 28 kg/m 2, C-peptide > 500 p
M. Treatments lasted 5 wk and were preceded by 3- wk washouts (WO). At the end of treatments and washouts, cardiac diastolic
function was determined with magnetic resonance imaging from left ventricle early peak-filling rate and left atrial passive emptying
fraction (primary and key secondary endpoints); systolic function from left ventricle ejection fraction (secondary endpoint) . Coupling
between cardiac function and fatty acid concentrations, was studied on a sep. day with a second scan after reduction of plasma
fatty acids with acipimox. Data are Mean ± standard error. Between treatment difference (ΔT: E-I) and treatments effects (ΔE: E-WO
or ΔI: I - WO) were evaluated using Students′ t-test or Wilcoxon signed rank test as appropriate. Results: Glucose concent rations
were similar, fatty acids, ketone bodies and lipid oxidation increased while insulin concentrations decreased on empagli flozin
compared with insulin treatment. Cardiac diastolic and systolic function were unchanged by either treatment. Acipimox decreased
fatty acids with 35% at all visits, and this led to reduced cardiac diastolic (ΔT: -51 ± 22 mL/s (p < 0.05) ; ΔE: - 33 ± 26 mL/s (ns); ΔI: 37 ±
26 (ns, p < 0.05 vs ΔE)) and systolic function (Δ T: -3 ± 1% (p < 0.05) ; ΔE: - 3 ± 1% (p < 0.05) : ΔI: 1 ± 2 (ns, ns vs Δ E)) under chronotropic
stress during empagliflozin compared to insulin treatment. Conclu sions: Despite signif icant metabolic differences, cardiac function
did not differ on empagliflozin compared with insulin treatment. Impaired cardiac function during acipimox treatment, could
suggest greater cardiac reliance on lipid metabolism for proper function during empagliflozin treatment in patients with type 2
diabetes. Trial registration: EudraCT 2017-002101-35, August 2017.
Keywords: Cardiac function; Hyperinsulinemia; Metabolism; Sodium-glucose linked transporter 2 inhibition ; Type 2 diabetes

203
Lignin impairs Cel7A degradation of in vitro lignified cellulose by impeding enzyme movement and not
by acting as a sink
By: Haviland, Zachary K.; Nong, Daguan; Zexer, Nerya; Tien, Ming; Anderson, Charles T.; Hancock, William O.
Biotechnology for Biofuels and Bioproducts (2024), 17(1), 7 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Cellulose degradation by cellulases has been studied for decades due to the potential of using lignocel lulosic
biomass as a sustainable source of bioethanol. In plant cell walls, cellulose is bonded together and streng thened by the polyph
enolic polymer, lignin. Because lignin is tightly linked to cellulose and is not digestible by cellul ases, is thought to play a dominant
role in limiting the efficient enzymic degradation of plant biomass. Removal of lignin via pretreatments currently limits the cost-
efficient production of ethanol from cellulose, motivating the need for a better underst anding of how lignin inhibits cellulase-
catalyzed degradation of lignocellulose. Work to date using bulk assays has suggested three possible inhibition mechanisms: lignin
blocks access of the enzyme to cellulose, lignin impedes progress of the enzyme along cellulose, or lignin binds cellulases directly
and acts as a sink. Results: We used single-mol. fluorescence microscopy to investigate the nanoscale dynamics of Cel7 A from Tricho
derma reesei, as it binds to and moves along purified bacterial cellulose in vitro. Lignified cellulose was generated by polyme rizing
coniferyl alc. onto purified bacterial cellulose, and the degree of lignin incorporation into the cellulose meshwork was analyzed by
optical and electron microscopy. We found that Cel7A preferentially bound to regions of cellulose where lignin was absent, and that
in regions of high lignin d., Cel7A binding was inhibited. With increasing degrees of lignifi cation, there was a decrease in the fraction
of Cel7A that moved along cellulose rather than statically binding. Furthe rmore, with increasing lignifi cation, the velocity of
processive Cel7A movement decreased, as did the distance that individual Cel7 A mols. moved during processive runs. Conclu sions:
In an in vitro system that mimics lignified cellulose in plant cell walls, lignin did not act as a sink to sequester Cel7A and prevent it
from interacting with cellulose. Instead, lignin both blocked access of Cel7 A to cellulose and impeded the processive movement of
Cel7A along cellulose. This work implies that strategies for improving biofuel production efficiency should target weakening intera
ctions between lignin and cellulose surface, and further suggest that nonspe cific adsorption of Cel7A to lignin is likely not a
dominant mechanism of inhibition .
204
Protective effect of tomato pomace extract encapsulated in combination with probiotics against
indomethacin induced enterocolitis
By: Fouda, Karem; Mabrouk, Ahmed M.; Abdelgayed, Sherein S.; Mohamed, Rasha S.
Tomato pomace (TP), an antioxidant-rich byproduct, may be suitable for noble applica tions. The regulation of R OS generation and
the anti-inflammatory response can help to prevent ulcera tion. The purpose of this study was to examine T P for antioxidants, in
silico anti-inflammatory properties, and its potential to protect against ulceration and erosion triggered by indomet hacin. Tomato
pomace extract (TPE) was encapsulated either alone or with probiotics to maximize its potential effect. These microca psules were
investigated in indomethacin-treated rats. T PE demonstrated antioxidant activity as well as high levels of carotenoids (15 mg/g
extract) and polyphenols. Because of their binding affinity as well as hydrop hobic and hydrogen bond interactions with the active
sites of TN F-α and IL-1β inflammatory cytokines, ellagic acid and rutin may be implicated in the anti- inflammatory effect of T PE,
according to the docking study. TPE microcapsules, either alone or in combination with probiotics, demonstrated a protective effect
against enterocolitis by reducing oxidative stress and inflamm ation, as evidenced by the decrease in stomach and intestinal M DA, N
O, IL-1β, IL-6, and TN F-α levels and the increase in C AT, SOD, and GSH activities. The produced microca psules are suggested to be
promising candidates for protection against gastric ulcers and erosion.
Keywords: Solanum extract human enterocolitis indomethacin probiotic encapsulation microcapsule

205
Production and characterization of melanin pigment from black fungus Curvularia soli AS21
ON076460 assisted gamma rays for promising medical uses
By: Abd-EL-Aziz, Amira S.; Abed, Nermine N.; Mahfouz, Amira Y. ; Fathy, Rasha Mohammad
Abstract: Owing to the growing need for natural materials in different fields, studying melanin production from biol. sources is
imperative. In the current study, the extracellular melanin pigment was produced by the fungus Curvularia soli A S21 ON076460.
The factors that affect the production of melanin were optimized by the Plackett-Burman design (P-BD). The effect of gamma irradi
ation on melanin produc tivity was investigated. The maximum melanin yield (3.376 mg/L) was elicited by a stimulus of gamma irradi
ation at 1.0 kGy. The results evoked that, Curvularia soli A S21 ON076460 melanin exhibited excellent antimic robial activity against
all tested bacteria and fungi. Klebsiella pneumoniae ATCC 13883 and P. digitatum were mostly affected by melanin regist ering the
inhibition zone diameters of 37.51 ± 0.012 and 44.25 ± 0.214 mm, resp. Moreover, Curvularia soli A S21 ON076460 melanin
indicated a significant antiviral efficacy (77% inhibition ) of Herpes simplex virus (HSV1). The melanin pigment showed antiox idant
activities with IC50 of 42 ± 0.021 and 17 ± 0.02 μg/m L against DPPH and NO, resp. Melanin had cytotoxic action against human
breast cancer and skin cancer cell lines (Mcf7and A431) as well as exerting a low percentage of cell death against normal skin cell
lines (Hfb4). Melanin was effective in wound management of human skin cells by 63.04 ± 1.83% compared with control (68.67 ±
1.10%). The novelty in the study is attributed to the possib ility of using gamma rays as a safe method in small economic doses to
stimulate melanin production from the fungi that have been isolated. In summary, melanin produced from fungi has significant
biol. activities that encourage its usage as a supportive medical route.
Keywords: Anticancer; Antimicrobial; Antioxidant; Curvularia soli; Gamma radiation; Melanin pigment
206
Regulation of mitochondrial metabolism by autophagy supports leptin-induced cell migration
By: Garcia-Miranda, Alin; Montes-Alvarado, Jose Benito; Sarmiento-Salinas, Fabiola Lili; Vallejo-Ruiz, Veronica; Castaneda-Saucedo,
Eduardo; Navarro-Tito, Napoleon; Maycotte, Paola
Abstract: Leptin is an adipokine secreted by adipose tissue, which promotes tumor progression by activating canonical signaling
pathways such as MAPK/ERK. Recent studies have shown that leptin induces autophagy, and this process is involved in leptin-
induced characteristics of malignancy. Autophagy is an intracellular degradation process associated with different hallmarks of
cancer, such as cell survival, migration, and metabolic reprogramming. However, its relationship with metabolic reprogramming has
not been clearly described. The purpose of this study was to determine the role of leptin-induced autophagy in cancer cell
metabolism and its association with cellular proliferation and migration in breast cancer cells. We used E R+/PR+ and triple-neg.
breast cancer cell lines treated with leptin, autophagy inhibition , or mitochondrial metabolism inhibitors. Our results show that
leptin induces autophagy, increases proliferation, mitochondrial ATP production and mitochondrial function in E R+/PR+ cells. Import
antly, autophagy was required to maintain metabolic changes and cell prolife ration driven by leptin. In triple- neg. cells, leptin did
not induce autophagy or cell proliferation but increased glycolytic and mitocho ndrial ATP production, mitochondrial function, and
cell migration. In triple neg. cells, autophagy was required to support metabolic changes and cell migration, and autophagy
inhibition decreased cellular migration similar to mitocho ndrial inhibitors. In conclusion, leptin-induced autophagy supports
mitochondrial metabolism in breast cancer cells as well as glycolysis in triple neg. cells. Import antly, leptin-induced mitochondrial
metabolism promoted cancer cell migration.

207
Investigation of the potential effects of estrogen receptor modulators on immune checkpoint

molecules
By: Abramenko, Nikita; Vellieux, Frederic; Vesela, Katerina; Kejik, Zdenek; Hajduch, Jan; Masarik, Michal; Babula, Petr; Hoskovec,
David; Pacak, Karel; Martasek, Pavel; et al
Abstract: Immune checkpoints regulate the immune system response. Recent studies suggest that flavon oids, known as phytoest
rogens, may inhibit the PD-1/PD-L1 axis. We explored the potential of estrogens and 17 Selective Estrogen Receptor Modulators (S E
RMs) as inhibiting ligands for immune checkpoint proteins (C TLA-4, PD-L1, PD-1, and CD80). Our docking studies revealed strong
binding energy values for quinestrol, quercetin, and bazedox ifene, indicating their potential to inhibit PD-1 and CTLA-4. Quercetin
and bazedoxifene, known to modulate E GFR and IL-6R alongside estrogen receptors, can influence the immune checkpoint functio
nality. We discuss the impact of S ERMs on PD-1 and CTLA-4, suggesting that these S ERMs could have therapeutic effects through
immune checkpoint inhibition . This study highlights the potential of S ERMs as inhibitory ligands for immune checkpoint proteins,
emphasizing the importance of considering PD-1 and CTLA-4 inhibition when evaluating S ERMs as therapeutic agents. Our findings
open new avenues for cancer immunotherapy by exploring the intera ction between various S ERMs and immune checkpoint
pathways.
208
Integrative modeling uncovers p21-driven drug resistance and prioritizes therapies for PIK3CA-mutant
breast cancer
By: Yip, Hon Yan Kelvin; Shin, Sung-Young; Chee, Annabel; Ang, Ching-Seng; Rossello, Fernando J.; Wong, Lee Hwa; Nguyen, Lan K.;
Papa, Antonella
Abstract: Utility of PI3Kα inhibitors like BYL719 is limited by the acquis ition of genetic and non-genetic mechanisms of resistance
which cause disease recurrence. Several combination therapies based on PI3K inhibition have been proposed, but a way to
systematically prioritize them for breast cancer treatment is still missing. By integr ating published and inhouse studies, we have
developed in silico models that quant. capture dynamics of PI3K signaling at the network- level under a BYL719-sensitive vs. BYL719
resistant-cell state. Computational predictions show that signal rewiring to alternative components of the PI3K pathway promote
resistance to BYL719 and identify PDK1 as the most effective co- target with PI3Kα rescuing sensitivity of resistant cells to BYL719. To
explore whether PI3K pathway-independent mechanisms further contribute to B YL719 resistance, we performed phosphopr
oteomics and found that selection of high levels of the cell cycle regulator p21 unexpe ctedly promoted drug resistance in T47 D
cells. Functionally, high p21 levels favored repair of B YL719-induced DNA damage and bypass of the associated cellular senesc ence.
Importantly, targeted inhibition of the check-point inhibitor CHK1 with M K-8776 effectively caused death of p21- high T47D cells,
thus establishing a new vulnera bility of BYL719-resistant breast cancer cells. Together, our integrated studies uncover hidden mol.
mediators causing resistance to PI3Kα inhibition and provide a framework to prioritize combin ation therapies for PI3K-mutant
breast cancer.

209
Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity
By: Wang, Sheng ; Klein, Sebastian O.; Urban, Sylvia; Staudt, Maximilian ; Barthes, Nicolas P. F. ; Willmann, Dominica; Bacher,
Johannes; Sum, Manuela; Bauer, Helena; Peng, Ling; et al
Abstract: Inhibition of epigenetic regulators by small mols. is an attractive strategy for cancer treatment. Recently, we charact erised
the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observ ation that the enzymic activity was
required for tumor cell proliferation identified K MT9 as a potential therapeutic target. Here, we report the develo pment of a potent
and selective KMT9 inhibitor (compound 4, KMI169) with cellular activity through structure-based drug design. K MI169 functions as
a bi-substrate inhibitor targeting the S AM and substrate binding pockets of K MT9 and exhibits high potency, select ivity, and cellular
target engagement. KMT9 inhibition selectively downregulates target genes involved in cell cycle regulation and impairs prolife
ration of tumors cells including castra tion- and enzalutamide-resistant prostate cancer cells. K MI169 represents a valuable tool to
probe cellular KMT9 functions and paves the way for the develo pment of clin. candidate inhibitors as therapeutic options to treat
malignancies such as therapy-resistant prostate cancer.
210
miR-181a plays the tumor-suppressor role in chronic myeloid leukemia CD34 + cells partially via
SERPINE1
By: Zhang, Xiuyan; Ma, Wenjuan; Xue, Wen; Wang, Yu; Chen, Pan; Li, Quanxue; Li, Yuan-Yuan; Hu, Xiaohui; Zhao, Yun; Zhou, Haixia
Abstract: The formation of the BCR-ABL fusion gene drives human chronic myeloid leukemia (C ML). The last 2 decades have
witnessed that specific tyrosine kinase inhibitors (TKIs, e.g., imatinib mesylate, IM) against ABL1 improve disease treatment,
although some patients still suffer from relapse and TKI resistance. Therefore, a better underst anding of the mol. pathol. of C ML is
still urgently needed. miR-181a-5p (miR-181a) acts as a tumor suppressor in C ML; however, the mol. mechanism of mi R-181a in CML
stem/progenitor cells remains elusive. Herein, we showed that mi R-181a inhibited the growth of C ML CD34+ cells, including the
quiescent subset, and sensitized them to IM treatment, while mi R-181a inhibition by a sponge sequence collab orated with BCR-ABL
to enhance the growth of normal CD34+ cells. Transcriptome data and biochem. anal. revealed that S ERPINE1 was a bona fide and
critical target of miR-181a, which deepened the understanding of the regulatory mechanism of S ERPINE1. Genetic and pharmacol.
inhibition of SERPINE1 led to apoptosis mainly mediated by caspase- 9 activation. The dual inhibition of SERPINE1 and BCR-ABL
exhibited a significantly stronger inhibitory effect than a single agent. Taken together, this study demons trates that a novel mi R-
181a/SERPINE1 axis modulates CML stem/progenitor cells, which likely provides an important approach to override T KI resistance.
Keywords: CD34+ cells; Chronic myeloid leukemia; Imatinib mesylate; S ERPINE1; miR-181a

211
MicroRNA-93-5p regulates odontogenic differentiation and dentin formation via KDM6B
By: Wu, Si; Xu, Xin; Gao, Shiqi; Huo, Sibei; Wan, Mian; Zhou, Xin; Zhou, Xuedong; Zheng, Liwei; Zhou, Yachuan
Abstract: Background: Epigenetic factors influence the odonto genic differentiation of dental pulp stem cells and play indispe nsable
roles during tooth development. Some microRNAs can epigenetically regulate other epigenetic factors like D NA methyltransferases
and histone modification enzymes, functioning as epigenetic-microRNAs. In our previous study, microarray anal. suggested microR
NA-93-5p (miR-93-5p) was differentially expressed during the bell stage in human tooth germ. Prediction tools indicated that mi R-
93-5p may target lysine- specific demethylase 6B (KDM6B). Therefore, we explored the role of mi R-93-5p as an epi-miRNA in tooth
development and further invest igated the underlying mechanisms of mi R-93-5p in regulating odontogenic differentiation and
dentin formation. Methods: The expression pattern of miR-93-5p and K DM6B of dental pulp stem cells (DPSCs) was examined
during tooth development and odontogenic differentiation. Dual luciferase reporter and ChIP-qPCR assay were used to validate the
target and downstream regulatory genes of miR-93-5p in human D PSCs (hDPSCs). Histol. analyses and q PCR assays were
conducted for investigating the effects of miR-93-5p mimic and inhibitor on odonto genic differentiation of hDPSCs. A pulpotomy rat
model was further established, microCT and histol. analyses were performed to explore the effects of K DM6B-overexpression and
miR-93-5p inhibition on the formation of tertiary dentin. Results: The expression level of mi R-93-5p decreased as odontoblast
differentiated, in parallel with elevated expression of histone demeth ylase KDM6B. In hDPSCs, miR-93-5p overexpression inhibited
the odontogenic differentiation and vice versa. Mi R-93-5p targeted 3′ untranslated region (UTR) of KDM6B, thereby inhibiting its
protein translation. Furthermore, KDM6B bound the promoter region of B MP2 to demethylate H3K27me3 marks and thus upregu
lated BMP2 transcription. In the rat pulpotomy model, KDM6B-overexpression or miR-93-5p inhibition suppressed H3K27me3 level
in DPSCs and conseq uently promoted the formation of tertiary dentin. Conclu sions: MiR-93-5p targets epigenetic regulator K DM6B
and regulates H3K27me3 marks on BMP2 promoters, thus modulating the odonto genic differentiation of DPSCs and dentin
formation.
Keywords: Dental pulp stem cells; KDM6B; MicroRNA-93-5p; Pulpotomy; Tertiary dentin

212
Effect of hormone-induced plasma membrane phosphatidylinositol 4,5-bisphosphate depletion on

receptor endocytosis suggests the importance of local regulation in phosphoinositide signaling
By: Toth, Daniel J.; Toth, Jozsef T.; Damouni, Amir; Hunyady, Laszlo; Varnai, Peter
Phosphatidylinositol 4,5-bisphosphate (PIP2) has been shown to be critical for the endocy tosis of G protein-coupled receptors (GPC
Rs). We have previously demons trated that depletion of PIP2 by chem. induced plasma membrane (P M) recruitment of a 5-phosph
atase domain prevents the internalization of the β2 adrenergic receptor (β2 AR) from the PM to early endosomes. In this study, we
tested the effect of hormone-induced PM PIP2 depletion on β2AR internalization using type-1 angiotensin receptor (AT1R) or M3
muscarinic acetylcholine receptor (M3 R). We followed the endocytic route of β2 ARs in HEK 293T cells using bioluminescence
resonance energy transfer between the receptor and endosome marker Rab5. To compare the effect of lipid depletion by different
means, we created and tested an AT1R fusion protein that is capable of both recrui tment-based and hormone-induced depletion
methods. The rate of PM PIP2 depletion was measured using a biosensor based on the P H domain of phospholipase Cδ1. As
expected, β2AR internalization was inhibited when PIP2 depletion was evoked by recruiting 5- phosphatase to PM-anchored AT1R. A
similar inhibition occurred when wild-type AT1R was activated by adding angiot ensin II. However, stimulation of the desensit
ization/internalization-impaired mutant A T1R (TSTS/4A) caused very little inhibition of β2AR internalization, despite the higher rate
of measurable PIP2 depletion. Interestingly, inhibition of PIP2 resynthesis with the selective PI4KA inhibitor GSK-A1 had little effect
on the change in PH-domain-measured PM PIP2 levels but did significantly decrease β2 AR internalization upon either AT1R or M3R
activation, indicating the importance of a locally synthe sized phosphoinositide pool in the regulation of this process.
Keywords: hormone plasma membrane PIP receptor endocytosis phosphoinositide signaling

213
Antibacterial, antibiofilm, and anticancer activity of silver-nanoparticles synthesized from the cell-
filtrate of Streptomyces enissocaesilis
By: Shaaban, Mohamed T.; Mohamed, Briksam S.; Zayed, Muhammad; El-Sabbagh, Sabha M.
BMC Biotechnology (2024), 24(1), 8 | Language: English, Database: CAplus and MEDLINE
Abstract: Silver nanoparticles (Ag-NPs) have a unique mode of action as antibac terial agents in addition to their anticancer and
antioxidant properties. In this study, microbial nanote chnol. is employed to synthesize Ag- NPs using the cell filtrate of Strept omyces
enissocaesilis BS1. The synthesized Ag-NPs are confirmed by UV-visible (UV-Vis), Fourier transform IR (FT-IR), X-ray diffraction (XRD),
energy dispersive X-ray spectroscopy (EDX), SEM (SEM), and transmission electron microscopy (T EM). Also, the effects of different
factors on Ag-NPs synthesis were evaluated to set the optimum synthesis condit ions. Also, the antibacterial, antibiofilm, and
anticancer activity of Ag-NPs was assessed. The X-ray diffraction (XRD) anal. confirmed the crystalline nature of the sample and
validated that the crystal structure under consideration is a face- centered cubic (FCC) pattern. The TEM examination displayed the
spherical particles of the Ag-NPs and their average size, which is 32.2 nm. Fourier transform I R spectroscopy (FTIR) revealed signif
icant changes in functionality after silver nanoparticle dispersion, which could be attributed to the potency of the cell filtrate of
Streptomyces enissocaesilis BS1 to act as both a reducing agent and a capping agent. The bioact ivity tests showed that our synthe
sized Ag-NPs exhibited remarkable antibacterial activity against different pathogenic strains. Also, when the preformed biofilms of
Pseudomonas aeruginosa A TCC 9027, Salmonella typhi A TCC 12023, Escherichia coli ATCC 8739, and Staphylococcus aureus ATCC
6598 were exposed to Ag NPs 50 mg/mL for 24 h, the biofilm biomass was reduced by 10.7, 34.6, 34.75, and 39.08%, resp. Furthe
rmore, the Ag-NPs showed in vitro cancer- specific sensitivity against human breast cancer M CF-7 cell lines and colon cancer cell line
Caco-2, and the IC50 was 0.160 mg/mL and 0.156 mg/m L, resp. The results of this study prove the ease and efficiency of the
synthesis of Ag-NPs using actinomycetes and demonstrate the significant potential of these Ag-NPs as anticancer and antibacterial
agents.
Keywords: Antibacterial activity; Anticancer activity; Biofilm inhibition ; Microbial nanotechnology; Nanoparticle synthesis; Silver
nanoparticles

214
Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting

ferroptosis
By: Du, Jing; Yu, Lingyan; Yang, Xinyi; Shao, Fangchun; Xia, Jun; Jin, Weidong; Zhang, Yinhao; Lei, Guojie; Wang, Ying; Li, Yanchun; et al
Abstract: Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast- acting and broad-spectrum.
However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is
imperative to develop more effective therapeutic agents for the treatment of P Q poisoning. In the present study, both the R NA-Seq
and the application of various cell death inhibitors reflected that ferrop tosis exerts a crucial regulatory role in P Q poisoning.
Moreover, we found PQ strengthens lipid peroxidation as evidenced by different exptl. approa ches. Of note, pretreatment of iron
chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferrop tosis-related events. Mechanistically, PQ
treatment intensively impaired mitocho ndrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux
and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (N COA4-FTH) axis. Importantly, the activation of
autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron
caused by the ferritinophagy process. Genetic and pharmacol. inhibition of ferritinophagy could alleviate the lethal oxidative
events, and rescue the ferroptotic cell death. Exciti ngly, in the mouse models of PQ poisoning, both the adminis tration of DFO and
adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathol.
characteristics of pulmonary fibrosis. In summary, the current work provides an in- depth study on the mechanism of P Q intoxic
ation, describes a framework for the further underst anding of ferroptosis in PQ-associated biol. processes, and demons trates
modulation of iron metabolism may act as a promising therapeutic agent for the management of P Q toxicity. Graphical Abstract:
[graphic not available: see fulltext]
Keywords: Autophagy; Ferritin; Ferritinophagy; Ferroptosis; NCOA4; Paraquat

215
Identification of new pharmacophore against SARS-CoV-2 spike protein by multi-fold computational

and biochemical techniques
By: Ullah, Atta; Ullah, Saeed; Halim, Sobia Ahsan; Waqas, Muhammad; Ali, Basharat; Ataya, Farid S.; El-Sabbagh, Nasser M.; Batiha,
Gaber El-Saber; Avula, Satya Kumar; Csuk, Rene; et al
Abstract: COVID-19 appeared as a highly contagious disease after its outbreak in Dec. 2019 by the virus, named S ARS-CoV-2. The
threat, which originated in Wuhan, China, swiftly became an international emergency. Among different genomic products, spike
protein of virus plays a crucial role in the initiation of the infection by binding to the human lung cells, therefore, SARS-CoV-2′s spike
protein is a promising therapeutic target. Using a combin ation of a structure-based virtual screening and biochem. assay, this study
seeks possible therapeutic candidates that specif ically target the viral spike protein. A database of ∼ 850 naturally derived
compounds was screened against SARS-CoV-2 spike protein to find natural inhibi tors. Using virtual screening and inhibitory experi
ments, we identified acetyl 11- keto-boswellic acid (A KBA) as a promising mol. for spike protein, which encouraged us to scan the
rest of AKBA derivatives in our inhouse database via 2 D-similarity searching. Later 19 compounds with > 85% similarity with A KBA
were selected and docked with receptor binding domain (RBD) of spike protein. Those hits declared signif icant interactions at the R
BD interface, best possess and excellent drug- likeness and pharmacokinetics properties with high gastrointestinal absorption (GIA)
without toxicity and allergenicity. Our in-silico observations were eventually validated by in vitro bioassay, interes tingly, 10
compounds (A3, A4, C3, C6A, C6B, C6C, C6E, C6H, C6I, and C6J) displayed significant inhibitory ability with good percent inhibition
(range: > 72-90). The compounds C3 (90.00%) , C6E (91.00%), C6C (87.20%), and C6D (86.23%) demonstrated excellent anti-SARS CoV-
2 spike protein activities. The docking interaction of high percent inhibition of inhibitor compounds C3 and C6 E was confirmed by
MD Simulation. In the mol. dynamics simulation, we observed the stable dynamics of spike protein inhibitor complexes and the
influence of inhibitor binding on the protein′s conformational arrangements. The binding free energy Δ GTOTAL of C3 (- 38.0 ± 0.08
kcal/mol) and C6E (-41.98 ± 0.08 kcal/mol) resp. indicate a strong binding affinity to Spike protein active pocket. These findings
demonstrate that these mols. particularly inhibit the function of spike protein and, therefore have the potential to be evaluated as
drug candidates against SARS-CoV-2.
Keywords: Boswellic acid; In-vitro assay; Molecular docking; S ARS CoV-2; Spike protein

216
Investigation of ternary Zn-Co-Fe layered double hydroxide as a multifunctional 2D layered adsorbent

for moxifloxacin and antifungal disinfection
By: Mahmoud, Rehab; Kotb, Nada M.; GadelHak, Yasser; El-Ela, Fatma I. Abo; Shehata, Ayman Z.; Othman, Sarah I.; Allam, Ahmed A.;
Rudayni, Hassan Ahmed; Zaher, Amal
Layered double hydroxides have recently gained wide interest as promising multifunctional nanomaterials. In this work, a multifun
ctional ternary Zn-Co-Fe LDH was prepared and characterized using XRD, FTIR, BET, TEM, SEM, and EDX. This LDH showed a typical
XRD pattern with a crysta llite size of 3.52 nm and a B ET surface area of 155.9 m2/g. This L DH was investigated, for the first time, as
an adsorbent for moxifloxacin, a common fluoroquinolones antibiotic, showing a maximum removal efficiency and equili brium time
of 217.81 mg/g and 60 min, resp. Its antifungal activity, for the first time, was investigated against Penicillium notatum, Aspergillus
flavus, Aspergillus fumigatus, Aspergillus niger, and Mucor fungi at various concent rations (1000-1.95μg/mL). This LDH was found to
be effective against a variety of fungal strains, particularly Penicillium and Mucor species and showed zones of inhibition of 19.3
and 21.6 mm for Penicillium and Mucor, resp., with an inhibition of 85% for Penici llium species and 68.3% for Mucormy cosis. The
highest antifungal efficacy results were obtained at very low MIC concentrations (33.3 and 62μg/mL) against Penicillium and Mucor,
resp. The results of this study suggest a promising multifunctional potential of this LDH for water and wastewater treatment and
disinfection applications.
Keywords: zinc cobalt iron hydroxide moxifoxacin adsorption wastewater treatment

217
Phytochemical screening and antimicrobial activity of Polygala sadebeckiana Gurke extracts on

bacterial isolates from Wound samples of patients with "Shimetere"
By: Zeleke, Bereket; Mekonnen, Zebene; Bireda, Meskele; Yitbarek, Melaku; Dendir, Andamlak
Abstract: Background: Modern medicine is not the choice of patients with "shime tere" in the Gurage community owing to their
perception of ′parenteral medication use severely aggravates the disease′. For this reason, the root part of Polygala sadebe ckiana
Gurke is commonly utilized as traditional medicine in the management of the disease. The aim of this study was to evaluate the
antimicrobial activity of Polygala sadebeckiana Gurke extract on bacterial isolates from wound samples of patients with "Shime
tere". Methods: The agar well diffusion method was used to evaluate antibac terial activity, and the agar dilution method was utilized
to determine min. inhibitory concentrations (MICs) and min. bacter icidal concentrations (MICs). The crude extract was tested
against isolated bacteria at concentrations of 25, 50, 75 and 100 mg/m L in triplicate (3x). The pos. controls were azithromycin (15
μg) and cloxacillin disk (5 μg), and the neg. control was dimethyls ulfoxide (5%). The group mean comparisons were made using one-
way ANOVA at a signif icance level of p < 0.05, and the results are presented as the mean ± standard deviation. The presence of
secondary metabolites from crude extract was checked by standard testing proced ures. Results: S. aureus and S. pyrogen were the
two identified bacteria from 9 (60%) and 3 (20%) wound samples, resp. All identified bacterial strains were susceptible to the
reference antibiotics. Tannins and saponins were the most abundant secondary metabo lites found in the crude extracts The
average inhibition zones of the plant extracts with 100, 75, 50 and 25 mg/m L concentrations were 27, 20.33, 15.25, and 11.96 mm
(p < 0.000) for S. aureus and 30.02, 24.50, 19.07, and 15.77 mm (p < 0.000) for S. pyrogen bacteria, resp. The MIC and M BC of the
crude extract were 1.67 and 10 mg/mL for S. aureus and 0.98 and 4 mg/m L for S. pyrogen. Conclu sion: Polygala sadebeckiana
Gurke contained significant tannins and saponins as secondary metabo lites and had antibac terial activities against isolated bacteria
(S. aureus and S. pyrogen) from "Shimetere". The potential mechanism of antibac terial action of the plant extract was cell wall
synthesis inhibition .
Keywords: Antibacterial activity; Methanol crude extract; Phytochemical screening; Polygala Sadebeckiana; Skin infection

218
Betulinic and ursolic acids from Nauclea latifolia roots mediate their antimalarial activities through
docking with PfEMP-1 and PfPKG proteins
By: Asanga, Edet Effiong; Ekpo, Ndifreke Daniel; Edeke, Affiong Asuquo; Ekeleme, Chinedum Martins; Okoroiwu, Henshaw Uchechi;
Edet, Uwem Okon; Umoh, Ekementeabasi A.; Umoaffia, Nikita Elkanah; Eseyin, Olorunfemi Abraham; Nkang, Ani; et al
Abstract: Background: Chemotherapies target the PfEMP-1 and PfPKG proteins in Plasmodium falcip arum, the parasite that causes
malaria, in an effort to prevent the disease′s high fatality rate. This work identified the phytochem. components of Nauclea latifolia
roots and docked the chem. compounds against target proteins, and examined the in vivo antiplasmodial effect of the roots on
Plasmodium berghei-infected mice. Methods: Standard protocols were followed for the collection of the plant′s roots, cleaning, and
drying of the roots, extraction and fraction preparation, assessment of the in vivo antipla smodial activity, retrieval of the Pf EMP-1
and PfPKG proteins, GCMS, ADME, and docking studies, chromatog. techniques were employed to sep. the residual fraction′s
components, and the Swis-ADME program made it possible to estimate the drug′s likeness and pharmaco kinetic properties. The
Auto Dock Vina 4.2 tool was utilized for mol. docking anal. Results: The residual fraction showed the best therapeutic response
when compared favorably to amodiaquine (80.5%) and artesunate (85.1%) . It also considerably reduced the number of parasites,
with the % growth inhibition of the parasite at 42.8% (D2) and 83.4% (D5) . Following purification, 25 compounds were isolated and
characterized with GCMS. Based on their low mol. weights, non- permeation of the blood-brain barrier, non- inhibition of metabo
lizing enzymes, and non-violation of Lipinski′s criteria, betulinic and ursolic acids were superior to chloro quine as the best phytoc
hems. Hence, they are lead compounds Conclu sion: In addition to identifying the bioactive compounds, A DME, and docking data of
the lead compounds as candidates for rational drug design processes as observed against Plasmodium falciparum target proteins
(PfEMP-1 and PfPKG), which are implicated in the pathogenesis of malaria, the study has validated that the residual fraction of N.
latifolia roots has the best antiplasmodial therapeutic index.
Keywords: Betulinic acid; Docking; GCMS; Malaria; Nauclea latifolia; Plasmodium berghei; Ursolic acid

219
Use of ginger extract and bacterial inoculants for the suppression of Alternaria solani causing early
blight disease in Tomato
By: Hyder, Sajjad; Gondal, Amjad Shahzad; Sehar, Anam; Khan, Aimen Razzaq; Riaz, Nadia; Rizvi, Zarrin Fatima; Iqbal, Rashid;
Elshikh, Mohamed S.; Alarjani, Khaloud M.; Rahman, Muhammed Habib ur; et al
Abstract: Early blight (EB), caused by Alternaria solani, is a serious problem in tomato production Plant growth- promoting rhizoba
cteria promote plant growth and inhibit plant disease. The present study explored the bio- efficacy of synergistic effect of rhizoba
cterial isolates and ginger powder extract (G PE) against tomato E B disease, singly and in combin ation. Six fungal isolates from
symptomatic tomato plants were identified as A. solani on the basis of morphol. features i.e., horizontal septation (6.96 to 7.93 μm) ,
vertical septation (1.50 to 2.22 μm), conidia length (174.2 to 187.6 μm) , conidial width (14.09 to 16.52 μm) , beak length (93.06 to
102.26 μm), and sporulation. Five of the twenty- three bacterial isolates recovered from tomato rhizos phere soil were nonpath
ogenic to tomato seedlings and were compatible with each other and with G PE. Out of five isolates tested individ ually, three
isolates (St-149D, Hyd-13Z, and Gb-T23) showed maximum inhibition (56.3%, 48.3%, and 42.0% resp.) against mycelial growth of A.
solani. Among combinations, St-149D + GPE had the highest mycelial growth inhibition (76.9%) over the untreated control. Bacterial
strains molecularly characterized as Pseudomonas putida, Bacillus subtilis, and Bacillus cereus and were further tested in pot trials
through seed bacterization for disease control. Seeds treated with bacterial consortia + G PE had the highest disease suppre ssion
percentage (78.1%), followed by St-149D + GPE (72.2%) and Hyd- 13Z + GPE (67.5%). Maximum seed germination was obtained in the
bacterial consortia + GPE (95.0 ± 2.04) followed by St- 149D + GPE (92.5 ± 1.44) and Hyd- 13Z + GPE (90.0 ± 2.04) over control (73.8 ±
2.39) and chem. control as standard treatment (90.0 ± 2). Ginger powder extracts also induce the activation of defense- related
enzymes (TPC, PO, PPO, PAL, and CAT) activity in tomato plants. These were highly signif icant in the testing bacterial inoculants
against A. solani infection in tomato crops.
Keywords: Alternaria solani; Bacterial inoculants; Early blight disease; Ginger extract; Plant growth promotion; Tomato crop

220
Receptor-based pharmacophore modeling, molecular docking, synthesis and biological evaluation of

novel VEGFR-2, FGFR-1, and BRAF multi-kinase inhibitors
By: Abdel-Mohsen, Heba T.; Ibrahim, Marwa A.; Nageeb, Amira M.; El Kerdawy, Ahmed M.
Abstract: A receptor-based pharmacophore model describing the binding features required for the multi- kinase inhibition of the
target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discrim inating
between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew′s correlation coefficient of
0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair,
the DFG motif Asp at the activation loop, and the allosteric back pocket next to the A TP binding site. Moreover, excluded volumes
were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual
screening of an inhouse scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within
the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimi dazole-based scaffold through (un)
substituted aryl substitution on 2 and 5 positions of the benzimi dazole ring. Mol. docking simulations and ADME properties predic
tions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmaco kinetic proper
ties, resp. The designed compounds 8a- u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity
at 10 μM. Compound 8u exhibited a potent inhibitory activity against the target kinases (V EGFR-2, FGFR-1, and BRAF) with IC50
values of 0.93, 3.74, 0.25 μM, resp. The benzimi dazole derivatives 8a-u were all selected by the N CI (USA) to conduct their anti-
proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, resp.
Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the N
CI panel of 60 different cancer cell lines were progressed further to N CI five-dose testing. The benzimi dazole derivatives 8a, 8d, 8h,
8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u
was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumu lating cells at the sub-G1 phase as a result of
cell apoptosis.
Keywords: Anti-cancer; BRAF; CADD; FGFR-1; Molecular docking; Multi- kinase; Pharmacophore; VEGFR-2

221
Pinpointing top inhibitors for GSK3β from pool of indirubin derivatives using rigorous computational
workflow and their validation using molecular dynamics (MD) simulations
By: Pandya, Vamangi ; Rao, Priyashi ; Prajapati, Jignesh ; Rawal, Rakesh M. ; Goswami, Dweipayan
Abstract: Glycogen synthase kinase-3β (GSK3β) is a pivotal protein kinase implicated in a spectrum of debili tating diseases, encomp
assing cancer, diabetes, and neurodege nerative disorders. While the therapeutic potential of GSK3β inhibition is widely recognized,
there remains an unmet need for a rigorous, systematic anal. probing the theor. inhibition dynamics of a compreh ensive library of
indirubin derivatives against GSK3β using advanced computational methodologies. Addressing this gap, this study embarked on an
ambitious endeavor, leveraging indirubin-a renowned scaffold-as a template to curate a vast library of 1000 indirubin deriva tives
from PubChem. These were enriched with varied substit utions and modific ations, identified via a structure similarity search with a
Tanimoto similarity threshold of 85%. Harnessing a robust virtual screening workflow, we meticulously identified the top 10
contenders based on XP docking scores. Delving deeper, we gauged the binding free energy differe ntials (ΔGBind) of these hits,
spotlighting the top three compounds that showcased unpara lleled binding prowess. A compar ative pharmacophore feature
mapping with the reference inhibitor OH8, co-crystallized with GSK3β (PDB ID: 6Y9R), was undertaken. The binding dynamics of
these elite compounds were further corroborated with 100 ns mol. dynamics simula tions, underlining their stable and potent intera
ctions with GSK3β. Remarkably, our findings unveil that these indirubin deriva tives not only match but, in certain scenarios, surpass
the binding affinity and specificity of OH8. By bridging this research chasm, our study amplifies the therap eutic promise of indirubin
derivatives, positioning them as frontrunners in the quest for groundb reaking GSK3β inhibitors, potentially revolutionizing
treatments for a myriad of ailments.

222
Palmitoylation of vacuole membrane protein 1 promotes small extracellular vesicle secretion via
interaction with ALIX and influences intercellular communication
By: Qu, Mengyuan; Liu, Xinyu; Wang, Xiaotong; Li, Zili; Zhou, Liquan; Li, Honggang
Abstract: Background: Small extracellular vesicles (E Vs), exemplified by exosomes, mediate interce llular communication by transp
orting proteins, mRNAs, and miRNAs. Post-translational modifications are involved in contro lling small E V secretion process.
However, whether palmitoylation regulates small E V secretion, remains largely unexplored. Methods: Vacuole Membrane Protein 1
(VMP1) was testified to be S- palmitoylated by Palmito ylation assays. VMP1 mutant plasmids were constructed to screen out the
exact palmitoylation sites. Small E Vs were isolated, identified and compared between wild- type VMP1 or mutant VMP1 transfected
cells. Electron microscope and immunofluorescence were used to detect multivesicular body (MVB) number and morphol. change
when VMP1 was mutated. Immunoprecipitation and Mass spectrum were adopted to identify the protein that interacted with
palmitoylated VMP1, while knock down experiment was used to explore the function of targeted protein A LIX. Taking human Sertoli
cells (SCs) and human spermat ogonial stem cell like cells (S SCLCs) as a model of intercellular communication, SSCLC maintenance
was detected by flow cytometry and qPCR at 12 days of differen tiation. In vivo, mouse model was established by i.p. injection with
palmitoylation inhibitor, 2- bromopalmitate (2BP) for 3 mo. Results: V MP1 was identified to be palmitoylated at cysteine 263,278 by
ZDHHC3. Specifically, palmitoylation of VMP1 regulated its subcellular location and enhanced the amount of small E V secretion.
Mutation of VMP1 palmitoylation sites interfered with the morphol. and biogenesis of M VBs through suppressing intraluminal
vesicle formation. Furthermore, inhibition of VMP1 palmitoylation impeded small E V secretion by affecting the interaction of VMP1
with ALIX, an accessory protein of the E SCRT machinery. Taking S Cs and S SCLCs as a model of interce llular communication, we
discovered VMP1 palmitoylation in SCs was vital to the growth status of S SCLCs in a coculture system. Inhibition of VMP1 palmito
ylation caused low self-maintenance, increased apoptosis, and decreased prolife ration rate of SSCLCs. In vivo, i.p. injection of 2 BP
inhibited VMP1 palmitoylation and exosomal marker expression in mouse testes, which were closely associated with the level of
spermatogenic cell apoptosis and prolife ration. Conclusions: Our study revealed a novel mechanism for small E V secretion
regulated by VMP1 palmitoylation in Sertoli cells, and demons trated its pivotal role in interce llular communication and SSC niche.
Keywords: Extracellular vesicles; Multivesicular bodies; Palmitoylation; Sertoli cells; Spermat ogonial stem cell like cells

223
HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-

integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling
By: Terri, Michela; Sandoval, Pilar; Bontempi, Giulio; Montaldo, Claudia; Tomero-Sanz, Henar; de Turris, Valeria; Trionfetti, Flavia;
Pascual-Anton, Lucia; Clares-Pedrero, Irene; Battistelli, Cecilia; et al
Abstract: Background: Peritoneal metastasis, which accounts for 85% of all epithelial ovarian carcinoma (E OC) metastases, is a
multistep process that requires the establishment of adhesive interactions between cancer cells and the peritoneal membrane.
Interrelations between EOC and the mesoth elial stroma are critical to facilitate the metastatic process. No data is available so far on
the impact of histone acetylation/deacetylation, a potentially relevant mechanism governing E OC metastasis, on mesothelial cells (M
Cs)-mediated adhesion. Methods: Static adhesion and peritoneal clearance experi ments were performed pretreating mesenchymal-
like MCs and platinum-sensitive/resistant EOC cell lines with M S-275-a Histone deacetylase (HDAC)1-3 pharmacol. inhibitor
currently used in combination trials. Results were acquired by confocal microscopy and were analyzed with an automated Opera
software. The role of HDAC1/2 was validated by genetic silencing. The role of α4- , α5-α1 Integrins and Fibronectin-1 was validated
using specific monoclonal antibodies. Quant. proteomic anal. was performed on primary MCs pretreated with M S-275. Decellu
larized matrixes were generated from either M S-275-exposed or untreated cells to study Fibron ectin-1 extracellular secretion. The
effect of MS-275 on β1 integrin activity was assessed using specific monoclonal antibo dies. The role of Talin- 1 in MCs/EOC adhesion
was analyzed by genetic silencing. Talin-1 ectopic expression was validated as a rescue tool from M S-275-induced phenotype. The in
vivo effect of MS-275-induced MC remodeling was validated in a mouse model of peritoneal E OC dissemination. Results: Treatment
of MCs with non-cytotoxic concentrations of MS-275 caused a consistent reduction of E OC adhesion. Proteomic anal. revealed
several pathways altered upon MC treatment with M S-275, including ECM deposition/remodeling, adhesion receptors and actin
cytoskeleton regulators. HDAC1/2 inhibition hampered actin cytoskeleton polymerization by downregulating actin regulators
including Talin-1, impairing β1 integrin activation, and leading to abnormal extrace llular secretion and distribution of Fibronectin-1.
Talin-1 ectopic expression rescued E OC adhesion to MS-275-treated MCs. In an exptl. mouse model of metastatic E OC, MS-275
limited tumor invasion, Fibronectin-1 secretion and the sub-mesothelial accumulation of MC-derived carcinoma-associated fibrob
lasts. Conclusion: Our study unveils a direct impact of H DAC-1/2 in the regulation of M C/EOC adhesion and highlights the regulation
of MC plasticity by epigenetic inhibition as a potential target for therap eutic intervention in EOC peritoneal metastasis.
Keywords: Actin cytoskeleton; Epithelial ovarian Cancer; Extrace llular matrix; Fibronectin-1; HDAC1–2; Integrin; MS-275; Mesothelial
to mesenchymal transition (M MT); Peritoneal Carcinom atosis; Peritoneum; Talin1

224
The effects of combined exercise training on glucose metabolism and inflammatory markers in
sedentary adults: a systematic review and meta-analysis
By: Silva, Fernanda M.; Duarte-Mendes, Pedro; Teixeira, Ana M.; Soares, Carlos M.; Ferreira, Jose P.
Meta-anal. of magnitude of the effect of combined exercise training on glucose metabolism markers, adipok ines, and inflammatory
cytokines in non-diabetic sedentary adults. PubMed, Web of Science, Scopus, Cochrane Library electronic databases and reference
lists of included studies were explored for randomized controlled trials (RCTs) that included phys. inactive adults and provided
combined training interventions (aerobic plus resistance exercise) . Effects on fasting glucose and insulin, Homeos tatic Model
Assessment of Insulin Resistance (HOMA-IR), HbA1c, adiponectin, leptin, IL-6, TN F-α , and C-reactive protein (CRP) in exercise vs
control groups were analyzed using random effects meta-anal. The Cochrane Risk of Bias Tool for Randomized Trials 2.0 (Ro B 2)
was used to assess the risk of bias. A total of 24 RCTs were included in the quant. anal. Combined exercise training significantly
decrease fasting glucose (standardized mean difference, SMD: - 0.474, 95% C I [- 0.829, - 0.120] , p = 0.009, 35 study arms) , fasting
insulin (SMD: - 1.024, 95% C I [- 1.502, - 0.545] , p < 0.001, 27 study arms) , HOMA-IR (SMD: - 0.946, 95% C I [- 1.450, - 0.442] , p < 0.001,
23 study arms), TN F-α (SMD: - 0.972, 95% C I [- 1.361, - 0.582] , p < 0.001, 10 study arms) , and CRP (SMD: - 0.507, 95% C I [- 0.818, -
0.196], p = 0.001, 14 study arms) . No significant effects were observed for HbA1c, adiponectin, leptin, and IL-6 levels. Random
effects meta-regression models by age, sex, and interv ention length were not able to explain any of the variation in the effect size of
HOMA-IR. Findings from this systematic review and meta- anal. suggest that combined exercise training improves some glucose
metabolism markers and inflammatory parameters in sedentary adults without diabetes.
Keywords: meta analysis exercise glucose metabolism
225
Biological effects of Lippia alba essential oil against Anopheles gambiae and Aedes aegypti
By: Coulibaly, Fangala Hamidou; Rossignol, Marie; Haddad, Mohamed; Carrasco, David; Azokou, Alain; Valente, Adeline; Ginibre,
Carole; Kone, Mamidou Witabouna; Chandre, Fabrice
Abstract: The management of mosquito resistance to chem. insecticides and the biting behavior of some species are motivating the
search for complementary and/or alternative control methods. The use of plants is increa singly considered as a sustainable biol.
solution for vector control. The aim of this study was to evaluate the biol. effects of the essential oil (EO) of Lippia alba harvested in
Abidjan (Cote d′Ivoire) against Anopheles gambiae and Aedes aegypti mosquitoes. Phytochem. compounds were identified by G C-M
S. Knockdown and mortality were determined according to the W HO test tube protocol. Contact irritancy was assessed by
observing the movement of mosquitoes from a treated WHO tube to a second untreated tube. Non- contact repellency was
assessed using a standardised high-throughput screening system (HITSS). Blood meal inhibition was assessed using a membrane
feeding assay treated with EO. The EO was identified as the citral chemotype. The E O gave 100% K D60 in both species at a concent
ration of 1%. Mortalities of 100% were recorded with An. gambiae and Ae. aegypti at concent rations of 1% and 5% resp. The highest
proportions of females escaping during the contact irritancy test were 100% for An. gambiae at 1% concent ration and 94% for Ae.
aegypti at 2.5% concentration The 1% concent ration produced the highest proportions of repelled mosquitoes in the non-contact
repellency tests: 76.8% (An. gambiae) and 68.5% (Ae. aegypti). The blood meal inhibition rate at a dose of 10% was 98.4% in Ae.
aegypti but only 15.5% in An. gambiae. The citral chemotype of L. alba EO has promising biol. effects in both species that make it a
potentially good candidate for its use in mosquito control. The results obtained in this study encourage the further evaluation of L.
alba EOs from other localities and of different chemot ypes, under laboratory and field condit ions.

226
Phytochemical characterization of forest leaves extracts and application to control apple postharvest
diseases
By: Hajji-Hedfi, Lobna; Rhouma, Abdelhak; Hlaoua, Wassila; Dmitry, Kucher E.; Jaouadi, Ryma; Zaouali, Yosr; Rebouh, Nazih Y.
The study investigated the antifungal and phytochem. properties of three forest plants (Eucalyptus globulus, Pistacia lentiscus, and
Juniperus phoenicea) against apple diseases caused by Colletotrichum gloeosporioides and Alternaria alternata. The determination
of the total polyphenol and flavonoid contents in the three aqueous extracts of studied plants showed that E. globulus exhibited the
highest contents than those of P. lentiscus and J. phoenicea. Furthermore, the three studied extracts showed very apprec iable
antioxidant activity with decreasing order: E. globulus, P. lentiscus, and J. phoenicea. The phytochem. anal. showed different
common phenolic acids in the three studied plants namely: quinic acid, gallic acid, chlorogenic acid, and caffeoylquinic acid as well
as other flavonoids mainly quercetin and catechin. The results of the current study demonstrated that the fungistatic activity of E.
globulus EO (4 and 2 μl/mL) seemed to be the most effective under laboratory conditions with an inhibition zone diameter above
16 mm. However, the poisoned food technique indicated that the aqueous extract (80%) and the essential oil (4 μl/mL) of E.
globulus exhibited the highest mycelial growth (> 67%) and spore germination (> 99%) inhibition . Preventive treatments with
essential oils (4 μl/mL) and aqueous extracts (80%) applied to apple fruits inoculated with A. alternata and C. gloeospo rioides
resulted in the lowest lesion diameter (< 6.80 mm) and disease severity index (< 15%) and the most favorable inhibitory growth (>
85.45%) and protective potentials (> 84.92%). The results suggest that E. globulus has a brilliant future in the management of anthra
cnose and Alternaria rot of apple and provide a basis for further studies on its effects under field condit ions.
Keywords: phytochem forest leave apple postharvest disease

227
In vitro and in vivo anti-tumor effect of Trichobakin fused with urokinase-type plasminogen activator
ATF-TBK
By: Pham, Dan Duc; Pham, Thi Hue; Bui, Thi Huyen; Britikova, Elena V.; Britikov, Vladimir V.; Bocharov, Eduard V.; Usanov, Sergey A.;
Phan, Van Chi; Le, Thi Bich Thao
Abstract: Background: Trichobakin (TBK), a member of type I ribosome- inactivating proteins (RIPs), was first successfully cloned
from Trichosanthes sp Bac Kan 8- 98 in Vietnam. Previous study has shown that T BK acts as a potential protein synthesis inhibitor;
however, the inhibition efficiency and specificity of TBK on cancer cells remain to be fully elucid ated. Methods and results: In this
work, we employed TBK and T BK conjugated with a part of the amino- terminal fragment (ATF) of the urokinase-type plasminogen
activator (uPA), which contains the Ω-loop that primarily interacts with urokinase- type plasminogen activator receptor, and can be a
powerful carrier in the drug delivery to cancer cells. Four different human tumor cell lines and BALB/c mice bearing Lewis lung
carcinoma cells (LLC) were used to evaluate the role of T BK and A TF-TBK in the inhibition of tumor growth. Here we showed that
the obtained ligand fused RIP (ATF-TBK) reduced the growth of four human cancer cell lines in vitro in the u PA receptor level-
dependent manner, including the breast adenoca rcinoma MDA-MB 231 cells and M CF7 cells, the prostate carcinoma LNCaP cells
and the hepatocellular carcinoma Hep G2 cells. Furthermore, the conjugate showed anti-tumor activity and prolonged the survival
time of tumor-bearing mice. The A TF-TBK also did not cause the death of mice with doses up to 48 mg/kg, and they were not signifi
cantly distinct on parameters of hematol. and serum biochem. between the control and experiment groups. Conclu sions: In conclu
sion, ATF-TBK reduced the growth of four different human tumor cell lines and inhibited lung tumor growth in a mouse model with
little side effects. Hence, the ATF-TBK may be a target to consider as an anticancer agent for clin. trials.
Keywords: ATF-TBK; Cytotoxic activity; Ribosome inactivating protein (RIP); Trichobakin (TBK); Urokinase plasminogen activator (uP
A)

228
The regulation of plasma gelsolin by DNA methylation in ovarian cancer chemo-resistance
By: Manzoor, Hafiza Bushra; Asare-Werehene, Meshach; Pereira, Satyajit Dey; Satyamoorthy, Kapaettu; Tsang, Benjamin K.
Abstract: Background: Ovarian cancer (OVCA) is the most lethal gynecol. cancer and chemores istance remains a major hurdle to
successful therapy and survival of OVCA patients. Plasma gelsolin (p GSN) is highly expressed in chemore sistant OVCA compared
with their chemosensitive counterparts, although the mechanism underlying the differ ential expression is not known. Also, its
overexpression significantly correlates with shortened survival of O VCA patients. In this study, we invest igated the methylation role
of Ten eleven translocation isoform-1 (TET1) in the regulation of differ ential pGSN expression and chemosen sitivity in OVCA cells.
Methods: Chemosensitive and resistant O VCA cell lines of different histol. subtypes were used in this study to measure p GSN and T
ET1 mRNA abundance (qPCR) as well as protein contents (Western blotting) . To investigate the role of D NA methylation specifically
in pGSN regulation and p GSN-induced chemoresistance, DNMTs and TETs were pharmacol. inhibited in sensitive and resistant O VC
A cells using specific inhibitors. DNA methylation was quantified using EpiTYPER MassARRAY system. Gain- and-loss-of-function
assays were used to investigate the relationship between TET1 and p GSN in OVCA chemoresponsiveness. Results: We observed
differential protein and m RNA expressions of pGSN and T ET1 between sensitive and resistant O VCA cells and cisplatin reduced
their expression in sensitive but not in resistant cells. We observed hypomethylation at p GSN promoter upstream region in
resistant cells compared to sensitive cells. Pharmacol. inhibition of DNMTs increased pGSN protein levels in sensitive O VCA cells
and decreased their responsiveness to cisplatin, however we did not observe any difference in methyl ation level at p GSN promoter
region. TETs inhibition resulted in hypermet hylation at multiple CpG sites and decreased p GSN protein level in resistant O VCA cells
which was also associated with enhanced response to cisplatin, findings that suggested the methylation role of T ETs in the
regulation of pGSN expression in O VCA cells. Further, we found that T ET1 is inversely related to p GSN but pos. related to
chemoresponsiveness of OVCA cells. Conclusion: Our findings broaden our knowledge about the epigenetic regulation of p GSN in O
VCA chemoresistance and reveal a novel potential target to re- sensitize resistant OVCA cells. This may provide a future therap eutic
strategy to improve the overall OVCA patient survival.
Keywords: Chemoresistance; DNA methylation; Ovarian cancer; Plasma gelsolin (p GSN); Ten eleven translo cation enzyme isoform 1
(TET1)

229
The response of salivary proinflammatory biomarkers to tooth extraction in individuals with type II
diabetes mellitus
By: Al Shehhi, Yousuf Ibrahim; Elemam, Noha M. ; Alsaegh, Mohammed Amjed

Abstract: Purpose: This study investigated the levels of salivary proinflammatory cytokines in the saliva of patients living with type I I
diabetes mellitus (DM) compared to those in healthy indivi duals three times: before tooth extraction and at 2 h and 2 days after
tooth extraction Methods: The study included 27 participants. Among them, 20 (n = 20; 74%) had type I I DM, and seven (n = 7; 26%)
were healthy control subjects. Saliva samples were collected at three time intervals: before tooth extraction and 2 h and 2 days
after tooth extraction The salivary biomarkers were investigated using a Luminex multiplex assay. These salivary biomarkers
included tumor necrosis factor - alpha ( TN F-α) , interleukin 6 (IL-6), interleukin 1-beta (IL-1β), and interferon-gamma (IFN-γ).
Results: At baseline, patients with type II DM had significantly lower levels of IL-1β (P = 0.016) . Moreover, 2 h after extrac tion,
patients with type II DM had significantly lower levels of IL-1β and TN F-α than did healthy control subjects (P = 0.046 and P = 0.020,
resp.). In addition, 2 days after tooth extrac tion, the DM group had significantly greater IL-6 levels (P = 0.010) than the control
group. Conclusions: In patients with type I I DM, salivary proinflammatory biomarker levels are generally comparable or lower than
those in healthy control subjects. Proinflammatory cytokines manifest differently in patients with type I I DM after tooth extraction
than in normal healthy individuals. There is generally a delayed early response of salivary proinfla mmatory markers in patients
living with type II DM who undergo tooth extraction
Keywords: IFN-γ; IL-1β; IL-6; Proinflammatory; Salivary cytokines; TN F-α ; Tooth extraction

230
Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a
therapeutic target for arrhythmogenic right ventricular cardiomyopathy
By: Fu, Mengxia; Hua, Xiumeng; Shu, Songren; Xu, Xinjie; Zhang, Hang; Peng, Zhiming; Mo, Han; Liu, Yanyun; Chen, Xiao; Yang,
Yicheng; et al
BMC Medicine (2024), 22(1), 11 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Dilation may be the first right ventri cular change and accelerates the progression of threatening ventricular
tachyarrhythmias and heart failure for patients with arrhyth mogenic right ventricular cardiomyopathy (ARVC), but the treatment for
right ventricular dilation remains limited. Methods: Single-cell RNA sequencing (scRNA-seq) of blood and biventr icular myocardium
from 8 study participants was performed, including 6 end- stage heart failure patients with A RVC and 2 normal controls. Sc RNA-seq
data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular develop
mental trajectories and interactions. An integrative anal. of our single-cell data and published genome- wide association study-
based data provided insights into the cell- specific contributions to the cardiac arrhythmia phenotype of A RVC. Desmoglein 2 (Dsg2)
mut/mut mice were used as the A RVC model to verify the therapeutic effects of pharmacol. interv ention on identified cellular cluster.
Results: Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and T NMD+ fibroblasts. Fibroblasts were
preferentially affected in ARVC and perturbations associated with A RVC overlap with those reside in genetic variants associated
with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibrob last. Pharmacol. inhibition of Nod-like receptor
protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other
myeloid subclusters, could significantly alleviate right ventri cular dilation and dysfunction in Dsg2 mut/mut mice (an A RVC mouse
model). Conclusions: This study provided a compreh ensive anal. of the lineage-specific changes in the blood and myocardium from
ARVC patients at a single- cell resolution Pharmacol. inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of
mice with ARVC.
Keywords: Arrhythmogenic right ventricular cardiomyopathy; NLRP3; Single-cell RNA sequencing

231
Gut dysbiosis induces the development of depression-like behavior through abnormal synapse
pruning in microglia-mediated by complement C3
By: Hao, Wenzhi; Ma, Qingyu; Wang, Lu; Yuan, Naijun; Gan, Hua; He, Liangliang; Li, Xiaojuan; Huang, Junqing; Chen, Jiaxu
Microbiome (2024), 12(1), 34 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Remodeling eubiosis of the gut microenv ironment may contribute to preventing the occurrence and develo
pment of depression. Mounting exptl. evidence has shown that complement C3 signaling is associated with the pathog enesis of
depression, and disruption of the gut microbiota may be an underlying cause of complement system activa tion. However, the
mechanism by which complement C3 participates in gut-brain crosstalk in the pathogenesis of depression remains unknown.
Results: In the present study, we found that chronic unpredictable mild stress (C UMS)-induced mice exhibited obvious depression-
like behavior as well as cognitive impairment, which was associated with signif icant gut dysbiosis, especially enrichment of Proteob
acteria and elevation of microb iota-derived lipopolysaccharides (LPS). In addition, peripheral and central complement C3 activation
and central C3/CR3-mediated aberrant synaptic pruning in microglia have also been observed Transpla ntation of gut microbiota
from CUMS-induced depression model mice into specific pathogen- free and germ-free mice induced depression-like behavior and
concomitant cognitive impairment in the recipient mice, accomp anied by increased activation of the complement C3/C R3 pathway
in the prefrontal cortex and abnormalities in microglia-mediated synaptic pruning. Conversely, antidepressants and fecal
microbiota transplantation from antidepr essant-treated donors improved depression-like behaviors and restored gut microbiome
disturbances in depressed mice. Concurr ently, inhibition of the complement C3/CR3 pathway, amelioration of abnormal microglia-
mediated synaptic pruning, and increased expression of the synapsin and postsy naptic d. protein 95 were observed Collect ively, our
results revealed that gut dysbiosis induces the development of depression-like behaviors through abnormal synapse pruning in
microglia-mediated by complement C3, and the inhibition of abnormal synaptic pruning is the key to targeting microbes to treat
depression. Conclusions: Our findings provide novel insights into the involv ement of complement C3/CR3 signaling and aberrant
synaptic pruning of chemotactic microglia in gut- brain crosstalk in the pathogenesis of depression. [media not available: see
fulltext]
Keywords: Complement C3; Depression; Fecal microbiota transpla ntation; Gut microb iota; Microglia; Synaptic pruning

232
Transcriptomic analysis identifies B-lymphocyte kinase as a therapeutic target for desmoplastic small
round cell tumor cancer stem cell-like cells
By: Magrath, Justin W.; Flinchum, Dane A.; Hartono, Alifiani B.; Sampath, Shruthi Sanjitha; O′Grady, Tina M.; Baddoo, Melody ;
Haoyang, Liang ; Xu, Xiaojiang; Flemington, Erik K.; Lee, Sean B.
Oncogenesis (2024), 13(1), 2 | Language: English, Database: CAplus and MEDLINE
Abstract: Desmoplastic small round cell tumor (D SRCT) is an aggressive pediatric cancer caused by the E WSR1-WT1 fusion oncopr
otein. The tumor is refractory to treatment with a 5- yr survival rate of only 15- 25%, necessitating the development of novel therape
utics, especially those able to target chemore sistant subpopulations. Novel in vitro cancer stem cell- like (CSC-like) culture conditions
increase the expression of stemness markers (SOX2, N ANOG) and reduce DSRCT cell line suscept ibility to chemotherapy while
maintaining the ability of DSRCT cells to form xenogr afts. To gain insights into this chemore sistant model, RNA-seq was performed
to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2- dimensional adherent state.
Commonly upregulated and downreg ulated genes were identified and utilized in pathway anal. revealing upregu lation of pathways
related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extrace llular
matrix organization. Alterations in chromatin assembly suggest a role for epigen etics in the DSRCT CSC-like state, which was further
investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks, including 4444 sphere accessible peaks and 6,
120 adherent accessible peaks. Accessible regions were associated with higher gene expres sion, including increased accessibility of
the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential C SC therapeutic
targets, leading to the identification of B-lymphocyte kinase (BLK) as a C SC-enriched, EWSR1-WT1-regulated, druggable target. B LK
inhibition and knockdown reduced C SC-like properties, including abrogation of tumorsphere formation and stemness marker
expression. Importantly, BLK knockdown reduced D SRCT CSC-like cell chemoresistance, making its inhibition a promising target for
future combination therapy.
233
SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-

acetylgalactosamine-4-sulfatase by p38 MAPK
By: Bhattacharyya, Sumit; Tobacman, Joanne K.

Signal Transduction and Targeted Therapy (2024), 9(1), 39 | Language: English, Database: CAplus and MEDLINE
Abstract: Immunostaining in lungs of patients who died with C OVID-19 infection showed increased intensity and distri bution of
chondroitin sulfate and decline in N- acetylgalactostamine-4-sulfatase (Arylsulfatase B; A RSB). To explain these findings, human
small airway epithelial cells were exposed to the SARS-CoV-2 spike protein receptor binding domain (S PRBD) and transcriptional
mechanisms were investigated. Phospho-p38 MAPK and phospho-SMAD3 increased following exposure to the SPRBD, and their
inhibition suppressed the promoter activation of the carboh ydrate sulfotransferases CHST15 and CHST11, which contributed to
chondroitin sulfate biosynthesis. Decline in ARSB was mediated by phospho-38 MAPK-induced N-terminal Rb phosphorylation and
an associated increase in Rb-E2F1 binding and decline in E2 F1 binding to the ARSB promoter. The increases in chondroitin sulfotran
sferases were inhibited when treated with phospho- p38-MAPK inhibitors, SMAD3 (SIS3) inhibitors, as well as antihistamine deslora
tadine and antibiotic monensin. In the mouse model of carrag eenan-induced systemic inflammation, increases in phospho-p38 MA
PK and expression of C HST15 and CHST11 and declines in DNA-E2F binding and ARSB expression occurred in the lung, similar to
the observed effects in this SPRBD model of COVID-19 infection. Since accumulation of chondroitin sulfates is associated with
fibrotic lung conditions and diffuse alveolar damage, increased attention to p38-MAPK inhibition may be beneficial in amelio rating
Covid-19 infections.

234
8-Br-cGMP suppresses tumor progression through EGFR/PLC γ1 pathway in epithelial ovarian cancer
By: Wu, Min; Mu, Chunyan; Yang, Huiwen; Wang, Yue; Ma, Ping; Li, Shibao; Wang, Zhongcheng; Lan, Ting
Abstract: Background: Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (P KG-I), a serine/threonine kinase, is
important in tumor development. The present study determines that the c GMP/PKG I pathway is essential for promoting cell prolife
ration and survival in human ovarian cancer cells, whereas c GMP analog has been shown to lead to growth inhibition and
apoptosis of various cancer cells. The role of cGMP/PKG I pathway in epithelial ovarian cancer (E OC), therefore, remains controv
ersial. We invest igated the effect of cGMP/PKG I pathway and the underlying mechanism in E OC. Methods and results: The results
showed that exogenous 8-Bromoguanosine-3′, 5′-cyclic monophosphate (8-Br-cGMP) (cGMP analog) could antagonize the effects by
EGF, including suppressing proliferation, invasion and migration of EOC cells. In vivo, 8-Br-cGMP hampered the growth of the
xenograft tumor. Addnl., the expressions of epidermal growth factor receptor (E GFR), matrix metallopeptidase 9 (MMP9), prolife
rating cell nuclear antigen and Ki67 in xenograft tumor were decreased after 8- Br-cGMP intervention. Further research demons
trated that 8-Br-cGMP decreased the phosphorylation of EGFR (Y992) and downstream proteins phospho lipase Cγ1 (PLC γ1) (Y783),
calmodulin kinase II (T286) and inhibited cytopl asmic Ca 2+ release as well as PKC transferring to cell membrane. It′s worth noting
that the inhibition was 8-Br-cGMP dose-dependent and 8-Br-cGMP showed similar inhibitory effect on E OC cells compared with U-
73122, a specific inhibitor of PLC γ1. Conclu sions: The activation of endogenous PKG I by addition of exogenous 8- Br-cGMP could
inhibit EOC development probably via EGFR/PLCγ1 signaling pathway. 8- Br-cGMP/PKG I provide a new insight and strategy for E OC
treatment.
Keywords: 8-Br-cGMP; EGFR; EOC; PKG I; PLCγ1

235
FFAR4 activation inhibits lung adenocarcinoma via blocking respiratory chain complex assembly
associated mitochondrial metabolism
By: Wang, Zhe; Li, Jinyou; Wang, LongFei; Liu, Yaowei; Wang, Wei; Chen, JiaYao; Liang, HuiJun; Chen, Y. Q.; Zhu, ShengLong
Abstract: Despite notable advancements in the investigation and management of lung adenoca rcinoma (LUAD), the mortality rate
for individuals afflicted with LUAD remains elevated, and attaining an accurate prognosis is challe nging. LUAD exhibits intricate
genetic and environmental components, and it is plausible that free fatty acid receptors (F FARs) may bridge the genetic and dietary
aspects. The objective of this study is to ascertain whether a correlation exists between FFAR4, which functions as the primary
receptor for dietary fatty acids, and various characteristics of LUAD, while also delving into the potential underlying mechanism. The
findings of this study indicate a decrease in FFAR4 expression in LUAD, with a pos. correl ation (P < 0.01) between F FAR4 levels and
overall patient survival (OS). Receiver operating characteristic (ROC) curve anal. demonstrated a signif icant diagnostic value [area
under the curve (AUC) of 0.933] associated with F FAR4 expression. Functional investigations revealed that the FFAR4-specific
agonist (TUG891) effectively suppressed cell prolife ration and induced cell cycle arrest. Furthe rmore, FFAR4 activation resulted in
significant metabolic shifts, including a decrease in oxygen consum ption rate (OCR) and an increase in extrace llular acidification
rate (ECAR) in A549 cells. In detail, the activation of F FAR4 has been observed to impact the assembly process of the mitocho ndrial
respiratory chain complex and the malate-aspartate shuttle process, resulting in a decrease in the transition of N AD+ to NADH and
the inhibition of LUAD. These discoveries reveal a previously unreco gnized function of FFAR4 in the neg. regulation of mitocho
ndrial metabolism and the inhibition of LUAD, indicating its potential as a promising therap eutic target for the treatment and
diagnosis of LUAD.
Keywords: FFAR4; LUAD; Metabolism reprogramming; OXPHOS

236
PRDX6-iPLA2 aggravates neuroinflammation after ischemic stroke via regulating astrocytes-induced

M1 microglia
By: Peng, Li; Ji, Yanyan; Li, Yixin; You, Yan; Zhou, Yang
The crosstalk between astrocytes and microglia plays a pivotal role in neuroinflammation following ischemic stroke, and phenotypic
distribution of these cells can change with the progre ssion of ischemic stroke. Peroxiredoxin (PRDX) 6 phospholipase A2 (iPLA2)
activity is involved in the generation of reactive oxygen species(ROS), with ROS driving the activation of microglia and astroc ytes;
however, its exact function remains unexplored. MJ33, PRDX6D140A mutation was used to block P RDX6-iPLA2 activity in vitro and
vivo after ischemic stroke. PRDX6T177A mutation was used to block the phosphor ylation of PRDX6 in CTX-TNA2 cell lines. N AC, GS
K2795039, Mdivi-1, U0126, and S B202190 were used to block the activity of R OS, NOX2, mitochondrial fission, E RK, and P38, resp., in
CTX-TNA2 cells. In ischemic stroke, PRDX6 is mainly expressed in astrocytes and P RDX6-iPLA2 is involved in the activation of
astrocytes and microglia. In co-culture system, Asp140 mutation in P RDX6 of CTX-TNA2 inhibited the polari zation of microglia,
reduced the production of ROS, suppressed N OX2 activation, and inhibited the Drp1- dependent mitochondrial fission following OG
D/R. These effects were further strengthened by the inhibition of ROS production In subsequent experi ments, U0126 and S
B202190 inhibited the phosphor ylation of PRDX6 at Thr177 and reduced P RDX6-iPLA2 activity. These results suggest that P RDX6-iPL
A2 plays an important role in the astrocyte- induced generation of ROS and activation of microglia, which are regulated by the
activation of Nox2 and Drp1-dependent mitochondrial fission pathways. Addnl., PRDX6-iPLA2 activity is regulated by M APKs via the
phosphorylation of PRDX6 at Thr177 in astroc ytes.
Keywords: peroxiredoxin 6 phospholipase A2 aggravate neuroinfl ammation ischemic stroke; astrocyte induced M1 microglia; Astroc
ytes; Drp1‑ dependent mitchondrial fission; Microglia; Nox2; PRDX6-iPLA2
237
AKT2S128/CCTαS315/319/323-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase

(FAK) inhibitors resistance via secreting phosphatidylcholines (PCs)
By: Chen, Jie; Zhang, Lingyuan; Zhu, Yuheng; Zhao, Di; Zhang, Jing; Zhu, Yanmeng; Pang, Jingyuan; Xiao, Yuanfan; Wu, Qingnan;
Wang, Yan; et al
Abstract: Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic resistance.
Present study employed multi-omics, including phosphoproteomics, untargeted metabolomics and lipidomics, to demonstrate that
the pAKT2 Ser 128 and pCCTα Ser315/319/323-pos. cancer-associated fibroblasts (CAFs) substantially release phosphatidylcholines (PCs)
, contributing to the resistance of focal adhesion kinase (F AK) inhibitors in esophageal squamous cell carcinoma (E SCC) treatment.
Addnl., we observed extremely low levels of FAK Tyr397 expression in CAFs, potentially offering no available target for FAK inhibitors
playing their anti-growth role in C AFs. Consequently, FAK inhibitor increased the intracellular concentration of Ca 2+ in CAFs,
promoting the formation of AKT2/CCTα complex, leading to phosphor ylation of CCTα Ser315/319/323 sites and eventually enhancing
stromal PC production This activation could stimulate the intrat umoral Janus kinase 2 (J AK2)/Signal transducer and activator of
transcription 3 (STAT3) pathway, triggering resistance to F AK inhibition . Anal. of clin. samples demonstrated that stromal p AKT2
Ser128 and pCCTα Ser315/319/323 are related to the tumor malignancy and reduced patient survival. Pseudo- targeted lipidomics and
further validation cohort quant. showed that plasma PCs enable to distinguish the malignant extent of ESCC patients. In conclusion,
inhibition of stroma-derived PCs and related pathway could be possible therap eutic strategies for tumor therapy.

238
MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose
tissue browning
By: Wang, Qinhao ; Su, Yuanyuan; Sun, Ruiqi; Xiong, Xin; Guo, Kai; Wei, Mengying; Yang, Guodong; Ru, Yi; Zhang, Zhengxiang; Li,
Jing; et al
Cell & Bioscience (2024), 14(1), 12 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The enrichment of peri-cancerous adipose tissue is a distin ctive feature of colorectal cancer (C RC), accele
rating disease progression and worsening prognosis. The communi cation between tumor cells and adjacent adipocytes plays a
crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the
mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell- adipocyte communi
cation and its role in promoting C RC. Results: M IIP expression was found to be decreased in C RC tissues and closely associated with
adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with M IIP-downregulated tumor supernatant
exhibited aggravated browning and lipolysis. This finding was further confirmed in s.c. allografted mice co-injected with adipocytes
and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobili zation factor AZGP1 and
regulated AZGP1′s glycosylation status by interf ering with its association with STT3A. MIIP downregulation promoted N-glycosylation
and over-secretion of AZGP1 in tumor cells. Subsequ ently, AZGP1 induced adipocyte browning and lipolysis through the c AMP-PKA
pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting C
RC cell proliferation, invasion, and apoptosis resist ance, accompanied by metabolic reprogramming. In a tumor-bearing mouse
model, inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in C
RC with abnormal M IIP expression. Conclusions: Our data demonstrate that MIIP plays a regulatory role in the communi cation
between CRC and neighboring adipose tissue by regulating A ZGP1 N-glycosylation and secretion. M IIP reduction leads to AZGP1
oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of β-adrenergic
receptor or FFA uptake, combined with oxaliplatin, may represent a promising therap eutic strategy for C RC with aberrant M IIP
expression.
Keywords: AZGP1; Adipose tissue browning; Colorectal cancer; M IIP

239
Engineered ice-binding protein (FfIBP) shows increased stability and resistance to thermal and
chemical denaturation compared to the wildtype
By: Nam, Yewon; Nguyen, Dieu Linh; Hoang, Trang; Kim, Bogeun; Lee, Jun Hyuck; Do, Hackwon
Abstract: Many polar organisms produce antifreeze proteins (AFPs) and ice-binding proteins (IBPs) to protect themselves from ice
formation. As IBPs protect cells and organisms, the potential of I BPs as natural or biol. cryopro tective agents (CPAs) for the cryopres
ervation of animal cells, such as oocytes and sperm, has been explored to increase the recovery rate after freezing- thawing.
However, only a few IBPs have shown success in cryoprese rvation, possibly because of the presence of protein denatu rants, such as
di-Me sulfoxide, alcs., or ethylene glycol, in freezing buffer condit ions, rendering the IBPs inactive. Therefore, we invest igated the
thermal and chem. stability of FfIBP isolated from Antarctic bacteria to assess its suitab ility as a protein-based impermeable
cryoprotectant. A mol. dynamics (M D) simulation identified and generated stability- enhanced mutants (FfIBP_CC1). The results
indicated that FfIBP_CC1 displayed enhanced resistance to denaturation at elevated temperatures and chem. concentr ations,
compared to wildtype FfIBP, and was functional in known C PAs while retaining ice- binding properties. Given that FfIBP shares an
overall structure similar to DUF3494 IBPs, which are recognized as the most widespread I BP family, these findings provide
important structural information on thermal and chem. stability, which could potent ially be applied to other DUF3494 IBPs for
future protein engineering.
Keywords: Ice-binding protein, Antifreeze protein, Cryopreservation, Chemical stability, Cold denaturation, DUF3494, Ice recrystal
lization inhibition , Thermal hysteresis

240
Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating
fetoplacental growth
By: Wu, Jiayi; Qin, Chuanmei; Tian, Fuju; Liu, Xueqing; Hu, Jianing; Wu, Fan; Chen, Cailian; Lin, Yi
BMC Medicine (2024), 22(1), 57 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Abnormal placental development is a signif icant factor contributing to perinatal morbidity and mortality,
affecting approx. 5-7% of pregnant women. Tropho blast syncytialization plays a pivotal role in the establi shment and maturation of
the placenta, and its dysregulation is closely associated with several pregnancy- related disorders, including preeclampsia and
intrauterine growth restriction. However, the underlying mechanisms and genetic determ inants of syncytialization are largely
unknown. Methods: We conducted a systematic drug screen using an epigenetic compound library to systematically investigate the
epigenetic mechanism essential for syncytialization, and identified mixed lineage leukemia 1 (M LL1), a histone 3 lysine 4 methyltra
nsferase, as a crucial regulator of trophoblast syncytialization. BeWo cells were utilized to investigate the role of M LL1 during tropho
blast syncytialization. RNA sequencing and C UT&Tag were further performed to search for potential target genes and the mol.
pathways involved. Human placenta tissue was used to investigate the role of M LL1 in TEA domain transcription factor 4 (T EAD4)
expression and the upstream signaling during syncytialization. A mouse model was used to examine whether inhibition of MLL1-
mediated H3K4me3 regulated placental TEAD4 expression and fetoplacental growth. Results: Genetic knockdown of M LL1 or
pharmacol. inhibition of the MLL1 methyltransferase complex (by M I-3454) markedly enhanced syncytialization, while overexp
ression of MLL1 inhibited forskolin (FSK)-induced syncytiotrophoblast formation. In human placental villous tissue, M LL1 was
predominantly localized in the nuclei of cytotrophoblasts. Moreover, a notable upregu lation in MLL1 expression was observed in
the villus tissue of patients with preeclampsia compared with that in the control group. Based on R NA sequencing and C UT&Tag
analyses, depletion of MLL1 inhibited the Hippo signaling pathway by suppre ssing TEAD4 expression by modulating H3 K4me3 levels
on the TEAD4 promoter region. TEAD4 overexpression significantly reversed the FSK-induced or MLL1 silencing-mediated tropho
blast syncytialization. Addnl., decreased hypoxia- inducible factor 1A (HIF1A) enrichment at the M LL1 promoter was observed during
syncytialization. Under hypoxic conditions, HIF1A could bind to and upregulate M LL1, leading to the activation of the M LL1/TEAD4
axis. In vivo studies demonstrated that the administration of MI-3454 significantly enhanced fetal vessel develo pment and
increased the thickness of the syncytial layer, thereby supporting fetoplacental growth. Conclusions: These results revealed a novel
epigenetic mechanism underlying the progression of syncytialization with MLL1, and suggest potential avenues for identi fying new
therapeutic targets for pregnancy- related disorders.
Keywords: H3K4me3; MLL1; Placenta; TEAD4; Trophoblast syncytialization

241
Effect of pharmacological selectivity of SGLT2 inhibitors on cardiovascular outcomes in patients with

type 2 diabetes: a meta-analysis
By: Sayour, Alex Ali; Olah, Attila; Ruppert, Mihaly; Barta, Balint Andras; Merkely, Bela; Radovits, Tamas
Abstract: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce major adverse cardiovascular events (M ACE) in type 2 diabetic
(T2DM) patients. Pharmacol. select ivity of these agents to SGLT2 over SGLT1 is highly variant, with unknown clin. relevance. Geneti
cally reduced S GLT1-but not SGLT2-activity correlates with lower risk of heart failure and mortality, therefore addnl. non- selective SG
LT1 inhibition might be beneficial. In this prespecified meta-anal., we included 6 random ized, placebo-controlled cardiovascular
outcome trials of SGLT2 inhibitors assessing M ACE in 57,553 patients with T2 DM. Mixed-effects meta-regression revealed that
pharmacol. selectivity of SGLT2 inhibitors (either as continuous or dichot omized variable) had no signif icant impact on most
outcomes. However, lower SGLT2 selectivity correlated with significantly lower risk of stroke (pseudo-R2 = 78%; p = 0.011) . Indeed,
dual SGLT1/2 inhibitors significantly reduced the risk of stroke (hazard ratio [H R], 0.78; 95% confidence interval [CI], 0.64-0.94),
unlike selective agents (p for interaction = 0.018). The risk of diabetic ketoacidosis and genital infections was higher in both
pharmacol. groups vs. placebo. However, hypotension occurred more often with non- selective SGLT2 inhibitors (odds ratio [OR],
1.87; 95% CI, 1.20-2.92) compared with selective agents (p for intera ction = 0.044). In conclusion, dual SGLT1/2 inhibition reduces
stroke in high-risk T2DM patients but has limited addnl. effect on other clin. outcomes.
242
Targeting apoptosis; design, synthesis and biological evaluation of new benzoxazole and thiazole
based derivatives
By: Helmy, Sama W.; Shahin, Mai I.; Samir, Nermin; Lasheen, Deena S.; Ella, Dalal A. Abou El
Abstract: Several novel approaches to target Bcl-2 proteins and apoptotic pathways have been identified in recent years for the
treatment of different types of cancer including colorectal cancer. However, no effective treatments were yet developed for
colorectal cancer. Twenty two novel benzoxazole and thiazole-based compounds were designed, synthe sized, and evaluated as
potential Bcl-2 inhibitors with anti-proliferative activity. Compounds 8g, 12e and 13d showed good to moderate antiproliferative
activity against most of the NCI 60 cell line panel with mean growth inhibition percent of 45.13, 42.29 and 29.25%, resp. They
showed the greatest cell growth inhibition percent to HCT-116 cell line with the values of 68.0, 59.11 and 43.44%, resp. The
aforementioned compounds were furtherly invest igated for their effect on H CT-116 cell cycle, and they showed increase in the total
apoptosis with 17, 22, and 5%, resp. Also, the apoptotic effect of compounds 8g, 12e and 13d, were tested by their effect on altering
caspase-3 expression level in HCT-116 human cell line. The three compounds showed an increase in the caspase- 3 levels by 6, 8 and
3 folds, resp. in comparison with the same untreated ones. Moreover, they were evaluated for their in-vitro Bcl-2 inhibitory activity
and they showed percent inhibition of 60.2, 69.2 and 50.0%, resp. Finally, the most potent compounds 8g and 12e showed 3.864
and 2.834 folds increase in Bax level compared to the control resp. On the other hand, Bcl-2 was down-regulated to 0.31 and 0.415
folds compared to the control. The induction of apoptosis through increase in caspase 3 expression and down-regulation of Bcl-2 is
the suggested mechanism of action.
Keywords: Apoptosis; Bcl-2; Benzoxazole; Caspase; Colorectal cancer; Thiazole

243
The impact of selected xanthophylls on oil hydrolysis by pancreatic lipase: in silico and in vitro studies
By: Dabrowski, Grzegorz; Czaplicki, Sylwester; Szustak, Marcin; Korkus, Eliza; Gendaszewska-Darmach, Edyta; Konopka, Iwona
Lipase inhibition is one of the directions to control obesity. In vitro assays have confirmed the inhibitory effect of selected xanthop
hylls, including astaxanthin, fucoxanthinol, fucoxanthin, and neoxan thin. Similarly, an in-silico study also demonstrated the
successful inhibition of pancreatic lipase by astaxa nthin. Unfortunately, the efficacy of these protocols in the emulsion state typical
of lipid digestion remains untested. To address this issue, the current study employed the pH-stat test, which mimics lipid digestion
in the gastrointestinal tract, to evaluate native and prepared sea buckthorn and rapeseed oils with varying xantho phyll contents
from 0 to 1400 mg/kg oil. Furthermore, a mol. docking of zeaxanthin and violax anthin (commonly found in plant- based foods),
astaxanthin (widely distributed in foods of marine origin) and orlistat (approved as a drug) was performed. The in- silico studies
revealed comparable inhibitory potential of all tested xanthophylls (variation from - 8.0 to - 9.3 kcal/mol) , surpassing that of orlistat
(- 6.5 kcal/mol). Nonetheless, when tested in an emulsified state, the results of p H-stat digestion failed to establish the inhibitory
effect of xanthophylls in the digested oils. In fact, lipolysis of native xantho phyll-rich sea buckthorn oil was approx. 22% higher than
that of the xanthophyll-low preparation The key insight derived from this study is that the amphip hilic properties of xantho phylls
during the digestion of xanthophyll-rich lipids/meals facilitate emulsion formation, which leads to enhanced fat lipolysis.
Keywords: xanthophyll oil hydrolysis pancreatic lipase
244
The oncolytic bacteria-mediated delivery system of CCDC25 nucleic acid drug inhibits neutrophil
extracellular traps induced tumor metastasis
By: Liu, Li-na ; Chen, Chen; Xin, Wen-jie; Li, Qiang; Han, Chao; Hua, Zi-chun
Abstract: Background: Neutrophil extracellular traps (N ETs), antibacterial weapons of neutrophils (NEs), have been found to play a
crucial role in cancer metastasis in recent years. More and more cancer research is focusing on anti-NETs. However, almost all anti-
NETs treatments have limitations such as large side effects and limited efficacy. Therefore, exploring new anti- NETs therapeutic
strategies is a long-term goal. Results: The transme mbrane protein coiled- coil domain containing 25 (CCDC25) on tumor cell
membranes can bind NETs-DNA with high specificity and affinity, enabling tumor cells to sense N ETs and thus promote distant
metastasis. We transformed shCCDC25 into VNP20009 (VNP), an oncolytic bacterium, to generate VNP-shCCDC25 and performed
preclin. evaluation of the inhibitory effect of shCCDC25 on cancer metastasis in B16 F10 lung metastasis and 4T1 orthotopic lung
metastasis models. VNP-shCCDC25 effectively blocked the downstream prometastatic signaling pathway of C CDC25 at tumor sites
and reduced the formation of NETs while recruiting more neutrophils and macrophages to the tumor core, ultimately leading to
excellent metastasis inhibition in the two lung metastasis models. Conclu sion: This study is a pioneer in focusing on the effect of
anti-NET treatment on C CDC25. shCCDC25 is effectively delivered to tumor sites via the help of oncolytic bacteria and has broad
application in the inhibition of cancer metastasis via anti-NETs. Graphical Abstract: [graphic not available: see fulltext]
Keywords: CCDC25; Metastasis; NETs; Neutrophils; Nucleic acid delivery; V NP20009

245
Correlations between genetically predicted lipid-lowering drug targets and inflammatory bowel
disease
By: Huang, Kuiyuan; Huang, Shenan; Xiong, Ming

Lipids in Health and Disease (2024), 23(1), 31 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Millions of individuals globally suffer from Inflam matory bowel diseases (IBDs). There is a dearth of large
population-based investigations on lipid metabolism and I BDs, and it is unclear whether lipid-lowering drugs target IBDs causally.
Consequently, the aim of this study was to invest igate the effects of lipid-lowering medication targets on the occurrence and progre
ssion of IBDs. Methods: Among the more than 400, 000 participants in the UK Biobank cohort and the more than 170, 000 partic
ipants in the Global Lipids Genetics Consor tium, a total of nine genes linked to lipid- lowering drug targets were obtained (A BCG5/AB
CG8, APOB, APOC3, LDLR, LPL, HMGCR, NPC1L1, PCSK9, and PPARA). IBD data were acquired from de Lange et al. (patients /sample
size of IBDs: 25042/59957; ulcerative colitis (UC): 12366/45,975; Crohn′s disease (C D): 12194/40,266) and the FinnGen cohort
(patients/total sample size of IBDs: 4420/176,899; CD: 1520/171,906; UC: 3325/173,711). All four datasets were cross- combined for
validation via Mendelian randomization anal., and potential mediating factors were explored via mediation anal. Results: Geneti
cally proxied APOC3 inhibition was related to increased IBD risk (odds ratio (95% confidence interval): 0.87 (0.80-0.95); P < 0.01) and
UC risk (0.83 (0.73-0.94); P < 0.01). IBD and CD risk were reduced by genetic mimicry of L DLR and LPL enhancements, resp. (odds
ratioLDLR: 1.18 (1.03-1.36); P = 0.018; odds ratioCD: 1.26 (1.11-1.43); P = 2.60E-04). Genetically proxied HMGCR inhibition was
associated with increased CD risk (0.68 (0.50-0.94); P = 0.018). These findings were confirmed through Mendelian anal. of the cross-
combination of four sep. datasets. A POC3-mediated triglyceride levels may contribute to IBDs partly through mediated triglyc erides,
Clostridium sensu stricto 1, Clostridiaceae 1, or the Lachnospiraceae FCS020 group. LDLR enhancement may contribute to IBDs
partly through increasing Lactobacillaceae. Conclusion: Vigilance is required to prevent adverse effects on IBDs (UC) for patients
receiving volanesorsen (an antisense oligonucleotide targeting Apo C3 mRNA) and adverse effects on CD for statin users. LPL and LD
LR show promise as candidate drug targets for C D and IBD, resp., with mechanisms that are potent ially independent of their lipid-
lowering effects.
Keywords: Inflammatory bowel disease; Lipids; Mendelian randomi zation

246
FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion
By: Zhao, Zeda; Qin, Juliang; Qian, Ying; Huang, Chenshen; Liu, Xiaohong; Wang, Ning; Li, Liqin; Chao, Yuqing; Tan, Binghe; Zhang,
Na; et al
Journal of Hematology & Oncology (2024), 17(1), 9 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Emerging evidences suggest that aberrant metabo lites contributes to the immunosuppressive microenv
ironment that leads to cancer immune evasion. Among tumor immunosup pressive cells, myeloid- derived suppressor cells (MDSCs)
are pathol. activated and extremely immunosuppressive, which are closely associated with poor clin. outcomes of cancer patients.
However, the correlation between M DSCs mediated immunosuppression and particular cancer metabolism remained elusive.
Methods: Spontaneous lung adenocarcinoma and s.c. mouse tumor models, gas chroma tog.-mass spectrometry (GC-MS) and
immunofluorescence assay of patient-derived lung adenocarcinoma tissues, and flow cytometry, R NA sequencing and Western
blotting of immune cells, were utilized. Results: Metabolite profiling revealed a significant accumulation of acetic acids in tumor
tissues from both patients and mouse model, which contribute to immune suppression and cancer progression significantly
through free fatty acid receptor 2 (FFAR2). Furthermore, FFAR2 is highly expressed in the myeloid- derived suppressor cells (MDSCs)
from the tumor of lung adenocarcinoma (LUAD) patients which is greatly associated with poor prognosis. Surpris ingly, whole or
myeloid Ffar2 gene deletion markedly inhibited urethane-induced lung carcinogenesis and syngeneic tumor growth with reduced M
DSCs and increased C D8+ T cell infiltr ation. Mechanistically, FFAR2 deficiency in M DSCs significantly reduced the expression of Arg1
through Gαq/Calcium/PPAR-γ axis, which eliminated T cell dysfun ction through relieving L-Arginine consumption in tumor microenvi
ronment. Therefore, repleni shment of L-Arginine or inhibition to PPAR-γ restored acetic acids/FFAR2 mediated suppression to T
cells significantly. Finally, FFAR2 inhibition overcame resistance to immune checkpoint blockade through enhancing the recrui tment
and cytotoxicity of tumor-infiltrating T cells. Conclu sion: Altogether, our results demonstrate that the acetic acids/FFAR2 axis
enhances MDSCs mediated immunosuppression through Gαq/calcium/PPAR-γ/Arg1 signaling pathway, thus contri buting to cancer
progression. Therefore, FFAR2 may serve as a potential new target to eliminate pathol. activated M DSCs and reverse immunosup
pressive tumor microenvironment, which has great potential in improving clin. outcomes of cancer immunot herapy.
Keywords: FFAR2; Immune evasion; Immunotherapy; MDSCs; SCFAs

247
Protective effect of Achyranthes aspera against compound 48/80, histamine and ovalbumin-induced
allergic disorders in murine model
By: Kaushik, Amit; Singh, Dewasya P.; Sahu, Mridula; Kumar, Ashish; Pratibha; Pandey, Pallavi; Patel, Manish K.; Chanda, Debabrata;
Sundaresan, Velusamy; Mani, Daya N.; et al
Abstract: Background: Achyranthes aspera L. (family Amarant haceae) is a plant species valued in Ayurveda for the treatment of
respiratory ailments. Scientific validation of its antial lergic potential was aimed. Methods and Results: Three extracts of A. aspera
[aqueous (AaAq), hydroalcoholic (AaHA), ethanolic (AaEt)] were evaluated for their potency against C48/80- induced anaphylaxis in
mice at 200 mg/kg BW oral dose. The ED of the most potent extract was determined through its effect on C48/80- induced anaphy
laxis, and was further analyzed through its effect on mast cell degranu lation, histamine-induced bronchospasm and ovalbumin (OV
A)-induced asthma in a murine model. Among the three extracts, Aa Aq was found to be most potent at 200 mg/kg B W. AaAq 400
(400 mg/kg BW) was found to be the most ED in terms of inhibition of mortality and histamine level. Aa Aq 400 prevented the
peritoneal and mesenteric mast cells from undergoing morphol. changes due to degranulation induced by C48/80. Further, Aa Aq
400 delayed pre-convulsive time in histamine-induced bronchospasm. In the OVA-induced asthma model, Aa Aq 400 inhibited the
level of inflammatory cell count in blood, bronchoa lveolar lavage fluid and peritoneal fluid of mice. The Th2 cytokines (I L-4, IL-5, IL-
13), TGF-β and OVA-specific IgE were also reduced as evaluated by E LISA. Also, signif icant reduction in IL-5 (an eosino philia
indicator) transcript abundance and lung inflammatory score was observed Aa Aq was safe up to 4000 mg/kg B W. Conclusions: Thus
AaAq 400 possesses significant antiallergic potential and acts via attenu ation of C48/80-induced anaphylaxis and inhibition of mast
cell degranulation. It reduces pre- convulsive dyspnea in histamine-induced bronchospasm and Th2 cytokines in asthmatic mice.
Keywords: Achyranthes aspera; Allergy; Anaphylaxis; Asthma; Bronchospasm; Mast cell degranu lation

248
The immune checkpoint TIGIT/CD155 promotes the exhaustion of CD8 + T cells in TNBC through
glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling
By: Huang, Mingyao; Yu, Xiaoqin; Wang, Qing; Jiang, Zirong; Li, Xiaofen; Chen, Wei; Song, Chuangui
Abstract: Objective: The CD155/TIGIT axis has attracted considerable interest as an emerging immune checkpoint with potential
applications in cancer immunotherapy. Our research focused on investi gating the role of C D155/TIGIT checkpoints in the progre
ssion of triple-neg. breast cancer (T NBC). Methods: We evaluated C D155 and TIGIT expression in TNBC tissues using both
immunohistochem. (IHC) and gene expression profiling. Our experi ments, both in vivo and in vitro, provided evidence that
inhibiting the CD155/TIGIT pathway reinstates the ability of C D8 + T cells to generate cytokines. To assess the impact of C D155/TIGIT
signaling blockade, we utilized Glucose Assay Kits and Lactate Assay Kits to measure alterations in glucose and lactate levels within
CD8 + T cells. We employed western blotting (W B) to investigate alterations in glycolytic-related proteins within the PI3K/AKT/mTOR
pathways following the inhibition of CD155/TIGIT signaling. Results: C D155 exhibits heightened expression within T NBC tissues and
exhibits a neg. correlation with the extent of infiltrating CD8 + T cells. Furthe rmore, patients with T NBC demonstrate elevated levels
of TIGIT expression. Our findings indicate that the interaction between CD155 and TIGIT disrupts the glucose metabolism of CD8 + T
cells by suppressing the activation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the reduced production of
cytokines by CD8 + T cells. Both in vivo and in vitro experi ments have conclusively demonstrated that the inhibition of CD155/TIGIT
interaction reinstates the capacity of C D8 + T cells to generate cytokines. Moreover, in vivo adminis tration of the blocking antibody
against TIGIT not only inhibits tumor growth but also augments the functio nality of CD8 + T lymphocytes. Conclusions: Our research
findings strongly suggest that CD155/TIGIT represents a promising therap eutic target for treating T NBC.
Keywords: CD155/TIGIT; CD8 + T cells; Immune checkp oint; Immunotherapy; TNBC

249
High-intensity intermittent training ameliorates methotrexate-induced acute lung injury
By: Rajizadeh, Mohammad Amin; Hosseini, Mahdiyeh Haj; Bahrami, Mina; Bahri, Faegheh; Rostamabadi, Fahimeh; Bagheri,
Fatemeh; Khoramipour, Kayvan; Najafipour, Hamid; Bejeshk, Mohammad-Abbas
BMC Pulmonary Medicine (2024), 24(1), 45 | Language: English, Database: CAplus and MEDLINE
Abstract: Inflammation and oxidative stress are recognized as two primary causes of lung damage induced by methotr exate, a drug
used in the treatment of cancer and immunol. diseases. This drug triggers the generation of oxidants, leading to lung injury. Given
the antioxidant and anti-inflammatory effects of high-intensity intermittent training (HIIT), our aim was to evaluate the therapeutic
potential of HIIT in mitigating methotrexate-induced lung damage in rats. Seventy male Wistar rats were randomly divided into five
groups: CTL (Control), HIIT (High-intensity intermittent training), ALI (Acute Lung Injury), HIIT+ALI (pretreated with HIIT), and ALI + HII
T (treated with H IIT). HIIT sessions were conducted for 8 wk. At the end of the study, assess ments were made on malondialdehyde,
total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidase (Gpx), myeloperoxidase (MPO), interleukin 10
(IL-10), tumor necrosis factor - alpha ( TN F-α) , gene expression of T-bet, GATA3, FOXP3, lung wet/dry weight ratio, pulmonary
capillary permeability, apoptosis (Caspase-3), and histopathol. indexes. Methotrexate administration resulted in increased levels of
TN F-α , MPO, GATA3, caspase-3, and pulmonary edema indexes, while reducing the levels of T AC, SOD, Gpx, I L-10, T-bet, and FOXP3.
Pretreatment and treatment with H IIT reduced the levels of oxidant and inflam matory factors, pulmonary edema, and other histop
athol. indicators. Concurrently, HIIT increased the levels of antiox idant and anti-inflammatory factors.
Keywords: Acute lung injury; High-intensity intermittent training; Inflam matory factors; Methotrexate; Mohammad Amin Rajizadeh,
Mahdiyeh Haj Hosseini, Mina Bahrami, Faegheh Bahri and Fahimeh Rostamabadi equally contributed as first author.; Oxidative
stress; Therapeutic effects

250
Association of lymphocyte subsets and cytokines with bone metabolism: a retrospective, cross-
sectional study
By: Peng, Cong; Yang, Qiao; Kong, Xiangrui; Sun, Zhengzhong; Wang, Liang; Xiao, Li
BMC Musculoskeletal Disorders (2024), 25(1), 43 | Language: English, Database: CAplus and MEDLINE
Previous research has shown that lymphocytes and cytokines can mediate bone metabolism This study explored the clin. associ
ation and predictive ability of lymphocytes and cytokines levels for bone metabolism A total of 162 patients were enrolled in this
study. The levels of N-terminal propeptide of type I procol lagen (P1NP), β-collagen degradation product (β-CTX), total T lympho
cytes, immature T lymphocytes, suppressor/cytotoxic T lymphocytes, helper/inducer T lymphocytes, B lymphocytes, natural killer (N
K) cells, Interf eron-gamma (IFN-γ), tumor necrosis factor - alpha ( TN F-α) , IFN- α , interleukin-1 beta (IL-1β), IL-2, IL-4, IL-5, IL-6, IL-8, I
L-10, and IL12p70 were evaluated. The relationship between these lymphocyte subsets and cytokines with bone metabolic status
was examined and their predictive ability for bone metabolic status was assessed. The principal component anal. (PCA) and correl
ation anal. results varied on differences in lymphocyte subsets and cytokines in various bone metabolism states. Differ ential anal.
revealed significant differences in the absolute counts of B lympho cytes (P < 0.05) , level of IL-12p70 (P < 0.05) , and IL-8 (P < 0.001) at
different P1NP levels. Significant differences were observed in the absolute counts of total T lympho cytes (P < 0.05) , B lymphocytes
(P < 0.05), the level of IL-6 (P < 0.05) , the percentage of B lymphocytes (P < 0.01) , and NK cells (P < 0.05) at different β- CTX levels.
Furthermore, the receiver operating characteristic (ROC) curve showed that the absolute count of B lympho cytes and levels of IL-
12p70 and IL-8 could be used to evaluate bone formation states, while the absolute counts of T and B lympho cytes, level of I L-6,
and percentages of NK cells and B lympho cytes could be used to evaluate bone resorption states. Conclu sion: The bone
metabolism status changed based on the lymphocyte subsets and cytokine levels. Differentially expressed lymphocytes and
cytokines could be used to distinguish bone metabolism status.
Keywords: IL2 IL4 IFNgamma CD4 CD8 lymphocyte bone metabolism; Bone metabolism; Bone turnover marker; Cytokine; Immune
system; Lymphocyte subset

251
Free heme induces neuroinflammation and cognitive impairment by microglial activation via the
TLR4/MyD88/NF-κB signaling pathway
By: Wei, Xin; Zhang, Fan; Cheng, Dan; Wang, Zhongyu; Xing, Na; Yuan, Jingjing; Zhang, Wei; Xing, Fei
Red blood cells (RBCs) transfusion is related to perioperative neurocognitive disorders. The toxic effect of free heme has been
identified in many pathologies. However, the underlying mechanisms of R BCs transfusion or free heme in cognitive impairment
have not been clearly explored. Therefore, this research was conducted to determine the mechanism of free heme-induced
neuroinflammation and cognitive impairment. Rats were received i.p. injection of hemin alone or combined with intracer ebrovent
ricular injection of Hemopexin (HPX), and MWM test was conducted to measure cognitive function. The amount of heme- HPX
complexes was evaluated by flow cytometry for CD91 + cells. The microglial inflammatory response in rat brain was observed by
immunofluorescence staining of Iba-1, and the inflammatory factors of TN F-α , IL-1β and IL-6 in rat brain and BV2 cells were
detected by ELISA anal. Furthermore, neuronal apoptosis in HT22 cells alone and in H T22 + BV2 coculture system was detected by
flow cytometry and immunofluorescence staining. Finally, western blot was conducted to detect T LR4/MyD88/NF-κB proteins in rat
brain and BV2 cells treated with hemin or combined with pathway inhibi tors. Addnl., the M1 surface marker CD86 was observed in
BV2 cells to further confirm neuroinfl ammation. I.p. injection of hemin induced cognitive impair ment, increase of C D91 + cells, up-
regulation of TN F-α and IL-1β, down-regulation of IL-6, activation of microglia, and activation of the T LR4/MyD88/NF-κB signaling
pathway in rat brain. Significantly, intracerebroventricular injection of HPX reduced the above effects. Hemin induced boost of TN F-
α , IL-1β and IL-6 in BV2 cells, as well as apoptosis in H T22 cells. Notably, when HT22 cells were cocultured with B V2 cells, apoptosis
was significantly increased. Hemin also induced activation of the T LR4/MyD88/NF-κB signaling pathway and increased the M1
surface marker CD86 in BV2 cells, and inhibiting this pathway reduced the inflam matory responses. Free heme induces cognitive
impairment, and the underlying mechanism may involve neuronal apoptosis and microglial inflam mation via the TLR4/MyD88/NF-κ
B signaling pathway. HPX may have potential therapeutic effects.
Keywords: hemopexin microglial TLR4 MyD88 NFkappaB neuroinflammation cognitive impairment; Cognitive function; Free heme;
Microglia activation; Neuroinflammation; Neuron; TLR4/MyD88/NF-κB

252
Synergism of fermented feed and ginseng polysaccharide on growth performance, intestinal

development, and immunity of Xuefeng black-bone chickens
By: Liu, Jie; Wang, Huan; Luo, Junyi; Chen, Ting; Xi, Qianyun; Sun, Jiajie; Wei, Limin; Zhang, Yongliang
BMC Veterinary Research (2024), 20(1), 13 | Language: English, Database: CAplus and MEDLINE
Microbial fermented feed (MF) is considered a valuable strategy to bring advantages to livestock and is widely practiced. Oral
supplementation of Ginseng polysac charide (Gps) eliminated weight loss in chickens following vaccin ation. This study invest igated
the effects of the combined use of Gps and MF on growth performance and immune indexes in Xuefeng black- bone chickens. A
total of 400 Xuefeng black-bone chickens at the age of 1 day were randomly assigned to four groups. Normal feed group (Control
group), ginseng polysaccharide (200 mg/kg) group (Gps group) , microbially fermented feed (completely replace the normal feed)
group (MF group), and microbially fermented feed and add ginseng polysac charide just before use (M F + Gps group). Each group
contained 5 pens per treatment and 20 birds per pen. The body weight and average daily gain in the Gps, MF, and M F + Gps groups
increased significantly (P < 0.01) , while the feed conversion ratio decreased significantly (P < 0.01) . The combined use of M F and Gps
showed a synergistic effect. There was no significant difference in villus height (cecal) between the exptl. group and the Con group.
The crypt depth of the three exptl. groups exhibited a significantly lower value compared to the Control group (P < 0.05) . The V/C
ratio of the Gps group and MF + Gps was significantly increased (P < 0.05) , but there was no signif icant difference in the MF group.
Moreover, the diarrhea rate of the Gps and the MF + Gps groups was lower than that of the Con group, while that of the M F + Gps
group decreased the mortality rate (P < 0.05). The serum tumor necrosis factor - alpha ( TN F-α) and interleukin 6 (IL-6) levels in the
MF, Gps, and M F + Gps groups decreased signifi cantly (P < 0.01) , the serum IgG (IgG) levels increased significantly (P < 0.01) , while
the combination of MF and Gps had a synerg istic effect. The combined use of Gps and M F not only further improved growth perfor
mance and immune parame ters, but also reduced the diarrhea rate and mortality.
Keywords: fermented feed ginseng polysaccharide intestinal development black bone chicken; Ginseng polysaccharide; Growth
performance; Immune parame ters; Microbial fermented feed; Synerg istic effect
253
Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion
By: Pallavi, Rani ; Gatti, Elena; Durfort, Tiphanie ; Stendardo, Massimo; Ravasio, Roberto ; Leonardi, Tommaso ; Falvo,
Paolo; Duso, Bruno Achutti ; Punzi, Simona; Xieraili, Aobuli; et al
Abstract: Caloric Restriction (CR) has established anti-cancer effects, but its clin. relevance and mol. mechanism remain largely
undefined. Here, we investigate CR′s impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyel ocytic
Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re- emerges.
Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is
associated with the non-genetic selection of Leukemia Initiating Cells and the downreg ulation of double-stranded RNA (dsRNA)
sensing and Interferon (IFN) signaling genes. The C R-induced adaptive phenotype is highly sensitive to pharmacol. or genetic
ablation of LSD1, a lysine demeth ylase regulating both stem cells and ds RNA/ IFN signaling. CR + LSD1 inhibition leads to the re-
activation of dsRNA/IFN signaling, massive R NASEL-dependent apoptosis, and complete leukemia eradication in ∼90% of mice.
Importantly, CR-LSD1 interaction can be modeled in vivo and in vitro by combining L SD1 ablation with pharmacol. inhibitors of
insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitizes blasts to LSD1-induced death by
inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-neg. breast
cancer xenografts. Our data provide a rationale for epi- metabolic pharmacol. combinations across multiple tumors.

254
Chalcone-derivative L6H21 attenuates the OVA-induced asthma by targeting MD2
By: Ge, Xiangting; Xu, Tingting; Wang, Meiyan; Gao, Lijiao; Tang, Yue; Zhang, Ningjie; Zheng, Rui; Zeng, Weimin; Chen, Gaozhi; Zhang,
Bing; et al
Abstract: Asthma represents a significant global challenge that affects indivi duals across all age groups and imposes substa ntial
social and economic burden. Due to heterogeneity of the disease, not all patients obtain benefit with current treatm ents. The
objective of this study was to explore the impact of MD2 on the progression of asthma using L6 H21, a novel M D2 inhibitor, to
identify potential targets and drug candidates for asthma treatment. To establish an asthma-related murine model and evaluate
the effects of L6H21, ovalbumin (OVA) was used to sensitize and challenge mice. Pathol. changes were examined with various
staining techniques, such as H&E staining, glycogen staining, and Masson staining. Inflam matory cell infilt ration and excessive
cytokine secretion were evaluated by analyzing BALF cell count, R T-PCR, and ELISA. The TLR4/MD2 complex formation, as well as the
activation of the MAPK and N F-B pathways, was examined using western blot and co- IP. Treatment with L6H21 demonstrated allevi
ation of increased airway resistance, lung tissue injury, inflammatory cell infilt ration and excessive cytokine secretion triggered by O
VA. In addition, it also ameliorated mucus production and collagen deposi tion. In the L6H21 treatment group, inhibition of MAPK
and NF-B activation was observed, along with the disruption of T LR4/MD2 complex formation, in contrast to the model group. Thus,
L6H21 effectively reduced the formation of the M D2 and TLR4 complex induced by O VA in a dose-dependent manner. This
reduction resulted in the attenuation of MAPKs/NF-κB activation, enhanced suppression of inflammatory factor secretion, reduced
excessive recruitment of inflammatory cells, and ultimately mitigated airway damage. M D2 emerges as a crucial target for asthma
treatment, and L6H21, as an MD2 inhibitor, shows promise as a potential drug candidate for the treatment of asthma.
Keywords: Asthma; Chalcone derivative; MD2 inhibitor; MD2 recombination; TLR4
255
Biomedical knowledge graph construction of Sus scrofa and its application in anti-PRRSV traditional
Chinese medicine discovery
By: Cui, Mingyang; Hao, Zhigang; Liu, Yanguang; Lv, Bomin; Zhang, Hongyu; Quan, Yuan; Qin, Li
Animal Diseases (2024), 4(1), 2 | Language: English, Database: CAplus
Abstract: As a new data management paradigm, knowledge graphs can integrate multiple data sources and achieve quick
responses, reasoning and better predictions in drug discovery. Characterized by powerful contagion and a high rate of morbidity
and mortality, porcine reproductive and respiratory syndrome (P RRS) is a common infectious disease in the global swine industry
that causes economically great losses. Traditional Chinese medicine (T CM) has advantages in low adverse effects and a relatively
affordable cost of application, and T CM is therefore conceived as a possib ility to treat PRRS under the current circumstance that
there is a lack of safe and effective approaches. Here, we constructed a knowledge graph containing common biomedical data from
humans and Sus Scrofa as well as information from thousands of T CMs. Subsequently, we validated the effectiveness of the Sus
Scrofa knowledge graph by the t-SNE algorithm and selected the optimal model (i.e., trans R) from six typical models, namely, trans
E, transR, DistMult, ComplEx, RESCAL and RotatE, according to five indica tors, namely, MRR, MR, HITS@1, HITS@3 and HITS@10.
Based on embedding vectors trained by the optimal model, anti-PRRSV TCMs were predicted by two paths, namely, V HC-Herb and V
HPC-Herb, and potential anti-PRRSV TCMs were identified by retrieving the H ERB database according to the pharmacol. properties
corresponding to symptoms of PRRS. Ultimately, Dan Shen′s (Salvia miltiorrhiza Bunge) capacity to resist PRRSV infection was
validated by a cell experiment in which the inhibition rate of PRRSV exceeded 90% when the concent rations of Dan Shen extract
were 0.004, 0.008, 0.016 and 0.032 mg/mL. In summary, this is the first report on the Sus Scrofa knowledge graph including T CM
information, and our study reflects the important applic ation values of deep learning on graphs in the swine industry as well as
providing accessible TCM resources for PRRS.

256
Microglia TREM1-mediated neuroinflammation contributes to central sensitization via the NF-κB

pathway in a chronic migraine model
By: Sun, Songtang; Fan, Zhenzhen; Liu, Xuejiao; Wang, Longde; Ge, Zhaoming
Journal of Headache and Pain (2024), 25(1), 3 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Neuroinflammation, mediated by the activation of microglia, contri butes to central sensitization, which is
associated with the development of chronic migraine (C M). TREM1 receptors amplify the inflammatory response. However, their
relationship to CM is unclear. Thus, this study endeav oured to elucidate the exact role of T REM1 in CM. Methods: Nitroglycerin (NTG)
was repeatedly administered i.p. to establish the C M model. Mech. and thermal sensiti vities were assessed using von Frey filaments
and hot plate assays. Using Western blotting, TREM1, NF-κB pathway, NLRP3 inflammasome components, and proinflammatory
cytokines were all detected. Immunofluorescence was used to examine the cellular distri bution of TREM1 and N LRP3, the number
of microglia, immunoreactivity, and morphol. changes. We examined the effects of T REM1 antagonists (LR12) and N F-κB inhibitors
(PDTC) on pain behavior, as well as the production of c- fos and CGRP. Addnl., we invest igated whether LR12 and PDTC affect the
activation of microglia and the NLRP3 inflammasome. We synthesized siRNA and TREM1-overexpressing plasmids to transfect BV2
cells treated with LPS and normal B V2 cells and treated T REM1-overexpressing BV2 cells with PDTC. The N F-κB pathway, NLRP3
inflammasome components, and proinflammatory cytokines were quantified using Western blotting. Results: Following N TG
administration, the expression of TREM1 was significantly upregulated and exclus ively localized in microglia in the T NC, and was
well co-localized with NLRP3. Furthermore, activation of the classical N F-κB pathway was observed Pre- treatment with LR12 and PD
TC effectively attenuated mech. hypersens itivity, suppressed the expression of c-fos and CGRP, and inhibited N F-κB activity in CM
mice. Addnl., inhibition of TREM1 and N F-κB activity mitigated NTG-induced microglia and N LRP3 activation, as well as proinfla
mmatory cytokines production In vitro, knockdown of T REM1 resulted in attenuated activation of the N F-κB pathway following
lipopolysaccharide (LPS) treatment and reduced expression of N LRP3 inflammasome components as well as proinfla mmatory
cytokines. After TREM1 overexpression, the NF-κB pathway was activated, N LRP3 inflammasome components and proinfla mmatory
cytokines were upregulated, and PDTC reversed this phenom enon. Conclusions: Our findings suggest that T REM1 regulates
microglia and NLRP3 activation via the NF-κB pathway, thereby contri buting to central sensitization and implicating its involvement
in chronic migraine pathogenesis.
Keywords: Central sensitization; Chronic migraine; Microglia; N F-κB; TREM1

257
Effect of micro-aeration on syntrophic and methanogenic activity in anaerobic sludge
By: Morais, Bruno P. ; Magalhaes, Carla P.; Martins, Gilberto ; Pereira, Maria Alcina ; Cavaleiro, Ana J.
Micro-aeration was shown to improve anaerobic digestion (A D) processes, although oxygen is known to inhibit obligate anaerobes,
such as syntrophic communities of bacteria and methan ogens. The effect of micro- aeration on the activity and microbial intera ction
in syntrophic communities, as well as on the potential establi shment of synergetic relationships with facultative anaerobic bacteria
(FAB) or aerobic bacteria (A B), was investigated. Anaerobic sludge was incubated with ethanol and increasing oxygen concent rations
(0-5% in the headspace). Assays with acetate or H2/CO2 (direct substrates for methanogens) were also performed. When compared
with the controls (0% O2), oxygen significantly decreased substrate consum ption and initial methane production rate (M PR) from
acetate or H2/CO2. At 0.5% O2, MPR from these substrates was inhibited 30- 40%, and close to 100% at 5% O2. With ethanol, signif
icant inhibition (>36%) was only observed for oxygen concent rations higher than 2.5%. Oxygen was consumed in the assays,
pointing to the stimulation of AB/FAB by ethanol, which helped to protect the syntrophic consortia under micro- aerobic conditions.
This highlights the importance of AB/FAB in maintaining functional and resilient syntrophic commun ities, which is relevant for real A
D systems (in which vestigial O2 amounts are frequently present), as well as for AD systems using micro-aeration as a process
strategy.
Keywords: anaerobic sludge microaeration syntrophic methanogenic activity; Facultative anaerobic bacteria; Methane; Micro-
aeration; Syntrophy
258
Fractionation of the Caspian sand goby epidermal exudates using membrane ultrafiltration and
reversed-phase chromatography: an investigation on bioactivities
By: Akhavan-Bahabadi, Mohammad; Paknejad, Hamed; Hedayati, Aliakbar; Habibi-Rezaei, Mehran

Abstract: Bioactive peptide-based drugs have gained exceeding attention as promising treatments for infectious and oxidative-
stress-related diseases, are exacerbated by the advent and spread of various multidrug- resistant bacteria and industrial lifest yles.
Fish skin mucus has been recognized as a potential source of bioactive peptides, providing the first line of fish defense against
invading pathogens which are targeted here to be explored as a new source of biopharmaceutics. Peptide fractions were isolated
from the epidermal exudates of Caspian sand goby, Neogobius fluviatilis pallasi, by solid-phase extraction (SPE), ultrafiltration, and
reversed-phase chromatog. The resulting fractions were characterized for their antibac terial and antioxidant properties, and results
showed that the mol. weight fraction < 5 kDa represented the highest (p < 0.05) bacterial inhibition activity against Staphylococcus
aureus and Bacillus subtilis as well as scavenging activity against DPPH and ABTS radicals. Overall, these results introduce the
epidermal mucus of Caspian sand goby as a valuable source of bioactive compounds that can be considered new and efficient
biopharmaceutics.

259
Spheroid architecture strongly enhances miR-221/222 expression and promotes oxidative

phosphorylation in an ovarian cancer cell line through a mechanism that includes restriction of miR-9
expression
By: Ward, Avery S.; Hall, Cody N.; Tree, Maya O.; Kohtz, D. Stave
Abstract: Background: Tumor cell spheroids are organized multice llular structures that form during the expansive growth of
carcinoma cells. Spheroids formation is thought to contribute to metastasis by supporting growth and survival of mobile tumor cell
populations. Methods and results: We invest igated how spheroid architecture affects OXPHOS activity, microRNA expression, and
i.p. survival of an ovarian carcinoma cell line using high resolution respirometry, quant. RT-PCR, and a rodent i.p. growth model.
Rates of oxidative phosphorylation/respiration per cell of cells growing as spheroids were nearly double those of a variant of the
same cell type growing in suspension as loosely aggregated cells. Further, inhibition of spheroid formation by treatment with C DH2
(N-cadherin) siRNA reduced the rate of O XPHOS to that of the non-spheroid forming variant. Cells growing as spheroids showed
greatly enhanced expression of miR-221/222, an oncomiR that targets multiple tumor suppressor genes and promotes invasion,
and reduced expression of miR-9, which targets mitochondrial tRNA-modification enzymes and inhibits O XPHOS. Consistent with
greater efficiency of ATP generation, tumor cells growing as spheroids injected into the nutrient- poor murine peritoneum survived
longer than cells growing in suspension as loosely associated aggregates. Conclusions: The data indicate that growth in spheroid
form enhances the OXPHOS activity of constituent tumor cells. In addition, spheroid archit ecture affects expression of microRNA
genes involved in growth control and mitochondrial function. During the mobile phase of metast asis, when ovarian tumor cells
disperse through nutrient-poor environments such as the peritoneum, enhanced OXPHOS activity afforded by spheroid archit
ecture would enhance survival and metastatic potential.
Keywords: Mitochondria; Ovarian cancer; Peritoneal Metast asis; Tumor cell spheroids; miR-221/222; miR-9
260
Attenuating human fear memory retention with minocycline: a randomized placebo-controlled trial
By: Xia, Yanfang ; Wehrli, Jelena; Abivardi, Aslan ; Hostiuc, Madalina; Kleim, Birgit; Bach, Dominik R.
Abstract: Pavlovian fear conditioning is widely used as a preclin. model to investigate methods for prevention and treatment of
anxiety and stress-related disorders. In this model, fear memory consoli dation is thought to require synaptic remode ling, which is
induced by signaling cascades involving matrix metalloproteinase 9 (M MP-9). Here we invest igated the effect of the tetracycline
antibiotic minocycline, an inhibitor of M MP-9, on fear memory retention. We conducted a pre- registered, randomized, double-blind,
placebo-controlled trial in N = 105 healthy humans (N = 70 female) , using a configural fear condit ioning paradigm. We administered
a single dose of minocycline before configural fear memory acquis ition and assessed fear memory retention seven days later in a
recall test. To index memory retention, we pre-registered fear-potentially startle (FPS) as our primary outcome, and pupil dilation as
the secondary outcome. As control indexes of memory acquisition, we analyzed skin conduc tance responses (SCR) and pupil
dilation. We observed attenuated retention of configural fear memory in individuals treated with minocycline compared to placebo,
as measured by our primary outcome. In contrast, minocycline did not affect fear memory acquis ition or declarative contingency
memory. Our findings provide in-vivo evidence for the inhibition of fear memory consolidation by minocycline. This could motivate
further research into primary prevention, and given the short uptake time of minocy cline, potentially also secondary prevention of
PTSD after trauma.

261
Exosome lncRNA IFNG-AS1 derived from mesenchymal stem cells of human adipose ameliorates
neurogenesis and ASD-like behavior in BTBR mice
By: Fu, Yu; Zhang, Yuan-lin; Liu, Rong-qi; Xu, Meng-meng; Xie, Jun-ling; Zhang, Xing-liao; Xie, Guang-ming; Han, Yao-ting; Zhang, Xin-
Min; Zhang, Wan-ting; et al
Abstract: Background: The transplantation of exosomes derived from human adipose- derived mesenchymal stem cells (hADSCs)
has emerged as a prospective cellular-free therapeutic intervention for the treatment of neurodeve lopmental disorders (NDDs), as
well as autism spectrum disorder (ASD). Nevertheless, the efficacy of h ADSC exosome transpla ntation for ASD treatment remains to
be verified, and the underlying mechanism of action remains unclear. Results: The exosomal long non-coding RNAs (lncRNAs) from
hADSC and human umbilical cord mesenc hymal stem cells (hUCMSC) were sequenced and 13,915 and 729 lnc RNAs were obtained,
resp. The lncRNAs present in h ADSC-Exos encompass those found in hUCMSC-Exos and are associated with neuroge nesis. The
biodistribution of hADSC-Exos in mouse brain ventricles and organoids was tracked, and the cellular uptake of h ADSC-Exos was
evaluated both in vivo and in vitro. hADSC-Exos promote neurogenesis in brain organoid and ameliorate social deficits in A SD
mouse model BTBR T + tf/J (B TBR). Fluorescence in situ hybridi zation (FISH) confirmed lncRNA Ifngas1 significantly increased in the
prefrontal cortex (PFC) of adult mice after h ADSC-Exos intraventricular injection. The lncRNA Ifngas1 can act as a mol. sponge for mi
R-21a-3p to play a regulatory role and promote neurog enesis through the miR-21a-3p/PI3K/AKT axis. Conclu sion: We demonstrated
hADSC-Exos have the ability to confer neuroprotection through functional restoration, attenuation of neuroinflammation,
inhibition of neuronal apoptosis, and promotion of neurog enesis both in vitro and in vivo. The h ADSC-Exos-derived lncRNA IFNG-A
S1 acts as a mol. sponge and facili tates neurogenesis via the miR-21a-3p/PI3K/AKT signaling pathway, thereby exerting a regulatory
effect. Our findings suggest a potential therapeutic avenue for indivi duals with ASD. Graphical Abstract: [graphic not available: see
fulltext]
Keywords: Neurogenesis; hADSC-Exos; hUCMSC-Exos; lncRNA IFNG-AS1; miR-21a-3p

262
Transcriptional response of Saccharomyces cerevisiae to lactic acid enantiomers
By: Drozdova, Polina ; Gurkov, Anton ; Saranchina, Alexandra ; Vlasevskaya, Anastasia ; Zolotovskaya, Elena ; Indosova,
Elizaveta ; Timofeyev, Maxim ; Borvinskaya, Ekaterina
Abstract: The model yeast, Saccharomyces cerevisiae, is a popular object for both fundam ental and applied research, including the
development of biosensors and industrial production of pharmac eutical compounds However, despite multiple studies exploring S.
cerevisiae transcriptional response to various substances, this response is unknown for some substances produced in yeast, such
as D-lactic acid (DLA). Here, we explore the transcri ptional response of the BY4742 strain to a wide range of D LA concentrations
(from 0.05 to 45 mM), and compare it to the response to 45 mM L-lactic acid (LLA). We recorded a response to 5 and 45 m M DLA
(125 and 113 differentially expressed genes (DEGs), resp.; > 50% shared) and a less pronounced response to 45 m M LLA (63 DEGs;
> 30% shared with at least one DLA treatment). Our data did not reveal natural yeast promoters quant. sensing D LA but provide the
first description of the transcriptome-wide response to DLA and enrich our underst anding of the LLA response. Some DLA-
activated genes were indeed related to lactate metabo lism, as well as iron uptake and cell wall structure. Addnl. analyses showed
that at least some of these genes were activated only by acidic form of DLA but not its salt, revealing the role of p H. The list of LLA-
responsive genes was similar to those published previously and also included iron uptake and cell wall genes, as well as genes
responding to other weak acids. These data might be instrumental for optimization of lactate production in yeast and yeast co-
cultivation with lactic acid bacteria. Key points: • We present the first dataset on yeast transcri ptional response to DLA. • Differential
gene expression was correlated with yeast growth inhibition . • The transcriptome response to DLA was richer in comparison to LL
A.
Keywords: Budding yeast; D-lactate; L-lactate; Lactic acid; Low p H stress; RNA-seq

263
Long non-coding RNA ACTA2-AS1 suppresses metastasis of papillary thyroid cancer via regulation of
miR-4428/KLF9 axis
By: Wu, Shuhui; Zhu, Jingjing; Jiang, Tingting; Cui, Ting; Zuo, Qi; Zheng, Guibin; Li, Guojun; Zhou, Jieyu; Chen, Xiang
Abstract: Background: Metastasis is the primary cause of recurrence and death in patients with papillary thyroid carcinoma (P TC).
LncRNA ACTA2-AS1, a long non-coding RNA, acts as a tumor suppressor in multiple types of human maligna ncies, while the role of A
CTA2-AS1 in PTC metastasis remains unclear. Methods: The A CTA2-AS1 expression in PTC tissues was analyzed. The sponged roles
of ACTA2-AS1 via miR-4428/KLF9 axis were identified using starBase tool. The function of ACTA2-AS1 in PTC was performed with in
vitro and in vivo experiments The correlation between DNA methylation and mRNA expressions of these gene in the T CGA dataset
was explored. Results: ACTA2-AS1 expression was downregulated in PTC tissues without metastasis and further decreased in P TC
tissues with lymph node metastasis compared with that in normal tissues. Functionally, the overexpression of ACTA2-AS1 inhibited
the growth, proliferation, and invasion of PTC cells, whereas its depletion exerted opposite effect. In vivo, A CTA2-AS1 expression
inhibited PTC metastasis. Furthermore, ACTA2-AS1 acted as a competing endogenous R NA for mi R-4428, thereby pos. regulating the
expression of miR-4428 target gene, KLF9. Finally, mi R-4428 overexpression enhanced invasive potential of PTC cells and signifi
cantly weakened the effects of A CTA2-AS1 on promotion and inhibition of KLF9 expression as well as invasive ability of P TC cells,
resp. In the TCGA dataset, the methylation level of ACTA2-AS1 was significantly correlated with its m RNA expression (r = 0.21, p =
2.1 x e-6). Conclusions: Our findings demonstrate that ACTA2-AS1 functions as a tumor suppressor in P TC progression at least partly
by regulating the miR-4428-dependent expression of KLF9. Graphical abstract: [graphic not available: see fulltext]
Keywords: ACTA2-AS1; KLF9; Papillary thyroid carcinoma; lnc RNA; miR-4428

264
Host-pathogen interaction between pitaya and Neoscytalidium dimidiatum reveals the mechanisms of
immune response associated with defense regulators and metabolic pathways
By: Wang, Meng; Wang, Zhouwen; Ding, Yi; Kang, Shaoling; Jiang, Senrong; Yang, Zhuangjia; Xie, Zhan; Wang, Jialin; Wei,
Shuangshuang; Huang, Jiaquan; et al
Understanding how plants and pathogens regulate each others gene expression during their intera ctions is key to revealing the
mechanisms of disease resistance and controlling the development of pathogens. Despite extensive studies on the mol. and genetic
basis of plant immunity against pathogens, the influence of pitaya immunity on N. dimidiatum metabolism to restrict pathogen
growth is poorly understood, and how N. dimidiatum breaks through pitaya defenses. In this study, we used the R NA-seq method
to assess the expression profiles of pitaya and N. dimidiatum at 4 time periods after interactions to capture the early effects of N.
dimidiatum on pitaya processes. The study defined the establishment of an effective method for analyzing transcr iptome intera
ctions between pitaya and N. dimidiatum and to obtain global expression profiles. We identified gene expression clusters in both
the host pitaya and the pathogen N. dimidiatum. The anal. showed that numerous differentially expressed genes (DEGs) involved in
the recognition and defense of pitaya against N. dimidi atum, as well as N. dimidi atums evasion of recognition and inhibition of
pitaya. The major functional groups identified by GO and KEGG enrichment were responsible for plant and pathogen recognition,
phytohormone signaling (such as salicylic acid, abscisic acid) . Furthermore, the gene expression of 13 candidate genes involved in
phytopathogen recognition, phytohormone receptors, and the plant resistance gene (P G), as well as 7 effector genes of N. dimidi
atum, including glycoside hydrolases, pectinase, and putative genes, were validated by q PCR. By focusing on gene expression
changes during interactions between pitaya and N. dimidi atum, we were able to observe the infection of N. dimidiatum and its
effects on the expression of various defense components and host immune receptors. Our data show that various regulators of the
immune response are modified during interactions between pitaya and N. dimidi atum. Furthermore, the activation and repression
of these genes are temporally coordinated. These findings provide a framework for better underst anding the pathogenicity of N.
dimidiatum and its role as an opportunistic pathogen. This offers the potential for a more effective defense against N. dimidi atum.
Keywords: cytochromeP450 cytochrome c oxidase pectinase signaling Neoscyta lidium; Host–pathogen interaction; N.dimidiatum;
Pitaya canker; Transcriptomics

265
MicroRNA-377-3p exacerbates chronic obstructive pulmonary disease through suppressing ZFP36L1

expression and inducing lung fibroblast senescence
By: Lu, Fang; Yao, Li-peng; Gao, Dan-dan; Alinejad, Tahereh; Jiang, Xin-qing; Wu, Qi; Zhai, Qiao-cheng; Liu, Ming; Zhu, Sheng-mei;
Qian, Mao-xiang; et al
Abstract: Chronic obstructive pulmonary disease (COPD) is a leading aging related cause of global mortality. Small airway narrowing
is recognized as an early and significant factor for COPD development. Senescent fibrob lasts were observed to accumulate in lung
of COPD patients and promote C OPD progression through aberrant extracellular matrix (ECM) deposition and senescence-
associated secretory phenotype (SASP). On the basis of our previous study, we further invest igated the the causes for the increased
levels of miR-377-3p in the blood of C OPD patients, as well as its regulatory function in the pathol. progre ssion of COPD. We found
that the majority of up-regulated miR-377-3p was localized in lung fibrob lasts. Inhibition of miR-377-3p improved chronic smoking-
induced COPD in mice. Mechanistically, miR-377-3p promoted senescence of lung fibrob lasts, while knockdown of mi R-377-3p
attenuated bleomycin-induced senescence in lung fibroblasts. We also identified ZFP36L1 as a direct target for mi R-377-3p that
likely mediated its pro senescence activity in lung fibroblasts. Our data reveal that mi R-377-3p is crucial for C OPD pathogenesis, and
may serve as a potential target for COPD therapy.
Keywords: COPD; Lung fibroblast; Senescence; ZFP36L1; miR-377-3p
266
Evaluation of ionic liquids based imidazolium salts as an environmentally friendly corrosion inhibitors
for carbon steel in HCl solutions
By: El-Nagar, Raghda A.; Khalil, N. A.; Atef, Y.; Nessim, Maher I.; Ghanem, Alaa
The features of this work on corrosion inhibition have been invest igated based on the ecol. awareness and according to the strict
environmental legislations. This was done by studying how different imidaz olium derivatives ionic liquids containing different alkyl
chains R8, R10 and R12 affected the corrosion reaction of carbon steel specimen immersed in 1 M hydroc hloric acid at various
temperatures Weight loss, potentio dynamic polarization and electr ochem. impedance spectroscopy were utilized to examine the
corrosion inhibition behavior on carbon steel. In addition, F T-IR spectroscopy was used to analyze the coated film that has been
formed on the metal surface. The prepared ionic liquids showed effective inhibition efficiency, where the corrosion rate after the
using of 100 ppm of R8-IL, R10 -IL and R12 -IL was decreased from 5.95 (μg cm -2 min-1) to 0.66, 0.56, and 0.44 (μg cm -2 min-1), resp. at
20 °C. In the polarization curves, the corrosion current, Icorr, decreases by I Ls addition and suggest that I Ls act as mixed type inhibi
tors. From EIS findings, the increase in Rct and decrease in Cdl values proves the adherence of inhibitor mols. on carbon steel
surface. The temperature effect was also studied on the film formed, where increasing the temper ature from 20 to 50 °C, the
corrosion rate increased and the inhibitors efficacy decreased. The increasing in the length of the attached alkyl chain, the efficacies
of the prepared inhibitors increases. Various thermodn. parameters such as the reaction activation free energy (ΔG*), the entropy
of activation (ΔS*), and the enthalpy of activation (ΔH*), as well as the adsorption isotherm were invest igated in order to interpret
the mechanism and obtain the most accurate perception.
Keywords: ionic liquid imidazolium salt corrosion inhibitor carbon steel hcl

267
Identification of potential inhibitor against Leishmania donovani mitochondrial DNA primase through
in-silico and in vitro drug repurposing approaches
By: Nath, Mitul; Bhowmik, Deep; Saha, Satabdi; Nandi, Rajat; Kumar, Diwakar
Abstract: Leishmania donovani is the causal organism of leishmaniasis with critical health implic ations affecting about 12 million
people around the globe. Due to less efficacy, adverse side effects, and resistance, the available therapeutic mols. fail to control
leishmaniasis. The mitochondrial primase of Leishmania donovani (Ldmt PRI1) is a vital cog in the D NA replication mechanism, as
the enzyme initiates the replication of the mitochondrial genome of Leishmania donovani. Hence, we target this protein as a
probable drug target against leishmaniasis. The de-novo approach enabled computational prediction of the three-dimensional
structure of LdmtPRI1, and its active sites were identi fied. Ligands from com. available drug compounds were selected and docked
against LdmtPRI1. The compounds were chosen for pharmaco kinetic study and mol. dynamics simulation based on their binding
energies and protein interactions. The LdmtPRI1 gene was cloned, overexp ressed, and purified, and a primase activity assay was
performed. The selected compounds were verified exptl. by the parasite and primase inhibition assay. Capecitabine was observed
to be effective against the promastigote form of Leishmania donovani, as well as inhibiting primase activity. This study′s findings
suggest capecitabine might be a potential anti-leishmanial drug candidate after adequate further studies.
268
ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial
function via AMPK- PPARα- CPT1A axis
By: Dong, Jian; Li, Muzi; Peng, Runsheng; Zhang, Yuchuan; Qiao, Zilin; Sun, Na
Abstract: Background: Non-alc. fatty liver disease (N AFLD) is a multifaceted metabolic disorder, whose global prevalence is rapidly
increasing. Acetyl CoA carboxylases 1 (ACACA) is the key enzyme that controls the rate of fatty acid synthesis. Hence, it is crucial to
investigate the function of ACACA in regulating lipid metabolism during the progress of N AFLD. Methods: Firstly, a fatty liver mouse
model was established by high-fat diet at 2nd, 12th, and 20th week, resp. Then, transcr iptome anal. was performed on liver samples
to investigate the underlying mechanisms and identify the target gene of the occurrence and develo pment of NAFLD. Afterwards,
lipid accumulation cell model was induced by palmitic acid and oleic acid (P A : OA molar ratio = 1:2). Next, we silenced the target
gene ACACA using small interf ering RNAs (siRNAs) or the CMS-121 inhibitor. Subsequently, experiments were performed comprehe
nsively the effects of inhibiting ACACA on mitochondrial function and lipid metabo lism, as well as on AMPK- PPARα- CPT1A pathway.
Results: This data indicated that the pathways significantly affected by high- fat diet include lipid metabolism and mitocho ndrial
function. Then, we focus on the target gene ACACA. In addition, the in vitro results suggested that inhibiting of A CACA in vitro
reduces intracellular lipid accumul ation, specifically the content of TG and TC. Furthermore, ACACA ameliorated mitochondrial
dysfunction and alleviate oxidative stress, including M MP complete, ATP and ROS production, as well as the expression of mitoch
ondria respiratory chain complex (MRC) and AMPK proteins. Meanwhile, A CACA inhibition enhances lipid metabolism through
activation of PPARα/CPT1A, leading to a decrease in intrace llular lipid accumul ation. Conclusion: Targeting ACACA can reduce lipid
accumulation by mediating the A MPK- PPARα- CPT1A pathway, which regulates lipid metabolism and alleviates mitocho ndrial
dysfunction.
Keywords: ACACA; AMPK/PPARα/CPT1A; Mitochondrial dysfunction; NAFLD

269
Mechanisms by which silencing long-stranded noncoding RNA KCNQ1OT1 alleviates myocardial

ischemia/reperfusion injury (MI/RI)-induced cardiac injury via miR-377-3p/HMOX1
By: Tan, Tongcai; Tu, Liang; Yu, Yanmei; He, MinJie; Zhou, Xingchao; Yang, Lei
BMC Cardiovascular Disorders (2024), 24(1), 19 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The key complication of myocardial infarction therapy is myocardial ischemia/reperfusion injury (M I/RI), and
there is no effective treatment. The present study elucidates the mechanism of action of lncRNA KCNQ1OT1 in alleviating MI/RI and
provides new perspectives and therapeutic targets for cardiac injury- related diseases. Methods: An ischemia/reperfusion (I/R) injury
model of human adult cardiac myocytes (HACMs) was constructed, and the expression of K CNQ1OT1 and mi R-377-3p was
determined by RT-qPCR. The levels of related proteins were detected by western blot anal. Cell prolife ration was detected by a C CK-
8 assay, and cell apoptosis and R OS content were determined by flow cytometry. S OD and MDA expression as well as Fe 2+ changes
were detected by related anal. kits. The target binding relationships between lnc RNA KCNQ1OT1 and mi R-377-3p as well as
between miR-377-3p and heme oxygenase 1 (H MOX1) were verified by a dual- luciferase reporter gene assay. Results: Myocardial
ischemia-reperfusion caused oxidative stress in H ACMs, resulting in elevated R OS levels, increased Fe 2+ levels, decreased cell
viability, and increased LDH release (a marker of myocardial injury), and apoptosis. KCNQ1OT1 and HMOX1 were upregulated in
I/R-induced myocardial injury, but the level of mi R-377-3p was decreased. A dual- luciferase reporter gene assay indicated that lnc R
NA KCNQ1OT1 targets mi R-377-3p and that mi R-377-3p targets HMOX1. Inhibition of HMOX1 alleviated miR-377-3p downregu
lation-induced myocardial injury. Furthermore, lncRNA KCNQ1OT1 promoted the level of H MOX1 by binding to mi R-377-3p and
aggravated myocardial injury. Conclusion: LncRNA KCNQ1OT1 aggravates ischemia-reperfusion-induced cardiac injury via mi R-377-
3P/HMOX1.
Keywords: HMOX1; Myocardial ischemia-reperfusion injury; Oxidative stress; lnc RNA KCNQ1OT1; miR-377-3p
270
Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use
By: Worthmann, Anna; Ridder, Julius; Piel, Sharlaine Y. L.; Evangelakos, Ioannis ; Musfeldt, Melina; Voss, Hannah; O'Farrell, Marie;
Fischer, Alexander W. ; Adak, Sangeeta; Sundd, Monica; et al
Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of
endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determ inants of PUFA
incorporation into complex lipids are insufficiently understood and may influence the onset and progre ssion of metabolic diseases.
Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary P UFA in mice and
humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylg lycerols (TAG) in mice
fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFS
D2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into T AG. Overall, the outcome of P UFA
supplementation may depend on the degree of endogenous D NL and combining PUFA supplementation and FASN inhibition
might be a promising approach to target metabolic disease.
Keywords: fatty acid synthase DGAT2 LPIN1 triacylglycerol lipogenesis metabolic disease

271
A potential patient stratification biomarker for Parkinson′s disease based on LRRK2 kinase-mediated
centrosomal alterations in peripheral blood-derived cells
By: Naaldijk, Yahaira ; Fernandez, Belen; Fasiczka, Rachel; Fdez, Elena; Leghay, Coline; Croitoru, Ioana; Kwok, John B.; Boulesnane,
Yanisse; Vizeneux, Amelie; Mutez, Eugenie; et al
Abstract: Parkinson′s disease (PD) is a common neurodegenerative movement disorder and leucine- rich repeat kinase 2 (LRRK2) is a
promising therapeutic target for disease interve ntion. However, the ability to stratify patients who will benefit from such treatment
modalities based on shared etiol. is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are
commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centro
somal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to invest igate whether such deficits may serve
as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we charact erized patient-derived cells from
distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early- stage idiopathic PD patients which
is mitigated by LRRK2 kinase inhibition , supporting a role for aberrant L RRK2 activity in idiopathic PD. Centrosomal defects are
detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they
accumulate prior to a clin. PD diagnosis. They are present in immort alized cells as well as in primary lymphocytes from peripheral
blood. These findings indicate that anal. of centrosomal defects as a blood-based patient stratification biomarker may help
nominate idiopathic PD patients who will benefit from L RRK2-related therapeutics.
272
Antibiofilm and antivirulence activities of laminarin-gold nanoparticles in standard and host-mimicking

media
By: Tabassum, Nazia; Khan, Fazlurrahman; Jeong, Geum-Jae; Oh, Dokyung; Kim, Young-Mog
Abstract: The rapidly rising antimicrobial resistance (AMR) in pathogenic bacteria has become one of the most serious public health
challenges, with a high death rate. Most pathogenic bacteria have been recognized as a source of A MR and a primary barrier to
antimicrobial treatment failure due to the develo pment of biofilms and the production of virulence factors. In this work, nanote
chnol. was employed as a substitute method to control the formation of biofilms and attenuate virulence features in Pseudo monas
aeruginosa and Staphylococcus aureus. We synthe sized biocompatible gold nanoparticles from marine-derived laminarin as
potential biofilm and virulence treatments. Laminarin-gold nanoparticles (Lam-AuNPs) have been identified as spherical, 49.84 ±
7.32 nm in size and - 26.49 ± 1.29 mV zeta potential. The M IC value of Lam- AuNPs against several drug-resistant microbial
pathogens varied from 2 to 1024 μg/mL in both standard and host- mimicking media. Sub-MIC values of Lam-AuNPs were reported
to effectively reduce the production of P. aeruginosa and S. aureus biofilms in both standard and host- mimicking growth media.
Furthermore, the sub-MIC of Lam-AuNPs strongly reduced hemolysis, pyocyanin, pyover dine, protease, and several forms of
flagellar and pili-mediated motility in P. aeruginosa. Lam-AuNPs also inhibited S. aureus hemolysis and the production of amyloid
fibrils. The Lam-AuNPs strongly dispersed the preformed mature biofilm of these pathogens in a dose- dependent manner. The
Lam-AuNPs would be considered an alternative antibiofilm and antivirulence agent to control P. aeruginosa and S. aureus infect
ions. Key points: • Lam-AuNPs were biosynthesized to control biofilm and virulence. • Lam- AuNPs show effective biofilm inhibition
in standard and host-mimicking media. • Lam-AuNPs suppress various virulence factors of P. aeruginosa and S. aureus.
Keywords: Antibiofilm; Antivirulence; Gold nanoparticles; Host-mimicking media; Laminarin; Pseudomonas aeruginosa; Staphyl
ococcus aureus

273
Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity
and liver pathogenesis
By: Dong, Ting; Hu, Guangan ; Fan, Zhongqi; Wang, Huirui; Gao, Yinghui; Wang, Sisi; Xu, Hao; Yaffe, Michael B. ; Vander Heiden,
Matthew G. ; Lv, Guoyue ; et al
Abstract: Kupffer cells are liver resident macrophages and play critical role in fatty liver disease, yet the underlying mechanisms
remain unclear. Here, we show that activation of G-protein coupled receptor 3 (G PR3) in Kupffer cells stimulates glycolysis and
protects mice from obesity and fatty liver disease. GPR3 activation induces a rapid increase in glycolysis via formation of complexes
between β-arrestin2 and key glycolytic enzymes as well as sustained increase in glycolysis through transcr iption of glycolytic genes.
In mice, GPR3 activation in Kupffer cells results in enhanced glycol ysis, reduced inflammation and inhibition of high-fat diet induced
obesity and liver pathogenesis. In human fatty liver biopsies, G PR3 activation increases expression of glycolytic genes and reduces
expression of inflammatory genes in a population of disease- associated macrophages. These findings identify G PR3 activation as a
pivotal mechanism for metabolic reprogramming of Kupffer cells and as a potential approach for treating fatty liver disease.
274
Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early

triple negative breast cancers
By: Derouane, Francoise; Desgres, Manon; Moroni, Camilla; Ambroise, Jerome; Berliere, Martine; Van Bockstal, Mieke R.; Galant,
Christine; van Marcke, Cedric; Vara-Messler, Marianela; Hutten, Stefan J.; et al
Abstract: Background: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early- stage triple neg. breast
cancers (TNBC). However, more than half of T NBC patients do not achieve a pathol. complete response (p CR) after N AC, and
residual cancer burden (RCB) is associated with dismal long- term prognosis. Underst anding the mechanisms underlying differential
treatment outcomes is therefore critical to limit RCB and improve N AC efficiency. Methods: Human TNBC cell lines and patient-
derived organoids were used in combin ation with real-time metabolic assays to evaluate the effect of N AC (paclitaxel and
epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre- NAC) from patients with early T NBC were
analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycol ysis-related gene signature. Results: Paclitaxel induced
a consistent metabolic switch to glycolysis, correlated with a reduced mitocho ndrial oxidative metabo lism, in TNBC cells. In pre-NAC
diagnostic biopsies from TNBC patients, glycolysis was found to be upregu lated in non-responders. Furthermore, glycolysis
inhibition greatly improved response to N AC in TNBC organoid models. Conclu sions: Our study pinpoints a metabolic adaptation to
glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycol ysis-related genes as
predictive biomarkers for NAC response, as well as the develo pment of inhibitors to overcome this glycol ysis-driven resistance to N
AC in human T NBC patients.
Keywords: Early triple negative breast cancer; Glycolysis; Metabolism; Neoadjuvant chemotherapy; Organoids; Therapy resistance

275
Hyperactivation and enhanced cytotoxicity of reduced CD8 + gamma delta T cells in the intestine of
patients with Crohn′s disease correlates with disease activity
By: Zhu, Tao; Zhu, Linlin; Sheng, Caixia; Wu, Danju; Gu, Qianru; Jiang, Zhinong; Xu, Jiaqi; Fu, Guoxiang; Jiang, Yujie
BMC Immunology (2024), 25(1), 15 | Language: English, Database: CAplus and MEDLINE
Abstract: Background and aims: We aimed to investigate the immune characte ristics of intestinal C D8+ gamma delta T (C D8+ γδ T)
cells in Crohn′s disease (CD) and their correlation with disease activity. Methods: The study cohorts included 21 C D patients and 21
healthy individuals. CD8+ γδ T cells were isolated from human ileal mucosa for detection by flow cytometry. The activation or
inhibition status of cells was detected by detecting the expression of activation marker H LA-DR and the immunosuppressive mol. P
D-1 on cells. The cytotoxicity of cells was assessed by detecting the expression of cytotoxic mols. (Perforin, Granzyme B, and T RAIL)
in cells. Ratios of investigated cells were calculated as prediction factors by receiver operating charact eristic curve (ROC) anal.
Results: The study revealed a reduction in intestinal CD8+ γδT cells among active C D patients, with a more pronounced reduction
observed in moderately active patients compared to mildly active patients. Moreover, active CD patients exhibited heightened
activation levels in their intestinal CD8+ γδT cells, whereas the activation was compara tively weakened in moderately active patients
compared with mildly active patients. Addnl., the cytotoxicity of intestinal CD8+ γδT cells was enhanced solely in mildly active
patients, while it was impaired in moderately active patients compared with mildly active patients. Furthermore, HLA-DR+ CD8+ γδT
cell ratio, CD8+ γδT ratio, and C D8+ γδT count were identified as indicators in the diagnosis of active C D. Meanwhile, the ratios of
Granzyme B+ CD8+ γδT cell and Perforin + CD8+ γδT cell were identified as indicators that distin guish mildly moderately active C D
cases. Conclusions: Intestinal CD8+ γδT was reduced in active C D patients, but their activation and cytoto xicity were enhanced.
However, with increased disease activity, intestinal CD8+ γδ T cells became dysfunc tional. CD-specific perturbations observed in
various phenotypic markers in CD8+ γδ T cells can be used as indicators to assist in diagnosing C D patients.
Keywords: CD8+ gamma delta T cell; Crohn’s disease; Disease activity; Immune characte ristics

276
Delineation and authentication of ferroptosis genes in ventilator-induced lung injury
By: Huang, Enhao; Han, Hanghang; Qin, Ke; Du, Xueke

BMC Medical Genomics (2024), 17(1), 31 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Mech. ventilation, a critical support strategy for indivi duals enduring severe respiratory failure and general
anesthesia, paradoxically engenders ventilator-induced lung injury (VILI). Ferrostatin-1 mitigates lung injury via ferroptosis
inhibition , yet the specific ferroptosis genes contributing significantly to VILI remain obscure. Methods: Leveraging the Gene
Expression Omnibus database, we acquired VILI-associated datasets and identified differe ntially expressed genes (DEGs). To
identify the hub genes, we constructed a protein-protein interaction network and used three parameters from Cyto Hubba.
Consequently, we identified hub genes and ferrop tosis genes as ferroptosis hub genes for V ILI (VFHGs). We conducted enrichment
anal. and established receiver operating characteristic (ROC) curves for VFHGs. Subsequently, to confirm the correctness of the VFH
Gs, control group mice and VILI mouse models, as well as external dataset valida tion, were established. For further research, a
gene-miRNA network was established. Finally, the C IBERSORT algorithm was used to fill the gap in the immune infilt ration changes
in the lung during VILI. Results: We identified 64 D EGs and 4 VFHGs (Il6,Ptgs2,Hmox1 and Atf3) closely related to ferrop tosis. ROC
curves demonstrated the excellent diagnostic performance of VFHGs in VILI. PCR and external dataset validation of the V ILI model
demonstrated the accuracy of VFHGs. Subsequently, the gene-miRNA network was successfully established. Ultimately, an Immune
cell infiltration anal. associated with VILI was generated. Conclusions: The results emphasize the importance of 4 V FHGs and their
involvement in ferroptosis in VILI, confirming their potential as diagnostic biomarkers for V ILI.
Keywords: Bioinformatics; Biomarkers; Ferroptosis; Ventilator-induced lung injury
277
Antimicrobial activity of lipids extracted from Hermetia illucens reared on different substrates
By: Franco, Antonio; Scieuzo, Carmen; Salvia, Rosanna; Pucciarelli, Valentina; Borrelli, Luca; Addeo, Nicola Francesco; Bovera, Fulvia;
Laginestra, Ambrogio; Schmitt, Eric; Falabella, Patrizia
As the problem of antimicrobial resistance is constantly increasing, there is a renewed interest in antimic robial products derived
from natural sources, particularly obtained from innovative and eco-friendly materials. Insect lipids, due to their fatty acid compos
ition, can be classified as natural antimic robial compounds In order to assess the antibac terial efficacy of Hermetia illucens lipids,
we extracted this component from the larval stage, fed on different substrates and we characterized it. Moreover, we analyzed the
fatty acid composition of the feeding substrate, to determine if and how it could affect the antimic robial activity of the lipid
component. The antimicrobial activity was evaluated against Gram- pos. Micrococcus flavus and Gram-neg. bacteria Escherichia coli.
Analyzing the fatty acid profiles of larval lipids that showed activity against the two bacterial strains, we detected significant differ
ences for C4: 0, C10:0, C16:1, C18:3 n3 (ALA), and C20:1. The strongest antimicrobial activity was verified against Microc occus flavus
by lipids extracted from larvae reared on strawberry, tangerine, and fresh manure substr ates, with growth inhibition zones ranged
from 1.38 to 1.51 mm, while only the rearing on manure showed the effect against Escherichia coli. Notably, the fatty acid profile of
H. illucens seems to not be really influenced by the substrate fatty acid profile, except for C18:0 and C18:2 CIS n6 (LA). This implies
that other factors, such as the rearing conditions, larval development stages, and other nutrients such as carbohy drates, affect the
amount of fatty acids in insects. Feeding substrates influence larval lipids and fatty acids (FA) • Generally, there is no direct correl
ation between substrate F As and the same larvae F As • Specific FAs influence more the antimic robial effect of B SF lipids.
Keywords: Hermetia feeding linoleic acid antibacterial Escherichia bacterial infection; Antimicrobial resistance; Black soldier fly;
Fatty acids; Insects oil

278
Discovery of a small molecule that inhibits Bcl-3-mediated cyclin D1 expression in melanoma cells
By: Saamarthy, Karunakar; Ahlqvist, Kristofer; Daams, Renee; Balagunaseelan, Navisraj; Rinaldo-Matthis, Agnes; Kazi, Julhash U.;
Sime, Wondossen; Massoumi, Ramin
Abstract: Mol. targeted therapy using a drug that suppresses the growth and spread of cancer cells via inhibition of a specific
protein is a foundation of precision medicine and treatment. High expression of the proto-oncogene Bcl-3 promotes the prolife
ration and metastasis of cancer cells origin ating from tissues such as the colon, prostate, breast, and skin. The develo pment of
novel drugs targeting Bcl-3 alone or in combination with other therapies can cure these patients or prolong their survival. As a proof
of concept, in the present study, we focused on metastatic melanoma as a model system. High-throughput screening and in vitro
experiments identified BCL3ANT as a lead mol. that could interfere with Bcl- 3-mediated cyclin D1 expression and cell prolife ration
and migration in melanoma. In exptl. animal models of melanoma, it was demonstrated that the use of a Bcl- 3 inhibitor can
influence the survival of melanoma cells. Since there are no other inhibitors against Bcl-3 in the clin. pipeline for cancer treatment,
this presents a unique opportunity to develop a highly specific drug against malignant melanoma to meet an urgent clin. need.
Keywords: Bcl-3; Cyclin D1; Melanoma; Proliferation
279
Effect of lignin in cellulose nanofibers on biodegradation and seed germination
By: Stocker, Craig W.; Wong, Vanessa N. L.; Patti, Antonio F.; Garnier, Gil
Chemical and Biological Technologies in Agriculture (2024), 11(1), 15 | Language: English, Database: CAplus
Abstract: Pure cellulose nanofibers (CNFs) rapidly degrade in soil, limiting their prospe ctive applications in agriculture. We incorp
orated lignin into CNFs as an antimicrobial and crossl inking agent to control the biodegradation rate. CNFs with different lignin
concentrations were prepared by mechan ochem. treatment in the presence of choline chloride- urea deep eutectic solvent. These
were characterized using conductometric titration, SEM, and FT-IR. The fibers were applied to soil to determine the effect of lignin
on soil respiration and nanocellulose degradation, and were used as a substrate for radish and cress seed germin ation. Modifying
the lignin content of the fibers successfully modulated the biodegradation rate in soil. Fibers containing 35% lignin degraded 5.7%
in 14 days, while fibers with 20% lignin degraded 20.8% in 14 days. Nanofiber suspensions showed low chem. inhibition for the
germination of radish and cress seeds but higher lignin contents reduced the imbibition rate as a seed coating. This study presents
the first use of lignin to control the biodegradation rate of cellulose nanofibers in a one- pot, scalable and sustainable system,
allowing the advancement of lignocellulose nanofibers for applications such as seed coatings, mulches, and controlled release fertil
izers. Graphical Abstract: [graphic not available: see fulltext]

280
Longitudinal single cell atlas identifies complex temporal relationship between type I interferon
response and COVID-19 severity
By: Lin, Quy Xiao Xuan; Rajagopalan, Deepa; Gamage, Akshamal M.; Tan, Le Min; Venkatesh, Prasanna Nori ; Chan, Wharton O. Y.
; Kumar, Dilip ; Agrawal, Ragini; Chen, Yao; Fong, Siew-Wai; et al
Abstract: Due to the paucity of longitudinal mol. studies of C OVID-19, particularly those covering the early stages of infection (Days
1-8 symptom onset) , our understanding of host response over the disease course is limited. We perform longit udinal single cell R N
A-seq on 286 blood samples from 108 age- and sex- matched COVID-19 patients, including 73 with early samples. We examine
discrete cell subtypes and continuous cell states longitudinally, and we identify upregu lation of type I IFN-stimulated genes (ISGs) as
the predominant early signature of subsequent worsening of symptoms, which we validate in an indepe ndent cohort and corrob
orate by plasma markers. However, I SG expression is dynamic in progressors, spiking early and then rapidly receding to the level of
severity-matched non-progressors. In contrast, cross-sectional anal. shows that ISG expression is deficient and IFN suppressors
such as SOCS3 are upregulated in severe and critical C OVID-19. We validate the latter in four indepe ndent cohorts, and S OCS3
inhibition reduces SARS-CoV-2 replication in vitro. In summary, we identify complexity in type I I FN response to COVID-19, as well as
a potential avenue for host-directed therapy.
281
C5a-C5AR1 axis as a potential trigger of the rupture of intracranial aneurysms
By: Okada, Akihiro; Shimizu, Kampei; Kawashima, Akitsugu; Kayahara, Tomomichi; Itani, Masahiko; Kurita, Hiroki; Miyamoto,
Susumu; Kataoka, Hiroharu; Aoki, Tomohiro
Abstract: Recent studies have indicated the involvement of neutrophil-mediated inflammatory responses in the process leading to
intracranial aneurysm (IA) rupture. Receptors mediating neutrophil recruitment could thus be therapeutic targets of unruptured I As.
In this study, complement C5a receptor 1 (C5AR1) was picked up as a candidate that may cause neutro phil-dependent inflammation
in IA lesions from comprehensive gene expression profile data acquired from rat and human samples. The induction of C5 AR1 in IA
lesions was confirmed by immunohistochem.; the up-regulations of C5AR1/C5ar1 stemmed from infilt rated neutrophils, which
physiol. express C5AR1/C5ar1, and advent itial fibroblasts that induce C5 AR1/C5ar1 in human/rat IA lesions. In in vitro experi ments
using NIH/3T3, a mouse fibrob last-like cell line, induction of C5ar1 was demons trated by starvation or pharmacol. inhibition of mTO
R signaling by Torin1. Immunohi stochem. and an experiment in a cell- free system using recombinant C5 protein and recomb inant
Plasmin indicated that the ligand of C5AR1, C5a, could be produced through the enzymic digestion by Plasmin in I A lesions. In
conclusion, we have identified a potential contri bution of the C5a-C5AR1 axis to neutrophil infiltration as well as inflammatory
responses in inflammatory cells and fibrob lasts of IA lesions. This cascade may become a therap eutic target to prevent the rupture
of IAs.

282
ChemR23 signaling ameliorates brain injury via inhibiting NLRP3 inflammasome-mediated neuronal
pyroptosis in ischemic stroke
By: Liu, Lan; Zhang, Jiawei; Lu, Kaili; Zhang, Yaxuan; Xu, Xiaofeng; Deng, Jiangshan; Zhang, Xiaojie; Zhang, Haibing; Zhao, Yuwu;
Wang, Xiuzhe
Abstract: Background: Inflammatory response has been recognized as a pivotal pathoph ysiol. process during cerebral ischemia.
ChemR23 signaling is involved in the pathoph ysiol. of various inflammatory diseases. Nevertheless, the role of ChemR23 signaling
in ischemic stroke remains largely unknown. Methods: Permanent ischemic stroke mouse model was accomplished by middle
cerebral artery occlusion (MCAO). Resolvin E1 (Rv E1) or chemerin-9 (C-9), the agonists of ChemR23, were administered by intracer
ebroventricular (i.c.v) injection before M CAO induction. Then, anal. of neurobehavioral deficits and brain sampling were done at
Day 1 after MCAO. The brain samples were further analyzed by histol. staining, immunofluo rescence, RNA sequencing, ELISA,
transmission electron microscope, and western blots. Furthe rmore, oxygen-glucose deprivation (OGD) was employed in SH-SY5Y to
mimic MCAO in vitro, and ChemR23 signaling pathway was further studied by overexp ression of ChemR23 or administration of
related agonists or antagonists. Anal. of cell death and related pathway markers were performed. Results: Chem R23 expression
was upregulated following MCAO. Under in vitro and in vivo ischemic condit ions, ChemR23 deficiency or inhibition contributed to
excessive NLRP3-mediated maturation and release of IL-1β and IL-18, as well as enhanced cleavage of GSDMD-N and neuronal
pyroptosis. These influences ultimately aggravated brain injury and neuronal damage. On the other hand, Chem R23 activation by
RvE1 or C-9 mitigated the above pathophysiol. abnormalities in vivo and in vitro, and overexp ression of ChemR23 in SH-SY5Y cells
also rescued OGD-induced neuronal pyroptosis. Blockade of NLRP3 mimics the protective effects of ChemR23 activation in vitro.
Conclusion: Our data indicated that ChemR23 modulates NLRP3 inflammasome-mediated neuronal pyroptosis in ischemic stroke.
Activation of ChemR23 may serve as a promising potential target for neuropro tection in cerebral ischemia.
Keywords: ChemR23; NLRP3 inflammasome; Neuron; Pyroptosis; Stroke

283
Novel drug therapy of acute hepatic failure induced in rats by a combination of tadalafil and Lepidium
sativum
By: Sabra, Mahmoud S.; Mohammed, Ahmed A.; Hassanein, Khaled M. Ahmed; Ahmed, Ahmed A. N.; Hassan, Dalia; Abdel-lah,
Ebtsam S.
Abstract: Background: Hepatocyte death and a systemic inflam matory response are the outcome of a complex chain of events
mediated by numerous inflammatory cells and chem. mediators. The point of this study was to find out if tadalafil and/or Lepidium
sativum (L. sativum) could help people who have been exposed to carbon tetrachloride (CCL4) and are experiencing acute moderate
liver failure. This was especially true when the two were used together. Method and materials: To cause mild liver failure 24 h
before sacrifice, a single oral dosage of CCL4 (2.5 mL/kg b.w.) (50% in olive oil) was utilized. Furthe rmore, immunohistochem.
expression of nuclear factor kappa B (NF-κB) as well as histol. abnormalities were performed on liver tissue. Results: The results
showed that tadalafil and/or L. sativum, especially in combination, performed well to cure acute mild liver failure caused by C CL4.
This was demonstrated by a decrease in N F-κB expression in the liver tissue and an improv ement in organ damage markers
observed in the blood and liver tissues. Furthermore, such therapy reduced interleukin1 beta (IL-1β) and tumor necrosis factor -
alpha ( TN F-α) levels in the liver tissue. It′s worth noting that the tested combin ation resulted in greater liver improv ement. Conclu
sions: According to the findings, tadalafil and L. sativum, partic ularly in combination, have the ability to protect the liver from the
neg. effects of CCL4 exposure. Because of its capacity to improve liver function, restore redox equili brium, and decrease inflam
matory mediators, it is a prospe ctive option for mitigating the neg. effects of common environ mental pollutants such as C CL4.
Keywords: Acute liver injury; CCL4 ; Inflammatory mediators; LS; NF-κB; Oxidative stress; Tadalafil
284
Molecular basis of VEGFR1 autoinhibition at the plasma membrane
By: Chakraborty, Manas Pratim; Das, Diptatanu ; Mondal, Purav ; Kaul, Pragya ; Bhattacharyya, Soumi; Kumar Das, Prosad
; Das, Rahul
Abstract: Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like E GFR, VEGFR2 is activated
spontaneously at high receptor concent rations VEGFR1, on the other hand, remains constit utively inactive in the unligated state,
making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in
endothelial cells. Recent studies, however, suggest that V EGFR1 signaling is indispe nsable in regulating various physiol. or pathol.
events. The reason why VEGFR1 is regulated differently from other V EGFRs remains unknown. Here, we elucidate a mechanism of
juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an ineffi cient kinase. The
juxtamembrane inhibition of VEGFR1 suppresses its basal phosphor ylation even at high receptor concent rations and transiently
stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosph atase activation or
removing juxtamembrane inhibition is sufficient to induce ligand- independent activation of VEGFR1 and sustain tyrosine phosphor
ylation.

285
AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and

degradation
By: Zhang, Lingxue; Lu, Yanqiao; An, Junqing; Wu, Yin; Liu, Zhixue; Zou, Ming-Hui
Abstract: Ketone bodies serve as an energy source, especially in the absence of carbohydrates or in the extended exercise.
Adenosine monophosphate (AMP)-activated protein kinase (A MPK) is a crucial energy sensor that regulates lipid and glucose
metabolism However, whether AMPK regulates ketone metabolism in whole body is unclear even though A MPK regulates ketoge
nesis in liver. Prolonged resulted in a signif icant increase in blood and urine levels of ketone bodies in wild- type (WT) mice. Interes
tingly, fasting AMPKα2-/- and AMPKα1-/- mice exhibited significantly higher levels of ketone bodies in both blood and urine
compared to fasting WT mice. BHB tolerance assays revealed that both A MPKα2-/- and AMPKα1-/- mice exhibited slower ketone
consumption compared to WT mice, as indicated by higher blood B HB or urine BHB levels in the AMPKα2-/- and AMPKα1-/- mice
even after the peak. Interestingly, fasting AMPKα2-/- and AMPKα1-/- mice exhibited significantly higher levels of ketone bodies in
both blood and urine compared to fasting WT mice. . Specifi cally, AMPKα2ΔMusc mice showed approx. a twofold increase in blood B
HB levels, and A MPKα2ΔMyo mice exhibited a 1.5- fold increase compared to their W T littermates after a 48- h fasting. However, blood
BHB levels in AMPKα1ΔMusc and AMPKα1ΔMyo mice were as same as in WT mice. Notably, A MPKα2ΔMusc mice demonstrated a slower
rate of BHB consumption in the BHB tolerance assay, whereas AMPKα1ΔMusc mice did not show such an effect. Declining rates of
body weights and blood glucoses were similar among all the mice. Protein levels of SCOT, the rate-limiting enzyme of ketolysis,
decreased in skeletal muscle of AMPKα2-/- mice. Moreover, S COT protein ubiquitination increased in C2C12 cells either transfected
with kinase-dead AMPKα2 or subjected to AMPKα2 inhibition . AMPKα2 physiol. binds and stabilizes S COT, which is dependent on A
MPKα2 activity.

286
KRAS is a molecular determinant of platinum responsiveness in glioblastoma
By: Zuchegna, Candida; Leone, Stefano; Romano, Antonella; Porcellini, Antonio; Messina, Samantha
Abstract: Background: KRAS is the undisputed champion of oncogenes, and despite its prominent role in oncoge nesis as mutated
gene, KRAS mutation appears infrequent in gliomas. Neverth eless, gliomas are considered K RAS-driven cancers due to its essential
role in mouse malignant gliomagenesis. Glioblastoma is the most lethal primary brain tumor, often associated with disturbed R AS
signaling. For newly diagnosed GBM, the current standard therapy is alkylating agent chemot herapy combined with radioth erapy.
Cisplatin is one of the most effective anticancer drugs and is used as a first-line treatment for a wide spectrum of solid tumors
(including medulloblastoma and neuroblastoma) and many studies are currently focused on new delivery modalities of effective
cisplatin in glioblastoma. Its mechanism of action is mainly based on D NA damage, inducing the formation of D NA adducts,
triggering a series of signal-transduction pathways, leading to cell- cycle arrest, DNA repair and apoptosis. Methods: Long-term
cultures of human glioblastoma, U87MG and U251MG, were either treated with cis- diamminedichloroplatinum (cisplatin, CDDP)
and/or MEK-inhibitor PD98059. Cytotoxic responses were assessed by cell viability (M TT), protein expression (Western Blot) , cell
cycle (PI staining) and apoptosis (T UNEL) assays. Further, gain-of-function experiments were performed with cells overexpressing
mutated hypervariable region (HVR) KRASG12V plasmids. Results: Here, we studied platinum- based chemosensitivity of long-term
cultures of human glioblastoma from the perspective of KRAS expression, by using C DDP and MEK-inhibitor. Endogenous high KRA
S expression was assessed at transcri ptional (qPCR) and translational levels (WB) in a panel of primary and long- term glioblastoma
cultures. Firstly, we measured immediate cellular adjustment through direct regulation of protein concentration of K-Ras4B in
response to cisplatin treatment. We found increased endogenous protein abundance and involvement of the effector pathway R A
F/MEK/ERK mitogen-activated protein kinase (M APK) cascade. Moreover, as many M EK inhibitors are currently being clin. evaluated
for the treatment of high-grade glioma, so we concomitantly tested the effect of the potent and selective non- ATP-competitive ME
K1/2 inhibitor (PD98059) on cisplatin-induced chemosensitivity in these cells. Cell-cycle phase distribution was examined using flow
cytometry showing a significant cell-cycle arrest in both cultures at different percen tage, which is modulated by M EK inhibition .
Cisplatin-induced cytotoxicity increased sub-G1 percentage and modulates G2/M checkpoint regulators cyclins D1 and A. Moreover,
ectopic expression of a constitutively active KRASG12V rescued CDDP-induced apoptosis and different HVR point mutations (partic
ularly Ala 185) reverted this phenotype. Conclu sion: These findings warrant further studies of clin. applic ations of MEK1/2 inhibitors
and KRAS as ′actionable target′ of cisplatin-based chemotherapy for glioblastoma.
Keywords: Chemosensitivity; Cisplatin; Glioblastoma; KRAS; MEK-inhibitor
287
Regulation of stress granule formation in human oligodendrocytes
By: Pernin, Florian; Cui, Qiao-Ling; Mohammadnia, Abdulshakour; Fernandes, Milton G. F. ; Hall, Jeffery A.; Srour, Myriam; Dudley,
Roy W. R.; Zandee, Stephanie E. J.; Klement, Wendy; Prat, Alexandre ; et al
Abstract: Oligodendrocyte (OL) injury and subsequent loss is a pathol. hallmark of multiple sclerosis (M S). Stress granules (S Gs) are
membrane-less organelles containing m RNAs stalled in transl ation and considered as participants of the cellular response to
stress. Here we show SGs in OLs in active and inactive areas of M S lesions as well as in normal- appearing white matter. In cultures
of primary human adult brain derived OLs, metabolic stress conditions induce transient S G formation in these cells. Combining pro-
inflammatory cytokines, which alone do not induce S G formation, with metabolic stress results in persis tence of SGs. Unlike sodium
arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also
induces persistent SGs indicating the dependence of S G formation and disassembly on the energetic glycolytic properties of human
OLs. We conclude that S G persistence in OLs in MS reflects their response to a combin ation of metabolic stress and pro- inflam
matory conditions.

288
Evaluation of the antidermatophytic activity of potassium salts of N-acylhydrazinecarbodithioates and

their aminotriazole-thione derivatives
By: Ciesielska, Anita ; Kowalczyk, Aleksandra ; Paneth, Agata ; Staczek, Pawel

Abstract: Nowadays, dermatophyte infections are relatively easy to cure, especially since the introd uction of orally administered
antifungals such as terbinafine and itraconazole. However, these drugs may cause side effects due to liver damage or their intera
ctions with other therape utics. Hence, the search for new effective chemother apeutics showing antidermatophyte activity seems to
be the urge of the moment. Potassium salts of N-acylhydrazinecarbodithioates are used commonly as precursors for the synthesis
of biol. active compounds Keeping that in mind, the activity of a series of five potassium N-acylhydrazinecarbodithioates (1a-e) and
their aminotriazole-thione derivatives (2a-e) was evaluated against a set of pathog enic, keratinolytic fungi, such as Trichophyton
ssp., Microsporum ssp. and Chrysosporium keratinophilum, but also against some Gram-pos. and Gram-neg. bacteria. All tested
compounds were found non-toxic for L-929 and HeLa cells, with the I C30 and IC50 values assessed in the M TT assay above 128
mg/L. The compound 5-amino-3-(naphtalene-1-yl)-4,5-dihydro-1H-1,2,4-triazole-5-thione (2d) was found active against all fungal
strains tested. SEM (SEM) revealed inhibition of mycelium development of Trichophyton rubrum cultivated on nail fragments and
treated with 2d 24 h after infection with fungal spores. Transmission Electron Microscopy (TEM) observation of mycelium treated
with 2d showed ultrastructural changes in the morphol. of germinated spores. Finally, the R NA-seq anal. indicated that a broad
spectrum of genes responded to stress induced by the 2d compound In conclusion, the results confirm the potential of N- acylhydra
zinecarbodithioate derivatives for future use as promising leads for new antiderm atophyte agents development.
Keywords: Aminotriazole-thiones; Antidermatophytic activity; Dermatophytes; N-acylhydrazinecarbodithioates; RNA-seq; SEM; TEM
289
SH3RF2 contributes to cisplatin resistance in ovarian cancer cells by promoting RBPMS degradation
By: Gong, Ting-Ting; Liu, Fang-Hua; Xiao, Qian; Li, Yi-Zi; Wei, Yi-Fan; Xu, He-Li; Cao, Fan; Sun, Ming-Li; Jiang, Feng-Li; Tao, Tao; et al
Abstract: Platinum-based chemotherapy remains one of the major choices for treatment of ovarian cancer (O C). However, primary
or acquired drug resistance severely impairs their efficiency, thereby causing chemotherapy failure and poor prognosis. S H3
domain containing ring finger 2 (SH3RF2) has been linked to the development of cancer. Here we find higher levels of S H3RF2 in the
tumor tissues from cisplatin-resistant OC patients when compared to those from cisplatin- sensitive patients. Similarly, cisplatin-
resistant OC cells also express higher levels of S H3RF2 than normal OC cells. Through in vitro and in vivo loss- of-function experi
ments, SH3RF2 is identified as a driver of cisplatin resist ance, as evidenced by increases in cisplatin-induced cell apoptosis and D NA
damage and decreases in cell proliferation induced by S H3RF2 depletion. Mechanistically, SH3RF2 can directly bind to the R NA-
binding protein mRNA processing factor (RBPMS). RBPMS has been reported as an inhibitor of cisplatin resistance in O C. As a E3
ligase, SH3RF2 promotes the K48-linked ubiquitination of RBPMS to increase its protea somal degradation and activator protein 1 (A
P-1) transactivation. Impairments in RBPMS function reverse the inhibitory effect of S H3RF2 depletion on cisplatin resistance.
Collectively, the SH3RF2-RBPMS-AP-1 axis is an important regulator in cisplatin resistance and inhibition of SH3RF2 may be a
potential target in preventing cisplatin resistance.

290
Inhibiting anti-angiogenic VEGF165b activates a miR-17-20a-Calcipressin-3 pathway that revascularizes

ischemic muscle in peripheral artery disease
By: Batan, Sonia; Kuppuswamy, Sivaraman; Wood, Madison; Reddy, Meghana; Annex, Brian ; Ganta, Vijay
Communications Medicine (2024), 4(1), 3 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: VEGF165a increases the expression of the microRNA-17-92 cluster, promoting developmental, retinal, and
tumor angiogenesis. We have previously shown that V EGF165b, an alternatively spliced anti-angiogenic VEGF-A isoform, inhibits the
VEGFR-STAT3 pathway in ischemic endoth elial cells (ECs) to decrease their angiogenic capacity. In ischemic macrop hages (Mos), VEG
F165b inhibits VEGFR1 to induce S100 A8/A9 expression, which drives M1-like polarization. Our current study aims to determine
whether VEGF165b inhibition promotes perfusion recovery by regulating the micro RNA(miR)-17-92 cluster in preclin. PAD. Methods:
Femoral artery ligation and resection was used as a preclin. PAD model. Hypoxia serum starvation (HSS) was used as an in vitro P AD
model. VEGF165b was inhibited/neutralized by an isoform- specific VEGF165b antibody. Results: Here, we show that V EGF165b-
inhibition induces the expression of miR-17-20a (within miR-17-92 (miR-17-18a-19a-19b-20a-92) cluster) in HSS-ECs and HSS-Mos
vs. resp. normal and/or isotype-matched IgG controls to enhance perfusion recovery. Consistent with the bioinfo rmatics anal. that
revealed RCAN3 as a common target of mi R-17 and miR-20a, Argonaute-2 pull-down assays showed decreased mi R-17-20a
expression and higher RCAN3 expression in the R NA-induced silencing complex of HSS-ECs and HSS-Mos vs. resp. controls.
Inhibiting miR-17-20a induced RCAN3 levels to decrease ischemic angiog enesis and promoted M1-like polarization to impair
perfusion recovery. Finally, using STAT3 inhibitors, S100A8/A9 silencers, and VEGFR1-deficient ECs and Mos, we show that V EGF165b-
inhibition activates the miR-17-20a-RCAN3 pathway indepe ndent of VEGFR1-STAT3 or VEGFR1-S100A8/A9 in ischemic-ECs and
ischemic-Mos resp. Conclu sions: Our data revealed a hereunto unreco gnized therapeutic ′miR-17-20a-RCAN3′ pathway in the
ischemic vasculature that is VEGFR1-STAT3/S100A8/A9 independent and is activated only upon V EGF165b- inhibition in PAD.
291
The mechanisms of condensed tannins inhibit Pediococcus pentosaceus
By: Huang, Rongzheng; Zhang, Fanfan; Wang, Xuzhe; Ma, Chunhui; Ma, Mingxin
Abstract: Background: The antibacterial mechanisms of action of condensed tannins (C Ts) obtained from tea are well known.
However, the antibacterial mechanism of CTs from legumes, such as sainfoin, against to Pediococcus pentosaceus was still unclear.
Using Pediococcus pentosaceus SF11 as a model organism, this study invest igated the antibacterial mechanism of CTs (extract from
sainfoin by 70% acetone aqueous solution). Methods: The mechanism of C Ts against Pediococcus pentosaceus was investigated
though determined the minimal inhibitory concentration (MIC) of CTs, effects of CTs on cell membrane, scanning and transm ission
electron microscopy anal. and global transcriptome anal., et al. Results: The results showed that C Ts decreased the activities of
enzymes such as lactic dehydrogenase, and inhibited the pentose phosphate (P P)/glycolytic pathway. The content of hydrogen
peroxide produced by CTs was increased in P. pentosaceus SF11, and antibacterial activity partly occurred due to this hydrogen
peroxide. The global transcriptome anal. showed that CTs upregulated the expression of 187 genes, most of which were involved in
hypothetical protein, followed by the PTS (phosphotransferase system) system, while three genes were involved in oxidative stress.
The expression of 161 genes was downregulated, most of which were involved in the phosphate A BC transporter system. Conclu
sion: These findings suggest that the mechanism of antibac terial action of sainfoin C Ts mainly operates through the inhibition of
protease activity, and is partly associated with oxidative stress induced by hydrogen peroxide. Graphical Abstract: [graphic not

292
Revealing the pharmacological effects of Remodelin against osteosarcoma based on network

pharmacology, acRIP-seq and experimental validation
By: Gao, Jia; Xu, Peili; Wang, Feng; Zhang, Wenjie; Min, Meipeng; Urba, Rafi; Fan, Lei
Abstract: Osteosarcoma (OS) is the most common primary malignant tumor of bone. Remodelin, an inhibitor of the N (4) -Acetylc
ytidine (ac4C) acetylation modifying enzyme N-acetyltransferase 10 (NAT10), has been shown to have therapeutic effects on cancer
in several studies, and our previous studies have confirmed the inhibitory effect of Remodelin on OS cells, however, the mechanism
of action has not yet been elucidated. We used network pharmacol. anal. to quantify the therap eutic targets of Remodelin against O
S. acRIP-seq and RNA-seq were performed to investigate the inhibitory activity of Remodelin on acetyl ation and its effect on the
transcriptome after intervening in OS cells U2OS with Remodelin in vitro. Key target genes were deduced based on their pharmacol.
properties, combined with network pharmacol. results and sequencing results. Finally, the deduced target genes were validated
with vitro experiments Network pharmacol. anal. showed that 2291 O S-related target genes and 369 Remodelin- related target
genes were obtained, and 116 overlapping genes were identified as Remodelin targets for O S treatment. Sequencing results
showed that a total of 13,736 statistically significant ac4C modification peaks were detected by acRIP-seq, including 6938 hypoacet
ylation modifications and 6798 hyperacetylation modifications. A total of 2350 statist ically significant mRNAs were detected by R NA-
seq, of which 830 were upregulated and 1520 were down-regulated. Association analyses identified a total of 382 genes that were
Hypoacetylated-down, consistent with inhibition of mRNA acetylation and expression by Remodelin. Five genes, C ASP3, ESR2, FGF
R2, IGF1 and MAPK1, were identified as key therapeutic targets of Remodelin against O S. Finally, in vitro experi ments, CCK-8 and qR
T-PCR demonstrated that Remodelin indeed inhibited the prolife ration of OS cells and reduced the expression of three genes: E SR2,
IGF1, and M APK1. In conclusion, ESR2, IGF1 and MAPK1 were identified as key therapeutic targets of Remodelin against O S. This
reveals the target of Remodelin′s pharmacol. action on O S and provides new ideas for the treatment of O S.

293
Effectiveness and brain mechanism of multi-target transcranial alternating current stimulation (tACS)
on motor learning in stroke patients: study protocol for a randomized controlled trial
By: Lai, Ming-Hui; Yu, Xiao-Ming; Lu, Yan; Wang, Hong-Lin; Fu, Wang; Zhou, Huan-Xia; Li, Yuan-Li; Hu, Jun; Xia, Jiayi; Hu, Zekai; et al
Trials (2024), 25(1), 97 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Transcranial a.c. stimulation (tACS) has proven to be an effective treatment for improving cognition, a crucial
factor in motor learning. However, current studies are predominantly focused on the motor cortex, and the potential brain
mechanisms responsible for the therapeutic effects are still unclear. Given the interco nnected nature of motor learning within the
brain network, we have proposed a novel approach known as multi-target tACS. This study aims to ascertain whether multi- target t
ACS is more effective than single- target stimulation in stroke patients and to further explore the potential underlying brain
mechanisms by using techniques such as transcranial magnetic stimulation (TMS) and magnetic resonance imaging (M RI). Methods:
This study employs a double-blind, sham-controlled, randomized controlled trial design with a 2- wk intervention period. Both partic
ipants and outcome assessors will remain unaware of treatment allocation throughout the study. Thirty- nine stroke patients will be
recruited and randomized into three distinct groups, including the sham tACS group (SS group), the single-target tACS group (ST
group), and the multi-target tACS group (M T group), at a 1: 1:1 ratio. The primary outcomes are series reaction time tests (S RTTs)
combined with electroencephalograms (EEGs). The secondary outcomes include motor evoked potential (M EP), central motor
conduction time (CMCT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), magnetic resonance imaging (M RI)
, Box and Block Test (BBT), and blood sample R NA sequencing. The tACS interventions for all three groups will be admini stered over
a 2-wk period, with outcome assessments conducted at baseline (T0) and 1 day (T1) , 7 days (T2), and 14 days (T3) of the interv
ention phase. Discussion: The study′s findings will determine the potential of 40- Hz tACS to improve motor learning in stroke
patients. Addnl., it will compare the effectiveness of multi-target and single-target approaches, shedding light on their resp. improv
ement effects. Through the utilization of techniques such as TMS and M RI, the study aims to uncover the underlying brain
mechanisms responsible for the therapeutic impact. Furthermore, the intervention has the potential to facilitate motor learning
efficiency, thereby contri buting to the advancement of future stroke rehabilitation treatment. Trial registration: Chinese Clin. Trial
Registry ChiCTR2300073465. Registered on 11 July 2023.
Keywords: 40-Hz multi-target stimulation; Motor learning; Stroke rehabilitation; Transcranial alternating current stimulation

294
VEGF and EGFR signaling pathways are involved in the baicalein attenuation of OVA-induced airway
inflammation and airway remodeling in mice
By: Peng, Wang; Xia, Qinxuan; Zhang, Yue; Cao, Danfeng; Zheng, Xiangrong
Abstract: Background: Although Traditional Chinese Medicine (TCM) has been used for treating asthma for centuries, the underst
anding of its mechanism of action is still limited. Thus, the purpose of this study was to explore the possible therap eutic effects, and
underlying mechanism of baicalein in the treatment of asthma. Methods: Freely availabled atabases (e.g. OMIM, TTD, Genecards, B
ATMAN-TCM, STITCH 5.0, SEA, SwissTargetPrediction) and software (e.g. Ligplot 2.2.5 and Py MoL) were used for disease drug target
prediction and mol. docking by network pharmacol. The efficacy and mechanism of action of baicalein in the treatment of asthma
were validated using an ovalbumin (OVA)-induced asthma mouse model and mol. biol. techni ques. Results: A total of 1655 asthma-
related genes and 161 baicalein- related targets were identified from public databases. Utilizing common databases and software
for network pharmacol. and mol. docking anal., seven potential target proteins for the therapeutic effects of baicalein on asthma
were selected, including v-akt murine thymoma viral oncogene homolog 1 (A KT1), vascular endothelial growth factor A (VEGFA),
epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase Src (S RC), mitogen-activated protein kinase 3 (M AP
K3), matrix metallopeptidase 9 (MMP9), and MAPK1. In vivo, baicalein treatment via i.p. injection at a dose of 50 mg/kg signifi cantly
reduced airway inflammation, collagen deposition, smooth muscle thickness, lung interleukin (IL)-4 and IL-13 levels, peripheral
blood Ig (Ig)E levels, as well as the count and ratio of eosino phils in bronchoalveolar lavage fluid (B ALF) in an OVA-induced asthma
mouse model. Further validation by reverse transcription quant. polymerase chain reaction (RT-qPCR) and western blotting anal.
revealed that the VEGF and EGFR signaling pathways involving V EGFA, MAPK1, MAPK3, and EGFR were inhibited by baicalein in the
asthma mouse model. Conclusion: Baicalein attenuates airway inflam mation and airway remodeling through inhibition of VEGF
and EGFR signaling pathways in an O VA-induced asthma mouse model. This will provide a new basis for the develo pment of
baicalein as a treatment for asthma and highlights the potential of network pharmacol. and mol. docking in drug discovery and
development.
Keywords: Asthma; Baicalein; Network pharmacology; Traditional Chinese Medicine
295
LOX-1 acts as an N 6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the

bacterial catalase
By: Zeng, Judeng; Xie, Chuan; Huang, Ziheng; Cho, Chi H.; Chan, Hung; Li, Qing; Ashktorab, Hassan; Smoot, Duane T.; Wong, Sunny
H.; Yu, Jun; et al
Abstract: The role of N6-methyladenosine (m 6A) modification of host m RNA during bacterial infection is unclear. Here, we show that
Helicobacter pylori infection upregu lates host m 6A methylases and increases m 6A levels in gastric epithelial cells. Reducing m 6A
methylase activity via hemizygotic deletion of methylase-encoding gene Mettl3 in mice, or via small interf ering RNAs targeting m 6A
methylases, enhances H. pylori coloniz ation. We identify LOX-1 mRNA as a key m 6A-regulated target during H. pylori infection. m 6A
modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for H. pylori catalase
and contributes to bacterial adhesion. Pharmacol. inhibition of LOX-1, or genetic ablation of Lox-1, reduces H. pylori coloniz ation.
Moreover, deletion of the bacterial catalase gene decreases adhesion of H. pylori to human gastric sections. Our results indicate
that m6A modification of host LOX-1 mRNA contributes to protection against H. pylori infection by downreg ulating LOX-1 and thus
reducing H. pylori adhesion.

296
Synthesis and biological evaluation of titanium dioxide/thiopolyurethane composite: anticancer and

antibacterial effects
By: El Sadda, Rana R. ; Eissa, Mai S.; Elafndi, Rokaya K.; Moawed, Elhossein A.; El-Zahed, Mohamed M.; Saad, Hoda R.
Abstract: Nanocomposites incorporating titanium dioxide (TiO2) have a significant potential for various industrial and medical
applications. These nanocom posites exhibit selectivity as antimicrobial and anticancer agents. Antimic robial activity is crucial for
medical uses, including applications in food processing, packaging, and surgical instru ments. Addnl., these nanocom posites exhibit
selectivity as anticancer agents. A stable nanocom posite as a new anticancer and antibac terial chem. was prepared by coupling
titanium dioxide nanoparticles with a polyurethane foam matrix through the thiourea group. The titanium dioxide/ thiopoly
urethane nanocomposite (TPU/TiO2) was synthesized from low-cost Ilmenite ore and com. polyur ethane foam. E DX anal. was used
to determine the elemental composition of the titanium dioxide (TiO2) matrix. TiO2NPs were synthesized and were characterized
using TEM, XRD, IR, and UV-Vis spectra. TiO2NPs and TPU foam formed a novel composite. The M TT assay assessed Cisplatin and
HepG-2 and MCF-7 cytotoxicity in vitro. Its I C50 values for HepG-2 and MCF-7 were 122.99 ± 4.07 and 201.86 ± 6.82 μg/m L, resp. The
TPU/TiO2 exhibits concentration-dependent cytotoxicity against MCF-7 and HepG-2 cells in vitro. The selective index was measured
against both cell lines; it showed its safety against healthy cells. Agar well-diffusion exhibited good inhibition zones against Escher
ichia coli (12 mm), Bacillus cereus (10 mm), and Aspergillus niger (19 mm). TEM of TPU/TiO2-treated bacteria showed ultrast ructure
changes, including plasma membrane detachment from the cell wall, which caused lysis and bacterial death. TPU/TiO2 can treat
cancer and inhibit microbes in dentures and other items. Also, TPU/TiO2 inhibits E. coli, B. cereus, and A. niger microbial strains.
Keywords: HepG-2; Ilmenite ore; M CF-7; Polyurethane foam; Selective index; Thiourea; Titanium dioxide

297
Ovarian cancer cells regulate their mitochondrial content and high mitochondrial content is associated
with a poor prognosis
By: Weigelt, Jil; Petrosyan, Mariam; Oliveira-Ferrer, Leticia; Schmalfeldt, Barbara; Bartmann, Catharina; Dietl, Johannes; Stuerken,
Christine; Schumacher, Udo
Abstract: Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes
energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesize the
energy rich substrate ATP, which provides the necessary energy to enable distant metastasis formation. However, mitoch ondria are
also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the
mitochondrial content in ovarian cancer cells and link its presence to the patient′s prognosis in order to analyze which of the two
opposing functions of mitochondria dominates during the malignant progre ssion of ovarian cancer. Monoclonal antibodies directed
against different mitochondrial specific proteins, namely heat shock proteins 60 (H SP60), fumarase and succinic dehydro genase,
were used in immunohistochem. in preliminary experiments to identify the antibody most suited to detect mitoch ondria in ovarian
cancer cells in clin. tissue samples. The clearest staining pattern, which even delineated individual mitochondria, was seen with the
anti-HSP60 antibody, which was used for the subsequent clin. study staining primary ovarian cancers (n = 155) , borderline tumors (n
= 24) and recurrent ovarian cancers (n = 26). The staining results were semi- quant. scored into three groups according to their
mitochondrial content: low (n = 26) , intermediate (n = 50) and high (n = 84) . Survival anal. showed that high mitocho ndrial content
correlated with a statistically significant overall reduced survival rate In addition to the clin. tissue samples, mitocho ndrial content
was analyzed in ovarian cancer cells grown in vitro (cell lines: OVCAR8, SKOV3, OVCAR3 and C OV644) and in vivo in severe
combined immunodeficiency (SCID) mice. In in vivo grown S KOV3 and OVCAR8 cells, the number of mitoch ondria pos. cells was
markedly down-regulated compared to the in vitro grown cells indicating that mitocho ndrial number is subject to regulatory
processes. As high mitochondrial content is associated with a poor prognosis, the provision of high energy substrates by the mitoch
ondria seems to be more important for metastasis formation than the inhibition of apoptotic cell death, which is also mediated by
mitochondria. In vivo and in vitro grown human ovarian cancer cells showed that the mitocho ndrial content is highly adaptable to
the growth condition of the cancer cells.
Keywords: Immunohistochemistry; Intraperitoneal metastases; Mitochondria; Ovarian cancer; Ovarian cancer prognosis; Ovarian
cancer xenografts

298
Next generation antibiotic combinations to combat pan-drug resistant Klebsiella pneumoniae
By: Kaur, Jan Naseer; Singh, Navaldeep; Smith, Nicholas M.; Klem, Jack F.; Cha, Raymond; Lang, Yinzhi; Chen, Liang; Kreiswirth, Barry;
Holden, Patricia N.; Bulitta, Jurgen B.; et al
Abstract: Antimicrobial resistance has emerged as one of the leading public health threats of the twenty- first century. Gram-neg.
pathogens have been a major contributor to the declining efficacy of antibiotics through both acquired resistance and tolerance. In
this study, a pan-drug resistant (P DR), NDM-1 and CTX-M-15 co-producing isolate of K. pneumoniae, CDC Nevada, (Kp Nevada) was
exposed to the clin. combination of aztreonam + ceftazidime/avibactam (ATM/CAZ/AVI) to overcome metallo-β-lactamases.
Unexpectedly, the β-lactam combination resulted in long filamentous cell formation induced by P BP3 inhibition over 168 h in the
hollow fiber infection model experiments with eventual reversion of the total population upon drug removal. However, the addition
of imipenem to the two drug β-lactam combination was highly synergistic with suppression of all drug resistant subpopu lations
over 5 days. SEM and fluorescence microscopy for all imipenem combin ations in time kill studies suggested a role for imipenem in
suppression of long filamentous persisters, via the formation of metabolically active spheroplasts. To complement the imaging
studies, salient transcriptomic changes were quantified using R T-PCR and novel cassette assay evaluated β- lactam permeability.
This showed significant upregulation of both sphero plast protein Y (S PY), a periplasmic chaperone protein that has been shown to
be related to spheroplast formation, and penicillin binding proteins (P BP1, PBP2, PBP3) for all combin ations involving imipenem.
However, with aztreonam alone, pbp1, pbp3 and spy remained unchanged while pbp2 levels were downregulated by > 25%.
Imipenem displayed 207-fold higher permeability as compared with aztreonam (mean permea bility coefficient of 17,200 nm/s).
Although the clin. combination of aztreonam/avibactam and ceftazidime has been proposed as an important treatment of M BL
Gram-negatives, we report the first occurrence of long filame ntous persister formation. To our knowledge, this is the first study that
defines novel β-lactam combinations involving imipenem via maximal suppre ssion of filamentous persisters to combat PDR CDC
Nevada K. pneumoniae.

299
Poly-3-hydroxybutyrate-co-3-hydroxyvalerate(PHBV)-Polyethylene glycol 20k(PEG20k) as a promising

delivery system for PT2399 in the treatment of disc degeneration
By: Li, Zhencong; Zhang, Weilin; Huang, Shengbang; Dai, Zhiwen; Liang, Jinguo; Qiu, Qiulan; Chen, Siyuan; Guo, Weixiong; Wang,
Zhongwei; Wei, Jinsong
Journal of Biological Engineering (2024), 18(1), 11 | Language: English, Database: CAplus and MEDLINE
Abstract: Disc degeneration often leads to a highly prevalent symptom known as low back pain. Healthy nucleus pulposus tissue
exhibited a hypoxic environment devoid of blood vessels, while degene rated nucleus pulposus experienced hypoxic deterioration
and the formation of new blood vessels. In this study, the expression of important genes like HIF-2α was found to vary between
normal and degenerated nucleus pulposus cells when compared to the hypoxic surroun dings. The aim of this study was to examine
how HIF-2α is controlled in nucleus pulposus cells under hypoxic conditions and its role in angiogenic mechan isms. To assess the
impact of gradual inhibition of HIF-2α on disk degener ation, we utilized PHBV-based synthetic materials loaded with inhibitors of H I
F-2α. Specifically, we employed LPS and PT2399 loaded PHBV-PEG20k (PP20) to intervene with human nucleus pulposus cells.
Addnl., we treated APD rat models with PT2399 loaded PP20 to evaluate its effects. The expression levels of target markers in
nucleus pulposus cells were detected using PCR, WB, and immunofluorescence. Addnl., the effect of drugs on disk degene ration
was identified through HE staining. The findings indicated that H IF-2α, CAIX, PPP1R15A, VEGFA, and EGLN3 could potentially serve as
new indicators of disk degeneration. Addnl., HIF-2α might contribute to the progre ssion of disk degeneration through involvement
in angiogenesis and the regulation of hypoxia. Furthe rmore, the utilization of PT2399 loaded PHBV-PEG20k (PP20) could potentially
offer a fresh alternative for treating disk degener ation.
Keywords: Anoxic environment; HIF-2α; Nucleus pulposus; PHBV; PT2399
300
Josephin domain containing 2 (JOSD2) promotes lung cancer by inhibiting LKB1 (Liver kinase B1)
activity
By: Yuan, Tao; Zeng, Chenming; Liu, Jiawei; Zhao, Chenxi; Ge, Fujing; Li, Yuekang; Qian, Meijia; Du, Jiamin; Wang, Weihua; Li,
Yonghao; et al
Abstract: Non-small cell lung cancer (N SCLC) ranks as one of the leading causes of cancer- related deaths worldwide. Despite the
prominence and effectiveness of kinase-target therapies in NSCLC treatment, these drugs are suitable for and beneficial to a mere
∼30% of NSCLC patients. Consequ ently, the need for novel strategies addressing N SCLC remains pressing. Deubiquitinases (DUBs),
a group of diverse enzymes with well-defined catalytic sites that are frequently overact ivated in cancers and associated with
tumorigenesis and regarded as promising therap eutic targets. Nevertheless, the mechanisms by which DUBs promote N SCLC
remain poorly understood. Through a global anal. of the 97 D UBs′ contribution to NSCLC survival possibilities using The Cancer
Genome Atlas (TCGA) database, we found that high expression of Josephin Domain- containing protein 2 (JOSD2) predicted the poor
prognosis of patients. Depletion of JOSD2 significantly impeded N SCLC growth in both cell/pa tient-derived xenografts in vivo. Mech.,
we found that JOSD2 restricts the kinase activity of L KB1, an important tumor suppressor generally inacti vated in NSCLC, by
removing K6-linked polyubiquitination, an action vital for mainta ining the integrity of the LKB1-STRAD-MO25 complex. Notably, we
identified the first small-mol. inhibitor of JOSD2, and observed that its pharmacol. inhibition significantly arrested N SCLC prolife
ration in vitro/in vivo. Our findings highlight the vital role of J OSD2 in hindering LKB1 activity, underscoring the therapeutic potential
of targeting JOSD2 in NSCLC, especially in those with inactivated LKB1, and presenting its inhibitors as a promising strategy for N SCL
C treatment.

301
Lonicera japonica protects Pelodiscus sinensis by inhibiting the biofilm formation of Aeromonas
hydrophila
By: Huo, Li-Chao; Liu, Nai-Yu; Wang, Chao-Jie; Luo, Yi ; Liu, Jing-Xia
Abstract: Aquaculture has suffered signif icant financial losses as a result of the infection of zoonotic Aeromonas hydrop hila, which
has a high level of resistance to classic antibiotics. In this study, we isolated an A. hydrophila strain B3 from diseased soft- shelled
turtle (Pelodiscus sinensis), which is one of the most com. signif icant freshwater farmed reptiles in East Asia, and found that A.
hydrophila was its dominant pathogen. To better understand the inhibition effect and action mechanism of Chinese herbs on A.
hydrophila, we conducted Chinese herbs screening and found that Lonicera japonica had a signif icant antibacterial effect on A.
hydrophila B3. Exptl. therapeutics of L. japonica on soft-shelled turtle showed that the supplement of 1% L. japonica to diet could
significantly upregulate the immunity- related gene expression of soft-shelled turtle and protect soft- shelled turtle against A.
hydrophila infection. Histopathol. section results validated the protective effect of L. japonica. As the major effective component of
L. japonica, chlorogenic acid demonstrated significant inhibitory effect on the growth of A. hydrophila with M IC at 6.4 mg/m L. The in
vitro assay suggested that chlorogenic acid could inhibit the hemolysin /protease production and biofilm formation of A. hydrophila
and significantly decrease the expression of quorum sensing, biofilm formation, and hemolysin- related genes in A. hydrop hila. Our
results showed that the Chinese herb L. japonica would be a promising candidate for the treatment of A. hydrophila infections in
aquaculture, and it not only improves the immune response of aquatic animals but also inhibits the virulence factor (such as biofilm
formation) expression of A. hydrophila. Key points: • A. hydrophila was the dominant pathogen of the diseased soft- shelled turtle. •
L. japonica can protect soft-shelled turtle against A. hydrophila infection. • Chloro genic acid inhibits the growth and biofilm
formation of A. hydrophila.
Keywords: Aeromonas hydrophila; Biofilm formation; Chinese herb; Chloro genic acid; Immune response; Soft-shelled turtle

302
Integrating bioinformatics and experimental validation to unveil disulfidptosis-related lncRNAs as

prognostic biomarker and therapeutic target in hepatocellular carcinoma
By: Xu, Lixia; Chen, Shu; Li, Qiaoqiao; Chen, Xinyi; Xu, Yuan; Zhou, Yongjian; Li, Juan; Guo, Zhixian; Xing, Jiyuan; Chen, Di
Abstract: Background: Hepatocellular carcinoma (HCC) stands as a prevalent malignancy globally, charact erized by signif icant
morbidity and mortality. Despite continuous advancements in the treatment of H CC, the prognosis of patients with this cancer
remains unsatisfactory. This study aims at constr ucting a disulfidoptosis-related long noncoding RNA (lncRNA) signature to probe
the prognosis and personalized treatment of patients with H CC. Methods: The data of patients with H CC were extracted from The
Cancer Genome Atlas (TCGA) databases. Univariate, multivariate, and least absolute selection operator Cox regression analyses
were performed to build a disulfidptosis-related lncRNAs (DRLs) signature. Kaplan-Meier plots were used to evaluate the prognosis
of the patients with HCC. Functional enrichment anal. was used to identify key D RLs-associated signaling pathways. Spearman′s
rank correlation was used to elucidate the association between the DRLs signature and immune microenvi ronment. The function of
TMCC1-AS1 in HCC was validated in two H CC cell lines (HEP3B and HEPG2). Results: We identified 11 prognostic D RLs from the TCG
A dataset, three of which were selected to construct the prognostic signature of D RLs. We found that the survival time of low- risk
patients was considerably longer than that of high- risk patients. We further observed that the compos ition and the function of
immune cell subpopulations were significantly different between high- and low- risk groups. Addnl., we identified that sorafenib, 5-
Fluorouracil, and doxorubicin displayed better responses in the low- score group than those in the high-score group, based on IC50
values. Finally, we confirmed that inhibition of TMCC1-AS1 impeded the proliferation, migration, and invasion of hepatoc ellular
carcinoma cells. Conclusions: The DRL signatures have been shown to be a reliable prognostic and treatment response indicator in
HCC patients. T MCC1-AS1 showed potential as a novel prognostic biomarker and therap eutic target for H CC.
Keywords: Disulfidptosis; Hepatocellular carcinoma; Immune microenvi ronment; Long non-coding RNA; Prognostic signature; T MC
C1-AS1

303
EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL
By: Pan, Mingang; Luo, Muyu; Liu, Lele; Chen, Yunmeng; Cheng, Ziyi; Wang, Kai; Huang, Luyi; Tang, Ni; Qiu, Jianguo; Huang, Ailong; et
al
Abstract: Background: Hepatocellular Carcinoma (HCC) is a matter of great global public health import ance; however, its current
therapeutic effectiveness is deemed inadeq uate, and the range of therap eutic targets is limited. The aim of this study was to
identify early growth response 1 (EGR1) as a transcription factor target in H CC and to explore its role and assess the potential of
gene therapy utilizing EGR1 for the management of H CC. Methods: In this study, both in vitro and in vivo assays were employed to
examine the impact of EGR1 on the growth of HCC. The mouse H CC model and human organoid assay were utilized to assess the
potential of EGR1 as a gene therapy for H CC. Addnl., the mol. mechanism underlying the regulation of gene expression and the
suppression of HCC growth by E GR1 was investigated. Results: The results of our investi gation revealed a notable decrease in the
expression of EGR1 in HCC. The decrease in E GR1 expression promoted the multipl ication of HCC cells and the growth of xenogr
afted tumors. On the other hand, the excessive expression of E GR1 hindered the proliferation of HCC cells and repressed the
development of xenografted tumors. Furthermore, the efficacy of EGR1 gene therapy was validated using in vivo mouse H CC
models and in vitro human hepatoma organoid models, thereby providing addnl. substantiation for the anti-cancer role of E GR1 in
HCC. The mechanistic anal. demonstrated that EGR1 interacted with the promoter region of phosphofru ctokinase-1, liver type (PFK
L), leading to the repression of P FKL gene expression and consequent inhibition of PFKL-mediated aerobic glycolysis. Moreover, the
sensitivity of HCC cells and xenogr afted tumors to sorafenib was found to be increased by E GR1. Conclusion: Our findings suggest
that EGR1 possesses therapeutic potential as a tumor suppressor gene in H CC, and that EGR1 gene therapy may offer benefits for H
CC patients.
Keywords: EGR1; Glycolysis; HCC; PFKL; Sorafenib

304
Zinc oxide nanoparticles functionalized with cinnamic acid for targeting dental pathogens receptor
and modulating apoptotic genes in human oral epidermal carcinoma KB cells
By: Ravikumar, O. V.; Marunganathan, Vanitha; Kumar, Meenakshi Sundaram Kishore; Mohan, Magesh; Shaik, Mohammed Rafi;
Shaik, Baji; Guru, Ajay; Mat, Khairiyah
Abstract: Background: Oral diseases are often attributed to dental pathogens such as S. aureus, S. mutans, E. faecalis, and C.
albicans. In this research work, a novel approach was employed to combat these pathogens by preparing zinc oxide nanoparticles
(ZnO NPs) capped with cinnamic acid (C A) plant compounds Methods: The synthe sized ZnO-CA NPs were characterized using SEM, F
TIR, and XRD to validate their compos ition and structural features. The antiox idant activity of ZnO-CA NPs was confirmed using DPP
H and ABTS free radical scavenging assays. The antimic robial effects of Zn O-CA NPs were validated using a zone of inhibition assay
against dental pathogens. Autodock tool was used to identify the interaction of cinnamic acid with dental pathogen receptors.
Results: ZnO-CA NPs exhibited potent antioxidant activity in both DPPH and ABTS assays, suggesting their potential as powerful
antioxidants. The minimal inhibitory concentration of ZnO-CA NPs against dental pathogens was found 25 μg/m L, indicating their
effective antimicrobial properties. Further, Zn O-CA NPs showed better binding affinity and amino acid intera ction with dental
pathogen receptors. Also, the ZnO-CA NPs exhibited dose-dependent (5 μg/mL, 15 μg/mL, 25 μg/mL, and 50 μg/mL) anticancer
activity against Human Oral Epidermal Carcinoma KB cells. The mechanism of action of apoptotic activity of Zn O-CA NPs on the KB
cells was identified through the upregulation of BCL-2, BAX, and P53 genes. Conclu sions: This research establ ishes the potential
utility of ZnO-CA NPs as a promising candidate for dental applica tions. The potent antioxidant, anticancer, and effective antimic
robial properties of Zn O-CA NPs make them a valuable option for combating dental pathogens.
Keywords: Antimicrobial; Cinnamic acid; Dental pathogen; Zinc oxide nanopa rticle

305
Intracellular calcium links milk stasis to lysosome-dependent cell death during early mammary gland
involution
By: Jeong, Jaekwang ; Lee, Jongwon; Talaia, Gabriel; Kim, Wonnam; Song, Junho; Hong, Juhyeon; Yoo, Kwangmin; Gonzalez, David
G.; Athonvarangkul, Diana; Shin, Jaehun; et al
Abstract: Involution of the mammary gland after lactation is a dramatic example of coordinated cell death. Weaning causes
distension of the alveolar structures due to the accumulation of milk, which, in turn, activates S TAT3 and initiates a caspase-indepe
ndent but lysosome-dependent cell death (LDCD) pathway. Although the importance of STAT3 and LDCD in early mammary
involution is well established, it has not been entirely clear how milk stasis activates S TAT3. In this report, we demons trate that
protein levels of the PMCA2 calcium pump are signifi cantly downregulated within 2-4 h of exptl. milk stasis. Reductions in P MCA2
expression correlate with an increase in cytoplasmic calcium in vivo as measured by multip hoton intravital imaging of GCaMP6f
fluorescence. These events occur concom itant with the appearance of nuclear p STAT3 expression but prior to signif icant activation
of LDCD or its previously implicated mediators such as L IF, IL6, and T GFβ3, all of which appear to be upregulated by increased
intracellular calcium. We further demons trate that increased intracellular calcium activates S TAT3 by inducing degrad ation of its
neg. regulator, SOCS3. We also observed that milk stasis, loss of P MCA2 expression and increased intracellular calcium levels
activate TFEB, an important regulator of lysosome biogenesis through a process involving inhibition of CDK4/6 and cell cycle progre
ssion. In summary, these data suggest that intrace llular calcium serves as an important proximal biochem. signal linking milk stasis
to STAT3 activation, increased lysosomal biogenesis, and lysosome-mediated cell death.
Keywords: Calcium; LDCD; PMCA2; STAT3; TFEB
306
Evolution of parasitism genes in the plant parasitic nematodes
By: Dayi, Mehmet

Abstract: The plant-parasitic nematodes are considered as one of the most destru ctive pests, from which the migratory and
sedentary endoparasitic plant parasitic nematodes infect more than 4000 plant species and cause over $100 billion crop losses
annually worldwide. These nematodes use multiple strategies to infect their host and to establish a successful parasitism inside the
host such as cell-wall degradation enzymes, inhibition of host defense proteins, and mol. mimicry. In the present study, the main
parasitism-associated gene families were identified and compared between the migratory and sedentary endopar asitic nematodes.
The results showed that the migratory and sedentary endoparasitic nematodes share a core conserved parasitism mechanism
established throughout the evolution of parasitism. However, genes involved in pectin degrad ation and hydrolase activity are
rapidly evolving in the migratory endoparasitic nematodes. Addnl., cell-wall degrading enzymes such as G H45 cellulases and pectate
lyase and peptidase and peptidase inhibitors were expanded in the migratory endoparasitic nematodes. The mol. mimicry
mechanism was another key finding that differs between the endoparasitic and sedentary parasitic nematodes. The PL22 gene
family, which is believed to play a significant role in the mol. mechanisms of nematode parasi tism, has been found to be present
exclusively in migratory endopar asitic nematodes. Phylogenetic anal. has suggested that it was de novo born in these nematodes.
This discovery sheds new light on the mol. evolution of these parasites and has significant implications for our underst anding of
their biol. and pathogenicity. This study contri butes to our underst anding of core parasitism mechanisms conserved throughout the
nematodes and provides unique clues on the evolution of parasitism and the direction shaped by the host.

307
Marinopyrrole derivative MP1 as a novel anti-cancer agent in group 3 MYC-amplified Medulloblastoma
By: Coulter, Don W.; Chhonker, Yashpal S.; Kumar, Devendra; Kesherwani, Varun; Aldhafiri, Wafaa N.; McIntyre, Erin M.; Alexander,
Gracey; Ray, Sutapa; Joshi, Shantaram S.; Li, Rongshi; et al
Abstract: Background: Medulloblastoma (MB) patients with M YC oncogene amplification or overexpression exhibit extremely poor
prognoses and therapy resistance. However, MYC itself has been one of the most challe nging targets for cancer treatment. Here,
we identify a novel marinopyrrole natural derivative, MP1, that shows desirable anti-MYC and anti-cancer activities in MB. Methods:
In this study, using MYC-amplified (Group 3) and non- MYC amplified MB cell lines in vitro and in vivo, we evaluated anticancer
efficacies and mol. mechanism(s) of MP1. Results: M P1 significantly suppressed M B cell growth and sphere counts and induced G2
cell cycle arrest and apoptosis in a MYC-dependent manner. Mechanistically, MP1 strongly downregulated the expression of MYC
protein. Our results with RNA-seq revealed that MP1 significantly modulated global gene expression and inhibited M YC-associated
transcriptional targets including translation/mTOR targets. In addition, MP1 inhibited MYC-target metabolism, leading to declined
energy levels. The combination of MP1 with an FDA-approved mTOR inhibitor temsirolimus synergistically inhibited M B cell
growth/survival by downregulating the expression of M YC and mTOR signaling compon ents. Our results further showed that as
single agents, both MP1 and temsirolimus, were able to significantly inhibit tumor growth and M YC expression in s.c. or orthoto
pically MYC-amplified MB bearing mice. In combin ation, there were further anti-MB effects on the tumor growth and M YC
expression in mice. Conclusion: These preclin. findings highlight the promise of marinop yrrole MP1 as a novel MYC inhibition
approach for MYC-amplified MB.
Keywords: MP1; MYC; Marinopyrroles; Medulloblastoma; Metabolism; mTOR/translation
308
Multiplexed multicolor antiviral assay amenable for high-throughput research
By: Li, Li-Hsin ; Chiu, Winston ; Huang, Yun-An; Rasulova, Madina ; Vercruysse, Thomas ; Thibaut, Hendrik Jan ; ter Horst,
Sebastiaan ; Rocha-Pereira, Joana ; Vanhoof, Greet; Borrenberghs, Doortje; et al
Abstract: To curb viral epidemics and pandemics, antiviral drugs are needed with activity against entire genera or families of
viruses. Here, we develop a cell-based multiplex antiviral assay for high- throughput screening against multiple viruses at once, as
demonstrated by using three distantly related orthoflav iviruses: dengue, Japanese enceph alitis and yellow fever virus. Each virus is
tagged with a distinct fluorescent protein, enabling individual monitoring in cell culture through high- content imaging. Specific
antisera and small-mol. inhibitors are employed to validate that multip lexing approach yields comparable inhibition profiles to
single-virus infection assays. To facilitate downstream anal., a kernel is developed to deconv olute and reduce the multidimensional
quant. data to three cartesian coordinates. The methodol. is applicable to viruses from different families as exempl ified by co-
infections with chikungunya, parainfluenza and Bunyamwera viruses. The multiplex approach is expected to facilitate the discovery
of broader-spectrum antivirals, as shown in a pilot screen of approx. 1200 drug- like small-mols.

309
Salicylic acid enhances cell growth, fatty acid and astaxanthin production in heterotrophic
Chromochloris zofingiensis without reactive oxygen species elevation
By: Zhang, Xinwei; Zhang, Zhao; Peng, Yanmei; Zhang, Yushu; Li, Qingyang; Sun, Dongzhe
Abstract: Background: The induction of lipid and astaxa nthin accumulation in microalgae is often achieved through abiotic stress.
However, this approach usually leads to oxidative stress, which results in relatively low growth rate. Phytohormones, as important
small mol. signaling substances, not only affect the growth and metabolism of microalgae but also influence the intrace llular
reactive oxygen species level. This study aimed to screen phytohormones that could promote the fatty acids and astaxa nthin yield
of heterotrophic Chromochloris zofingiensis without causing oxidative damage, and further invest igate the underlying mechanisms.
Results: In the present study, among all the selected phytohormones, the addition of exogenous salicylic acid (S A) could effectively
promote cell growth along with the yield of total fatty acids (TFA) and astaxanthin in heterotrophic C. zofingi ensis. Notably, the
highest yields of TFA and astaxanthin were achieved at 100 μ M SA, 43% and 97.2% higher compared with the control, resp. Interes
tingly, the intracellular reactive oxygen species (R OS) levels, which are usually increased with elevated T FA content under abiotic
stresses, were significantly decreased by S A treatment. Comparative transcriptome anal. unveiled significant alterations in overall
carbon metabolism by SA. Specifically, the upregulation of fatty acid synthesis pathway, upregu lation of β-carotene-4-ketolase (BKT)
in carotenoid synthesis aligned with biochem. findings. Weighted gene co-expression network anal. highlighted ABC transporters
and GTF2B-like transcription factor as potential key regulators. Conclusion: This study found that salicylic acid can serve as an
effective regulator to promote the celling growth and accumulation of fatty acids and astaxanthin in heterotrophic C. zofing iensis
without ROS elevation, which provides a promising approach for heterot rophic production of T FA and astaxanthin without growth
inhibition . Graphical Abstract: [graphic not available: see fulltext]
Keywords: Astaxanthin; Chromochloris zofingiensis; Phytohormone; Reactive oxygen species; Salicylic acid; Total fatty acids

310
Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-
virulent Streptococcus pyogenes
By: Toelken, Lea A.; Paulikat, Antje D.; Jachmann, Lana H.; Reder, Alexander; Salazar, Manuela Gesell; Medina, Laura M. Palma;
Michalik, Stephan; Voelker, Uwe; Svensson, Mattias; Norrby-Teglund, Anna; et al
Abstract: Background: Streptococcus pyogenes (group A strepto coccus, GAS) causes a variety of diseases ranging from mild superf
icial infections of the throat and skin to severe invasive infect ions, such as necrotizing soft tissue infections (N STIs). Tissue passage
of GAS often results in mutations within the genes encoding for control of virulence (Cov) R/S two component system leading to a
hyper-virulent phenotype. Dendritic cells (D Cs) are innate immune sentinels specia lized in antigen uptake and subsequent T cell
priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild- type and
natural covR/S mutant infections. Methods: Human primary monocyte-derived (mo)DCs were used. DC maturation and release of
pro-inflammatory cytokines in response to infections with wild- type and covR/S mutants were assessed via flow cytometry. Global
proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes
and macrophages was determined Results: In vitro infections of mo DCs and other monocytic cells with natural G AS covR/S mutants
resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffe
cted. Inhibition of caspase-8 restored secretion of both mols. Knock- out of streptolysin O in GAS strain with unaffected CovR/S
even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced N STI GAS isolates, 28 harbored mutations resulting in
dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such
mutations. Conclusions: Our data demonstrate that strains, which harbor covR/S mutations, interfere with I L-18 and IL-8 responses
in monocytic cells by utilizing the caspase-8 axis. Future experi ments aim to identify the underlying mechanism and conseq uences
for NSTI patients.
Keywords: CovR/S; Dendritic cells; Interleukin-18; Necrotizing soft tissue infection; Streptoc occus pyogenes

311
Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting

glycolytic energy supply that drives tumor angiogenesis
By: Liu, Xin Tracy; Huang, Yu; Liu, Da; Jiang, Yingxin Celia; Zhao, Min; Chung, Long Hoa; Han, Xingxing Daisy; Zhao, Yinan; Chen,
Jinbiao; Coleman, Paul; et al
Abstract: Background: Hepatocellular carcinoma (HCC) remains a leading life- threatening health challenge worldwide, with pressing
needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexp
ressed in a multitude of maligna ncies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates H C
C progression in mice. Therefore, the develo pment of PF-543, a highly selective Sph K1 inhibitor, opens a new avenue for H CC
treatment. However, the anti-cancer efficacy of PF-543 has not yet been invest igated in primary cancer models in vivo, thereby
limiting its further translation. Methods: Building upon the identification of the active form of Sph K1 as a viable therapeutic target in
human HCC specimens, we assessed the capacity of P F-543 in suppressing tumor progression using a diethylnitrosamine-induced
mouse model of primary HCC. We further delineated its underlying mechanisms in both H CC and endothelial cells. Key findings
were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. Results: Sph K1 activity was found to be
elevated in human HCC tissues. Adminis tration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed
HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor
neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543
induced proteasomal degradation of the critical glycolytic enzyme 6- phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus
restricting the energy supply essential for tumor angioge nesis. These effects of PF-543 could be reversed upon S1 P suppleme
ntation in an S1P receptor-dependent manner. Conclusions: This study provides the first in vivo evidence supporting the potential
of PF-543 as an effective anti-HCC agent. It also uncovers previously undesc ribed links between the pro- cancer, pro-angiogenic and
pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Import antly, unlike conventional anti-HCC drugs that target individual pro-
angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angioge nesis, representing a novel
and potentially safer therapeutic strategy for H CC.
Keywords: Angiogenesis; Glycolysis; Hepatocellular carcinoma; PF-543; PFKFB3; Sphingosine kinase

312
Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal-regulating kinase 1 (ASK1)

inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment
By: Zaky, Yara A.; Rashad, Mai W.; Zaater, Marwa A.; El Kerdawy, Ahmed M.
Abstract: In the current study we suggest a novel approach to curb non-alc. steatohepatitis (NASH) progression, and we suggest
privileged scaffolds for the design of novel compounds for this aim. NASH is an advanced form of non-alc. fatty liver disease that
can further progress into fibrosis, cirrhosis, and hepatocellular carcinoma. It is a widely emerging disease affecting 25% of the
global population and has no current approved treatments. Protein kinases are key regulators of cellular pathways, of which, Rho-
associated protein kinase 1 (R OCK1) and apoptosis signal- regulating kinase 1 (A SK1) play an important role in the progre ssion of NA
SH and they stand out as promising targets for N ASH therapy. Interestingly, their kinase domains are found to be similar in
sequence and topol.; therefore, dual inhibition of ROCK1 and A SK1 is expected to be amenable and could achieve a more
favorable outcome. To reach this goal, a training set of ROCK1 and A SK1 protein structures co- crystalized with type 1 (ATP-compet
itive) inhibitors was constructed to manually generate receptor-based pharmacophore models representing ROCK1 and A SK1 inhibi
tors′ common pharmacophoric features. The models produced were assessed using a test set of both R OCK1 and A SK1 actives and
decoys, and their performance was evaluated using different assessment metrics. The best pharmac ophore model obtained,
showing a Mathew′s correlation coefficient (MCC) of 0.71, was then used to screen the Z INC purchasable database retrieving 6178
hits that were filtered accordingly using several medicinal chem. and pharmaco kinetics filters returning 407 promising compounds
To confirm that these compounds are capable of binding to the target kinases, they were subjected to mol. docking simulations at
both protein structures. The results were then assessed indivi dually and filtered, setting the spotlight on various privileged scaffolds
that could be exploited as the nucleus for designing novel ROCK1/ASK1 dual inhibitors.
Keywords: ASK1; Kinase inhibitor; MAP3K5; Molecular docking; N ASH; Pharmacophore modeling; R OCK1; Virtual screening
313
Myosin-independent stiffness sensing by fibroblasts is regulated by the viscoelasticity of flowing actin
By: Mittal, Nikhil; Michels, Etienne B.; Massey, Andrew E.; Qiu, Yunxiu; Royer-Weeden, Shaina P.; Smith, Bryan R.; Cartagena-Rivera,
Alexander X. ; Han, Sangyoon J.
Communications Materials (2024), 5(1), 6 | Language: English, Database: CAplus
The stiffness of the extracellular matrix induces differential tension within integrin- based adhesions, triggering differential
mechanoresponses. However, it has been unclear if the stiffness- dependent differential tension is induced solely by myosin activity.
Here, we report that in the absence of myosin contractility, 3T3 fibroblasts still transmit stiffness-dependent differential levels of
traction. This myosin-independent differential traction is regulated by polymerizing actin assisted by actin nucleators Arp2/3 and
formin where formin has a stronger contribution than Arp2/3 to both traction and actin flow. Intrigu ingly, despite only slight
changes in F-actin flow speed observed in cells with the combined inhibition of Arp2/3 and myosin compared to cells with sole
myosin inhibition , they show a 4- times reduction in traction than cells with myosin- only inhibition . Our analyses indicate that tradit
ional models based on rigid F- actin are inadequate for capturing such dramatic force reduction with similar actin flow. Instead,
incorporating the F-actin network's viscoelastic properties is crucial. Our new model including the F- actin viscoelasticity reveals that
Arp2/3 and formin enhance stiffness sensitivity by mech. reinfo rcing the F-actin network, thereby facilitating more effective transm
ission of flow-induced forces. This model is validated by cell stiffness measur ement with at. force microscopy and exptl. observ ation
of model-predicted stiffness-dependent actin flow fluctuation.
Keywords: fibroblast flowing actin viscoelasticity myosin independent stiffness sensing

314
LL-37_Renalexin hybrid peptide exhibits antimicrobial activity at lower MICs than its counterpart single
peptides
By: Narh, Julius Kwesi; Casillas-Vega, Nestor G.; Zarate, Xristo

Abstract: An alarming global public health and economic peril has been the emergence of antibiotic resistance resulting from clin.
relevant bacteria pathogens, including Enterococcus faecium, Staphyl ococcus aureus, Klebsiella pneumonia, Acinetobacter
baumannii, Pseudomonas aeruginosa, and Enterobacter species constantly exhibiting intrinsic and extrinsic resistance mechanisms
against last-resort antibiotics like gentamycin, ciprofloxacin, tetracycline, colistin, and standard ampicillin prescr iption in clin.
practices. The discovery and applications of antimicrobial peptides (A MPs) with antibacterial properties have been considered and
proven as alternative antimicrobial agents to antibiotics. In this study, we have designed, produced, and purified a recomb inant
novel multifunctional hybrid antimicrobial peptide LL-37_Renalexin for the first time via the applic ation of newly designed flexible G
S peptide linker coupled with the use of our previously charact erized small metal- binding proteins SmbP and CusF3H+ as carrier
proteins that allow for an enhanced bacterial expression, using BL21(DE3) and SHuffle T7(DE3) Escherichia coli strains, and purifi
cation of the hybrid peptide via immobi lized metal affinity chromatog. The purified tag- free LL-37_Renalexin hybrid peptide
exhibited above 85% reduction in bacteria colony-forming units and broad- spectrum antimicrobial effects against Staphylococcus
aureus, Escherichia coli, Methicillin-resistant Staphylococcus aureus (MRSA), and Klebsiella pneumoniae bacteria clin. isolates at a
lower min. inhibition concentration level (10- 33 μM) as compared to its counte rpart single-AMPs LL-37 and Renalexin (50- 100 μM).
Key points: • The hybrid antimicrobial peptide LL-37_Renalexin has been designed using a G S linker. • The peptide was expressed
with the carrier proteins SmbP and CusF3H+. • The hybrid peptide shows antibac terial potency against clin. bacterial isolates.
Keywords: CusF3H+; Fusion proteins; Hybrid antimic robial peptide; I MAC; LL-37; Recombinant peptides; Renalexin; SmbP; Time-
killing kinetics
315
circEPB41L2 blocks the progression and metastasis in non-small cell lung cancer by promoting TRIP12-
triggered PTBP1 ubiquitylation
By: Wang, Yan; Wang, Yihao; Wu, Chunjie; Ji, Yunfei; Hou, Pingfu; Wu, Xueqing; Li, Zhongwei ; Li, Minle; Chu, Sufang; Ning,
Qianqian; et al
Abstract: The metastasis of non-small cell lung cancer (N SCLC) is the leading death cause of N SCLC patients, which requires new
biomarkers for precise diagnosis and treatment. Circular RNAs (circRNAs), the novel noncoding RNA, participate in the progression
of various cancers as microRNA or protein sponges. We revealed the mechanism by which circ EPB41L2 (hsa_circ_0077837) blocks
the aerobic glycolysis, progression and metastasis of N SCLC through modulating protein metabolism of P TBP1 by the E3 ubiquitin
ligase TRIP12. With rRNA-depleted RNA seq, 57 upregu lated and 327 downreg ulated circRNAs were identified in L UAD tissues. circ E
PB41L2 was selected due to its dramat ically reduced levels in N SCLC tissues and N SCLC cells. Interestingly, circEPB41L2 blocked
glucose uptake, lactate production, NSCLC cell proliferation, migration and invasion in vitro and in vivo. Mechanis tically, acting as a
scaffold, circEPB41L2 bound to the RRM1 domain of the PTBP1 and the E3 ubiquitin ligase T RIP12 to promote TRIP12-mediated PTB
P1 polyubiquitylation and degradation, which could be reversed by the H ECT domain mutation of T RIP12 and circEPB41L2
depletion. As a result, circEPB41L2-induced PTBP1 inhibition led to PTBP1-induced PKM2 and Vimentin activation but PKM1 and E-
cadherin inactivation. These findings highlight the circ EPB41L2-dependent mechanism that modulates the "Warburg Effect" and E M
T to inhibit NSCLC development and metastasis, offering an inhibitory target for N SCLC treatment. [graphic not available: see
fulltext]

316
The clustering status of detached gastric cancer cells inhibits anoikis-induced ferroptosis to promote
metastatic colonization
By: Sun, Juan; Li, Jie; Pantopoulos, Kostas; Liu, Yuqin; He, Yixuan; Kang, Weiming; Ye, Xin
Abstract: Background and purpose: Ferroptosis is a form of regulated cell death charact erized by iron-dependent lipid peroxidation
Its role in cancer metastasis remains unclear. In this study, we aimed to investigate the potential involvement of ferroptosis in
gastric cancer (GC) metastasis. Methods: GC cells (AGS, MKN45, HGC27) were used to explore the role of ferrop tosis in single and
clustered cells with extracellular matrix (ECM) detachment in vitro. We overexp ressed glutathione peroxidase 4 (GPX4) to inhibit
ferroptosis and assessed the changes in cell prolife ration, migration, invasion, and epithe lial-mesenchymal transition (EMT). Then
tumor tissues from 54 GC patients with and without lymphatic metastasis were collected for immunohi stochem. staining to invest
igate the expression of ferroptosis and EMT markers. Finally, Kaplan- Meier survival curves were used to invest igate the relationship
between overall survival and expression of GPX4 in 178 GC patients. Results: Detached single cells had lower viability than adherent
cells, but cell clustering improved their survival under matrix-detached conditions. Detached single cells exhibited an induction of
iron-dependent reactive oxygen species (R OS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of ACSL4,
TFRC and HO-1, increased iron levels, and changes in mitocho ndrial morphol. Opposite effects were observed in detached clustered
cells, including the upregulation of the ferroptosis suppressors GPX4 and SLC7A11. Overexpression of GPX4 inhibited ferroptosis
and promoted GC cell proliferation, migration, invasion, and E MT. Immunohistochem. anal. of tumor tissues from G C patients
indicated that lymphatic metastasis was associated with higher potential for ferroptosis inhibition and EMT induction. Finally,
Kaplan-Meier survival curves demonstrated a signif icant decrease in overall survival among G C patients with high G PX4 expression.
Conclusions: Our study provides the first evidence that inhibition of ferroptosis is a crucial mechanism promoting G C metastasis. G
PX4 may be a valuable prognostic factor for G C patients. These findings suggest that targeting ferrop tosis inhibition may be a
promising strategy for GC patients with metastatic potential. Trial regist ration The ethical approval code of this study in Institu tional
Review Board of Peking Union Medical College Hospital is No: K1447.
Keywords: Anoikis; Epithelial-mesenchymal transformation; Ferroptosis; Gastric cancer; Metastatic colonization

317
Restraining of glycoprotein VI- and integrin α2β1-dependent thrombus formation by platelet PECAM1
By: Jooss, Natalie J.; Diender, Marije G.; Fernandez, Delia I.; Huang, Jingnan; Heubel-Moenen, Floor C. J.; van der Veer, Arian; Kuijpers,
Marijke J. E.; Poulter, Natalie S.; Henskens, Yvonne M. C.; te Loo, Maroeska; et al
Abstract: The platelet receptors, glycoprotein VI (GPVI) and integrin α2β1 jointly control collagen- dependent thrombus formation via
protein tyrosine kinases. It is unresolved to which extent the ITIM (immunoreceptor tyrosine-based inhibitory motif) receptor PECA
M1 and its downstream acting protein tyrosine phosph atase PTPN11 interfere in this process. Here, we hypoth esized that integrin
α2β1 has a co-regulatory role in the PECAM1- and PTPN11-dependent restraint of thrombus formation. We invest igated platelet
activation under flow on collagens with a different GPVI dependency and using integrin α2β1 blockage. Blood was obtained from
healthy subjects and from patients with Noonan syndrome with a gain-of-function mutation of PTPN11 and variable bleeding
phenotype. On collagens with decreasing GPVI activity (types I, III, IV), the surface-dependent inhibition of PECAM1 did not alter
thrombus parameters using control blood. Blockage of α2β1 generally reduced thrombus parameters, most effectively on collagen I
V. Strikingly, simultaneous inhibition of PECAM1 and α2β1 led to a restor ation of thrombus formation, indicating that the suppre
ssing signaling effect of P ECAM1 is masked by the platelet-adhesive receptor α2β1. Blood from 4 out of 6 Noonan patients showed
subnormal thrombus formation on collagen IV. In these patients, effects of α2β1 blockage were counterbalanced by PECAM1
inhibition to a normal phenotype. In summary, we conclude that the suppre ssion of GPVI-dependent thrombus formation by either
PECAM1 or a gain- of-function of PTPN11 can be overruled by α2β1 engage ment.
Keywords: Collagens; Microfluidics; Microspots; Noonan syndrome; PTPN11; SHP2

318
Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by

regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute
myeloid leukemia
By: Feng, Shuya; Yuan, Yigang; Lin, Zihan; Li, Min; Ye, Daijiao; Shi, Liuzhi; Li, Danyang; Zhao, Min; Meng, Chen; He, Xiaofei; et al
Abstract: Background: Ferroptosis is a new form of nonapoptotic and iron-dependent type of cell death. Glutathione peroxidase-4
(GPX4) plays an essential role in anti- ferroptosis by reducing lipid peroxidation Although acute myeloid leukemia (A ML) cells,
especially relapsed and refractory (R/R)-AML, present high GPX4 levels and enzyme activities, pharmacol. inhibition of GPX4 alone
has limited application in AML. Thus, whether inhibition of GPX4 combined with other therapeutic reagents has effective applic
ation in AML is largely unknown. Methods: Lipid reactive oxygen species (R OS), malondialdehyde (MDA), and glutathione (GSH)
assays were used to assess ferroptosis in AML cells treated with the hypometh ylating agent (HMA) decitabine (DAC), ferroptosis-
inducer (FIN) RAS-selective lethal 3 (RSL3), or their combination. Combination index (CI) anal. was used to assess the synerg istic
activity of DAC + RSL3 against AML cells. Finally, we evaluated the synerg istic activity of DAC + RSL3 in murine AML and a human
R/R-AML-xenografted NSG model in vivo. Results: We first assessed G PX4 expression and found that GPX4 levels were higher in AM
L cells, especially those with M LL rearrangements, than in NCs. Knockdown of GPX4 by shRNA and indirect inhibition of GPX4
enzyme activity by RSL3 robustly induced ferroptosis in AML cells. To reduce the dose of R SL3 and avoid side effects, low doses of D
AC (0.5 μ M) and R SL3 (0.05 μM) synergistically facilitate ferroptosis by inhibiting the A MP-activated protein kinase (A MPK)-SLC7A11-
GPX4 axis. Knockdown of AMPK by shRNA enhanced ferroptosis, and overexp ression of SLC7A11 and GPX4 rescued DAC + RSL3-
induced anti-leukemogenesis. Mechanistically, DAC increased the expression of M AGEA6 by reducing M AGEA6 promoter hypermeth
ylation. Overexpression of MAGEA6 induced the degradation of AMPK, suggesting that DAC inhibits the AMPK-SLC7A11-GPX4 axis by
increasing MAGEA6 expression. In addition, DAC + RSL3 synergistically reduced leukemic burden and extended overall survival
compared with either DAC or RSL3 treatment in the M LL-AF9-transformed murine model. Finally, D AC + RSL3 synergistically
reduced viability in untreated and R/R-AML cells and extended overall survival in two R/R- AML-xenografted NSG mouse models.
Conclusions: Our study first identify vulnera bility to ferroptosis by regulating M AGEA6-AMPK-SLC7A11-GPX4 signaling pathway.
Combined treatment with HMAs and FINs provides a potential therapeutic choice for A ML patients, especially for R/R-AML.
Keywords: AMPK; Acute myeloid leukemia; Ferrop tosis; Glutathione peroxidase-4; Hypomethylating agent
319
Child inhibited temperament and caregiver distraction encouragement jointly predict children′s delay
of gratification competencies
By: Luerssen, Anna; Ugurlu, Ozge; Mauss, Iris; Ayduk, Ozlem

Abstract: A cool attentional focus during the classic delay of gratifi cation (DG) task involves shifting attention away from the
emotion-arousing features and is a key mechanism that underlies children′s ability to resist temptation and wait. Yet, we know
relatively little about what gives rise to individual differences in cool focus in the first place. The current study (N = 162, M age = 6.86
years) addressed this question by focusing on key aspects of child temperament (i.e., behavioral inhibition , BI) and caregiver
emotion socialization (i.e., distraction encouragement) as joint predictors of cool focus. We theorized that because children are left
alone in an unfamiliar environment for an undefined duration, the D G task would be especially taxing for children higher in B I,
hindering their ability to deploy a cool focus and wait. We also reasoned that caregiver encouragement of distraction would serve
as a protective factor by allowing children higher in BI to more easily activate a cool focus even when experi encing a taxing task.
Results were partially consistent with these hypotheses, shedding new light on precursors to a central ingredient of D G ability.

320
The secondary somatosensory cortex gates mechanical and heat sensitivity
By: Taub, Daniel G. ; Jiang, Qiufen; Pietrafesa, Francesca; Su, Junfeng ; Carroll, Aloe ; Greene, Caitlin; Blanchard, Michael R.;
Jain, Aakanksha; El-Rifai, Mahmoud; Callen, Alexis; et al
Abstract: The cerebral cortex is vital for the processing and perception of sensory stimuli. In the somatosensory axis, information is
received primarily by two distinct regions, the primary (S1) and secondary (S2) somatosensory cortices. Top-down circuits stemming
from S1 can modulate mech. and cooling but not heat stimuli such that circuit inhibition causes blunted perception. This suggests
that responsiveness to particular somatosensory stimuli occurs in a modality specific fashion and we sought to determine addnl.
cortical substrates. In this work, we identify in a mouse model that inhibition of S2 output increases mech. and heat, but not cooling
sensitivity, in contrast to S1. Combining 2- photon anatomical reconstruction with chemogenetic inhibition of specific S2 circuits, we
discover that S2 projections to the secondary motor cortex (M2) govern mech. and heat sensit ivity without affecting motor perfor
mance or anxiety. Taken together, we show that S2 is an essential cortical structure that governs mech. and heat sensit ivity.
321
MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in
cancer
By: Zhang, Hanghang; Huang, Chen; Gordon, John; Yu, Sijia; Morton, George; Childers, Wayne; Abou-Gharbia, Magid; Zhang, Yi;
Jelinek, Jaroslav; Issa, Jean-Pierre J.
Abstract: Background: Inhibition of cyclin-dependent kinase 9 (CDK9), a novel epigenetic target in cancer, can reactivate epigene
tically silenced genes in cancer by dephospho rylating the SWI/SNF chromatin remodeler BRG1. Here, we characterized the anti-
tumor efficacy of M C180295, a newly developed C DK9 inhibitor. Methods: In this study, we explored the pharmaco kinetics of M
C180295 in mice and rats, and tested the anti- tumor efficacy of M C180295, and its enantiomers, in multiple cancer cell lines and
mouse models. We also combined CDK9 inhibition with a DNA methyltransferase (DNMT) inhibitor, decitabine, in multiple mouse
models, and tested MC180295 dependence on T cells. Drug toxicity was measured by checking body weights and complete blood
counts. Results: MC180295 had high specificity for CDK9 and high potency against multiple neoplastic cell lines (median I C50 of 171
nM in 46 cell lines repres enting 6 different malignancies), with the highest potency seen in A ML cell lines derived from patients with
MLL translocations. MC180295 is a racemic mixture of two enanti omers, MC180379 and M C180380, with MC180380 showing higher
potency in a live-cell epigenetic assay. Both M C180295 and M C180380 showed efficacy in in vivo A ML and colon cancer xenograft
models, and significant synergy with decitabine in both cancer models. Lastly, we found that C DK9 inhibition -mediated anti-
tumoral effects were partially dependent on CD8 + T cells in vivo, indicating a signif icant immune component to the response.
Conclusions: MC180380, an inhibitor of cyclin-dependent kinase 9 (CDK9), is an efficacious anti-cancer agent worth advancing
further toward clin. use.
Keywords: Anti-tumoral effects; CDK9; Epigenetic therapy; Immunosensitization; MC180380

322
Bone marrow mesenchymal stem cell-derived exosomes promote osteoblast proliferation, migration
and inhibit apoptosis by regulating KLF3-AS1/miR-338-3p
By: Liu, Dacheng; Zhao, Xuechao; Zhang, Qiang; Zhou, Fei; Tong, Xiangyang
BMC Musculoskeletal Disorders (2024), 25(1), 122 | Language: English, Database: CAplus and MEDLINE
Abstract: Aim: This study aimed to investigate the effect and mechanism of bone marrow mesenc hymal stem cell-derived exosomes
on osteoblast function. Methods: The expression of KLF3-AS1 and mi R-338-3p in serum of fracture patients was detected by q RT-PC
R. Exosomes from BMSCs were isolated by ultrafast centrifu gation. MC3T3-E1 cells were cultured in vitro as exptl. cells. Intrace llular
gene expression was regulated by transfection of si-KLF3-AS1 or miR-338-3p inhibitors. MTT assay, Transwell assay and flow
cytometry were used to evaluate cell viability, migration, and apoptosis. The luciferase reporter gene was used to verify the
targeting relationship between KLF3-AS1 and mi R-338-3p. Bioinformatics anal. was used to identify the basic functions and possible
enrichment pathways of miR-338-3p target genes. Results: The expres sions of KLF3-AS1 and mi R-338-3p in the serum of fracture
patients were down-regulated and up-regulated, resp. The expression of K LF3-AS1 was increased in M C3T3-E1 cells cultured with B
MSCs-Exo, while the viability and migration ability of M C3T3-E1 cells were enhanced, and the apoptosis ability was weakened.
Further anal. revealed miR-338-3p was the target gene of K LF3-AS1. The expression of miR-338-3p was downregulated in MC3T3-E1
cells cultured with BMSCs-Exo. Inhibition of miR-338-3p in M C3T3-E1 cells enhanced the viability and migration ability of M C3T3-E1
cells when cultured with BMSCs-Exo, while suppressing apoptosis. Bioinformatics anal. demonstrated that the target genes of mi R-
338-3p were predominantly localized at the axon′s initiation site, involved in biol. processes such as develo pment and growth
regulation, and mainly enriched in M APK and ErbB signaling pathways. Conclu sion: In vitro, BMSCs-Exo exhibits the capacity to
enhance proliferation and migration while inhibiting apoptosis of M C3T3-E1 cells, potentially achieved through modulation of KLF3-
AS1 and mi R-338-3p expression in M C3T3-E1 cells.
Keywords: Bone marrow mesenchymal stem cells; Exosomes; K LF3-AS1; miR-338-3p

323
Gaillardin inhibits autophagy and induces apoptosis in MCF-7 breast cancer cells by regulating
JAK/STAT pathway
By: Rajabi, Sadegh; Tahmasvand, Zahra; Maresca, Marc; Hamzeloo-Moghadam, Maryam

Abstract: Background: Gaillardin is a potent anticancer sesquiterpene lactone found in Inula oculus-christi. Aim: The present study
examined the effects of gaillardin on apoptosis and autophagy in the MCF-7 breast cancer cell line. Methods: The M TT assay was
used to unravel the antiproliferative effects of gaillardin on MCF-7 cells. The expression of apoptosis-related genes including CASP3,
BAX, BCL2, STAT3, and JAK2, and key markers of autophagy such as A TG1, ATG4, ATG5, ATG7, ATG12, BECN1, and MAP1LC3A were
measured by real time-PCR method. The protein expression of Caspase 3, phospho rylated JAK2, phosphorylated STAT3, ATG1, AT
G4, ATG5, ATG12, Beclin1, and L C-III was determined using western blotting. Results: Gaillardin treatment signifi cantly decreased
the proliferation of MCF-7 cells with a parallel upregu lation of the level of pro-apoptotic caspase-3 enzyme with no effect on Bax
and Bcl2 expression. The levels of phosphorylated and active forms of J AK2 and S TAT3 proteins were reduced following the
treatment of MCF-7 cells with gaillardin. This sesquiterpene lactone com-pound considerably downregulated the levels of six
autophagy markers, including ATG1, ATG4, ATG5, ATG12, Beclin1, and L C-III in MCF-7 cells. Conclusion: These data indicated the
apoptosis-inducing activity of gaillardin in M CF-7 cells by a mechanism that inhibits the J AK/STAT signaling pathway. Further,
autophagy inhibition was the other phenomenon caused by gaillardin in M CF-7 cells. These results can provide evidence to
highlight the role of gaillardin as a novel therapeutic for the treatment of breast cancer. Graphical Abstract: [graphic not available:
see fulltext]
Keywords: Apoptosis; Autophagy; Breast cancer; Gaillardin; JAK2; STAT3

324
Phenotypic, molecular, and in silico characterization of coumarin as carbapenemase inhibitor to fight

carbapenem-resistant Klebsiella pneumoniae
By: Abdel-Halim, Mahmoud Saad ; El-Ganiny, Amira M.; Mansour, Basem; Yahya, Galal; Latif, Hemat K. Abd El; Askoura, Momen
BMC Microbiology (2024), 24(1), 67 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Carbapenems represent the first line treatment of serious infections caused by drug- resistant Klebsiella
pneumoniae. Carbapenem-resistant K. pneumoniae (C RKP) is one of the urgent threats to human health worldwide. The current
study aims to evaluate the carbapenemase inhibitory potential of coumarin and to test its ability to restore meropenem activity
against CRKP. Disk diffusion method was used to test the antimic robial susceptibility of K. pneumoniae clin. isolates to various
antibiotics. Carbapenemase genes (N DM-1, VIM-2, and OXA-9) were detected using PCR. The effect of sub-MIC of coumarin on CRKP
isolates was performed using combined disk assay, enzyme inhibition assay, and checkerboard assay. In addition, q RT-PCR was
used to estimate the coumarin effect on expression of carbapenemase genes. Mol. docking was used to confirm the intera ction
between coumarin and binding sites within three carbapenemases. Results: K. pneumoniae clin. isolates were found to be multi-
drug resistant and showed high resistance to meropenem. All bacterial isolates harbor at least one carbape nemase-encoding gene.
Coumarin significantly inhibited carbape nemases in the crude periplasmic extract of CRKP. The checkerboard assay indicated that
coumarin-meropenem combination was synergistic exhibiting a fractional inhibitory concent ration index ≤ 0.5. In addition, q RT-PCR
results revealed that coumarin significantly decreased carbape nemase-genes expression. Mol. docking revealed that the binding
energies of coumarin to NDM1, VIM-2, OXA-48 and OXA-9 showed a free binding energy of - 7.8757, -7.1532, -6.2064 and - 7.4331
Kcal/mol, resp. Conclusion: Coumarin rendered CRKP sensitive to meropenem as evidenced by its inhibitory action on hydrolytic
activity and expression of carbapenemases. The current findings suggest that coumarin could be a possible solution to overcome
carbapenems resistance in CRKP.
Keywords: Klebsiella pneumoniae ; Carbapenem-resistant; Checkerboard assay; Coumarin; Molecular docking; q RT-PCR

325
Stabilization of KPNB1 by deubiquitinase USP7 promotes glioblastoma progression through the YBX1-
NLGN3 axis
By: Li, Jie; Zhang, Bin; Feng, Zishan; An, Dandan; Zhou, Zhiyuan; Wan, Chao; Hu, Yan; Sun, Yajie; Wang, Yijun; Liu, Xixi; et al
Abstract: Background: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. It is an aggressive
tumor characterized by rapid proliferation, diffuse tumor morphol., and poor prognosis. Unfortu nately, current treatments, such as
surgery, radiotherapy, and chemotherapy, are unable to achieve good outcomes. Therefore, there is an urgent need to explore new
treatment targets. A detailed mechanistic exploration of the role of the nuclear pore transp orter KPNB1 in GBM is lacking. This
study demonstrated that KPNB1 regulated GBM progression through a transcription factor YBX1 to promote the expression of
post-protrusion membrane protein N LGN3. This regulation was mediated by the deubiqui tinating enzyme USP7. Methods: A tissue
microarray was used to measure the expression of KPNB1 and USP7 in glioma tissues. The effects of K PNB1 knockdown on the
tumorigenic properties of glioma cells were charact erized by colony formation assays, Transwell migration assay, Ed U proliferation
assays, CCK-8 viability assays, and apoptosis anal. using flow cytometry. Transcr iptome sequencing identified N LGN3 as a
downstream mol. that is regulated by KPNB1. Mass spectrometry and immunoprecipitation were performed to analyze the
potential interaction between K PNB1 and YBX1. Moreover, the nuclear translo cation of YBX1 was determined with nuclear-cytopl
asmic fractionation and immunofluorescence staining, and chromatin immunoprec ipitation assays were conducted to study D NA
binding with YBX1. Ubiquitination assays were performed to determine the effects of USP7 on KPNB1 stability. The intracranial
orthotopic tumor model was used to detect the efficacy in vivo. Results: In this study, we found that the nuclear receptor KPNB1 was
highly expressed in GBM and could mediate the nuclear translo cation of macromols. to promote GBM progression. Knockdown of
KPNB1 inhibited the progression of GBM, both in vitro and in vivo. In addition, we found that K PNB1 could regulate the downstream
expression of Neuroligin-3 (NLGN3) by mediating the nuclear import of transcr iption factor YBX1, which could bind to the N LGN3
promoter. NLGN3 was necessary and sufficient to promote glioma cell growth. Furthe rmore, we found that deubiquitinase USP7
played a critical role in stabilizing KPNB1 through deubiquitination. Knockdown of USP7 expression or inhibition of its activity could
effectively impair GBM progression. In vivo experiments also demonstrated the promoting effects of USP7, KPNB1, and NLGN3 on
GBM progression. Overall, our results suggested that K PNB1 stability was enhanced by U SP7-mediated deubiquitination, and the
overexpression of KPNB1 could promote GBM progression via the nuclear translo cation of YBX1 and the subsequent increase in N L
GN3 expression. Conclusion: This study identified a novel and targetable U SP7/KPNB1/YBX1/NLGN3 signaling axis in G BM cells.
Keywords: Deubiquitination; Glioblastoma; KPNB1; NLGN3; Nuclear translocation; USP7

326
Structure based docking and biological evaluation towards exploring potential anti-cancerous and
apoptotic activity of 6-Gingerol against human prostate carcinoma cells
By: Khan, Habiba; Azad, Iqbal; Arif, Zeeshan; Parveen, Shama; Kumar, Saurabh; Rais, Juhi; Ansari, Jamal Akhtar; Nasibullah, Malik;
Kumar, Sudhir; Arshad, Md
Abstract: Background: 6-Gingerol (6-G) is the primary active phytocomponent of ginger and has been shown to regulate multiple
targets against cancer and its treatment. Androgen receptors (ARs) remain critical in the progression of prostate cancer (P Ca). This
study focuses on investigating 6-G as a promising anti-cancerous agent that inhibits A R activity significantly. Methods: In this study,
mol. docking simulation was done to investigate the binding affinity of 6- G and control drug Bicalu tamide (BT) against oncogenic AR
and tumor suppressor estrogen receptor β (ERβ). The crystal structure of A R and E Rβ was retrieved from Protein Data Bank (P DB)
and docked with 3D Pubchem structures of 6- G using iGEMDOCK and Auto Dock. Further in vitro study was done to evaluate the
antioxidant, anti-cancerous, apoptotic, and wound healing potential of 6- G. Results: The result displays that 6- G shows good binding
affinity with AR and E Rβ. Condensation of the nucleus, change in mitocho ndrial membrane potential (MMP) and the ability to
induce reactive oxygen species (ROS) were done in human PCa PC-3 cells. Results from the M TT assay demonstrated that 6-G and
control drug BT showed significant (p < 0.01) dose and time dependent inhibition of human PCa PC-3 cells. 6-G increased the ROS
generation intracellularly and decreased the M MP, and cell migration in treated P Ca PC-3 cells. 6-G treated cells showed fragme
nted, condensed chromatin and nuclear apoptotic bodies. Conclu sions: Thus, this study validates 6- G as a potential drug candidate
against human PCa. However, further study of the anticancer potency of 6- G has to be done before its use for PCa treatment.
Keywords: 6-Gingerol; Androgen receptor; Anticancer; Molecular docking; Prostate cancer

327
Mechanisms predictive of Tibetan Medicine Sophora moorcroftiana alkaloids for treatment of lung
cancer based on the network pharmacology and molecular docking
By: Ji, Peng; Zhao, Nian-Shou; Wu, Fan-Lin; Wei, Yan-Ming; Laba, Ci-Dan; Wujin, Cuo-Mu; Hua, Yong-Li; Yuan, Zi-Wen; Yao, Wan-Ling
Abstract: Background: Leguminous Sophora moorcroftiana (SM) is a genuine medicinal material in Tibet. Many research results
have reveal the Sophora moorcroftiana alkaloids (SMA), as the main active substance, have a wide range of effects, such as antibac
terial, antitumor and antipar asitic effects. However, there are few reports on the inhibition of lung cancer (LC) and its inhibitory
mechanism, and the pharmacol. mechanism of SMA is still unclear, Therefore, exploring its mechanism of action is of great signifi
cance. Methods: The SMA active components were obtained from the literature database. Whereas the corresp onding targets were
screened from the PubChem and PharmMapper database, UniProt database were conducted the correction and transfo rmation of
UniProt ID on the obtained targets. The GeneCards and O MIM databases identified targets associated with L C. Venny tools
obtained the intersection targets of S MA and LC. R language and Cytoscape software constr ucted the visual of S MA - intersection
targets - LC disease network. The intersection targets protein-protein interaction (PPI) network were built by the S TRING database.
The functions and pathways of the common targets of SMA and LC were enriched by gene ontol. (G O) and Kyoto Encyclopedia of
Genes and Genomes (KEGG). Subsequently, mol. docking And A549 cells vitro experiment were performed to further validate our
finding. Results: We obtained six kinds of alkaloids in SM, 635 potential targets for these compounds, and 1, 303 genes related to LC.
SMA and LC intersection targets was 33, including A LB, CCND1, ESR1, NOTCH1 and AR. GO enrichment indicated that biol. process
of SMA was mainly involved in the pos. regulation of transcr iption and nitric oxide biosyn thetic process, and DNA-templated, etc.
Biol. functions were mainly involved in transcription factor binding and enzyme binding, etc. Cell components were mainly involved
in protein complexes, extracellular exosome, cytoplasm and nuclear chromatin, etc., Which may be associated with its anti- LC
effects. KEGG enrichment anal. showed that main pathways involved in the anti- LC effects of SMA, including pathway in cancer, non
small-cell lung cancer, p53, P I3K-Akt and FOXO signaling pathways. Mol. docking analyses revealed that the six active compounds
had a good binding activity with the main therapeutic targets 2 W96, 2CCH and 1O96. Experiments in vitro proved that S MA
inhibited the proliferation of LC A549 cells. Conclu sions: Results of the present study, we have succes sfully revealed the SMA
compounds had a multi-target and multi-channel regulatory mechanism in treatment L C, These findings provided a solid theor.
reference of SMA in the clin. treatment of L C.
Keywords: Alkaloids; Lung cancer; Molecular docking; Network pharmacology; Sophora Moorcroftiana; Vitro Verification

328
Erianin promotes endogenous neurogenesis in traumatic brain injury rats
By: Li, Qingquan; Gan, Xiaokui; Zhang, Ming; Zhang, Guangmin; Li, Yingbin; Gao, Liang
Abstract: The objective of this study was to explore the pos. influence and potential mechanism of Erianin on the recovery of brain
cells following a traumatic brain injury (TBI). TBI rat models were prepared and treated with Erianin injection via tail vein. The
assessment included evaluating the rats′ levels of oxidative stress, inflammation, neuronal damage, mitocho ndrial damage,
neuronal regeneration, transformation of pro-inflammatory microglial cells, activation status of the E RK signal pathway, and the
functionality of their learning and memory. After adminis tering Erianin, there was a suppre ssion of oxidative stress, inflamm ation,
nerve cell damage, and mitochondrial damage in the T BI rats. Addnl., there was an increase in neuronal regene ration in the cortex
and hippocampus, inhibition of pro-inflammatory microglial cell transfo rmation in the cortex, improvement in learning and
memory function in TBI rats, and simult aneous inhibition of the activation of the ERK1/c-Jun signal pathway. The findings suggest
that Erianin has the potential to reduce oxidative stress and inflammatory reaction in rats with T BI, safeguard nerve cells against
apoptosis, stimulate the growth of new neural cells, ultimately enhancing the cognitive abilities and memory function of the rats.
The inhibition of the ERK signaling pathway could be closely associated with these effects.
329
CLEC19A overexpression inhibits tumor cell proliferation/migration and promotes apoptosis

concomitant suppression of PI3K/AKT/NF-κB signaling pathway in glioblastoma multiforme
By: Mohajerani, Fatemeh; Tehrankhah, Zahra Moazezi; Rahmani, Saeid; Afsordeh, Nastaran; Shafiee, Sajad; Pourgholami,
Mohammad Hossein; Soltani, Bahram M.; Sadeghizadeh, Majid
Abstract: Background: GBM is the most frequent malignant primary brain tumor in humans. The C LEC19A is a member of the C-
type lectin family, which has a high expression in brain tissue. Herein, we sought to carry out an in- depth anal. to pinpoint the role
of CLEC19A expression in GBM. Methods: To determine the localization of CLEC19A, this protein was detected using Western blot,
Immunocytochem./Immunofluorescence, and confocal microscopy imaging. C LEC19A expression in glioma cells and tissues was
evaluated by qRT-PCR. Cell viability, proliferation, migration, and apoptosis were examined through M TT assay, CFSE assay, colony
formation, wound healing assay, transwell test, and flow cytometry resp. after CLEC19A overexpression. The effect of CLEC19A
overexpression on the PI3K/AKT/NF-κB signaling pathway was invest igated using Western blot. An in vivo experiment substan tiated
the in vitro results using the glioblastoma rat models. Results: Our in- silico anal. using TCGA data and measuring C LEC19A
expression level by qRT-PCR determined significantly lower expression of C LEC19A in human glioma tissues compared to healthy
brain tissues. By employment of ICC/IF, confocal microscopy imaging, and Western blot we could show that C LEC19A is plausibly a
secreted protein. Results obtained from several in vitro readouts showed that CLEC19A overexpression in U87 and C6 glioma cell
lines is associated with the inhibition of cell proliferation, viability, and migration. Further, q RT-PCR and Western blot anal. showed
CLEC19A overexpression could reduce the expression levels of PI3K, VEGFα, MMP2, and N F-κB and increase PTEN, TIMP3, RECK, and
PDCD4 expression levels in glioma cell lines. Furthe rmore, flow cytometry results revealed that C LEC19A overexpression was
associated with significant cell cycle arrest and promotion of apoptosis in glioma cell lines. Interes tingly, using a glioma rat model
we could substantiate that CLEC19A overexpression suppresses glioma tumor growth. Conclu sions: To our knowledge, this is the
first report providing in-silico, mol., cellular, and in vivo evidences on the role of C LEC19A as a putative tumor suppressor gene in G
BM. These results enhance our underst anding of the role of C LEC19A in glioma and warrant further explor ation of CLEC19A as a
potential therapeutic target for G BM.
Keywords: C-type lectin; CLEC19A; Glioblastoma; PI3K/AKT/NF-κB pathway; Tumor suppressor gene

330
Identification of genetics and hormonal factors involved in Quercus robur root growth regulation in
different cultivation system
By: Koscielniak, Paulina; Glazinska, Paulina; Kesy, Jacek; Mucha, Joanna; Zadworny, Marcin
Abstract: Understanding the mol. processes and hormonal signals that govern root growth is of paramount importance for
effective forest management. While Arabidopsis studies have shed light on the role of the primary root in root system develo pment,
the structure of root systems in trees is considerably more intricate, posing challenges to comprehend taproot growth in acorn-
sown and nursery- cultivated seedlings. In this study, we invest igated Quercus robur seedlings using rhizot rons, containers, and
transplanted containers to rhizotrons, aiming to unravel the impact of forest nursery practices on processes governing taproot
growth and root system development. Root samples were subjected to R NA-seq anal. to identify gene expression patterns and
perform differential gene expression and phytohormone anal. Among studied cultiv ation systems, differentially expressed genes (D
EGs) exhibited significant diversity, where the number of co-occurring DEGs among cultivation systems was significantly smaller
than the number of unique DEGs in different cultivation systems. Moreover, the results imply that container cultiv ation triggers the
activation of several genes associated with linolenic acid and peptide synthesis in root growth. Upon transplantation from
containers to rhizotrons, rapid enhancement in gene expression occurs, followed by gradual reduction as root growth progre sses,
ultimately reaching a similar expression pattern as observed in the taproot of rhizotron-cultivated seedlings. Phytohormone anal.
revealed that taproot growth patterns under different cultivation systems are regulated by the interplay between auxin and
cytokinin concentrations Moreover, the diversif ication of hormone levels within the root zone and cultiv ation systems allows for
taproot growth inhibition and prompt recovery in transplanted seedlings. Our study highlights the crucial role of hormone intera
ctions during the early stages of taproot elonga tion, influencing root system formation across.
Keywords: Gene; Hormone; Oak; RNA-Seq; Root; Transcriptome

331
The diversity and clinical implications of genetic variants influencing clopidogrel bioactivation and
response in the Emirati population
By: Khasawneh, Lubna Q.; Alsafar, Habiba; Alblooshi, Hiba; Allam, Mushal; Patrinos, George P.; Ali, Bassam R.
Human Genomics (2024), 18(1), 2 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmac ogenes to exert its
anti-platelet function. Genetic variations in the genes encoding its transp orter, metabolizing enzymes, and target receptor lead to
variability in its activation and platelet inhibition and, consequently, its efficacy. This variab ility increases the risk of secondary
cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescr ibing clopidogrel.
Methods: Our study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis
individuals. The study used whole exome sequencing (W ES) data to comprehensively analyze pertinent variations of these genes,
including their minor allele frequencies, haplotype distribution, and their resulting phenot ypes. Results: Our data shows that
approx. 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classif ication as
intermediate or poor C YP2C19 metabolizers. Addnl., more than 50% of the studied cohort exhibited variants in A BCB1, PON1, and
P2YR12 genes, potentially influencing clopidogrel′s transport, enzymic clearance, and receptor perfor mance. Conclusions: Recogn
izing these alleles and genotype freque ncies may explain the clin. differences in medication response across different ethnic ities
and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with
potential implications for implem enting personalized anti-platelet therapy among Emiratis based on their genetic profiles.
Keywords: ABCB1; CYP2C19; Clopidogrel; Emirati population; Genetic variants; P2Y12R; PON1; Pharmacogenomics

332
Pre-operative levels of angiopoietin protein-like 3 (ANGPTL3) in women diagnosed with high-grade

serous carcinoma of the ovary
By: Wong Chong, Emilie; Joncas, France-Helene; Douville, Pierre; Bachvarov, Dimcho; Diorio, Caroline; Calon, Frederic; Bergeron,
Ann-Charlotte; Blais, Jonatan; Leung, Shuk On Annie; Seidah, Nabil Georges; et al
Lipids in Health and Disease (2024), 23(1), 59 | Language: English, Database: CAplus and MEDLINE
Abstract: Cancer cells need constant supplies of lipids to survive and grow. Lipid dependence has been observed in various types of
cancer, including high-grade serous ovarian carcinomas (H GSOC), which is a lethal form of gynecol. malign ancy. ANGPTL3, PCSK9,
and Apo CIII are pivotal lipid-modulating factors, and therapeutic antibodies have been developed against each one (Evinac umab,
Evolocumab and Volanesorsen, resp.). The roles - if any- of ANGPTL3, PCSK9, and Apo C III in HGSOC are unclear. Moreover, levels of
these lipid-modulating factors have never been reported before in H GSOC. In this study, circul ating levels of ANGPTL3, PCSK9, and
Apo CIII, along with lipid profiles, are examined to verify whether one or many of these lipid- regulating factors are associated with H
GSOC. Methods E LISA kits were used to measure ANGPTL3, PCSK9 and Apo C III levels in plasma samples from 31 women with H GS
OC and 40 women with benign ovarian lesions (B OL) before treatment and surgery. A Roche Modular anal. platform measured lipid
panels, Apo B and Lp(a) levels. Results ANGPTL3 levels were higher in women with H GSOC (84 ng/mL, SD: 29 ng/mL, n = 31) than in
women with BOL (67 ng/mL, SD: 31 ng/mL, n = 40; H GSOC vs. BOL P = 0.019). Associations between the lipid panel and A NGPTL3,
and the inverse relationship between HDL-cholesterol and triglycerides, were present in women with B OL but not with HGSOC. PCS
K9 and Apo C III were not associated with H GSOC. Conclusions In this cohort of 71 women, A NGPTL3 levels were increased in HGSO
C patients. The presence of H GSOC disrupted the classic inverse relati onship between HDL and triglycerides, as well as the associ
ation between the lipid panel and A NGPTL3. These associations were only maintained in cancer- free women. Given the availability
of Evinacumab, a therapeutic antibody against ANGPTL3, the current finding prompts an assessment of whether A NGPTL3
inhibition has therapeutic potential in HGSOC.
Keywords: ANGPTL3; Apo CIII; Evinacumab; High-grade serous ovarian cancer; Lipid profile; Lp (a); PCSK9
333
Surface characterization and antibacterial efficiency of well-ordered TiO 2 nanotube surfaces fabricated
on titanium foams
By: Durdu, Salih; Sivlin, Dila; Ozcan, Kadriye; Kalkan, Selin; Keles, Ozgul; Usta, Metin
Titanium (Ti)-based implants are not compatible enough due to their bio- inert character, insufficient antibacterial capabilities and
stress-shielding problem for dental and orthop aedic implant applications. Thus, this work focused to fabricate, analyze and
improve antibacterial properties titanium dioxide (TiO2) nanotube array surfaces on Ti foam by anodic oxidation (A O) process. The
well-ordered nanotube arrays with approx. 75 nm were succes sfully fabricated at 40 V for 1 h on Ti foams. Ti and O were observed
as major elements on AO-coated Ti foam surfaces. In addition, the existence of 2 structure was proved on A O-coated foam Ti
surfaces. For potential dental and orthopedic implant application, in vitro antibac terial properties were investigated vs. Staphyl
ococcus aureus and Escherichia coli. For both bacteria, antibac terial properties of 2 nanotube surface were greater than bare Ti
foam. The bacterial inhibition vs. Staphylococcus aureus and Escherichia coli of 2 nanotube surfaces are improved as 53.3% and
69.4% compared to bare Ti foam.
Keywords: titanium oxide nanotube delivery antibacterial Staphylococcus Escherichia infection

334
T-type voltage-gated channels, Na +/Ca2+-exchanger, and calpain-2 promote photoreceptor cell death
in inherited retinal degeneration
By: Yan, Jie; Wang, Lan; Yang, Qian-Lu; Yang, Qian-Xi; He, Xinyi; Dong, Yujie; Hu, Zhulin; Seeliger, Mathias W.; Jiao, Kangwei; Paquet-
Durand, Francois
Abstract: Inherited retinal degenerations (IRDs) are a group of untreatable and commonly blinding diseases charact erized by progre
ssive photoreceptor loss. IRD pathol. has been linked to an excessive activation of cyclic nucleo tide-gated channels (CNGC) leading
to Na+- and Ca 2+ -influx, subsequent activation of voltage- gated Ca 2+ -channels (VGCC), and further Ca 2+ influx. However, a
connection between excessive Ca2+ influx and photore ceptor loss has yet to be proven. Here, we used whole- retina and single-cell R
NA-sequencing to compare gene expression between the rd1 mouse model for I RD and wild-type (wt) mice. Differentially
expressed genes indicated links to several Ca2+ -signalling related pathways. To explore these, rd1 and wt organo typic retinal
explant cultures were treated with the intracellular Ca 2+ -chelator BAPTA-AM or inhibitors of different Ca 2+ -permeable channels,
including CNGC, L-type VGCC, T-type VGCC, Ca 2+ -release-activated channel (CRAC), and Na+/Ca2+ exchanger (NCX). Moreover, we
employed the novel compound NA-184 to selectively inhibit the Ca 2+ -dependent protease calpain-2. Effects on the retinal activity of
poly(ADP-ribose) polymerase (PARP), sirtuin-type histone-deacetylase, calpains, as well as on activation of calpain- 1, and - 2 were
monitored, cell death was assessed via the TUNEL assay. While rd1 photoreceptor cell death was reduced by B APTA-AM, Ca 2+ -
channel blockers had divergent effects: While inhibition of T-type VGCC and N CX promoted survival, blocking C NGCs and C RACs did
not. The treatment-related activity patterns of calpains and PARPs corresponded to the extent of cell death. Remarkably, sirtuin
activity and calpain-1 activation were linked to photoreceptor protection, while calpain-2 activity was related to degeneration. In
support of this finding, the calpain-2 inhibitor NA-184 protected rd1 photoreceptors. These results suggest that Ca 2+ overload in rd1
photoreceptors may be triggered by T- type VGCCs and N CX. High Ca 2+ -levels likely suppress protective activity of calpain-1 and
promote retinal degeneration via activation of calpain-2. Overall, our study details the complexity of Ca 2+ -signalling in photore
ceptors and emphasizes the importance of targeting degene rative processes specifically to achieve a therapeutic benefit for I RDs.
[media not available: see fulltext]
Keywords: Calcium channels; HDAC; PAR; Retinitis pigmentosa; SOCE; cGMP

335
Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated
pancreatic ductal adenocarcinoma
By: Rampioni Vinciguerra, Gian Luca ; Capece, Marina ; Reggiani Bonetti, Luca; Nigita, Giovanni; Calore, Federica; Rentsch,
Sydney; Magistri, Paolo; Ballarin, Roberto; Di Benedetto, Fabrizio; Distefano, Rosario ; et al
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmop lastic reaction that
compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraor dinary capability to thrive
and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively
documented in PDAC. Here, we identified the transcr iption factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the
adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived
PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically,
we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR,
modulated the autophagic flux and sustained PDAC growth in nutrient depriv ation. In a genetic mouse model, Mir15a KO PDAC
showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved
the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra- 2 in the cellular stress
response due to nutrient restriction typical of pancreatic cancer and support I GF1R as a promising and vulnerable target in mi R-15a
downmodulated PDAC.

336
Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer
progression
By: Meng, Qingfei; Sun, Huihui; Zhang, Yanghe; Yang, Xiangzhe; Hao, Shiming; Liu, Bin; Zhou, Honglan; Xu, Zhi-Xiang; Wang, Yishu
Abstract: Background: Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) is identified as an oncogene involved in multiple
regulation of tumor progression, but specific mechanisms remain unclear in cervical cancer. Lactate- mediated lactylation modulates
protein function. Whether DCBLD1 can be modified by lactylation and the function of DCBLD1 lactylation are unknown. Therefore,
this study aims to investigate the lactylation of DCBLD1 and identify its specific lactylation sites. Herein, we elucidated the
mechanism by which lactylation modification stabilizes the DCBLD1 protein. Furthermore, we investigated DCBLD1 overexpression
activating pentose phosphate pathway (PPP) to promote the progression of cervical cancer. Methods: D CBLD1 expression was
examined in human cervical cancer cells and adjacent non-tumorous tissues using quant. reverse transcr iption-polymerase chain
reaction, western blotting, and immunohistochem. In vitro and in vivo studies were conducted to invest igate the impact of D CBLD1
on the progression of cervical cancer. Untargeted liquid chroma tog.-tandem mass spectrometry (LC-MS/MS) metabolomics studies
were used to characterize DCBLD1-induced metabolite alterations. Western blot, immunofuo rescence and transm ission electron
microscopy were performed to detect DCBLD1 degradation of G6PD by activating autophagy. Chromatin immunoprecipitation, dual
luciferase reporter assay for detecting the mechanism by which lactate increases DCBLD1 transcription. LC-MS/MS was employed to
verify specific modification sites within the DCBLD1 protein. Results: We found that lactate increased D CBLD1 expression, activating
the PPP to facilitate the proliferation and metastasis of cervical cancer cells. D CBLD1 primarily stimulated PPP by upregulating
glucose-6-phosphate dehydrogenase (G6PD) expression and enzyme activity. The mechanism involved the increased enrichment of
HIF-1α in the DCBLD1 promoter region, enhancing the D CBLD1 mRNA expression. Addnl., lactate-induced DCBLD1 lactylation
stabilized DCBLD1 expression. We identified D CBLD1 as a lactylation substrate, with a predominant lactylation site at K172. DCBLD1
overexpression inhibited G6PD autophagic degradation, activating PPP to promote cervical cancer progression. In vivo, 6-An
mediated inhibition of G6PD enzyme activity, inhibiting tumor prolife ration. Conclusions: Our findings revealed a novel post- transla
tional modification type of DCBDL1, emphasizing the significance of lactylation-driven DCBDL1-mediated PPP in promoting the
progression of cervical cancer. Graphical Abstract: Schematic illust ration of DCBLD1-induced G6PD-mediated reprogramming of PPP
metabolism in promoting cervical cancer progression. [graphic not available: see fulltext]
Keywords: Autophagy; Cervical cancer; DCBLD1; G6PD; HIF-1α; Lactylation; Pentose phosphate pathway

337
METTL3 drives NSCLC metastasis by enhancing CYP19A1 translation and oestrogen synthesis
By: Meng, Wangyang; Xiao, Han; Zhao, Rong; Chen, Jiaping; Wang, Yangwei; Mei, Peiyuan; Li, Hecheng; Liao, Yongde
Abstract: Background: METTL3 plays a signif icant role as a catalytic enzyme in mediating N6- methyladenosine (m 6A) modification,
and its importance in tumor progression has been extensively studied in recent years. However, the precise involv ement of METTL3
in the regulation of translation in non-small cell lung cancer (N SCLC) remains unclear. Results: Here we discovered by clin. investi
gation that METTL3 expression is correlated with N SCLC metastasis. Ablation of METTL3 in NSCLC cells inhibits invasion and
metastasis in vitro and in vivo. Subsequently, through translatomics data mining and exptl. valida tion, we demonstrated that METT
L3 enhances the translation of aromatase (CYP19A1), a key enzyme in estrogen synthesis, thereby promoting estrogen production
and mediating the invasion and metastasis of NSCLC. Mechanistically, METTL3 interacts with translation initiation factors and binds
to CYP19A1 mRNA, thus enhancing the translation efficiency of CYP19A1 in an m 6A-dependent manner. Pharmacol. inhibition of ME
TTL3 enzymic activity or translation initiation factor eIF4E abolishes C YP19A1 protein synthesis. Conclu sions: Our findings indicate
the crucial role of METTL3-mediated translation regulation in N SCLC and reveal the signif icance of METTL3/eIF4E/CYP19A1 signaling
as a promising therapeutic target for anti- metastatic strategies against N SCLC. Graphical abstract: [graphic not available: see
fulltext]
Keywords: Estrogen; METTL3; NSCLC; Small molecule inhibitor; Transl ation regulation
338
Application of cold argon plasma on germination, root length, and decontamination of soybean
cultivars
By: Sayahi, Khadijeh; Sari, Amir Hossein ; Hamidi, Aidin; Nowruzi, Bahareh; Hassani, Farshid
Applying cold discharge plasma can potentially alter plants germination characteristics by triggering their physiol. activi ties. As a
main crop in many countries, soybean was examined in the present study using cultivars such as Arian, Katoul, Saba, Sari, and
Williams in a cold argon plasma. This study has been motivated by the importance of plant production worldwide, considering
climate change and the increasing needs of human populations for food. This study was performed to inspect the effect of cold
plasma treatment on seed germination and the impact of argon plasma on microbial decontam ination was investigated on
soybeans. Also, the employed cultivars have not been studied until now the radicals generated from argon were detected by optical
emission spectrometry (OES), and a collisional radiative model was used to describe electron d. The germin ation properties,
including final germination percentage (FGP), mean germination time (MGT), root length, and elec. conduc tivity of biomols. released
from the seeds, were investigated after the plasma treatments for 30, 60, 180, 300, and 420 s. The decontam ination effect of the
plasma on Aspergillus flavus (A.flavus) and Fusarium solani (F.solani) was also examined The plasma for 60 s induced a maximum F
GP change of 23.12 ± 0.34% and a lowest M GT value of 1.40 ± 0.007 days. Moreover, the ultimate root length was 56.12 ± 2.89%, in
the seeds treated for 60 s. The plasma exposure, however, failed to yield a significant enhancement in elec. conductivity, even when
the discharge duration was extended to 180 s or longer. Therefore, the plasma duration of 180 s was selected for the blotter
technique. Both fungi showed successful sterilization; their infectivity inhibition was 67 ± 4 and 65 ± 3.1%, resp. In general, the cold
plasma used for soybeans in the present study preserved their healthy qualities and reduced the degree of fungal contamination.
Keywords: soybean cold argon plasma germination root length decontam ination; Argon; Aspergillus flavus; Cold plasma; Electrical
conductivity; Fusarium solani; Root length; Seed germin ation; Soybean

339
Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a
comprehensive review on challenges ahead of proteasome inhibitors
By: Pakjoo, Mahdi; Ahmadi, Seyed Esmaeil; Zahedi, Mohammad; Jaafari, Niloofar; Khademi, Reyhane; Amini, Ali; Safa, Majid
Abstract: The current scientific literature has extensively explored the potential role of proteasome inhibitors (P Is) in the N F-κB
pathway of leukemia and lymphoma. The ubiquitin-proteasome system (UPS) is a critical component in regulating protein degrad
ation in eukaryotic cells. PIs, such as BTZ, are used to target the 26S proteasome in hematol. maligna ncies, resulting in the
prevention of the degradation of tumor suppressor proteins, the activation of intrinsic mitocho ndrial-dependent cell death, and the
inhibition of the NF-κB signaling pathway. N F-κB is a transcription factor that plays a critical role in the regulation of apoptosis, cell
proliferation, differentiation, inflammation, angiogenesis, and tumor migration. Despite the successful use of P Is in various hematol.
malignancies, there are limitations such as resistant to these inhibitors. Some reports suggest that PIs can induce N F-κB activation,
which increases the survival of malignant cells. This article discusses the various aspects of PIs′ effects on the N F-κB pathway and
their limitations. [media not available: see fulltext]
Keywords: Lymphoma; NF-κB, leukemia; Proteasome; Proteasome inhibitors
340
Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
By: Liu, Jiye ; Xing, Lijie; Li, Jiang ; Wen, Kenneth; Liu, Ning; Liu, Yuntong; Wu, Gongwei ; Wang, Su ; Ogiya, Daisuke; Song,
Tian-Yu ; et al
Abstract: Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (M M); however, drug
resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-
wide CRISPR screens probing Daratu mumab resistance, KDM6A as an important regulator of sensit ivity to Daratumumab-mediated
antibody-dependent cellular cytotoxicity (ADCC). Loss of K DM6A leads to increased levels of H3K27me3 on the promoter of C D38,
resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratu mumab-mediated ADCC. Re-introd
ucing CD38 does not reverse Daratu mumab-mediated ADCC fully, which suggests that addnl. K DM6A targets, including CD48 which
is also downregulated upon KDM6A loss, contribute to Daratu mumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2
inhibitor resulted in CD38 and CD48 upregulation and restored sensit ivity to Daratumumab. These findings suggest K DM6A loss as
a mechanism of Daratumumab resistance and lay down the proof of principle for the therap eutic application of EZH2 inhibitors,
one of which is already FDA-approved, in improving M M responsiveness to Daratumumab.

341
The oncogenic role and regulatory mechanism of PGK1 in human non-small cell lung cancer
By: Tian, Tian; Leng, Yahui; Tang, Bingbing; Dong, Xiaoxia; Ren, Qiulei; Liang, Jingyin; Liu, Tianhui; Liu, Yanni; Feng, Wenxiao; Liu,
Song; et al
Biology Direct (2024), 19(1), 1 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Phosphoglycerate kinase 1 (P GK1) is a metabolic enzyme that partic ipates in various biol. and pathol.
processes. Dysregulated PGK1 has been observed in numerous maligna ncies. However, whether and how PGK1 affects non-small
cell lung cancer (NSCLC) is not yet fully elucid ated. Methods: Herein, the non-metabolic function of PGK1 in N SCLC was explored by
integrating bioinformatics analyses, cellular experiments, and nude mouse xenograft models. The upstream regulators and
downstream targets of PGK1 were examined using multiple techniques such as R NA sequencing, a dual-luciferase reporter assay,
Co-immunoprecipitation, and Western blotting. Results: We confirmed that P GK1 was upregulated in N SCLC and this upregu lation
was associated with poor prognosis. Further in vitro and in vivo experiments demonstrated the promoting effects of PGK1 on N SCL
C cell growth and metast asis. Addnl., we discovered that PGK1 interacted with and could be O- GlcNAcylated by OGT. The inhibition
of PGK1 O-GlcNAcylation through OGT silencing or mutation at the T255 O- GlcNAcylation site could weaken PGK1-mediated NSCLC
cell proliferation, colony formation, migration, and invasion. We also found that a low mi R-24-3p level led to an increase in O GT
expression. Addnl., PGK1 exerted its oncogenic properties by augmenting E RK phosphorylation and M CM4 expression. Conclusions:
PGK1 acted as a crucial mediator in contro lling NSCLC progression. The mi R-24-3p/OGT axis was responsible for PGK1 O-GlcN
Acylation, and ERK/MCM4 were the downstream effectors of P GK1. It appears that PGK1 might be an attractive therapeutic target
for the treatment of NSCLC.
Keywords: Malignant progression; NSCLC; Oncogene; PGK1
342
A carboxy-terminal ubiquitylation site regulates androgen receptor activity
By: Arai, Seiji ; Gao, Yanfei; Yu, Ziyang; Xie, Lisha; Wang, Liyang; Zhang, Tengfei; Nouri, Mannan ; Chen, Shaoyong ; Asara,
John M.; Balk, Steven P.
Degradation of unliganded androgen receptor (AR) in prostate cancer cells can be prevented by proteasome inhibition , but this is
associated with only modest increases in polyubiquitylated AR. An inhibitor (VLX1570) of the deubiquitylases associated with the
proteasome did not increase ubiquitylation of unliganded AR, indicating that AR is not targeted by these deubiqui tylases. We then
identified a series of AR ubiquitylation sites, including a not previously identified site at K911, as well as methyl ation sites and
previously identified phosphorylation sites. Mutagenesis of K911 increases AR stability, chromatin binding, and transcri ptional
activity. We further found that K313, a previously reported ubiquitylation site, could also be methylated and acetyl ated. Mutage
nesis of K313, in combination with K318, increases AR transcriptional activity, indicating that distinct posttranslational modifications
at K313 differentially regulate AR activity. Together these studies expand the spectrum of A R posttranslational modifications, and
indicate that the K911 site may regulate AR turnover on chromatin.
Keywords: androgen receptor activity regulation carboxy terminal ubiquitylation

343
The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through
inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis
By: Liu, Shuolin; Bi, Yaguang; Han, Tianting; Li, Yiran E.; Wang, Qihang; Wu, Ne Natalie; Xu, Chenguo; Ge, Junbo; Hu, Ronggui; Zhang,
Yingmei
Abstract: Inflammasome activation and pyroptotic cell death are known to contribute to the pathog enesis of cardiovascular
diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly
understood. Here we report that expression levels of the E3 ubiquitin ligase membrane- associated RING finger protein 2 (M ARCH2)
were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial
infarction and cardiac dysfunction upon myocardial I/R injury. Single- cell RNA-seq anal. suggested that loss of MARCH2 prompted
activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (P GAM5) was found to act as a
novel regulator of MAVS-NLRP3 signaling by forming liquid- liquid phase separation condensates with MAVS and fostering the recrui
tment of NLRP3. MARCH2 directly interacts with P GAM5 to promote its K48-linked polyubiquitination and proteasomal degradation,
resulting in reduced PGAM5-MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiom
yocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altoge
ther, our findings reveal a novel mechanism where M ARCH2-mediated ubiquitination neg. regulates the PGAM5/MAVS/NLRP3 axis to
protect against cardiomyocyte pyroptosis and myocardial I/R injury.
344
Neurofibromin 1 controls metabolic balance and Notch-dependent quiescence of murine juvenile

myogenic progenitors
By: Wei, Xiaoyan; Rigopoulos, Angelos ; Lienhard, Matthias ; Poehle-Kronawitter, Sophie; Kotsaris, Georgios ; Franke, Julia;
Berndt, Nikolaus; Mejedo, Joy Orezimena ; Wu, Hao ; Boerno, Stefan; et al
Abstract: Patients affected by neurofibromatosis type 1 (N F1) frequently show muscle weakness with unknown etiol. Here we show
that, in mice, Neurofibromin 1 (Nf1) is not required in muscle fibers, but specif ically in early postnatal myogenic progen itors (MPs),
where Nf1 loss led to cell cycle exit and differentiation blockade, depleting the M P pool resulting in reduced myonuclear accretion
as well as reduced muscle stem cell numbers This was caused by precocious induction of stem cell quiescence coupled to metabolic
reprogramming of M Ps impinging on glycolytic shutdown, which was conserved in muscle fibers. We show that a Mek/Erk/N OS
pathway hypersensitizes Nf1-deficient MPs to Notch signaling, consequently, early postnatal Notch pathway inhibition ameliorated
premature quiescence, metabolic reprogramming and muscle growth. This reveals an unexpected role of Ras/Me k/Erk signaling
supporting postnatal MP quiescence in concert with Notch signaling, which is controlled by Nf1 safegu arding coordinated muscle
growth and muscle stem cell pool establishment. Furthermore, our data suggest transm ission of metabolic reprogramming across
cellular differentiation, affecting fiber metabolism and function in N F1.

345
β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly
targeting PI3K
By: Nie, Shiyun; Chang, Lizhong; Huang, Ying; Zhou, Heyang; Yang, Qianqing; Kong, Lingmei; Li, Yan
Abstract: Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell prolife ration, metastasis and differen tiation.
Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (C RCs). In this study, we identified
iso-Pr 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC50 value of 4.28 μ
M. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence anal. and western
blotting data demonstrated that Z86 effect ively attenuated PI3K/AKT pathway. Z86 caused dramatic prolife ration inhibition of CRCs
through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present
study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and
migration, but also elucidated a reasonable mol. mechanism of Z86 in the Wnt signaling pathway inhibition . Graphical Abstract:
Keywords: Cell cycle arrest; Colorectal cancer; PI3K; Proliferation; Z86
346
Disease suppression, growth promotion and colonization attributes of resident endophytic bacteria
against white root rot (Dematophora necatrix Hartig) of apple
By: Pal, Joginder ; Sharma, Satish K.; Sharma, Anju

Antonie van Leeuwenhoek (2024), 117(1), 15 | Language: English, Database: CAplus and MEDLINE
Abstract: The inherent potential of apple plants was investigated to explore bacterial endophytes and their role in suppre ssing
Dematophora necatrix, the causative pathogen of white root rot disease. Result antly 34 endophytic bacteria isolated from healthy
apple plants, and subsequently 6 most efficient isolates viz., Bacillus megaterium strain E A3, Enterobacter sp. strain E A7, Bacillus
megaterium strain EK2, Stenotrophomonas maltophilia strain EK6, Acinetobacter nosocomialis strain ES2 and Pseudo monas
aeruginosa strain ES8 depicting anti-pathogen interactions through preliminary screening were assessed further under in vitro,
glasshouse and field conditions against white root rot pathogen/disease. Maximum mycelial growth inhibition (80.37%) was
obtained with S. maltophilia strain EK6 encouraging for its seed treatment and soil applic ation thereby providing signif icant effective
control (87.91%) of white root rot under glasshouse conditions to other five bacterial endophytes evaluated simultaneously,
followed by field efficacy of 83.70%. In addition, it has significantly enhanced the growth parameters of apple trees under both
glasshouse and field conditions. The inoculated healthy plants were assessed for endophytic coloni zation which revealed maximum
endosphere colonialism by S. maltophilia strain EK6. Addnl., confocal microscopic images of transverse sections of root cells
colonized by bacterial endophytes as compared to untreated control implied their persistence and establishment in endosphere of
apple seedlings. The study provides the first report on interaction between apple associated bacterial root endophytes and D.
necatrix. The obtained endophytic strains could be employed as alternative for mitigating white root rot disease in future.
Keywords: Anti-pathogen interaction; Bacterial endoph ytes; Colonization; Confocal microscopic images; Root rot; Sequence analysis

347
In vitro study: methylene blue-based antibacterial photodynamic inactivation of Pseudomonas

aeruginosa
By: Zada, Laiq; Anwar, Shahzad; Imtiaz, Sana; Saleem, Muhammad; Shah, Aamer Ali
Abstract: Pseudomonas aeruginosa is one of the most antibi otic-resistant and opportunistic pathogens in immunocompromised
and debilitated patients. It is considered the cause of most severe skin infections and is frequently found in hospital burn units. Due
to its high antibiotic resistance, eliminating P. aeruginosa from skin infections is quite challe nging. Therefore, this study aims to
assess the novel in vitro antibacterial activity of methylene blue using a 635- nm diode laser to determine the effective power and
energy densities for inhibition of P. aeruginosa. The strain was treated with various concent rations of methylene blue and 635- nm
diode laser at powers of 300 mW/cm2 and 250 mW/cm2. The diode laser′s potency in the photo- destruction of methylene blue and
its degradation through P. aeruginosa were also evaluated. Colony- forming unit (C FU)/mL, fluorescence spectroscopy, optical d., and
confocal microscopy were used to measure the bacterial killing effect. As a result, the significant decrease of P. aeruginosa was 2.15-
log10 , 2.71-log10 , and 3.48-log10 at 60, 75, and 90 J/cm 2 after excitation of M B for 240, 300, and 360 s at a power of 250 m W/cm2,
resp. However, a maximum decrease in CFU was observed by 2.54- log10 at 72 J/cm 2 and 4.32-log10 at 90 and 108 J/cm 2 after 300 m
W/cm2 of irradiation Fluorescence images confirmed the elimination of bacteria and showed a high degree of photo- destruction
compared to treatment with methylene blue and light alone. In conclusion, MB-induced aPDT demonstrated high efficacy, which
could be a potential approach against drug-resistant pathogenic bacteria. Key points: • Combin ation of methylene blue with 635- nm
diode laser for antibacterial activity. • Methylene blue photosen sitizer is employed as an alternative to antibiotics. • aPDT showed
promising antibacterial activity against Pseudomonas aeruginosa.
Keywords: Antibiotics; Diode laser; Methylene blue; Photosen sitizer; Pseudomonas aeruginosa; aPDT
348
The emerging role of ectodermal neural cortex 1 in cancer
By: He, Lingling; Zhang, Chiyu; He, Wenjing; Xu, Minjuan

Abstract: Ectodermal neural cortex 1 (ENC1) is a protein that plays a crucial role in the regulation of various cellular processes such
as cell proliferation, differentiation, and apoptosis. Numerous studies have shown that E NC1 is overexpressed in various types of
cancers, including breast, lung, pancreatic, and colorectal cancer, and its upregu lation is correlated with a poorer prognosis. In
addition to its role in cancer growth and spreading, ENC1 has also been linked to neuronal process develo pment and neural crest
cell differentiation. In this review, we provide an overview of the current knowledge on the relati onship between ENC1 and cancer.
We discuss the mol. mechanisms by which ENC1 contributes to tumorigenesis, including its involvement in multiple oncogenic
signaling pathways. We also summarize the potential of targeting ENC1 for cancer therapy, as its inhibition has been shown to
significantly reduce cancer cell invasion, growth, and metast asis. Finally, we highlight the remaining gaps in our underst anding of EN
C1′s role in cancer and propose potential directions for future research.

349
Long noncoding RNA SNHG1 promotes breast cancer progression by regulating the miR-641/RRS1 axis
By: Deng, Lin; Wang, Jun; Song, Junying; Wu, Qinglan; Gong, Zunshuang; Song, Jinlian; Hou, Lin
Abstract: An increasing number of studies have indicated the crucial involvement of long non-coding RNAs (lncRNAs) in the onset
and progression of malignancies. However, a complete underst anding of the mol. mechanism underlying the effect of abnormally
expressed lncRNAs on breast cancer (B C) remains elusive. This study aimed to elucidate the influence of the lnc RNA small nucleolar
RNA host gene 1 (S NHG1) on BC progression and its underlying mechanism. Our findings revealed a conspi cuous up-regulation of S
NHG1 in both BC tissues and cells. The downreg ulation of SNHG1 was observed to inhibit BC cell proliferation, migration, invasion,
and epithelial-mesenchymal transition (EMT) processes, while simultaneously promoting apoptosis. Furthermore, dual-luciferase
reporter gene and RNA pull-down assays established that SNHG1 targeted miR-641 expression, while miR-641 targeted RRS1.
Rescue studies demonstrated that in vitro S NHG1 silencing could be reversed by the mi R-641 inhibitor, as well as by R RS1 upregul
ation. Moreover, in vivo downreg ulation of SNHG1 was found to inhibit BC growth. Through the inhibition of the miR-641 level, SN
HG1 elevated the level of the downstream target R RS1, thereby fostering BC growth, migration, and invasion while inhibiting
apoptosis. These findings suggest that SNHG1 may represent a potential therap eutic target for B C treatment.
350
Loss of Dec1 inhibits alcohol-induced hepatic lipid accumulation and circadian rhythm disorder
By: Sato, Fuyuki; Bhawal, Ujjal K.; Oikawa, Kosuke; Muragaki, Yasuteru
BMC Molecular and Cell Biology (2024), 25(1), 1 | Language: English, Database: CAplus and MEDLINE
Abstract: Chronic alc. exposure increases liver damage such as lipid accumulation and hepatitis, resulting in hepatic cirrhosis.
Chronic alc. intake is known to disturb circadian rhythms in humans and animals. DEC1, a basic helix-loop-helix transcription factor,
plays an important role in the circadian rhythm, inflammation, immune responses, and tumor progre ssion. We have previously
shown that Dec1 deficiency inhibits stresses such as periodontal inflammation and perivascular fibrosis of the heart. However, the
significance of Dec1 deficiency in chronic alc. consum ption remains unclear. In the present study, we invest igated whether the biol.
stress caused by chronic alc. intake is inhibited in Dec1 knockout mice. We treated control and Dec1 knockout mice for three
months by providing free access to 10% alc. The Dec1 knockout mice consumed more alc. than control mice, however, we observed
severe hepatic lipid accumulation and circadian rhythm distur bance in control mice. In contrast, Dec1 knockout mice exhibited little
effect on these outcomes. We also investigated the expression of peroxisome proliferator-activated receptors (PPARs) and AMP-
activated protein kinase (A MPK), which are involved in the regulation of fatty acid metabolism Immunohi stochem. anal. revealed
increases of phosphorylation AMPK and PPARa but decreases PPARg in Dec1 knockout mice compared to that in control mice. This
indicates a mol. basis for the inhibition of hepatic lipid accumu lation in alc.-treated Dec1 knockout mice. These results suggest a
novel function of Dec1 in alc.-induced hepatic lipid accumulation and circadian rhythm disorders.
Keywords: AMPK; Alcohol; Dec1; Immunohistochemistry; PPARs

351
Potential role of the lncRNA "HOTAIR"/miRNA "206"/BDNF network in the alteration in expression of
synaptic plasticity gene arc and BDNF level in sera of patients with heroin use disorder through the
PI3K/AKT/mTOR pathway compared to the controls
By: Khalifa, Fatma Nada; Hussein, Riham F.; Mekawy, Dina M.; Elwi, Heba M.; Alsaeed, Shimaa Ahmed; Elnawawy, Yassmin; Shaheen,
Somaya H.
Abstract: Introduction: Heroin use disorder (HUD) is a seriously increasing health issue, accounting for most deaths among drug
abusers. Studying non-coding RNA gene expression among drug abusers is a promising approach, as it may be used in diagnosis
and therapeutics. Participants and methods: A total of 49 male heroin- dependent patients and 49 male control partic ipants were
recruited from Kasr Al Ainy Psychiatry and Addiction outpatient clinics, Faculty of Medicine, Cairo University. Sera were gathered. q R
T-PCR was utilized for the detection of gene expression of non- coding RNAs such as "HOX transcript antisense RNA" (HOTAIR),
micro-RNA (miRNA-206), phosphatidylinositol 3-kinase (PI3K), protein kinase B (A KT), mechanistic target of rapamycin (mTOR), and
Activity Regulated Cytoskeleton Associated Protein (Arc). Sera Brain-Derived Neurotrophic Factor (BDNF) levels were assessed using
ELISA. Using a western blot made it possible to determine the protein expression of P I3K, AKT, and mTOR. Results: The study
demonstrated that gene expressions of HOTAIR, AKT, PI3K, and Arc were considerably lowered between cases and controls, while
gene expressions of miR-206 and mTOR1 were significantly raised. PI3K and A KT protein expres sions were downregulated, while m
TOR expressions were upregulated. BDNF levels were significantly decreased in some cases. Conclu sion: The results of this study
suggest that decreased HOTAIR in HUD relieves miR-206 inhibition , which thus increases and affects downstream PI3K/AKT/mTOR,
ARC, and BDNF expression. This may be shared in addictive and relapsing behaviors. Graphical Abstract: [graphic not available: see
fulltext]
Keywords: BDNF; Expression; HOTAIR; Heroin abuse; mTOR; miRNA-206
352
Dual-targeting nanomedicine achieves synergistic multimodal therapy for tumor
By: Zhang, Weidong; Dai, Liang; Wang, Na; Liu, Yunhe; Hao, Zining; He, Yaqian; Ni, Song; Wang, Yimin; Gao, Dawei
Cancer Nanotechnology (2024), 15(1), 6 | Language: English, Database: CAplus
Abstract: Background: The poor targeting delivery efficiency and limited efficacy of single therap eutic approach have consis tently
posed significant challenges in tumor manage ment. Results: In this research, we have conceived and synthe sized a dual-targeting
nanodrug delivery system denoted as PDA-DEM-Fe3O4@M, which incorp orates a polydopamine nanoparticle (PDA) with photot
hermal properties, di-Et maleate (DEM) as a chemotherapy agent accelerating tumor apoptosis, iron oxide nanopar ticles (Fe3O4)
eliciting magnetic targeting effects, and tumor cell membranes (M) contributing to homologous targeting capabilities. The synerg
istic effect of PDA-induced photothermal therapy and DEM-mediated chemotherapy has been demons trated in this study to exert a
robust inhibitory and cytotoxic influence on tumor cells. Addnl., the biocompatibility of this system has also been demonst rated.
Conclusions: Through the synerg istic effects of PDA′s photothermal therapy and DEM′s chemotherapy, this system demonstrated
excellent inhibition and killing effects on tumor cells. Furthe rmore, we established its excellent biol. safety profile. This study
demonstrated the potential of this nanoma terial for clin. application in tumor therapy.

353
IDH2/R140Q mutation confers cytokine-independent proliferation of TF-1 cells by activating

constitutive STAT3/5 phosphorylation
By: Yang, Jie; Chen, Jiao; Chang, Jingjie; Sun, Xiaoyan; Wei, Qingyun; Cai, Xueting; Cao, Peng
Abstract: Background: R140Q mutation in isocitrate dehydro genase 2 (IDH2) promotes leukemogenesis. Targeting IDH2/R140Q
yields encouraging therapeutic effects in the clin. setting. However, therap eutic resistance occurs in 12% of I DH2/R140Q inhibitor
treated patients. The IDH2/R140Q mutant converted T F-1 cells to proliferate in a cytokine-independent manner. This study invest
igated the signaling pathways involved in T F-1(R140Q) cell proliferation conversion as alternative therapeutic strategies to improve
outcomes in patients with acute myeloid leukemia (AML) harboring IDH2/R140Q. Methods: The effects of IDH2/R140Q mutation on
TF-1 cell survival induced by G M-CSF withdrawal were evaluated using flow cytometry assay. The expression levels of apoptosis-
related proteins, total or phospho rylated STAT3/5, ERK, and AKT in wild-type TF-1(WT) or TF-1(R140Q) cells under different
conditions were evaluated using western blot anal. Cell viability was tested using MTT assay. The m RNA expression levels of GM-CS
F, IL-3, IL-6, G-CSF, leukemia inhibitory factor (LIF), oncostatin M (O SM), and IL-11 in TF-1(WT) and TF-1(R140Q) cells were quantified
via RT-PCR. The secretion levels of GM-CSF, OSM, and LIF were determined using ELISA. Results: Our results showed that S TAT3 and
STAT5 exhibited aberrant consti tutive phosphorylation in TF-1(R140Q) cells compared with T F-1(WT) cells. Inhibition of STAT3/5
phosphorylation suppressed the cytokine-independent proliferation of TF-1(R140Q) cells. Moreover, the autocrine GM-CSF, LIF and
OSM levels increased, which is consistent with consti tutive STAT5/3 activation in TF-1(R140Q) cells, as compared with T F-1(WT) cells.
Conclusions: The autocrine cytokines, including GM-CSF, LIF, and OSM, contribute to constitutive STAT3/5 activation in TF-1(R140Q)
cells, thereby modulating IDH2/R140Q-mediated malignant proliferation in TF-1 cells. Targeting STAT3/5 phosphorylation may be a
novel strategy for the treatment of AML in patients harboring the I DH2/R140Q mutation. [media not available: see fulltext]
Keywords: Acute myeloid leukemia; Cytokine-independent proliferation; Isocitrate dehydrogenase 2; R140Q mutation; Signal
transducer and activator of transcription 3/5

354
Synergistic suppression of ovarian cancer by combining NRF2 and GPX4 inhibitors: in vitro and in vivo
evidence
By: Li, Ning; Jiang, Xingmei; Zhang, Qingyu; Huang, Yongmei; Wei, Jinbin; Zhang, Haitao; Luo, Hui
Abstract: Ovarian cancer is a significant challenge in women′s health due to the lack of effective screening and diagnostic methods,
often leading to late detection and the highest mortality rate among all gynecol. tumors worldwide. Recent research has shown that
ovarian cancer has an "iron addiction" phenotype which makes it vulnerable to ferroptosis inducers. We tested the combin ation of
NRF2-targeted inhibitors with GPX4-targeted inhibitors in ovarian cancer through in vitro and in vivo experiment The data showed
that combination treatment effectively suppressed adherent cell growth, inhibited suspended cell spheroid formation, and
restrained the ability of spheroid formation in 3D-culture. Mechanistically, the combination induced accumulation of ROS, 4-HNE, as
well as activation of caspase-3 which indicates that this combin ation simultaneously increases cell ferrop tosis and apoptosis.
Notably, inhibition of GPX4 or NRF2 can suppress ovarian cancer spreading and growth in the peritoneal cavity of mice, while the
combination of NRF2 inhibitor ML385 with GPX4 inhibitors showed a signif icant synergistic effect compared to individual drug
treatment in a syngeneic mouse ovarian cancer model. Overall, these findings suggest that combining NRF2 inhibitors with GPX4
inhibitors results in a synergy suppression of ovarian cancer in vitro and in vivo, and maybe a promising therap eutic strategy for the
treatment of ovarian cancer.
Keywords: Apoptosis; Ferroptosis; GPX4; NRF2; Ovarian cancer
355
Cannabidiol-loaded microparticles embedded in a porous hydrogel matrix for biomedical applications
By: David, Carla ; de Souza, Jaqueline F.; Silva, Adriana F.; Grazioli, Guillermo; Barboza, Andressa S.; Lund, Rafael G.; Fajardo, Andre
R.; Moraes, Rafael R.
Journal of Materials Science: Materials in Medicine (2024), 35(1), 14 | Language: English, Database: CAplus and MEDLINE
Abstract: In this study, poly (lactic-co-glycolic acid) (P LGA) microparticles loaded with cannab idiol (CBD) were synthesized (PLGA@CB
D microparticles) and embedded up to 10 wt% in a chondr oitin sulfate/polyvinyl alc. hydrogel matrix. In vitro chem., phys., and biol.
assays were carried out to validate the potential use of the modified hydrogels as biomaterials. The microparticles had spherical
morphol. and a narrow range of size distribution. CBD encapsulation efficiency was around 52%, loading was approx. 50%. Micropa
rticle addition to the hydrogels caused minor changes in their morphol., F TIR and thermal analyses confirmed these changes.
Swelling degree and total porosity were reduced in the presence of microparticles, but similar hydrop hilic and degradation in
phosphate buffer solution behaviors were observed by all hydrogels. Rupture force and maximum strain at rupture were higher in
the modified hydrogels, whereas modulus of elasticity was similar across all materials. Viability of primary human dental pulp cells
up to 21 days was generally not influenced by the addition of PLGA@CBD microparticles. The control hydrogel showed no antimic
robial activity against Staphylococcus aureus, whereas hydrogels with 5% and 10% P LGA@CBD microparticles showed inhibition
zones. In conclusion, the PLGA@CBD microparticles were fabricated and successfully embedded in a hydrogel matrix. Despite the
hydrophobic nature of CBD, the physicochem. and morphol. properties were generally similar for the hydrogels with and without
the CBD-loaded microparticles. The data reported in this study suggested that this original biomat erial loaded with CBD oil has
characteristics that could enable it to be used as a scaffold for tissue/c ellular regeneration. Graphical Abstract: [graphic not
Keywords: Biomaterials; Chondroitin sulfate; Composite materials; Phytocann abinoids; Polyvinyl alcohol; Scaffolds

356
Synthesis and preclinical evaluation of [ 11C]EAI045 as a PET tracer for imaging tumors expressing
mutated epidermal growth factor receptor
By: Hoegnaesbacka, Antonia A.; Poot, Alex J.; Plisson, Christophe; Bergare, Jonas; Bonsall, David R.; McCluskey, Stuart P.; Wells, Lisa
A.; Kooijman, Esther; Schuit, Robert C.; Verlaan, Mariska; et al
EJNMMI Research (2024), 14(1), 19 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Mutations in the epidermal growth factor receptor (E GFR) kinase domain are common in non- small cell lung
cancer. Conventional tyrosine kinase inhibitors target the mutation site in the A TP binding pocket, thereby inhibiting the receptor′s
function. However, subsequent treatment resistance mutations in the ATP binding site are common. The E GFR allosteric inhibitor, E
AI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling indepe ndent of the ATP-binding site.
The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for E AI045, thus increasing the
potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential,
and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium. Results: 2- (5-fluoro-2-hydroxy
phenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoi
ndolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of E AI045, resp. [ 11 C]EAI045 was
synthesized using [ 11 C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochem. yield (decay corrected to end of [ 11 C]CO2
production), > 97% radiochem. purity and 26 ± 1 G Bq/μmol molar activity (determined at end of synthesis) in 51 min. [ 3H]EAI045
was synthesized by a tritium- halogen exchange in a 0.2% radiochem. yield, 98% radiochem. purity, and 763 k Bq/nmol molar activity.
The ability of [11 C]EAI045 to differentiate between L858 R/T790M mutated E GFR expressing H1975 xenografts and wild- type EGFR
expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975
xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between E A
I045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [
3H]EAI045 in vitro, this could not be confirmed in vivo when tumor- bearing mice were administered cetuximab (0.5 mg) , 24 h prior
to injection of [11 C]EAI045. Conclusions: EAI045 was successfully labeled with tritium and carbon- 11, and the in vivo results
indicated [11 C]EAI045 may be able to distin guish between mutated and non- mutated EGFR in non-small cell lung cancer mouse
models. Cetuximab was hypothesized to increase EAI045 uptake; however, no signif icant effect was observed on the uptake of [ 11 C]
EAI045 in vivo or [ 3H]EAI045 in vitro in H1975 xenografts and cells.
Keywords: EAI045; EGFR; Epidermal growth factor receptor; TKI; Tyrosine kinase inhibitor

357
Naturally occurring quercetin and myricetin as potent inhibitors for human ectonucleotide
pyrophosphatase/phosphodiesterase 1
By: Duangiad, Peeradon; Nutho, Bodee; Chaijarasphong, Thawatchai; Morales, Noppawan Phumala; Pongtharangkul, Thunyarat;
Hamachi, Itaru; Ojida, Akio; Wongkongkatep, Jirarut
Abstract: Ecto-nucleotide pyrophosphatases/phosphodiesterases 1 (ENPP1) is a key enzyme in purinergic signaling pathways

responsible for cell-to-cell communications and regulation of several fundam ental pathophysiol. processes. In this study, Kyoto
Green, a rapid chem. sensor of pyrophosphate, was employed to screen for effective E NPP1 inhibitors among five representative
flavonoids (quercetin, myricetin, morin, kaempferol, and quercetin-3-glucoside), five nucleosides (adenosine, guanosine, inosine,
uridine, and cytidine), and five deoxynucleosides (2′- and 3′- deoxyadenosine, 2′-deoxyguanosine, 2′-deoxyinosine, and 2′- deoxyu
ridine). Conventional colorimetric, fluorescence, and bioluminescence assays revealed that E NPP1 was effectively inhibited by
quercetin (K i ∼ 4 n M) and myricetin ( K i ∼ 32 n M) when ATP was used as a substrate at p H 7.4. In silico anal. indicated that the
presence of a chromone scaffold, particularly one containing a hydroxyl group at the 3′ position on the B ring, may promote binding
to the active site pocket of ENPP1 and enhance inhibition . This study demons trated that the naturally derived quercetin and
myricetin could effectively inhibit ENPP1 enzymic activity and may offer health benefits in arthritis manage ment.
358
Phyllosphere bacteria with antiquorum sensing and antibiofilm activities against fish pathogenic
bacteria
By: Lukman, Griselda; Waturangi, Diana Elizabeth; Julyantoro, Pande Gde Sasmita; Papuangan, Nurmaya
BMC Research Notes (2024), 17(1), 5 | Language: English, Database: CAplus and MEDLINE
Abstract: Objective: This research aims to quantify antiquorum sensing and antibiofilm activity of f phyllosphere bacteria against
biofilm formed by pathogenic fish bacteria such as Aeromonas hydrophila, Streptococcus agalactiae, and Vibrio harveyi. Results:
Antiquorum sensing assay using Chromobacter violaceum as indicator bacteria and antibi ofilm assay showed six phyllo sphere
bacteria have antiquorum sensing and antibiofilm activities against tested bacteria. The highest inhibition and destruction activity
was showed by metabolite of JB 3B and EJB 5 F against A. hydrop hila, resp. Determination using light microscope and scanning
electron microscope performed decreaing in biomass of biofilm observed after treated with metabolite from phyllosphere bacteria.
Keywords: Antibiofilm; Aquaculture system; Fish pathogenic bacteria; Quorum quenching; Quorum sensing

359
Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse
model
By: Wang, Yanyan; Zhao, Derrick; Su, Lianyong; Tai, Yun-Ling; Way, Grayson W.; Zeng, Jing; Yan, Qianhua; Xu, Ying; Wang, Xuan;
Gurley, Emily C.; et al
Abstract: Background and aims: Primary sclerosing cholangitis (PSC) is a chronic liver disease charact erized by progressive biliary
inflammation and bile duct injury. Berberine (B BR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple
beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therap eutic
effect of BBR on cholestatic liver injury in a P SC mouse model (Mdr2 -/- mice) and elucidate the underlying mechan isms. Methods:
Mdr2-/- mice (12-14 wk old, both sexes) received either B BR (50 mg/kg) or control solution daily for eight weeks via oral gavage.
Histol. and serum biochem. analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were
used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in
regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by q RT-PCR or Western
blot anal. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distri bution of BBR were
measured by LC-MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histol. anal. The impact
on the gut microbiome was assessed using 16S rRNA gene sequencing. Results: BBR treatment significantly ameliorated cholestatic
liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct prolife ration and hepatic fibrosis, as
shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substa ntial inhibition of fibrotic
and inflammatory gene expression. BBR also mitigated E R stress by downreg ulating Chop, Atf4 and Xbp- 1 expression. In addition, B
BR modulated bile acid metabolism by altering key gene expres sions in the liver and small intestine, resulting in restored bile acid
homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthe
rmore, BBR significantly improved intestinal barrier function and reduced bacterial translo cation by modulating the gut microb iota.
Conclusion: BBR effectively attenuates cholestatic liver injury, suggesting its potential as a therap eutic agent for P SC and other
cholestatic liver diseases.
Keywords: Berberine; Bile acids; Cholestasis; Gut microbiome; Inflammation

360
Establishment of a prognostic risk prediction model incorporating disulfidptosis-related lncRNA for

patients with prostate cancer
By: Mulati, Yelisudan; Lai, Cong; Luo, Jiawen; Hu, Jintao; Xu, Xiaoting; Kong, Degeng; Xiao, Yunfei; Liu, Cheng; Xu, Kewei
Abstract: Purpose: Prostate cancer (PCa) is one of the major tumor diseases that threaten men′s health globally, and biochem.
recurrence significantly impacts its prognosis. Disulfidptosis, a recently discovered cell death mechanism triggered by intrace llular
disulfide accumulation leading to membrane rupture, is a new area of research in the context of P Ca. Currently, its impact on PCa
remains largely unexplored. This study aims to invest igate the correlation between long non-coding RNAs (lncRNAs) associated with
disulfidptosis and the prognosis of PCa, seeking potential connections between the two. Methods: Transcr iptomic data for a P Ca
cohort were obtained from the Cancer Genome Atlas database. Disulfidptosis-related lncRNAs (DDRLs) were identified through
differential expression and Pearson correlation anal. DDRLs associated with biochem. recurrence-free survival (BRFS) were precisely
identified using univariate Cox and LASSO regression, resulting in the development of a risk score model. Clin. factors linked to B RF
S were determined through both univariate and multiv ariate Cox analyses. A prognostic nomogram combined the risk score with
key clin. variables. Model performance was assessed using Receiver Operating Charact eristic (ROC) curves, Decision Curve Anal. (DC
A), and calibration curves. The functional impact of a critical D DRL was substantiated through assays involving C CK8, invasion,
migration, and cell cloning. Addnl., immunohistochem. (IHC) staining for the disulfidptosis-related protein SLC7A11 was conducted.
Results: The prognostic signature included AC026401.3, SNHG4, SNHG25, and U73166.1 as key compon ents. The derived risk score
from these signatures stood as one of the independent prognostic factor for PCa patients, correlating with poorer BRFS in the high-
risk group. By combining the risk score with clin. variables, a practical nomogram was created, accurately predicting B RFS of PCa
patients. Notably, silencing AC026401.3 significantly hindered PCa cell proliferation, invasion, migration, and colony formation. I HC
staining revealed elevated expression of the dithiosulfatide-related protein SLC7A11 in tumor tissue. Conclu sions: A novel
prognostic signature for PCa DDRLs, possessing commendable predictive power, has been constr ucted, simultaneously providing
potential therapeutic targets associated with disulfid ptosis, among which AC026401.3 has been validated in vitro and demons trated
inhibition of PCa tumorigenesis after its silencing.
Keywords: AC026401.3; Biochemical recurrence-free survival; Disulfidptosis; Prostate cancer; lnc RNA

361
E-cadherin variants associated with oral facial clefts trigger aberrant cell motility in a REG1A-
dependent manner
By: Pereira, Joana; Melo, Soraia; Ferreira, Rui M.; Carneiro, Patricia; Yang, Vitor; Maia, Andre F.; Carvalho, Joao; Figueiredo, Ceu;
Machado, Jose Carlos; Morais-de-Sa, Eurico; et al
Abstract: Background: Germline mutations of E-cadherin contribute to hereditary diffuse gastric cancer (H DGC) and congenital
malformations, such as oral facial clefts (OFC). However, the mol. mechanisms through which E-cadherin loss-of-function triggers
distinct clin. outcomes remain unknown. We postulate that E-cadherin-mediated disorders result from abnormal interactions with
the extracellular matrix and consequent aberrant intrace llular signalling, affecting the coordination of cell migration. Methods:
Herein, we developed in vivo and in vitro models of E-cadherin mutants associated with either O FC or HDGC. Using a Drosophila
approach, we addressed the impact of the different variants in cell morphol. and migration ability. By combining gap closure
migration assays and time-lapse microscopy, we further invest igated the migration pattern of cells expressing OFC or HDGC
variants. The adhesion profile of the variants was evaluated using high-throughput ECM arrays, whereas R NA sequencing technol.
was explored for identification of genes involved in aberrant cell motility. Results: We have demons trated that cells expressing OFC
variants exhibit an excessive motility performance and irregular leading edges, which prevent the coordi nated movement of the
epithelial monolayer. Importantly, we found that O FC variants promote cell adhesion to a wider variety of extrace llular matrixes
than HDGC variants, suggesting higher plasticity in response to different microenvi ronments. We unveiled a distinct transcr iptomic
profile in the OFC setting and pinpointed R EG1A as a putative regulator of this outcome. Consistent with this, specific R NAi-
mediated inhibition of REG1A shifted the migration pattern of O FC expressing cells, leading to slower wound closure with coordi
nated leading edges. Conclu sions: We provide evidence that E- cadherin variants associated with O FC activate aberrant signalling
pathways that support dynamic rearrangements of cells towards improved adapta bility to the microenvironment. This profic iency
results in abnormal tissue shaping and movement, possibly underlying the development of orofacial malformations. Graphical
Abstract: [graphic not available: see fulltext]
Keywords: Cell migration; E-cadherin; Extracellular matrix; Hereditary diffuse gastric cancer; Oral facial clefts; R EG1A

362
Insights into the regulatory role of bacterial sncRNA and its extracellular delivery via OMVs
By: He, Mengdan; Yin, Shuanshuan; Huang, Xinlei; Li, Yi; Li, Biaoxian; Gong, Tian; Liu, Qiong
Abstract: Small noncoding RNAs (sncRNAs) play important regulatory roles in bacterial physiol. processes and host- pathogen
interactions. Meanwhile, bacterial outer membrane vesicles (O MVs), as naturally secreted outer membrane structures, play a vital
role in the interaction between bacteria and their living enviro nment, including the host environment. However, most current
studies focus on the biol. functions of sncRNAs in bacteria or hosts, while neglecting the roles and regulatory mechanisms of the O
MVs that encapsulate these sncRNAs. Therefore, this review aims to summarize the intrace llular regulatory roles of bacterial sncRN
As in promoting pathogen survival by regulating virulence, modulating bacterial drug resist ance, and regulating iron metabo lism,
and their extracellular regulatory function for influe ncing host immunity through host-pathogen interactions. Addnl., we introduce
the key role played by OMVs, which serve as important cargoes in bacterial snc RNA-host interactions. We propose emerging
pathways of sncRNA action to further discuss the mode of host- pathogen interactions, highlighting that the inhibition of sncRNA
delivery by OMVs may prevent the occurrence of infection to some extent. Hence, this review lays the foundation for future prophy
lactic treatments against bacterial infections and strategies for addressing bacterial drug resist ance. Key points: •sncRNAs have
intracellular and extracellular regulatory functions in bacterial physiol. processes and host- pathogen interactions. •OMVs are
potential mediators between bacterial sncRNAs and host cells. •O MVs encapsulating sncRNAs have more potential biol. functions.
Keywords: Host-pathogen interaction; Outer membrane vesicles (O MVs); Small non- coding RNA (sncRNA); Virulence
363
Aneuploid serves as a prognostic marker and favors immunosuppressive microenvironment in

ovarian cancer
By: Du, Ming; Cai, Qingqing; Sun, Jiaan; Zhang, Mingxing; Zhang, Shuo; Liu, Xiaoxia; Zhang, Mengyu; Zhang, Xiaoyan
Abstract: Ovarian cancer is the most lethal gynecol. neoplasm, and most patients experience recurrence and chemoresistance.
Even the promising immunotherapy showed limited efficacy in ovarian cancer, probably due to the immunosup pressive microenvi
ronment. However, the behind mechanisms of the immune exclusion or cold phenotype in ovarian cancer still remain to be
explored. As a cancer dominated by copy number variations instead of mutations, ovarian cancer contains a high fraction of
aneuploid, which might correlate with immune inhibition . Nevertheless, whether or how aneuploid affects ovarian cancer is still
unclear. For exploring the role of aneuploid cancer cells and the potential ploidy-immune relationship, herein, the ploidy inform
ation was first comprehensively analyzed combining the karyotype data and copy number variation data obtained from Mitelman
and cBioPortal databases, resp. Ovarian cancer showed strong ploidy heterog eneity, with high fraction of aneuploid and recurrent
arm-level and whole chromosome changes. Furthe rmore, clin. parameters were compared between the highly- aneuploid and the
near-diploid ovarian cancers. Aneuploid indicated high grade, poor overall survival and poor disease- free survival in ovarian cancer.
To understand the biofunction affected by aneuploid, the differe ntially expressed genes between the highly- aneuploid and the
near-diploid groups were analyzed. Transcr iption data suggested that aneuploid cancer correlated with deregu lated MHC expres
sion, abnormal antigen presentation, and less infilt ration of macrophages and activated T cells and higher level of T cell exclusion.
Furthermore, the ploidy-MHC association was verified using the Human Protein Atlas database. All these data supported that
aneuploid might be promising for cancer management and immune surveillance in ovarian cancer.
Keywords: Aneuploid; Antigen presentation; Chromosome alteration; Immune microenvironment; Ovarian cancer

364
Petrosamine isolated from marine sponge Petrosia sp. demonstrates protection against neurotoxicity
in vitro and in vivo
By: Ribeiro, Joana ; Araujo-Silva, Henrique; Fernandes, Mario ; da Silva, Joilna Alves ; Pinto, Francisco das Chagas L. ;
Pessoa, Otilia Deusdenia L. ; Santos, Helcio Silva ; de Menezes, Jane Eire Silva Alencar ; Gomes, Andreia C.
Abstract: According to The World Alzheimer Report 2023 by Alzheimer′s Disease International (ADI) estimates that 33 to 38.5 million
people worldwide suffer from Alzheimer′s Disease (AD). A crucial hallmark associated with this disease is associated with the
deficiency of the brain neurotransmitter acetylcholine, due to an affected acetylcholinesterase (AChE) activity. Marine organisms
synthesize several classes of compounds, some of which exhibit significant AChE inhibition , such as petrosamine, a colored pyridoa
cridine alkaloid. The aim of this work was to characterize the activity of petrosamine isolated for the first time from a Brazilian
marine sponge, using two neurotoxicity models with aluminum chloride, as exposure to aluminum is associated with the develo
pment of neurodegenerative diseases. The in vitro model was based in a neurobl astoma cell line and the in vivo model exploited
the potential of zebrafish (Danio rerio) embryos in mimicking hallmarks of AD. To our knowledge, this is the first report on petrosa
mine′s activity over these parame ters, either in vitro or in vivo, in order to charac terize its full potential for tackling neuroto xicity.
Graphical Abstract: [graphic not available: see fulltext]
Keywords: Aluminium-induced neurotoxicity; Neuroprotection; Petrosamine; Petrosia sp.
365
Human archetypal pluripotent stem cells differentiate into trophoblast stem cells via endogenous
BMP5/7 induction without transitioning through naive state
By: Tietze, Ethan; Barbosa, Andre Rocha; Araujo, Bruno; Euclydes, Veronica; Spiegelberg, Bailey; Cho, Hyeon Jin; Lee, Yong Kyu;
Wang, Yanhong; McCord, Alejandra; Lorenzetti, Alan; et al
Abstract: Primary human trophoblast stem cells (TSCs) and T SCs derived from human plurip otent stem cells (hPSCs) can potentially
model placental processes in vitro. Yet, the pluripotent states and factors involved in the differen tiation of hPSCs to TSCs remain
poorly understood. In this study, we demons trate that the primed pluripotent state can generate T SCs by activating pathways such
as Epidermal Growth Factor (EGF) and Wingless-related integration site (WNT), and by suppressing tumor growth factor beta (T GFβ),
histone deacetylases (HDAC), and Rho-associated protein kinase (R OCK) signaling pathways, all without the addition of exogenous
Bone morphogenetic protein 4 (BMP4)-a condition we refer to as the T S condition. We charact erized this process using temporal
single-cell RNA sequencing to compare T S conditions with differen tiation protocols involving BMP4 activation alone or BMP4
activation in conjunction with WNT inhibition . The TS condition consistently produced a stable, prolife rative cell type that closely
mimics first-trimester placental cytotrophoblasts, marked by the activation of endogenous retroviral genes and the absence of
amnion expression. This was observed across multiple cell lines, including various primed induced plurip otent stem cell (i PSC) and
embryonic stem cell (ESC) lines. Primed-derived TSCs can prolif erate for over 30 passages and further specify into multinu cleated
syncytiotrophoblasts and extravillous trophoblast cells. Our research establ ishes that the differentiation of primed h PSCs to TSC
under TS conditions triggers the induction of T MSB4X, BMP5/7, GATA3, and TFAP2A without progressing through a naive state.
These findings propose that the primed hPSC state is part of a continuum of potency with the capacity to differe ntiate into T SCs
through multiple routes.

366
Inactivation of pentraxin 3 suppresses M2-like macrophage activity and immunosuppression in colon

cancer
By: Chen, Feng-Wei; Wu, Yung-Ling; Cheng, Chao-Chun; Hsiao, Yu-Wei; Chi, Jhih-Ying; Hung, Liang-Yi; Chang, Chih-Peng; Lai, Ming-
Derg; Wang, Ju-Ming
Abstract: Background: The tumor microenv ironment is characterized by inflammation-like and immunosuppression situations.
Although cancer-associated fibroblasts (CAFs) are among the major stromal cell types in various solid cancers, including colon
cancer, the interactions between C AFs and immune cells remains largely uncharac terized. Pentraxin 3 (P TX3) is responsive to
proinflammatory cytokines and modulates immunity and tissue remode ling, but its involvement in tumor progression appears to
be context-dependent and is unclear. Methods: Open-access databases were utilized to examine the associ ation of PTX3 expression
and the fibroblast signature in colon cancer. Loss-of-function assays, including studies in tamoxifen- induced Ptx3 knockout mice
and treatment with an anti-PTX3 neutralizing antibody (WHC-001), were conducted to assess the involvement of PTX3 in colon
cancer progression as well as its immunosuppressive effect. Finally, bioinformatic analyses and in vitro assays were performed to
reveal the downstream effectors and decipher the involvement of the CREB1/CEBPB axis in response to PTX3 and PTX3-induced
promotion of M2 macrophage polarization. Results: Clin., higher P TX3 expression was pos. correlated with fibrob lasts and inflam
matory response signatures and associated with a poor survival outcome in colon cancer patients. Blockade of P TX3 significantly
reduced stromal cell-mediated tumor development. The decrease of the M2 macrophage population and an increase of the
cytotoxic CD8+ T-cell population were observed following P TX3 inactivation in allografted colon tumors. We further revealed that
activation of cAMP-responsive element-binding protein 1 (C REB1) mediated the PTX3-induced promotion of M2 macrophage polariz
ation. Conclusions: PTX3 contributes to stromal cell-mediated protumor immunity by increasing M2- like macrophage polarization,
and inhibition of PTX3 with WHC-001 is a potential therapeutic strategy for colon cancer.
Keywords: Cancer-associated fibroblasts; Colon cancer; Immunosuppression; M2-like macrophages; PTX3
367
Distinct patterns of proteostasis network gene expression are associated with different prognoses in
melanoma patients
By: Wellman, Rachel; Jacobson, Daniel; Secrier, Maria; Labbadia, John

Abstract: The proteostasis network (PN) is a collection of protein folding and degrad ation pathways that spans cellular compar
tments and acts to preserve the integrity of the proteome. The differ ential expression of PN genes is a hallmark of many cancers,
and the inhibition of protein quality control factors is an effective way to slow cancer cell growth. However, little is known about
how the expression of PN genes differs between patients and how this impacts survival outcomes. To address this, we applied
unbiased hierarchical clustering to gene expression data obtained from primary and metastatic cutaneous melanoma (C M)
samples and found that two distinct groups of individuals emerge across each sample type. These patient groups are disting uished
by the differential expression of genes encoding A TP-dependent and ATP-independent chaperones, and proteasomal subunits.
Differences in PN gene expression were associated with increased levels of the transcr iption factors, MEF2A, SP4, ZFX, CREB1 and A
TF2, as well as markedly different survival outcomes. However, surpris ingly, similar PN alterations in primary and metastatic
samples were associated with discordant survival outcomes in patients. Our findings reveal that the expression of PN genes
demarcates CM patients and highlights several new proteo stasis sub-networks that could be targeted for more effective suppre
ssion of CM within specific indivi duals.

368
In vitro anti-HIV, cytotoxicity and nutritional analysis of Trianthema portulacastrum L. (Aizoaceae)
By: Jimoh, Mahboob Adekilekun; Jimoh, Muhali Olaide; Bello, Mujidat; Raimi, Idris Olawale; Okunlola, Gideon Olarewaju; Mkhwanazi,
Nompumelelo; Laubscher, Charles Petrus
The development of antiretroviral therapy has brought a tremendous relief to the world as it minimizes mortality, reduces H IV
transmission, and suppresses progression in infected patients. However, the orthodox antiret roviral therapy is faced with limita
tions which have necessitated a continuous search for more novel plant- based antiviral compounds, which can bypass the existing
barriers created by drug resistance and target more viral proteins. Despite the edibility and enormous pharmacol. benefits of T.
portulacastrum, little is known about its nutrient profiles and potential use as a natural source of antiviral drug. This study focuses
on the full feed anal. and anti-HIV potential of two biotypes of T. portulacastrum. Ethanolic extracts of both biotypes of T. portula
castrum (T01 and T02) had signif icant inhibitory effects on the level of replication of the HIV-1. Both extracts induced the inhibition
of at least 50% of the HIV-1 viral load at consid erably low IC50 values of 1.757 mg/m L (T01) and 1.205 mg/m L (T02) which is
comparable to the AZT standard The protein compos ition ranged between 8.63-22.69%; fat (1.84-4.33%); moisture (7.89-9.04%);
fiber (23.84-49.98%); and carbohydrate content (38.54-70.14%). Mineral contents of tested T. portula castrum varied considerably in
different parts of the plant. Nitrogen N mineral ranged between 13.8-36.3 mg/g; sodium Na (2.0-14.0 mg/g); potassium K (14.0-82.0
mg/g); magnesium Mg (2.8-7.1 mg/g); calcium Ca (9.1- 24.7 mg/g); phosphorus P (1.3-3.6 mg/g); iron Fe (193.5-984.0 ppm); zinc Zn
(42.5-96.0 ppm); manganese Mn (28.5-167.5 ppm); and copper Cu (2.0-8.5 ppm). These mineral values are comparable or higher
than values quoted for common vegetables, suggesting that T. portula castrum is a nutrient-dense vegetable that could provide
alternative sources of antiviral nutrients to HIV-infected individuals. Further studies are recomm ended to unravel key metabolites
responsible for high nutrient profiles and antiret roviral effects in T. portulacastrum.
Keywords: Trianthema portulacastrum antiHIV cytotoxicity nutritional analysis; Aizoaceae; Antiretroviral drugs; Antiviral nutrients;
Botanical ingredients; Trianthema portulacastrum
369
1H-NMR metabolomics analysis identifies hypoxanthine as a novel metastasis-associated metabolite in

breast cancer
By: Shakartalla, Sarra B.; Ashmawy, Naglaa S.; Semreen, Mohammad H.; Fayed, Bahgat; Al Shareef, Zainab M.; Jayakumar, Manju N.;
Ibrahim, Saleh; Rahmani, Mohamed; Hamdy, Rania; Soliman, Sameh S. M.
Abstract: Breast cancer is one of the leading causes of death in females, mainly because of metastasis. Oncometabolites, produced
via metabolic reprogramming, can influence metastatic signaling cascades. Accord ingly, and based on our previous results, we
propose that metabolites from highly metastatic breast cancer cells behave differ ently from less-metastatic cells and may play a
significant role in metastasis. For instance, we aim to identify these metabo lites and their role in breast cancer metast asis. Less
metastatic cells (MCF-7) were treated with metabo lites secreted from highly metastatic cells (M DA-MB-231) and the gene
expression of three epithelial-to-mesenchymal transition (EMT) markers including E-cadherin, N-cadherin and vimentin were
examined Some metabolites secreted from M DA-MB-231 cells significantly induced EMT activity. Specifically, hypoxanthine demons
trated a signif icant EMT effect and increased the migration and invasion effects of M CF-7 cells through a hypoxia-associated
mechanism. Hypoxanthine exhibited pro-angiogenic effects via increasing the VEGF and PDGF gene expression and affected lipid
metabolism by increasing the gene expression of PCSK-9. Notably, knockdown of purine nucleoside phospho rylase, a gene
encoding for an important enzyme in the biosynthesis of hypoxanthine, and inhibition of hypoxanthine uptake caused a signif icant
decrease in hypoxanthine-associated EMT effects. Collectively for the first time, hypoxa nthine was identified as a novel metastasis-
associated metabolite in breast cancer cells and represents a promising target for diagnosis and therapy.

370
Dietary lysozyme and avilamycin modulate gut health, immunity, and growth rate in broilers
By: Abdel-Latif, Mervat A.; El-Hamid, Hatem S. Abd; Emam, Mohamed; Noreldin, Ahmed. E.; Helmy, Yosra A.; El-Far, Ali H.; Elbestawy,
Ahmed R.
BMC Veterinary Research (2024), 20(1), 28 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Attempts to use dietary lysozyme (LYZ) as an alternative to antibiotics in broilers have been succes sful, but
further research is needed for effective use. Here, we compared the differences between L YZ and avilamycin (AVI) feed additives for
growth performance, gut health and immunity of broilers. One- day old, one hundred and twenty broiler chicks (Ross 308) were
randomly allocated into three groups consisting forty birds in each group. Standard diet without supplementation was applied as
the control group (I), while the chicks of the other groups were supple mented with 100 mg of A VI per kg diet (A VI, group II), and 90
mg LYZ per kg diet (LYZ, group III) for five consecutive weeks. Results: Body weight, feed conversion ratio, body weight gain, and
European production efficiency factor were markedly (p < 0.05) increased in both AVI and LYZ groups in relation to C ON group, but
the feed intake and protein efficiency ratio were not affected. Both AVI and LYZ significantly (p < 0.001) upregu lated the mRNA
expression of ileal interleukin-18 (IL-18), interferon-gamma (IFN-γ), and interleukin-10 (IL-10), interleukin-2 (IL-2), and glutathione
peroxidase (GSH-PX) genes compared to C ON group. However, I L-2, IL-10, IL-18, and GSH-PX genes were markedly (p < 0.01) upregu
lated in LYZ compared to the AVI group. LYZ treated group had a signif icant increase (p < 0.05) in the serol. hemagglu tination
inhibition titers of H5N1 vaccination and a signif icant decrease (p < 0.0001) in coliform counts compared to control and A VI groups,
but all growth parameters were nearly similar between AVI and LYZ groups. The VH and VH/CD were markedly higher in LYZ than AV
I and control groups. Conclu sion: Exogenous dietary lysozyme supplementation by a dose of 90 mg/kg broilers′ diet induced better
effects on intestinal integrity, fecal bacterial counts, immune response, and growth performance which were comparable to avilam
ycin. Therefore, dietary lysozyme could safely replace avilamycin in the broiler chickens′ diet. However, further exptl. studies
regarding the use of lysozyme in com. broilers, both in vitro and in vivo, targeting more communities of intestinal microbiome and
explaining more details about its beneficial effects need to be conducted.
Keywords: Avilamycin; Broilers; Gut health; Lysozyme; Perfor mance

371
Characterization of gastric cancer-stimulated signaling pathways and function of CTGF in cancer-

associated fibroblasts
By: Choi, Kyoung-Min; Kim, Boram; Lee, Su-Min; Han, Jisoo; Bae, Ha-Song; Han, Su-Bhin; Lee, Dagyeong; Ham, In-Hye; Hur, Hoon;
Kim, Eunjung; et al
Abstract: Background: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenv ironment (TME) that play an
important role in cancer progression. Although the mechanism by which C AFs promote tumorigenesis has been well investi gated,
the underlying mechanism of CAFs activation by neighb oring cancer cells remains elusive. In this study, we aim to invest igate the
signaling pathways involved in CAFs activation by gastric cancer cells (G C) and to provide insights into the therap eutic targeting of C
AFs for overcoming GC. Methods: Alteration of receptor tyrosine kinase (R TK) activity in CAFs was analyzed using phospho-RTK
array. The expression of CAFs effector genes was determined by R T-qPCR or ELISA. The migration and invasion of G C cells co-
cultured with CAFs were examined by transwell migration /invasion assay. Results: We found that condit ioned media (CM) from GC
cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array anal.
showed that CM from GC cells activated PDGFR tyrosine phosphor ylation, but only AKT activation was PDGFR-dependent. Furthe
rmore, we found that connective tissue growth factor (C TGF), a member of the CCN family, was the most pronouncedly induced CA
Fs effector gene by G C cells. Knockdown of C TGF impaired the ability of C AFs to promote GC cell migration and invasion. Although
the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacol. inhibition affected neither CTGF
induction nor CAFs-induced GC cell migration. Unexpec tedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and
saracatinib, significantly impaired C TGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC
inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured
with CAFs, as well as CAFs-induced aggregate formation in a 3 D tumor spheroid model. Conclu sions: This study provides a characte
rization of the signaling pathways and effector genes involved in C AFs activation, and strategies that could effect ively inhibit it in the
context of GC. [media not available: see fulltext]
Keywords: Cancer-associated fibroblasts (CAFs); Connective tissue growth factor (CTGF); Gastric cancer (GC); Tumor microenv
ironment (TME)

372
Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis
By: Casanova, Alexandre G.; Roth, Gael S.; Hausmann, Simone; Lu, Xiaoyin ; Bischoff, Ludivine J. M.; Froeliger, Emilie M.;
Belmudes, Lucid; Bourova-Flin, Ekaterina; Flores, Natasha M.; Benitez, Ana Morales; et al
Abstract: Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to
metastatic spread. A better understanding of the mechanisms at play will provide better insights for altern ative treatments to
prevent breast cancer cell dispersion. Here, we identify the lysine methyltra nsferase SMYD2 as a clin. actionable master regulator of
breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary
tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary
tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiol. substrate of S MYD2 in breast cancer cells.
BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl- binding domain present in FMNLs proteins.
These actin cytoskeleton regulators are recruited at the cell edges by the S MYD2 methylation signaling and modulate lamell ipodia
properties. Breast cancer cells with impaired B CAR3 methylation lose migration and invasi veness capacity in vitro and are ineffe
ctive in promoting metastases in vivo. Remark ably, SMYD2 pharmacol. inhibition efficiently impairs the metastatic spread of breast
cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative
therapeutic prevention of malignant breast cancer metastatic progre ssion by targeting the S MYD2-BCAR3-FMNL axis.
373
Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer
By: Larsson, Peter; Pettersson, Daniella; Olsson, Maxim; Sarathchandra, Sithumini; Abramsson, Alexandra; Zetterberg, Henrik; Ittner,
Ella; Forssell-Aronsson, Eva; Kovacs, Aniko; Karlsson, Per ; et al
Abstract: Triple-neg. breast cancer (T NBC) is associated with poor prognosis and limited treatment options due to the lack of
important receptors (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [H ER2])
used for targeted therapy. However, high-throughput in vitro drug screening of cell lines is a powerful tool for identi fying effective
drugs for a disease. Here, we determine the intrinsic chemosensitivity of TNBC cell lines to proteasome inhibitors (P Is), thereby
identifying potentially potent 2-drug combinations for TNBC. Eight TNBC cell lines (B T-549, CAL-148, HCC1806, HCC38, HCC70, MDA-
MB-436, MDA-MB-453, and MDA-MB-468) and two controls (M CF-10A and M CF-7) were first exposed to 18 drugs (11 P Is and 7 clin.
relevant chemotherapeutic agents) as monoth erapy, followed by prediction of potent 2- drug combinations using the IDACombo
pipeline. The synergistic effects of the 2-drug combinations were evaluated with Synergy Finder in four TNBC cell lines (C AL-148, HC
C1806, HCC38, and MDA-MB-468) and three controls (BT-474, MCF-7, and T47D) in vitro, followed by further evaluation of tumor
regression in zebrafish tumor models established using HCC1806 and M CF-7 cells. Monotherapy identified nine effective drugs
(bortezomib, carfilzomib, cisplatin, delanzomib, docetaxel, epoxomicin, MLN-2238, MLN-9708, and nedaplatin) across all cell lines. P
Is (e.g., bortez omib, delanzomib, and epoxomicin) were highly potent drugs in T NBC cells, of which bortezomib and delanzomib
inhibited the chymotrypsin-like activity of the 20 S proteasome by 100% at 10 μ M. Moreover, several potent 2-drug combinations
(e.g., bortezomib+nedaplatin and epoxomicin+epirubicin) that killed virtually 100% of cells were also identi fied. Although HCC1806-
and MCF-7-derived xenografts treated with bortezo mib+nedaplatin and carboplatin+paclitaxel were smaller, HCC1806 cells
frequently metastasized to the trunk region. Taken together, we show that P Is used in combin ation with platinum agents or topoiso
merase inhibitors exhibit increased efficiency with almost 100% inhibition in TNBC cell lines, indicating that P Is are therefore
promising compounds to use as combination therapy for TNBC.

374
Investigation the effects of bee venom and H-dental-derived mesenchymal stem cells on non-small cell
lung cancer cells (A549)
By: Sengul, Fatma ; Vatansev, Husamettin ; Ozturk, Bahadir

Lung cancer, one of the most common oncol. diseases worldwide, continues to be the leading cause of cancer-related deaths. The
development of new approaches for lung cancer, which still has a low survival rate despite medical advances, is of great import
ance. In this study, bee venom (B V), conditioned medium of M SCs isolated from dental follicles (M SC-CM) and cisplatin were applied
at different doses and their effects on A549 cell line were evaluated. Dental follicles were used as a source of MSCs source and
differentiation kits, and characte rization studies (flow cytometry) were performed. Cell viability was measured by the M TT method
and apoptosis was measured by an Annexin V-FITC/PI kit on flow cytometer. I C50 dose values were determined according to the
24th hour and were determined as 15.8μg/mL for BV, 10.78% for M SC-CM and 5.77μg/mL for cisplatin. I C50 values found for B V
and MSC-CM were also given in combin ation and the effects were observed It was found that the applied substances caused B V to
decrease in cell viability and induced apoptosis in cells. In addition to the induction of apoptosis in BV, MSC-CM, and combined use,
all three applications led to an increase in Bax protein expression and a decrease in Bcl- 2 protein expression. The mol. mechanism
of anticancer activity through inhibition of Bax and Bcl- 2 proteins and the N F-κB signaling pathway may be suggested. Isolated M S
Cs in our study showed anticancer activity and B V and MSC-CM showed synerg istic antiproliferative and apoptotic effects.
Keywords: bee venom apamin melittin PLA2 anticancer CD19 Bcl2 NSCLC; A549; Apoptosis; Bee venom; Mesenc hymal stem cells;
Western blot
375
cGAS-STING pathway expression correlates with genomic instability and immune cell infiltration in
breast cancer
By: Chen, Mengting; Yu, Shibo; van der Sluis, Tineke; Zwager, Mieke C.; Schroeder, Carolien P.; van der Vegt, Bert ; van Vugt,
Marcel A. T. M.
npj Breast Cancer (2024), 10(1), 1 | Language: English, Database: CAplus and MEDLINE
Abstract: Genomic instability, as caused by oncogene- induced replication stress, can lead to the activation of inflam matory
signaling, involving the cGAS-STING and JAK-STAT pathways. Inflam matory signaling has been associated with pro- tumorigenic
features, but also with favorable response to treatment, including to immune checkpoint inhibition . In this study, we aim to explore
relations between inflammatory signaling, markers of replic ation stress, and immune cell infilt ration in breast cancer. Expression
levels of cGAS-STING signaling components (S TING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and pR
PA), replication stress-related proto-oncogenes (Cyclin E1 and c- Myc) and immune cell markers (C D20, CD4, and C D57) are
determined immunohistochem. on primary breast cancer samples (n = 380) . RNA-sequencing data from T CGA (n = 1082) and M ETA
BRIC (n = 1904) are used to calculate c GAS-STING scores. pTBK1, pSTAT1 expression and c GAS-STING pathway scores are all
increased in triple-neg. breast cancers compared to other subtypes. Expression of γ H2AX, pRPA, Cyclin E1, c-Myc, and immune cell
infiltration pos. correlate with p-STAT1 expression (P < 0.001) . Addnl., we observe signif icant pos. associations between expression
of pTBK1 and γH2AX, pRPA, c-Myc, and number of C D4+ cells and CD20+ cells. Also, c GAS-STING scores are correlated with genomic
instability metrics, such as homologous recombi nation deficiency (P < 0.001) and tumor mutational burden (P < 0.01) . Moreover,
data from the I-SPY2 clin. trial (n = 71) confirms that higher c GAS-STING scores are observed in breast cancer patients who
responded to immunotherapy combined with chemoth erapy. In conclusion, the cGAS-STING pathway is highly expressed in T NBCs
and is correlated with genomic instability and immune cell infiltr ation.

376
Exploring the therapeutic mechanisms and prognostic targets of Biochanin A in glioblastoma via
integrated computational analysis and in vitro experiments
By: Ge, Wanwen; Yuan, Guoqiang; Wang, Dongping; Dong, Li

Abstract: Glioblastoma (GBM) is the most aggressive brain tumor and is charact erized by a poor prognosis and high recurrence and
mortality rates. Biochanin A (BCA) exhibits promising clin. anti- tumor effects. In this study, we aimed to explore the pharmacol.
mechanisms by which BCA acts against GBM. Network pharmacol. was employed to identify overla pping target genes between B CA
and GBM. Differentially expressed genes from the Gene Expression Profiling Intera ctive Anal. 2 (GEPIA2) database were visualized
using VolcaNose. Interactions among these overlapping genes were analyzed using the Search Tool for the Retrieval of Intera cting
Genes/Proteins database. Protein- protein interaction networks were constructed using Cytoscape 3.8.1. The Kyoto Encycl opedia of
Genes and Genomes pathway and Gene Ontol. enrichment analyses were conducted using the Database for Annotation, Visuali
zation, and Integrated Discovery. Survival analyses for these genes were performed using the G EPIA2 database. The Chinese Glioma
Genome Atlas database was used to study the correlations between key prognostic genes. Mol. docking was confirmed using the
DockThor database and visualized with Py Mol software. Cell viability was assessed via the C CK-8 assay, apoptosis and the cell cycle
stages were examined using flow cytometry, and protein expression was detected using western blotting. In all, 63 genes were
initially identified as potential targets for BCA in treating GBM. Enrichment anal. suggested that the pharmacol. mechanisms of BCA
primarily involved cell cycle inhibition , induction of cell apoptosis, and immune regula tion. Based on these findings, A KT1, EGFR, CA
SP3, and M MP9 were preliminarily predicted as key prognostic target genes for B CA in GBM treatment. Furthermore, mol. docking
anal. suggested stable binding of BCA to the target protein. In vitro experi ments revealed the efficacy of BCA in inhibiting GBM, with
an IC50 value of 98.37 ± 2.21 μ M. BCA inhibited cell prolife ration, induced cell apoptosis, and arrested the cell cycle of G BM cells.
Furthermore, the anti-tumor effects of BCA on U251 cells were linked to the regulation of the target protein. We utilized integrated
bioinformatics analyses to predict targets and confirmed through experi ments that BCA possesses remarkable anti-tumor activities.
We present a novel approach for multi-target treatment of GBM using BCA.
377
Inflammation drives pathogenesis of early intestinal failure-associated liver disease
By: Fligor, Scott C.; Tsikis, Savas T.; Hirsch, Thomas I.; Jain, Ashish; Sun, Liang; Rockowitz, Shira; Gura, Kathleen M.; Puder, Mark
Abstract: Patients with intestinal failure who receive long-term parenteral nutrition (P N) often develop intestinal failure- associated
liver disease (IFALD). Although there are identified risk factors, the early pathog enesis is poorly understood and treatment options
are limited. Here, we perform a transcriptomic anal. of liver tissue in a large animal I FALD model to generate mechanistic insights
and identify therapeutic targets. Preterm Yorkshire piglets were provided P N or bottle-fed with sow-milk replacer for 14 days.
Compared to bottle-fed controls, piglets receiving PN developed biochem. cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9
mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Anal. identified 747 differe ntially expressed genes (343
upregulated and 404 downreg ulated) with an adjusted P < 0.05 and a fold- change of > |1|. Enriched canonical pathways were
identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progre ssion. Potential therap
eutics including infliximab, glucocorticoids, statins, and obetic holic acid were identified as predicted upstream master regulators
that may reverse the PN-induced gene dysregulation. The early driver of I FALD in neonates may be inflam mation with an immature
liver; identified therapeutics that target the inflammatory response in the liver should be invest igated as potential treatments.

378
Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung
adenocarcinoma via remodeling the tumor microenvironment
By: Qiao, Meng; Zhou, Fei; Liu, Xinyu; Jiang, Tao; Wang, Haowei; Li, Xuefei; Zhao, Chao; Cheng, Lei; Chen, Xiaoxia; Ren, Shengxiang; et
al
Abstract: Background: KRAS mutation is one of the most common oncogenic drivers in N SCLC, however, the response to immunot
herapy is heterogeneous owing to the distinct co-occurring genomic altera tions. KRAS/LKB1 co-mutated lung adenocarcinoma
displays poor response to PD-1 blockade whereas the mechanism remains undete rmined Methods: We explored the specific
characteristics of tumor microenv ironment (TME) in KL tumors using syngeneic KRASG12D LKB1-/- (KL) and KRASG12D TP53-/- (KP) lung
cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on K L lung tumors was investigated in vitro and in vivo
through evaluation of both KL cell lines and K L lung cancer mouse models. Results: We identified K L tumors as "immune-cold"
tumors with excessive extracellular matrix (ECM) collagen deposition that formed a phys. barrier to block the infilt ration of CD8+T
cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the
formation of the unique TME of KL tumors. FAK inhibition with a small mol. inhibitor could remodel the T ME by inhibiting C AFs
activation, decreasing collagen deposition and further facili tating the infiltration of anti-tumor immune cells, including C D8+ T cells,
DC cells and M1-like macrophages into tumors, hence, converting "immune- cold" KL tumors into "immune-hot" tumors. The
combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of K L tumors.
Conclusions: Our study identified F AK as a promising interv ention target for K L tumors and provided basis for the combin ation of F
AK inhibitor with PD-1 blockade in the management of K L lung cancers.
Keywords: Drug resistance; Focal adhesion kinase; K RAS; LKB1; Tumor microenvironment
379
A randomized double-blind placebo-controlled trial of an inhibitor of plasminogen activator inhibitor-1

(TM5614) in mild to moderate COVID-19
By: Hirai, Toyohiro; Asano, Koichiro; Ito, Isao; Miyazaki, Yasunari; Sugiura, Hisatoshi; Agirbasli, Mehmet; Kobayashi, Seiichi;
Kobayashi, Makoto; Shimada, Daishi; Natsume, Ichiro; et al
An inhibitor of plasminogen activator inhibitor (PAI)-1, TM5614, inhibited thrombosis, inflammation, and fibrosis in several exptl.
mouse models. To evaluate the efficacy and safety of TM5614 in human C OVID-19 pneumonia, phase IIa and IIb trials were
conducted. In an open-label, single-arm trial, 26 Japanese C OVID-19 patients with mild to moderate pneumonia were treated with
120-180 mg of T M5614 daily, and all were discharged without any notable side effects. Then, a random ized, double-blind, placebo-
controlled trial was conducted in Japanese C OVID-19 patients with mild to moderate pneumonia. The number of study partic ipants
was set to be 50 in each arm. Even after extension of the enrollment period, the number of study participants did not reach the
initially intended sample size, and 75 patients were enrolled in the study. The total oxygenation scale from Day 1 to Day 14 as the
primary endpoint was 1.5 in the TM5614 group vs 4.0 in the placebo group (p = 0.22) , and the number of days of oxygen adminis
tration required as the secondary endpoint was 2.0 days in the T M5614 group vs 3.5 days in the placebo group (p = 0.34) . Further
studies will be necessary to verify the efficacy of PAI-1 inhibition for the treatment of C OVID-19 pneumonia.
Keywords: TM5614 PAI1 inhibitor anticoronaviral agent COVID19

380
Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas
By: Hariharan, Seethalakshmi; Whitfield, Benjamin T. ; Pirozzi, Christopher J.; Waitkus, Matthew S. ; Brown, Michael C.; Bowie,
Michelle L.; Irvin, David M.; Roso, Kristen; Fuller, Rebecca; Hostettler, Janell; et al
Abstract: Stimulating the innate immune system has been explored as a therap eutic option for the treatment of gliomas. Inacti
vating mutations in ATRX, defining mol. altera tions in IDH-mutant astrocytomas, have been implicated in dysfunc tional immune
signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we
generated ATRX-deficient glioma models in the presence and absence of the I DH1R132H mutation. A TRX-deficient glioma cells are
sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T- cell infiltration in vivo. However,
the presence of IDH1R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by
genetic and pharmacol. IDH1R132H inhibition . IDH1R132H co-expression does not interfere with the A TRX deficiency-mediated sensit
ivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work
reveals innate immunity as a therapeutic vulnerability of astrocytomas.
381
Exploring the mechanism of action of Sparganii Rhizoma-Curcumae Rhizoma for in treating castration-
resistant prostate cancer: a network-based pharmacology and experimental validation study
By: Wu, Litong ; Long, Yan; Qiu, Junfeng; Dai, Xinjun; You, Xujun; Li, Tiantian; Chen, Haijun
Abstract: Sparganii Rhizoma-Curcumae Rhizoma (S R-CR) is a classic drug pair for the treatment of castra tion-resistant prostate
cancer (CRPC), but its mechanism has not been clarified. The study aims to elucidate the potential mechanism of S R-CR in the
management of CRPC. The present study employed the T CMSP as well as the SwissTargetPrediction platform to retrieve the chem.
composition and targets of S R-CR. The therapeutic targets of C RPC were identified through screening the GeneCards, Disgenet, and
OMIM databases. Subsequently, the Venny online platform was utilized to identify the shared targets between the S R-CR and C RPC.
The shared targets were enrichment anal. using the Bioconductor and Kyoto encyclopedia of genes and genomes (K EGG)
databases. The active ingredients and core targets were verified through mol. docking and were validated using P C3 cells in the
exptl. validation phase. A total of 7 active ingredients and 1126 disease targets were screened from S R-CR, leading to a total of 59
shared targets. Gene Ontol. (GO) anal. resulted in 1309 G O entries. K EGG pathways anal. yielded 121 pathways, primarily involving
cancer-related signaling pathways. The results from mol. docking revealed stable binding intera ctions between the core ingred ients
and the core targets. In vitro cellular assays further demonstrated that SR-CR effectively suppressed the activation of the Prostate
cancer signaling pathway in PC3 cells, leading to the inhibition of cell proliferation and promotion of apoptosis. The S R-CR exert
therapeutic effects on CRPC by inhibiting cell prolife ration and promoting apoptosis through the Prostate cancer signaling pathway.

382
The prostate-specific membrane antigen holds potential as a vascular target for endogenous
radiotherapy with [177Lu]Lu-PSMA-I&T for triple-negative breast cancer
By: Heesch, Amelie; Florea, Alexandru; Maurer, Jochen; Habib, Pardes; Werth, Laura S.; Hansen, Thomas; Stickeler, Elmar; Sahnoun,
Sabri E. M.; Mottaghy, Felix M.; Morgenroth, Agnieszka
Abstract: Introduction: Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-neg. breast
cancer (TNBC) presents a promising avenue for targeted endogenous radiot herapy with [ 177Lu]Lu-PSMA-I&T. This study aimed to
assess and compare the therapeutic efficacy of a single dose with a fracti onated dose of [ 177Lu]Lu-PSMA-I&T in an orthotopic model
of TNBC. Methods: Rj:NMRI-Foxn1 nu/nu mice were used as recipients of M DA-MB-231 xenografts. The single dose group was treated
with 1 x 60 ± 5 MBq dose of [ 177Lu]Lu-PSMA-I&T, while the fractionated dose group received 4 x a 15 ± 2 M Bq dose of [ 177Lu]Lu-PS
MA-I&T at 7 day intervals. The control group received 0.9% Na Cl. Tumor progression was monitored using [ 18 F]FDG-PET/CT. Ex vivo
anal. encompassed immunostaining, TUNEL staining, H&E staining, microauto radiog., and autoradiog. Results: Tumor volumes were
significantly smaller in the single dose (p < 0.001) and fracti onated dose (p < 0.001) groups. Tumor growth inhibition rates were
38% (single dose) and 30% (fractionated dose). Median survival was notably prolonged in the treated groups compared to the
control groups (31d, 28d and 19d for single dose, fractionated dose and control, resp.) . [ 177Lu]Lu-PSMA-I&T decreased the size of
viable tumor areas. We further demonstrated, that [ 177Lu]Lu-PSMA-I&T binds specifically to the tumor-associated vasculature.
Conclusion: This study highlights the potential of [ 177Lu]Lu-PSMA-I&T for endogenous radiotherapy of TNBC. Graphical abstract:
Keywords: Anti-angiogenic therapy; Endogenous radiotherapy; Orthotopic xenograft; Prostate- specific membrane antigen; Triple-
383
Targeting the NF-κB pathway as a potential regulator of immune checkpoints in cancer

immunotherapy
By: Ebrahimi, Nasim; Abdulwahid, Al-Hasnawi Rasool Riyadh; Mansouri, Atena; Karimi, Nasrin; Bostani, Rashid Jafardoust;
Beiranvand, Sheida; Adelian, Samaneh; Khorram, Roya; Vafadar, Reza; Hamblin, Michael R.; et al
Abstract: Advances in cancer immunotherapy over the last decade have led to the develo pment of several agents that affect
immune checkpoints. Inhibitory receptors expressed on T cells that neg. regulate the immune response include cytotoxic T-
lymphocyte antigen 4 (C TLA4) and programmed cell death protein 1 (P D1), which have been studied more than similar receptors.
Inhibition of these proteins and other immune checkp oints can stimulate the immune system to attack cancer cells, and prevent
the tumor from escaping the immune response. However, the administration of anti-PD1 and anti-CTLA4 antibodies has been
associated with adverse inflammatory responses similar to autoimmune diseases. The current review discussed the role of the N F-κ
B pathway as a tumor promoter, and how it can govern inflam matory responses and affect various immune checkp oints. More
precise knowledge about the communication between immune checkp oints and NF-κB pathways could increase the effecti veness of
immunotherapy and reduce the adverse effects of checkpoint inhibitor therapy. Graphical abstract: [graphic not available: see
fulltext]
Keywords: Immune checkpoint inhibitors; Immune-related adverse events; Immunooncology; Receptor activator of nuclear factor
kappa-Β ligand; Regulatory T cells

384
Green synthesis of MnO 2 NPs using Arabic gum: assessing its potential antiviral activity against
influenza A/H1N1
By: Baghban, Neda; Momeni, Safieh; Behboudi, Emad; Dianat-Moghadam, Hassan; Darabi, Amirhossein; Targhi, Hadiseh Shokouhi;
Keshavarz, Mohsen
Virology Journal (2024), 21(1), 48 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The antiviral properties of metal nanoparticles against various viruses, including those resistant to drugs, are
currently a subject of intensive research. Recently, the green synthesis of nanoparticles and their anti-viral function have attracted a
lot of attention. Previous studies have shown promising results in the use of Arabic gum for the green synthesis of nanoparticles
with strong antiviral properties. In this study we aimed to invest igate the antiviral effects of MnO2 nanoparticles (MnO2-NPs) synthe
sized using Arabic gum, particularly against the influenza virus. Methods: Arabic gum was used as a natural polymer to extract and
synthesize MnO2-NPs using a green chem. approach. The synthe sized MnO2-NPs were characterized using SEM and T EM. To
evaluate virus titration, cytotoxicity, and antiviral activity, T CID50, MTT, and Hemagglutination assay (HA) were performed, resp. Mol.
docking studies were also performed to investigate the potential antiviral activity of the synthesized MnO2-NPs against the influenza
virus. The mol. docking was carried out using AutoDock Vina software followed by an anal. with V MD software to investigate the
interaction between Arabic gum and the hemaggl utinin protein. Results: Simultaneous combination treatment with the green-
synthesized MnO2-NPs resulted in a 3.5 log H A decrement and 69.7% cellular protec tion, which demonstrated the most significant
difference in cellular protection compared to the virus control group (p-value < 0.01). The docking results showed that binding
affinities were between - 3.3 and - 5.8 kcal/mol relating with the interaction between target with Mn O2 and beta-D-galactopy
ranuronic acid, resp. Conclu sion: The results of the study indicated that the Mn O2-NPs synthesized with Arabic gum had signif icant
antiviral effects against the influenza virus, highlighting their potential as a natural and effective treatment for inhibition of respir
atory infections.
Keywords: Antiviral; Arabic gum; Influenza; MnO2; Nanoparticle
385
Enhancing tumor-specific recognition of programmable synthetic bacterial consortium for precision

therapy of colorectal cancer
By: Zhou, Tuoyu; Wu, Jingyuan; Tang, Haibo; Liu, Dali; Jeon, Byong-Hun ; Jin, Weilin; Wang, Yiqing; Zheng, Yuanzhang; Khan, Aman;
Han, Huawen; et al
npj Biofilms and Microbiomes (2024), 10(1), 6 | Language: English, Database: CAplus and MEDLINE
Abstract: Probiotics hold promise as a potential therapy for colorectal cancer (CRC), but encounter obstacles related to tumor specif
icity, drug penetration, and dosage adjusta bility. In this study, genetic circuits based on the E. coli Nissle 1917 (Ec N) chassis were
developed to sense indicators of tumor microenvironment and control the expression of therapeutic payloads. Integr ation of XOR
gate amplify gene switch into EcN biosensors resulted in a 1.8- 2.3-fold increase in signal output, as confirmed by math. model
fitting. Co-culturing programmable EcNs with CRC cells demonstrated a signif icant reduction in cellular viability ranging from 30% to
50%. This approach was further validated in a mouse s.c. tumor model, revealing 47%-52% inhibition of tumor growth upon
administration of therapeutic strains. Addnl., in a mouse tumorig enesis model induced by AOM and DSS, the use of synthetic
bacterial consortium (SynCon) equipped with multiple sensing modules led to approx. 1.2- fold increased colon length and 2.4- fold
decreased polyp count. Gut microbiota anal. suggested that SynCon maintained the abundance of butyrate- producing bacteria
Lactobacillaceae N K4A136, whereas reducing the level of gut inflammation-related bacteria Bacteroides. Taken together,
engineered EcNs confer the advantage of specific recogn ition of CRC, while SynCon serves to augment the synerg istic effect of this
approach.

386
Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy

in the early stage of Alzheimer′s disease
By: Mao, Rui; Hu, Mengsha; Liu, Xuan; Ye, Lei; Xu, Bingsong; Sun, Min; Xu, Siyi; Shao, Wenxuan; Tan, Yi; Xu, Yun; et al
Abstract: Background: Patients with Alzhei mer′s disease (AD) are often co-morbid with unprovoked seizures, making clin. diagnosis
and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic
transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can
promote GABA release and suppress epileptogenesis, but its effects on cognition in A D are still controversial. Methods: Four-
month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of A D in this study. Acute/c hronic chem.-
kindling epilepsy models were established with pentylenetetrazol. EEG and Racine scores were performed to assess seizures.
Behavioral tests were used to assess cognition and emotion. Electrophysiol., western blot and immunoflu orescence were
performed to detect the alterations in synapses, GABAergic system components and N RG1-ErbB4 signaling. Furthermore, NRG1 was
administrated intracerebroventricularly into APP mice and then its antiepi leptic and cognitive effects were evaluated. Results: A PP
mice had increased susceptibility to epilepsy and resulting hippoc ampal synaptic damage and cognitive impair ment. Electrophysiol.
anal. revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction
in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of G ABA synthesis and transport. We also found
impaired NRG1-ErbB4 signaling which mediated by P V+ Ins loss. And N RG1 administration could effectively reduce seizures and
improve cognition in four-month-old APP mice. Conclusion: Our results indicated that abnormal G ABAergic transmission mediated
hippocampal hyperexcitability, further excitation/ inhibition imbalance, and promoted epilepto genesis in the early stage of A D.
Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a
potential direction for intervening in the co-morbidity of AD and epilepsy.
Keywords: Alzheimer's disease; Cognition; Epilepsy; ErbB4; GABAergic transmission; NRG1; Parvalbumin interneurons
387
Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone
homeostasis in mice
By: Zhang, Fengwei ; Qiao, Wei ; Wei, Ji-an; Tao, Zhengyi ; Chen, Congjia ; Wu, Yefeng; Lin, Minghui; Ng, Ka Man Carmen;
Zhang, Li ; Yeung, Kelvin Wai-Kwok ; et al
Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventro medial
hypothalamus, from which the central neural system controls satiety, energy metabo lism, and bone homeostasis. However, the
functional significance of secretin in the ventro medial hypothalamus remains unclear. Here we show that the loss of ventro medial
hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished c AMP
response element-binding protein phosphor ylation and upregulation in peripheral sympat hetic activity. Moreover, the ventro
medial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermog enesis,
resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventro medial hypothalamus promotes
bone mass accrual in mice of both sexes. Collectively, our findings identify an unappre ciated secretin signaling in the central neural
system for the regulation of energy and bone metabolism, which may serve as a new target for the clin. management of obesity
and osteoporosis.
Keywords: secretin ventromedial hypothalamus energy metabolism bone homeostasis

388
Potential anti-acne loaded nanogel formulations of Origanum majorana L. and Chrysanthemum

morifolium Ramat. essential oils
By: Kotb, Eman A.; El-Shiekh, Riham A.; Hassan, Mariam; Abd-Elsalam, Wessam Hamdy; El Tanbouly, Nebal; El Senousy, Amira
Safwat
Applied Biological Chemistry (2024), 67(1), 9 | Language: English, Database: CAplus
Abstract: Acne is a highly prevalent skin disease with a great psychol. impact on patients as self-perception, self-confidence, and
depression. This work aimed to develop an anti- acne preparation from active anti-bacterial medicinal plants to circumvent the
severe side effects and drug resistance commonly reported with topical erythromycin anti-acne preparations Essential oils: Salvia
officinalis L. (sage), Rosmarinus officinalis L. (rosemary), Commiphora myrrha Nees Engl. (myrrh), Origanum majorana L. (marjoram) ,
Pelargonium zonale L. L′Heŕ. ex Aiton (geranium) and Chrysan themum morifolium Ramat. (chrysan themum) were extracted by
hydrodistillation and analyzed using gas chromato g./mass spectrometry (GC/MS). The anti-acne activities of the oils against Cutibac
terium acnes A TCC 6919 were evaluated by microdi lution methods to determine the min. inhibitory concent ration (MIC) and min.
bactericidal concentration (MBC). The most active essential oils were loaded in a film- forming nanogel prepared with chitosan,
pluronic F127 and glycerol in the ratio of 3:1:1, prior to investigation in a murine acne in vivo model. Marjoram and chrysan themum
oils showed the highest antimicrobial activity against C. acnes (M IC = 0.156% volume/ volume and 0.125% volume/volume, resp.). G
C/MS of the actives showed that gamma- terpinene (26.46%) and terpinen-4-ol (22.24%) were the predominant constituents in
marjoram, whereas chrysanthenone (32.79%) was the main component in chrysan themum. The formulated essential oil-loaded
film-forming nanogels of both oils exhibited signif icant anti-acne activity in mice via reducing the bacterial loads, activating the
antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and inhibiting the inflam matory tumor necrosis factor -
alpha ( TN F-α) pathway. Further studies should be designed to evaluate the clin. evidence for the use of marjoram and chrysan
themum oil products in acne treatment. Graphical Abstract: [graphic not available: see fulltext]
389
Embryo development is impaired by sperm mitochondrial-derived ROS
By: Mateo-Otero, Yentel ; Llavanera, Marc; Torres-Garrido, Marc; Yeste, Marc

Biological Research (2024), 57(1), 5 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Basal energetic metabolism in sperm, partic ularly oxidative phosphorylation, is known to condition not only
their oocyte fertilising ability, but also the subsequent embryo develo pment. While the mol. pathways underlying these events still
need to be elucidated, reactive oxygen species (R OS) could have a relevant role. We, therefore, aimed to describe the mechanisms
through which mitochondrial activity can influence the first stages of embryo develo pment. Results: We first show that embryo
development is tightly influenced by both intrace llular ROS and mitocho ndrial activity. In addition, we depict that the inhibition of
mitochondrial activity dramatically decreases intracellular ROS levels. Finally, we also demons trate that the inhibition of mitocho
ndrial respiration pos. influences sperm DNA integrity, most likely because of the depletion of intrace llular ROS formation. Conclu
sion: Collectively, the data presented in this work reveals that impairment of early embryo develo pment may result from the
accumulation of sperm DNA damage caused by mitocho ndrial-derived ROS.
Keywords: Cyanide; Embryo development; Mitochondrial respiration; Oocyte fertilisation; Oxidative phosphorylation; Sperm
metabolism; electron transport chain

390
Heat shock factor 1 directly regulates transsulfuration pathway to promote prostate cancer
proliferation and survival
By: Hauck, J. Spencer ; Moon, David; Jiang, Xue; Wang, Mu-En; Zhao, Yue; Xu, Lingfan; Quang, Holly ; Butler, William; Chen, Ming
; Macias, Everardo; et al
Abstract: There are limited therapeutic options for patients with advanced prostate cancer (P Ca). We previously found that heat
shock factor 1 (HSF1) expression is increased in PCa and is an actionable target. In this manusc ript, we identify that HSF1 regulates
the conversion of homocysteine to cystathionine in the transsulfuration pathway by altering levels of cystath ionine-β-synthase (CBS)
. We find that HSF1 directly binds the CBS gene and upregu lates CBS mRNA levels. Targeting CBS decreases PCa growth and
induces tumor cell death while benign prostate cells are largely unaffected. Combined inhibition of HSF1 and CBS results in more
pronounced inhibition of PCa cell proliferation and reduction of transsulfuration pathway metabolites. Combination of HSF1 and C
BS knockout decreases tumor size for a small cell P Ca xenograft mouse model. Our study thus provides new insights into the mol.
mechanism of HSF1 function and an effective therapeutic strategy against advanced P Ca.
391
A prefrontal-thalamic circuit encodes social information for social recognition
By: Chen, Zihao; Han, Yechao ; Ma, Zheng ; Wang, Xinnian; Xu, Surui; Tang, Yong ; Vyssotski, Alexei L. ; Si, Bailu ; Zhan,
Yang
Abstract: Social recognition encompasses encoding social inform ation and distinguishing unfamiliar from familiar indivi duals to
form social relationships. Although the medial prefrontal cortex (mPFC) is known to play a role in social behavior, how identity
information is processed and by which route it is commun icated in the brain remains unclear. Here we report that a ventral midline
thalamic area, nucleus reuniens (Re) that has reciprocal connections with the mPFC, is critical for social recogn ition in male mice. In
vivo single-unit recordings and decoding anal. reveal that neural popula tions in both mPFC and Re represent different social stimuli,
however, mPFC coding capacity is stronger. We demons trate that chemogenetic inhibitions of Re impair the mPFC-Re neural
synchronization and the mPFC social coding. Projection pathway- specific inhibitions by optogenetics reveal that the reciprocal
connectivity between the mPFC and the Re is necessary for social recogn ition. These results reveal an m PFC-thalamic circuit for
social information processing.

392
Genome-wide CRISPR screen identifies ESPL1 limits the response of gastric cancer cells to apatinib
By: Zhang, Bei; Chen, Yan; Chen, Xinqi; Ren, Zhiyao; Xiang, Hong; Mao, Lipeng; Zhu, Guodong
Abstract: Apatinib was the first anti-angiogenic agent approved for treatment of metastatic gastric cancer (G C). However, the
emergence of resistance was inevitable. Thus investigating new and valuable off-target effect of apatinib directly against cancer cells
is of great significance. Here, we identified extra spindle pole bodies- like 1 (ESPL1) was responsible for apatinib resistance in GC
cells through CRISPR genome-wide gain-of-function screening. Loss of function studies further showed that E SPL1 inhibition
suppressed cell proliferation, migration and promoted apoptosis in vitro, and accord ingly ESPL1 knockdown sensitized GC cells to
apatinib. In addition, we found ESPL1 interacted with mouse double minute 2 (M DM2), a E3 ubiquitin protein ligase, and the combin
ation of MDM2 siRNA with apatinib synergistically ameliorated the resistance induced by E SPL1 overexpression. In summary, our
study indicated that ESPL1 played a critical role in apatinib resistance in G C cells. Inhibition of MDM2 could rescue the sensitivity of
GC cells to apatinib and reverse E SPL1-mediated resistance.
Keywords: Apatinib resistance; CRISPR screening; E SPL1; Gastric cancer; MDM2
393
Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell

carcinoma
By: Singla, Nirmish; Nirschl, Thomas R.; Obradovic, Aleksandar Z.; Shenderov, Eugene; Lombardo, Kara; Liu, Xiaopu; Pons, Alice;
Zarif, Jelani C.; Rowe, Steven P.; Trock, Bruce J.; et al
Abstract: Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephre ctomy for high-risk,
non-metastatic clear cell renal cell carcinoma (cc RCC). We conducted a prospe ctive, phase I trial of neoadjuvant nivolumab prior to
nephrectomy in 15 evaluable patients with non- metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of P
D-1 inhibition on immune cell popula tions in ccRCC and correlate the evolving immune milieu with anti- PD-1 response. We found
that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infilt ration within the
primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and
subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the
basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide
the rationale for perioperative strategies of novel I CI combinations.

394
Glyoxal-derived advanced glycation end products (GO-AGEs) with UVB critically induce skin
inflammaging: in vitro and in silico approaches
By: Sultana, Razia; Parveen, Amna; Kang, Min-Cheol; Hong, Seong-Min; Kim, Sun Yeou
Advanced glycation end products (AGEs) have potential implications on several diseases including skin inflam mation and aging. AG
Es formation can be triggered by several factors such as UVB, glyoxal and methylglyoxal etc. However, little attention has been paid
to glyoxal-derived AGEs (GO-AGEs) and UVB-induced skin inflammaging, with none have invest igated together. This study aimed to
investigate the possible role of G O-AGEs and UVB in skin inflammaging focusing on revealing its mol. mechan isms. The effects of G
O-AGEs in the presence or absence of U VB were studied by using enzyme linked immunos orbent assay, western blotting, q PCR, flow
cytometry and in silico approaches. In HaCaT cells, GO-AGEs in the presence of UVB irradiation (125 mJ/cm 2) dramatically enhanced
the release of different pro-inflammatory cytokines (IL-1β, IL-6, and TN F-α) with further activation of R AGE signaling pathways (N F-κ
B, COX 2, and IL- 1β) and increased oxidative stress also noticed in N HEK cells. In N HDF cells, extracellular matrix disruption noted
via increasing matrix metalloproteinase release and decreasing collagen type 1 and S IRT1 expression. Besides that, the docking
scores obtained from the mol. docking study support the above-mentioned results. This study strongly suggests the pivotal role of G
O-AGEs in skin inflammaging and illuminates novel mol. pathways for searching most effective and updated anti- aging therapy.
Keywords: glyoxal glycation end product UVB skin inflammaging in vitro; silico approach

395
Dietary Bacillus spp. supplementation to both sow and progenies improved post-weaning growth rate,
gut function, and reduce the pro-inflammatory cytokine production in weaners challenged with
Escherichia coli K88
By: Sampath, Vetriselvi; Cho, Sungbo; Jeong, Jinuk; Mun, Seyoung; Lee, Choon Han; Hermes, Rafael Gustavo; Taechavasonyoo,
Apichaya; Smeets, Natasja; Kirwan, Susanne; Han, Kyudong; et al
Animal Microbiome (2024), 6(1), 3 | Language: English, Database: CAplus and MEDLINE
The use of probiotics (PRO) in late gestation sow and their impact on progenies perfor mance during the post-weaning stage has
received more attention from the researchers recently. This study aimed to analyze the effect of probiotic mixture (Bacillus subtilis
and Bacillus licheniformis) on both sow and offsprings perfor mance. First experiment (Exp.1) was conducted from the 100th day of
gestation through to post-weaning. A total of twenty sows and their litters were assigned to one of two dietary treatm ents, Control
(CON) based diet and PRO- CON+ 0.05% probiotic mixture Dietary treatments were arranged in a split- plot pattern with sow and
weaner treatment (CON and PRO diet) as the main and sub plot. Exp.2. E. coli challenge study was carried out two weeks after
weaning with 40 piglets. Dietary treatments remained same while all pigs were orally administered with a 1.5 m L suspension of
1010 CFU of K88 strain of E. coli per m L. Result: PRO group sow showed signifi cantly decreased backfat thickness difference and
body weight difference after farrowing and at the end of weaning d21. The nutrient digestibility of PRO group sows was signifi cantly
higher at the end of weaning. Moreover, piglets born from PRO group sow showed higher weaning weight and tend to increase
average daily gain at the end of d21. The addition of mixed probiotic in sow and weaner diet had suppressed the production of TN
F-α and interleukin-6 in E. coli challenged pigs. The phyla Firmicutes and Bactero idetes in E. coli - challenged pigs were highly
abundant while, the relative abundance of clostridium_sensu_stricto_1 at genus level was significantly reduced by the inclusion of
probiotic in both the sow and weaner diet. Also, taxonomic distribution anal. showed significantly lower prevalence of Clostridium
and Brachyspira and higher prevalence of Lactob acilli in E. coli- challenged pigs that were born from PRO group sow and fed C ON
and PRO weaner diet. This study reveals that the inclusion of 0.05% mixed probiotics (Bacillus spp.) to both sow and their progenies
diet would be more beneficial to enhance the post-weaning growth rate, gut health, and immune status of E. coli challenged pigs.
Keywords: probiotic TNFalpha growth gut function immune Bacillus Escherichia pig; Cytokine immune response; Growth perfor
mance; Gut microb iome; Probiotics; Weanling pig

396
The SOX4/EZH2/SLC7A11 signaling axis mediates ferroptosis in calcium oxalate crystal deposition-
induced kidney injury
By: Yan, Xinzhou; Xia, Yuqi; Li, Bojun; Ye, Zehua; Li, Lei; Yuan, Tianhui; Song, Baofeng; Yu, Weimin; Rao, Ting; Ning, Jinzhuo; et al
Abstract: Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal
cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic
regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demons trated that the
upregulation of enhancer of zeste homolog 2 (E ZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. Ca Ox crystal
deposition promoted ferroptosis in vivo and in vitro. Usage of liproxs tatin-1 (Lip-1), a ferroptosis inhibitor, mitigated Ca Ox-induced
kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochem. and western blotting analyses revealed that
EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate- stimulated HK-2 cells. Experiments involving in vivo
EZH2 knockout, in vitro E ZH2 knockdown, and in vivo GSK-126 (an E ZH2 inhibitor) treatment confirmed the protective effects of E Z
H2 inhibition on kidney injury and ferrop tosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprec ipitation
assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (S LC7A11) expression
through trimethylation of histone H3 lysine 27 (H3 K27me3) modification. Addnl., SOX4 regulated ferroptosis by directly modulating
EZH2 expression. Thus, this study demons trated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3
K27me3-mediated suppression of SLC7A11. Graphical Abstract: [graphic not available: see fulltext]
Keywords: EZH2; Ferroptosis; Kidney injury; Kidney stones; S OX4
397
Migrasomal autophagosomes relieve endoplasmic reticulum stress in glioblastoma cells
By: Lee, Seon Yong; Choi, Sang-Hun; Kim, Yoonji; Ahn, Hee-Sung; Ko, Young-Gyu; Kim, Kyunggon; Chi, Sung Wook; Kim, Hyunggee
BMC Biology (2024), 22(1), 23 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Glioblastoma (GBM) is more difficult to treat than other intrac table adult tumors. The main reason that G BM
is so difficult to treat is that it is highly infiltrative. Migrasomes are newly discovered membrane structures observed in migrating
cells. Thus, they can be generated from GBM cells that have the ability to migrate along the brain parenc hyma. However, the
function of migrasomes has not yet been elucidated in GBM cells. Results: Here, we describe the compos ition and function of
migrasomes generated along with GBM cell migration. Proteomic anal. revealed that L C3B-pos. autophagosomes were abundant in
the migrasomes of GBM cells. An increased number of migrasomes was observed following treatment with chloro quine (CQ) or
inhibition of the expression of STX17 and SNAP29, which are involved in autophag osome/lysosome fusion. Furthermore, depletion
of ITGA5 or TSPAN4 did not relieve endopl asmic reticulum (ER) stress in cells, resulting in cell death. Conclu sions: Taken together,
our study suggests that increasing the number of autophagosomes, through inhibition of autophagosome/lysosome fusion,
generates migrasomes that have the capacity to alleviate cellular stress.
Keywords: Autophagosome; Cell death; E R stress; ITGA5; Migrasome; Retraction fiber; T SPAN4

398
Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem
cells
By: Zhu, Qiuhong ; Liang, Panpan; Meng, Hao; Li, Fangzhen; Miao, Wei; Chu, Cuiying; Wang, Wei; Li, Dongxue; Chen, Cong; Shi, Yu
; et al
Abstract: The peptidyl-prolyl cis-trans isomerase Pin1 is a pivotal therap eutic target in cancers, but the regulation of Pin1 protein
stability is largely unknown. High Pin1 expression is associated with SUMO1-modified protein hypersumoylation in glioma stem
cells (GSCs), but the underlying mechanisms remain elusive. Here we demons trate that Pin1 is deubiqui tinated and stabilized by U S
P34, which promotes isomeri zation of the sole S UMO E2 enzyme Ubc9, leading to S UMO1-modified hypersumoylation to support G
SC maintenance. Pin1 interacts with U SP34, a deubiquitinase with preferential expression and oncogenic function in GSCs. Such
interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Disruption of U SP34 or inhibition of Plk1 promotes poly-ubiquit
ination and degradation of Pin1. Furthermore, Pin1 isomerizes Ubc9 to upregulate Ubc9 thioester formation with S UMO1, which
requires CDK1-mediated phosphorylation of Ubc9. Combined inhibition of Pin1 and C DK1 with sulfopin and R O3306 most effect
ively suppresses orthotopic tumor growth. Our findings provide multiple mol. targets to induce Pin1 degrad ation and suppress
hypersumoylation for cancer treatment.
399
Engineering Strategies for Suppressing the Shuttle Effect in Lithium-Sulfur Batteries
By: Li, Jiayi; Gao, Li; Pan, Fengying; Gong, Cheng; Sun, Limeng; Gao, Hong; Zhang, Jinqiang; Zhao, Yufei; Wang, Guoxiu; Liu, Hao
Nano-Micro Letters (2024), 16(1), 12 | Language: English, Database: CAplus and MEDLINE
A review. Lithium-sulfur (Li-S) batteries are supposed to be one of the most potential next- generation batteries owing to their high
theor. capacity and low cost. Nevertheless, the shuttle effect of firm multistep two-electron reaction between sulfur and lithium in
liquid electrolyte makes the capacity much smaller than the theor. value. Many methods were proposed for inhibiting the shuttle
effect of polysulfide, improving corresp onding redox kinetics and enhancing the integral perfor mance of Li-S batteries. Here, we will
comprehensively and systematically summarize the strategies for inhibiting the shuttle effect from all components of Li- S batteries.
First, the electrochem. principles/mechanism and origin of the shuttle effect are described in detail. Moreover, the efcient strate
gies, including boosting the sulfur conversion rate of sulfur, confning sulfur or lithium polysu lfdes (LPS) within cathode host,
confning LPS in the shield layer, and preventing L PS from contacting the anode, will be discussed to suppress the shuttle effect.
Then, recent advances in inhibition of shuttle effect in cathode, electr olyte, separator, and anode with the aforementioned
strategies have been summarized to direct the further design of efcient materials for Li-S batteries. Finally, we present prospects for
inhibition of the LPS shuttle and potential develo pment directions in Li-S batteries.
Keywords: review engineering strategy suppressing shuttle effect lithium sulfur battery; Designed strate gies; Lithium polysulfides;
Li–S battery; Shuttle effect

400
Binding of small molecule inhibitors to RNA polymerase-Spt5 complex impacts RNA and DNA stability
By: Gallardo, Adan; Dutagaci, Bercem

Journal of Computer-Aided Molecular Design (2024), 38(1), 1 | Language: English, Database: CAplus and MEDLINE
Abstract: Spt5 is an elongation factor that associates with RNA polymerase II (Pol I I) during transcription and has important
functions in promoter-proximal pausing and elongation processivity. Spt5 was also recognized for its roles in the transcr iption of
expanded-repeat genes that are related to neurodege nerative diseases. Recently, a set of Spt5- Pol II small mol. inhibitors (S PIs)
were reported, which selectively inhibit mutant huntingtin gene transcr iption. Inhibition mechanisms as well as interaction sites of
these SPIs with Pol II and Spt5 are not entirely known. In this study, we predicted the binding sites of three selected S PIs at the Pol I
I-Spt5 interface by docking and mol. dynamics simula tions. Two mols. out of three demons trated strong binding with Spt5 and Pol I
I, while the other mol. was more loosely bound and sampled multiple binding sites. Strongly bound S PIs indirectly affected R NA and
DNA dynamics at the exit site as D NA became more flexible while R NA was stabilized by increased intera ctions with Spt5. Our
results suggest that the transcription inhibition mechanism induced by S PIs can be related to Spt5- nucleic acid interactions, which
were altered to some extent with strong binding of SPIs.
Keywords: DRB sensitivity-inducing factor; Molecular dynamics simula tions; RNA polymerase II; Small molecule inhibitors; Transcr
iption elongation
401
In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy
By: Hou, Da-Yong ; Cheng, Dong-Bing ; Zhang, Ni-Yuan; Wang, Zhi-Jia; Hu, Xing-Jie; Li, Xin; Lv, Mei-Yu; Li, Xiang-Peng; Jian, Ling-
Rui; Ma, Jin-Peng; et al
Abstract: Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a
prominent therapeutic strategy for tumor suppre ssion. However, the wide applic ation of GPX4 inhibitors in tumor therapy is
hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-
assembly, we develop a peptide- ferriporphyrin conjugate with tumor microenv ironment specific activation to improve tumor penetr
ation, endocytosis and GPX4 inhibition , ultimately enhancing its anticancer activity via ferrop tosis. Briefly, a GPX4 inhibitory peptide
is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferripo rphyrin to produce the peptide-
ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenv ironment of the tumor, the Gi-F-CAA self-assembles into large
nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of C AA, improving tumor endocytosis efficiency.
Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (A EB) effect, augmenting the
oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our
findings suggest that this peptide-ferriporphyrin conjugate design with A EB effect can improve the therapeutic effect via induction
of ferroptosis, providing an alternative strategy for overcoming chemores istance.

402
Growth control of Marchantia polymorpha gemmae using nonthermal plasma irradiation
By: Tsuboyama, Shoko; Okumura, Takamasa; Attri, Pankaj; Koga, Kazunori; Shiratani, Masaharu; Kuchitsu, Kazuyuki
Abstract: Several studies have documented that treatment by cold atm. pressure plasma (CAPP) on plants foster seed germin ation
and growth in recent years. However, the mol. processes that underlie the action of CAPP on the seeds and plants remain mostly
enigmatic. We here introduce gemmae of Marchantia polymorpha, a basal liverwort, as a novel model plant material suitable for C A
PP research. Treating the gemmae with C APP for a constant time interval at low power resulted in consistent growth enhanc ement,
while growth inhibition at higher power in a dose- dependent manner. These results distinctly demons trate that CAPP irradiation
can pos. and neg. regulate plant growth depending on the plasma intensity of irradiation, offering a suitable exptl. system for
understanding the mol. mechanisms underlying the action of C APP in plants.
403
Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM
By: Zhu, Hanwen; Hixson, Patricia; Ma, Wen ; Sun, Ji

Abstract: LRRK2 is one of the most promising drug targets for Parkin son′s disease. Though type I kinase inhibitors of L RRK2 are
under clin. trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type
I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is
lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near- at.-resolution structures of LRR
K2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and G ZD-824) inhibitors, uncovering the structural
basis of LRRK2 inhibition and conformational plasticity of the kinase domain with mol. dynamics (M D) simulations. Type I and I I
inhibitors bind to LRRK2 in active-like and inactive conform ations, so LRRK2-inhibitor complexes further reveal general structural
features associated with LRRK2 activation. Our study provides at. details of LRRK2-inhibitor interactions and a framework for
understanding LRRK2 activation and for rational drug design.

404
Periapical bacterial disinfection is critical for dental pulp regenerative cell therapy in apical
periodontitis in dogs
By: Iohara, Koichiro; Tominaga, Michiyo; Watanabe, Hideto; Nakashima, Misako

Stem Cell Research & Therapy (2024), 15(1), 17 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Application of pulp regenerative cell therapy for mature teeth with periapical lesions is a critical clin.
challenge. The bacterial infection in inaccessible location within the root canal system and in the periapical lesions could cause
resistance and impediment, leading to limitations in successful therapy. Thus, the aim of this study was to examine the effect of
residual bacteria on the outcome of pulp regeneration in mature teeth with apical periodo ntitis in dogs. Methods: Periapical lesions
were induced in 32 root canals of 4 dogs in two different models in severities, model A and model B. Model A (moderate infection) :
the canal exposed to the oral cavity for 2 wk and then closed for 2 wk. Model B (severe infection): the canal exposed to the oral
cavity for 2 mo and then closed for 5 mo. All root canals were irrigated with 6% sodium hypochlorite, and 3% E DTA and further with
0.015% levofloxacin-containing nanobubbles, which was also used as an intracanal medica ment. The aseptic conditions were
examined by bacterial anaerobic culture and/or PCR analyses. The root canal treatment was repeated several times, and allogeneic
dental pulp stem cells were transplanted into the root canals. The radiog. evaluation of periapical lesions was performed by cone-
beam computed tomog. before the first treatment, just after cell transpla ntation, and after 2 mo and 6 mo in both model A, model
B, resp. The animals were then sacrificed and the jaw blocks were harvested for histol. and histobacteriol. evaluations of pulp
regeneration and periapical tissue healing. Furthe rmore, the DiI-labeled DPSCs were transplanted into the root canals after
complete disinfection (n = 4) or without root canal treatment (n = 4) in the apical periodo ntitis model (model A) in one dog, and cell
localization was compared 72 h after transpla ntation. Results: In 8 out of 12 canals from model A, and 10 out of 15 canals from
model B, pulp regeneration with good vascular ization, innervation, and a signif icant reduction in the radiolucent area of the
periapical lesions were observed However, in the other 4 canals and 5 canals from model A and model B, resp., no pulp tissue was
regenerated, and inflammation in the periapical tissue, and external resorption or healed external resorption were detected. The
presence of residual bacteria in the periapical tissues and severe inflammation were significantly associated with inhibition of
regenerated pulp tissue in these 9 unsucc essful canals (P < 0.05, each) (O R = 0.075, each) analyzed by multiple logistic regression
anal. For cellular kinetics, transplanted cells remained in the disinf ected root canals, while they were not detected in the infected
root canals, suggesting their migration through the apical foramen under the influence of inflammation. Conclusions: A true pulp-
dentin complex was regenerated in the root canal by the pulp regene rative therapy in mature teeth with apical lesions. The
successful pulp regeneration was neg. associated both with residual bacteria and inflam mation in the periapical tissue.
Keywords: Allogeneic cell transplantation; Dental pulp stem cells; Periodo ntitis; Periradicular disinfection; Pulp regeneration apical

405
Stimulating VAPB-PTPIP51 ER-mitochondria tethering corrects FTD/ALS mutant TDP43 linked Ca 2+ and
synaptic defects
By: Markovinovic, Andrea; Martin-Guerrero, Sandra M.; Morotz, Gabor M.; Salam, Shaakir; Gomez-Suaga, Patricia; Paillusson,
Sebastien; Greig, Jenny; Lee, Younbok; Mitchell, Jacqueline C.; Noble, Wendy; et al
Acta Neuropathologica Communications (2024), 12(1), 32 | Language: English, Database: CAplus and MEDLINE
Abstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (A LS) are clin. linked major neurodegenerative diseases.
Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene
encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiol.
functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitocho ndria. This signaling is
mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of E R to the mitochondrial surface so as to facilitate
inter-organelle communications. Several studies have now shown that disrupted E R-mitochondria signaling including breaking of
the VAPB-PTPIP51 tethers are features of FTD/ALS and that for T DP43 and other familial genetic FTD/ALS insults, this involves
activation of glycogen kinase-3β (GSK3β). Such findings have prompted sugges tions that correcting damage to E R-mitochondria
signaling and the VAPB-PTPIP51 interaction may be broadly therapeutic. Here we provide evidence to support this notion. We show
that overexpression of VAPB or PTPIP51 to enhance ER-mitochondria signaling corrects mutant T DP43 induced damage to inositol 1,
4,5-trisphosphate (IP3) receptor delivery of Ca 2+ to mitochondria which is a primary function of the V APB-PTPIP51 tethers, and to
synaptic function. Moreover, we show that ursodeoxycholic acid (UDCA), an FDA approved drug linked to F TD/ALS and other
neurodegenerative diseases therapy and whose precise therap eutic target is unclear, corrects T DP43 linked damage to the VAPB-PT
PIP51 interaction. We also show that this effect involves inhibition of TDP43 mediated activation of GSK3β. Thus, correcting damage
to the VAPB-PTPIP51 tethers may have therapeutic value for F TD/ALS and other age- related neurodegenerative diseases.
Keywords: Alzheimer’s disease; Amyotr ophic lateral sclerosis; Frontotemporal dementia; Neurodegenerative diseases; Parkinson’s
disease; TDP43

406
Mechanosensitive channel of large conductance enhances the mechanical stretching-induced

upregulation of glycolysis and oxidative metabolism in Schwann cells
By: Shan, Fangzhen; Zhang, Nannan; Yao, Xiaoying; Li, Yi; Wang, Zihao; Zhang, Chuanji; Wang, Yuzhong
Abstract: Background: Phys. exercise directly stretching the peripheral nerve promotes nerve regener ation; however, its action
mechanism remains elusive. Our present study aimed to investigate the effects of mechanosensitive channel of large conduc tance
(MscL) activated by mech. stretching on the cultured Schwann cells (S Cs) and explore the possible mechanism. Methods: Primary S
Cs from neonatal mice at 3- 5 days of age were derived and transf ected with the lentivirus vector expressing a mutant version of
MscL, MscL-G22S. We first detected the cell viability and calcium ion (Ca 2+ ) influx in the MscL-G22S-expressing SCs with low-intensity
mech. stretching and the controls. Proteomic and energy metabolomics analyses were performed to invest igate the comprehensive
effects of MscL-G22S activation on S Cs. Measurement of glycolysis- and oxidative phosphorylation-related mols. and ATP
production were resp. performed to further validate the effects of MscL-G22S activation on S Cs. Finally, the roles of phosphatidylin
ositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (m TOR) signaling pathway in the mechanism of energy metabolism
modulation of SCs by Msc L-G22S activation was investigated. Results: Mech. stretc hing-induced MscL-G22S activation significantly
increased the cell viability and Ca2+ influx into the S Cs. Both the proteomic and targeted energy metabo lomics anal. indicated the
upregulation of energy metabolism as the main action mechanism of Msc L-G22S-activation on SCs. MscL-G22S-activated SCs
showed significant upregulation of glycolysis and oxidative phosphor ylation when SCs with stretching alone had only mild upregu
lation of energy metabolism than those without stimuli. Msc L-G22S activation caused signif icant phosphorylation of the PI3K/AK
T/mTOR signaling pathway and upregu lation of HIF-1α/c-Myc. Inhibition of PI3K abolished the Msc L-G22S activation-induced
upregulation of HIF-1α/c-Myc signaling in S Cs and reduced the levels of glycol ysis- and oxidative phosphorylation-related substrates
and mitochondrial activity. Conclusion: Mech. stretching activates MscL-G22S to significantly promote the energy metabolism of S Cs
and the production of energic substrates, which may be applied to enhance nerve regene ration via the glia-axonal metabolic
coupling.
Keywords: Energy metabolism; Mechanical stretching; Mechanosensitive channel of large conduc tance; Schwann cells

407
Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control
presynaptic function and gene expression
By: Guhathakurta, Debarpan; Petruskova, Aneta; Akdas, Enes Yagiz; Perello-Amoros, Bartomeu; Frischknecht, Renato; Anni, Daniela;
Weiss, Eva-Maria; Walter, Martin; Fejtova, Anna
Abstract: Ketamine is clin. used fast-acting antidepressant. Its metabolite hydroxynorketamine (HNK) shows a robust antidep ressant
effect in animal studies. It is unclear, how these chem. distinct compounds converge on similar neuronal effects. While KET acts
mostly as N-methyl-d-aspartate receptor (N MDAR) antagonist, the mol. target of HNK remains enigmatic. Here, we show that K ET
and HNK converge on rapid inhibition of glutamate release by reducing the release competence of synaptic vesicles and induce
nuclear translocation of pCREB that controls expression of neuroplasticity genes connected to K ET- and HNK-mediated antidep
ressant action. Ro25-6981, a selective antagonist of Glu N2B, mimics effect of KET indicating that GluN2B-containing NMDAR might
mediate the presynaptic effect of KET. Selective antagonist of α7 nicotinic acetylc holine receptors (α7nAChRs) or genetic deletion of
Chrna7, its pore-forming subunit, fully abolishes H NK-induced synaptic and nuclear regula tions, but leaves K ET-dependent cellular
effects unaffected. Thus, K ET or HNK-induced modulation of synaptic transmission and nuclear translo cation of pCREB can be
mediated by selective signaling via NMDAR or α7nAChRs, resp. Due to the rapid metabolism of K ET to HNK, it is conceivable that
subsequent modulation of glutamatergic and cholinergic neurotransmission affects circuits in a cell-type-specific manner and contri
butes to the therapeutic potency of K ET. This finding promotes further explor ation of new combined medications for mood
disorders.
408
Elimination of Curtobacterium sp. strain A7_M15, a contaminant in Prunus rootstock tissue culture
production, using reduced graphene oxide-silver-copper and silver-selenium nanocomposites
By: Tekielska, Dorota; Pecenka, Jakub; Hakalova, Eliska; Cechova, Jana; Bytesnikova, Zuzana; Richtera, Lukas; Kiss, Tomas; Eichmeier,
Ales; Baranek, Miroslav
Abstract: Background: Bacterial contamination poses a high risk to the successful establi shment and mainte nance of plant tissue
cultures. The aim of this study was to identify the isolates representing the frequent bacterial contaminants of Prunus rootstock
tissue cultures and to determine the most effective concentration of nanomaterials for Curtobacterium sp. strain A7_M15 elimin
ation without a neg. impact on explants. Results: Six Curtoba cterium sp. strains were isolated and identi fied, and the whole-genome
sequence was obtained for strain A7_M15. Two nanocomposites, reduced graphene oxide- copper-silver and silver-selenium, with
the highest bactericidal activity were selected for elimin ation of Curtobacterium sp. contamination in Gisela 5 rootstock tissue
cultures. Both nanocomposites showed 100% inhibition of bacterial plaque formation on culture medium at concent rations of 100,
200 and 400 mg L-1 Ag (2 x- 8 x MBC). The quantity of Curtoba cterium sp. on culture medium assessed using cfu enumer ation was
reduced by 92% and 74% in comparison to the pos. control after treatment with reduced graphene oxide-silver-copper and silver-
selenium at a concent ration of 200 mg L -1 Ag, resp. None of the tested concent rations resulted in a decrease in Curtoba cterium sp.
quantity in explants. Curtobacterium sp. was detected in donor Gisela 5 plants, indicating an endophytic character of this
bacterium. The dry weight of explants was not neg. affected by the application of nanocomposites regardless of concent ration, and
no detrimental effect of either nanocom posite at 100 or 200 mg L -1 Ag on the surface covered by plants was observed Conclu sions:
Reduced graphene oxide-silver-copper and silver-selenium nanocomposites at 200 mg L -1 Ag effect ively limited the Curtobacterium
sp. presence in micropropagated Prunus rootstock without causing phytoto xicity; therefore, those treatments could be offered as
prevention with a high activity against bacterial contamination in plant tissue cultures. Graphical Abstract: [graphic not available:
see fulltext]

409
Targeting KCa3.1 channels to overcome erlotinib resistance in non-small cell lung cancer cells
By: Todesca, Luca Matteo ; Gerke, Matthias; Bulk, Emma Etmar; Bachmann, Magdalena; Rudersdorf, Alisa; Antonuzzo, Lorenzo;
Pillozzi, Serena; Duefer, Martina; Szabo, Ildiko ; Schwab, Albrecht
Abstract: Almost all non-small cell lung cancer (N SCLC) patients initially responding to E GFR tyrosine kinase inhibitors (T KIs) develop
acquired resistance. Since K Ca3.1 channels, expressed in mitoch ondria and plasma membrane, regulate similar behavioral traits of
NSCLC cells as EGFR, we hypothesized that their blockade contri butes to overcoming E GFR-TKI resistance. Meta-anal. of microarray
data revealed that K Ca3.1 channel expression in erlotinib- resistant NSCLC cells correlates with that of genes of integrin and
apoptosis pathways. Using erlotinib-sensitive and - resistant NSCLC cells we monitored the role of mitocho ndrial K Ca3.1 channels in
integrin signaling by studying cell-matrix adhesion with single-cell force spectroscopy. Apoptosis was quantified with fluores cence-
based assays. The function of mitochondrial K Ca3.1 channels in these processes was assessed by measuring the mitocho ndrial
membrane potential and by quantifying ROS production Functional assays were supple mented by biochem. analyses. We show that
K Ca3.1 channel inhibition with senicapoc in erlotinib- resistant NSCLC cells increases cell adhesion by increasing β1- integrin expres
sion, that in turn depends on mitocho ndrial ROS release. Increased adhesion impairs migration of N SCLC cells in a 3 D matrix. At the
same time, the senicapoc-dependent ROS production induces cytochrome C release and triggers apoptosis of erlotinib- resistant NS
CLC cells. Thus, K Ca3.1 channel blockade overcomes E GFR-TKI resistance by inhibiting N SCLC motility and inducing apoptosis.
410
Splenic monocytes drive pathogenic subretinal inflammation in age-related macular degeneration
By: Roubeix, Christophe; Nous, Caroline; Augustin, Sebastien; Ronning, Kaitryn E.; Mathis, Thibaud; Blond, Frederic; Lagouge-
Roussey, Pauline; Crespo-Garcia, Sergio; Sullivan, Patrick M.; Gautier, Emmanuel L.; et al
Journal of Neuroinflammation (2024), 21(1), 22 | Language: English, Database: CAplus and MEDLINE
Abstract: Age-related macular degeneration (AMD) is invariably associated with the chronic accumu lation of activated mononu clear
phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte- derived
cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate
directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor
(ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well unders
tood. Using acute inflam matory and well-phenotyped AMD models, we demons trate that angiotensin II mobilizes ATR1 + splenic
monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functi onally from
bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist
and splenectomy reduces the subretinal mononu clear phagocyte accumu lation and pathol. choroidal neovascul arization formation.
In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splene ctomy also inhibit the chronic retinal
inflammation and associated cone degene ration that characterizes these mice. Our observation of elevated levels of plasma angiot
ensin II in AMD patients, suggests that similar events take place in clin. disease and argue for the therap eutic potential of A TR1
antagonists to inhibit splenic monocytes for the treatment of blinding A MD.
Keywords: Age-related macular degeneration; Angiotensin; Neuroinflammation; Splenic monocytes

411
Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome
doxorubicin to optimize therapeutic responses of immune checkpoint blockade
By: Zhang, Baoyuan; Li, Ning; Gao, Jiaming; Zhao, Yuxi; Jiang, Jun; Xie, Shuang; Zhang, Cuiping; Zhang, Qingyu; Liu, Leo; Wang, Zaiqi;
et al
Abstract: Backgrounds: Immune checkpoint blockade (I CB) is widely considered to exert long-term treatment benefits by activating
antitumor immunity. However, many cancer patients show poor clin. responses to ICB due in part to the lack of an immuno genic
niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However,
evidence illustrates that targeting FAK is most effective in combin ation therapy rather than in monoth erapy. Methods: Here, we
used drug screening, in vitro and in vivo assays to filter out that doxorubicin and its liposomal form pegylated liposome doxoru
bicin (PLD) showed synergistic anti-tumor effects in combination with FAK inhibitor IN10018. We hypothesized that anti-tumor
immunity and immunogenic cell death (I CD) may be involved in the treatment outcomes through the data anal. of our clin. trial
testing the combination of IN10018 and PLD. We then performed cell-based assays and animal studies to detect whether F AK
inhibition by IN10018 can boost the I CD of PLD/doxorubicin and further established syngeneic models to test the antitumor effect
of triplet combination of PLD, IN10018, and ICB. Results: We demons trated that the combination of FAK inhibitor IN10018, and PL
D/doxorubicin exerted effective antitumor activity. Notably, the doublet combin ation regimen exhibited response latency and long-
lasting treatment effects clin., outcomes frequently observed in immunot herapy. Our preclin. study confirmed that the 2- drug
combination can maximize the ICD of cancer cells. This approach primed the tumor microenvi ronment, supplementing it with
sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Finally, different animal studies confirmed that the
antitumor effects of ICB can be significantly enhanced by this doublet regimen. Conclu sions: We confirmed that targeting F AK by I
N10018 can enhance the I CD of PLD/doxorubicin, further benefiting the anti-tumor effect of I CB. The animal tests of the triplet
regimen warrant further discovery in the real world.
Keywords: FAK; Immune checkpoint blockade (ICB); Immunogenic cell death (I CD); Pegylated liposome doxoru bicin (PLD); Synergy
412
ΔNp63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1
By: Aljagthmi, Amjad A.; Hira, Akshay; Zhang, Jin; Cooke, Mariana; Kazanietz, Marcelo G.; Kadakia, Madhavi P.
Abstract: ΔNp63α, a member of the p53 family of transcr iption factors, plays a critical role in mainta ining the proliferative potential
of stem cells in the stratified epithelium. Although ΔNp63α is considered an oncogene and is frequently overexp ressed in
squamous cell carcinoma, loss of ΔNp63α expression is associated with increased tumor cell invasion and metast asis. We recently
identified a ΔNp63α/miR-320a/PKCγ signaling axis that regulates cancer cell invasion by inhibiting phosphor ylation of the small G T
Pase Rac1, a master switch of cell motility that pos. regulates cell invasion in multiple human cancers. In this study, we identified a
novel mechanism by which ΔNp63α neg. regulates Rac1 activity, by inhibiting the expression of the Rac- specific Guanine Exchange
Factor PREX1. ΔNp63α knockdown in multiple squamous cell carcinoma cell lines leads to increased Rac1 activa tion, which is
abrogated by treatment with the Rac1 inhibitor NSC23766. Furthermore, ΔNp63α neg. regulates P REX1 transcript and protein levels.
Using a Rac-GEF activation assay, we also showed that Δ Np63α reduces the levels of active P REX1. The inhibition of the PREX1-Rac1
signaling axis by ΔNp63α leads to impaired cell invasion, thus establ ishing the functional relevance of this link. Our results
elucidated a novel mol. mechanism by which ΔNp63α neg. affects cancer cell invasion and identifies the Δ Np63α/Rac1 axis as a
potential target for metastasis.

413
HTLV-1 reverse transcriptase homology model provides structural basis for sensitivity to existing
nucleoside/nucleotide reverse transcriptase inhibitors
By: Tardiota, Nicolas; Jaberolansar, Noushin; Lackenby, Julia A.; Chappell, Keith J.; O′Donnell, Jake S.
Virology Journal (2024), 21(1), 14 | Language: English, Database: CAplus and MEDLINE
Abstract: The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-
limited regions. Infections persist for life and are associated with increased suscept ibility to opportunistic infections and severe
diseases including adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. No HTLV-1-
specific anti-retrovirals have been developed and it is unclear whether existing anti- retrovirals developed for treatment of human
immunodeficiency virus (HIV) have efficacy against HTLV-1. To understand the structural basis for therap eutic binding, homol.
modeling and machine learning were used to develop a structural model of the HTLV-1 reverse transcriptase. With this, mol.
docking experiments using a panel of FDA-approved inhibitors of viral reverse transcr iptases to assess their capacity for binding,
and in turn, inhibition . Importantly, nucleoside/nucleotide reverse transcr iptase inhibitor but not non-nucleoside reverse transcr
iptase inhibitors were predicted to bind the HTLV-1 reverse transcriptase, with similar affinity to H IV-1 reverse transcriptase. By
strengthening the rationale for clin. testing of therapies such as tenofovir alafen amide, zidovudine, lamivudine, and azvudine for
treatment of HTLV-1, this study has demons trated the power of in silico structural biol. approaches in drug design and therap eutic
testing.
414
Icariin exerts anti-tumor activity by inducing autophagy via AMPK/mTOR/ULK1 pathway in triple-
By: Zhao, Mei; Xu, Panling; Shi, Wenjing; Wang, Juan; Wang, Ting; Li, Ping
Abstract: Background: Breast cancer is the most prevalent female tumor, of which triple- neg. breast cancer (T NBC) accounts for
about 15%. Characterized by its aggressive nature and limited treatment options, T NBC currently stands as a signif icant clin.
challenge. This study aimed to investigate the effects of icariin (ICA) on TNBC and explore the underlying mol. mechanism. Methods:
Cell viability was assessed using CCK-8 assay, whereas the impact of I CA on cell proliferation was determined using colony
formation assay and detection of proliferating cell nuclear antigen protein. Wound healing and transwell assays were used to
evaluate the effects of ICA on cell migration and invasion, resp. Flow cytometry was used to analyze cell cycle distri bution and
apoptosis. Transmission electron microscopy and monodansy lcaverine staining were performed to detect the induction of
autophagy, whereas mol. docking was conducted to predict the potential targets associated with autophagy. The in vivo anti-tumor
effects of ICA were evaluated using a T NBC 4T1 xenograft mouse model. Protein expression levels were examined using immunob
lotting and immunohistochem. Results: In vitro, I CA effectively suppressed the viability, proliferation, migration, and invasion of T NB
C cells and induced G0/G1 phase cell cycle arrest, apoptosis, and autophagy in T NBC cells by regulating the adenosine monopho
sphate-activated protein kinase (A MPK)/mammalian target of rapamycin (m TOR)/Unc-51-like kinase 1 (ULK1) signaling pathway. The
knockdown of AMPK and inhibition of autophagy with 3- methyladenine reversed the effects of ICA, highlighting the importance of
AMPK and autophagy in the anti-cancer mechanism of ICA. In vivo, ICA significantly inhibited T NBC growth, promoted autophagy,
and regulated AMPK/mTOR/ULK1 pathway. Conclusions: Our findings demonstrated that ICA exerts anti-cancer effects against TNB
C and the associated mol. mechan isms. This study will help to facilitate further preclin. and clin. investi gations for the treatment of
TNBC.
Keywords: AMPK; Apoptosis; Autophagy; Icariin; TNBC

415
Combinatorial regulation by ERK1/2 and CK1δ protein kinases leads to HIF-1α association with
microtubules and facilitates its symmetrical distribution during mitosis
By: Arseni, Christina; Samiotaki, Martina; Panayotou, George; Simos, George ; Mylonis, Ilias
Hypoxia-inducible factor-1 (HIF-1) is the key transcriptional mediator of the cellular response to hypoxia and is also involved in
cancer progression. Regulation of its oxygen- sensitive HIF-1α subunit involves posttranslational modifications that control its
stability, subcellular localization, and activity. We have previously reported that phosphor ylation of the HIF-1α C-terminal domain by
ERK1/2 promotes HIF-1α nuclear accumulation and stimulates H IF-1 activity while lack of this modifi cation triggers HIF-1α nuclear
export and its association with mitochondria. On the other hand, modifi cation of the N-terminal domain of HIF-1α by C K1δ impairs
HIF-1 activity by obstructing the formation of a HIF-1α/ARNT heterodimer. Investigation of these two antagonistic events by
expressing double phospho-site mutants in HIF1A-/- cells under hypoxia revealed independent and additive phosphor ylation effects
that can create a gradient of HIF-1α subcellular localization and transcri ptional activity. Furthermore, modification by C K1δ caused
mitochondrial release of the non-nuclear HIF-1α form and binding to microt ubules via its N-terminal domain. In agreement,
endogenous HIF-1α could be shown to co- localize with mitotic spindle microtubules and interact with tubulin, both of which were
inhibited by CK1δ silencing or inhibition . Moreover, CK1δ expression was necessary for equal partit ioning of mother cell-produced
HIF-1α to the daughter cell nuclei at the end of mitosis. Overall, our results suggest that phosphor ylation by C K1δ stimulates the
association of non-nuclear HIF-1α with microtu bules, which may serve as a means to establish a sym. distri bution of HIF-1α during
cell division under low oxygen conditions.
Keywords: mitosis microtubule HIF1 ERK1 ERK2 CK1delta; Casein kinase 1δ; E RK1/2; HIF-1α; Hypoxia; Microtubules; Mitosis
416
Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic
steatohepatitis in mice
By: Zhang, Weitao; Lu, Junfeng; Feng, Lianshun; Xue, Hanyue; Shen, Shiyang; Lai, Shuiqing; Li, PingPing ; Li, Ping; Kuang, Jian; Yang,
Zhiwei ; et al
Abstract: Sonic hedgehog (SHH) and heat shock protein 90β (H SP90β) have been implicated in nonalc oholic steatohepatitis (NASH)
but their mol. mechanisms of action remain elusive. We find that HSP90β is a key S HH downstream mol. for promoting N ASH
process. In hepatocytes, SHH reduces HSP90β ubiquitylation through deubiquitylase USP31, thus preventing HSP90β degradation
and promoting hepatic lipid synthesis. HSP90β significantly increases in N ASH mouse model, leading to secretion of exosomes
enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes N F-κB transcriptional
activity in macrophages and stimulates the expression of inflam matory factors. Genetic deletion, pharmacol. inhibition of the SHH-
HSP90β axis, or delivery of mi R-28-5p to macrophages in the male mice liver, impairs N ASH symptomatic development. Import
antly, there is a markedly higher abundance of mi R-28-5p in N ASH patient sera. Taken together, the SHH-HSP90β-miR-28-5p axis
offers promising therapeutic targets against N ASH, and serum mi R-28-5p may serve as a N ASH diagnostic biomarker.

417
Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress
By: Liu, Shixin; Yang, Pingshan; Wang, Lu; Zou, Xiaofang; Zhang, Dongdong; Chen, Wenyou; Hu, Chuang; Xiao, Duqing; Ren,
Hongzheng; Zhang, Hao; et al
Abstract: Chemoresistance poses a signif icant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-
activated kinase 4 (P AK4) has been implicated in N SCLC progression by invasion and migration. However, the involv ement of PAK4
in cisplatin resistance is not clear. Here, we presented a comprehensive investigation into the involvement of PAK4 in cisplatin
resistance within NSCLC. Our study revealed enhanced P AK4 expression in both cisplatin- resistant NSCLC tumors and cell lines.
Notably, PAK4 silencing led to a remarkable enhanc ement in the chemosensitivity of cisplatin-resistant NSCLC cells. Cisplatin
evoked endoplasmic reticulum stress in N SCLC. Furthermore, inhibition of PAK4 demonstrated the potential to sensitize resistant
tumor cells through modulating endoplasmic reticulum stress. Mechanistically, we unveiled that the suppression of the MEK1-GR
P78 signaling pathway results in the sensiti zation of NSCLC cells to cisplatin after PAK4 knockdown. Our findings establish P AK4 as a
promising therapeutic target for addressing chemores istance in NSCLC, potentially opening new avenues for enhancing treatment
efficacy and patient outcomes.
418
EN1 promotes lung metastasis of salivary adenoid cystic carcinoma by regulating the PI3K-AKT
pathway and epithelial-mesenchymal transition
By: Cui, Yajuan; Zhang, Ye; Liu, Yuping; Zhou, Zheng; Zhu, Lijing; Zhou, Chuan-Xiang
Abstract: Background: Engrailed homeobox 1 (E N1) is a candidate oncogene that is epigene tically modified in salivary adenoid
cystic carcinoma (SACC). We invest igated the expression of EN1 in S ACC tissues and cells, E N1 promoter methyl ation, and the role
of EN1 in tumor progre ssion in SACC. Methods: Thirty-five SACC samples were screened for key transcr iption factors that affect
tumor progression. In vitro and in vivo assays were performed to determine the viability, tumorige nicity, and metastatic ability of S
ACC cells with modulated E N1 expression. Quant. methylation-specific polymerase chain reaction anal. was performed on SACC
samples. Results: EN1 was identified as a transcr iption factor that was highly overexp ressed in SACC tissues, regardless of clin.
stage and histol. subtype, and its level of expression correlated with distant metastasis. EN1 promoted cell invasion and migration
through epithelial-mesenchymal transition in vitro and enhanced S ACC metastasis to the lung in vivo. R NA-seq combined with in
vitro assays indicated that EN1 might play an oncogenic role in S ACC through the PI3K-AKT pathway. EN1 mRNA levels were neg.
correlated with promoter hypermethylation, and inhibition of DNA methylation by 5-aza-dC increased EN1 expression. Conclu
sions: The transcription factor EN1 is overexpressed in SACC under methylation regulation and plays a pivotal role in S ACC progre
ssion through the PI3K-AKT pathway. These results suggest that E N1 may be a diagnostic biomarker and a potential therap eutic
target for SACC.
Keywords: Engrailed 1; Epithelial-mesenchymal transition; Metastasis; Methylation; Salivary adenoid cystic carcinoma

419
A pivotal role for the IL-1β and the inflammasome in preterm labor
By: Lopez, T. E.; Zhang, H.; Bouysse, E.; Neiers, F.; Ye, X. Y.; Garrido, C.; Wendremaire, M.; Lirussi, Frederic
Abstract: During labor, monocytes infiltrate massively the myometrium and differentiate into macrop hages secreting high levels of
reactive oxygen species and of pro-inflammatory cytokines (i.e. IL-1β), leading to myometrial contraction. Although IL-1β is clearly
implicated in labor, its function and that of the inflammasome complex that cleaves the cytokine in its active form, has never been
studied on steps preceding contraction. In this work, we used our model of lipopolysa ccharide-induced preterm labor to highlight
their role. We demonstrated that IL-1β was secreted by the human myometrium during labor or in presence of infection and was
essential for myometrial efficient contractions as its blockage with an I L-1 receptor antagonist (Anakinra) or a neutra lizing antibody
completely inhibited the induced contractions. We evaluated the implic ation of the inflammasome on myometrial contractions and
differentiation stages of labor onset. We showed that the effects of macrop hage-released IL-1β in myometrial cell transact ivation
were blocked by inhibition of the inflammasome, suggesting that the inflammasome by producing I L-1β was essential in
macrophage/myocyte crosstalk during labor. These findings provide novel innovative approaches in the management of preterm
labor, specifically the use of an inflammasome inhibitor to block the precursor stages of labor before the acquis ition of the contra
ctile phenotype.
420
FOXM1: a new therapeutic target of extramammary Paget disease
By: Ito, Takamichi; Tanaka, Yuka; Kaku-Ito, Yumiko; Oda, Yoshinao; Nakahara, Takeshi
Abstract: Extramammary Paget disease (EMPD) is a rare skin cancer that primarily affects older indivi duals predominantly in areas
with apocrine sweat glands. Although most early EMPD lesions are indolent, patients with metastatic E MPD have a poor prognosis
due to the lack of effective systemic treatment. In this study, we investigated the role of forkhead box M1 (F OXM1), a potent transcr
iption factor, in E MPD and assessed the potential of F OXM1 as a therapeutic target. Immunohi stochem. of 112 primary and 17
metastatic EMPD samples revealed that FOXM1 expression increased with tumor progre ssion. Patients in whom F OXM1 was
expressed in more than 10% of tumor cells had significantly shorter disease-specific survival than the other patients (p = 0.0397) . In
in vitro studies using our newly established EMPD cell line, K S-EMPD-1, we found high expression of FOXM1. Knockdown of FOXM1
impaired tumor cell viability, migration, and invasion. Inhibition of FOXM1 using thiostrepton also reduced tumor cell viability in a
dose-dependent manner. These findings suggest that F OXM1 is a promising therap eutic target for patients with E MPD.
Keywords: Cell line; FOXM1; Skin cancer; Targeted therapy; Thiostrepton

421
NKG2D knockdown improves hypoxic-ischemic brain damage by inhibiting neuroinflammation in

neonatal mice
By: Liu, Lin; Yang, Yuxin; Wu, Ting; Du, Junrong; Long, Fangyi
Abstract: Hypoxic-ischemic brain damage (HIBD) is a leading cause of neonatal death and neurol. dysfun ction. Neuroinflammation is
identified as one of the crucial pathol. mechanisms after HIBD, and natural killer group 2 member D (N KG2D) is reported to be
implicated in the pathogenesis of immunoinflammatory diseases. However, the role of N KG2D in neonatal HIBD is seldomly investi
gated. In this study, a neonatal mice model of H IBD was induced, and the role of the N KG2D in neuroinflammation and brain injury
was explored by intracerebroventricular injection of lentivirus to knockdown N KG2D in neonatal mice with HIBD. The results
showed that a significant increase in N KG2D protein level in the brain of neonatal mice with H IBD. The NKG2D knockdown in the
brain significantly alleviated cerebral infarc tion, neurobehavioral deficits, and neuronal loss in neuronal H IBD. Moreover, the
neuroprotective effect of N KG2D knockdown was associated with inhibition of the activation of microglia and astroc ytes,
expression of NKG2D ligands (NKG2DLs) and DAP10, and the nuclear translo cation of NF-κB p65. Our findings reveal N KG2D
knockdown may exert anti-inflammatory and neuroprotective effects in the neonatal mice with HIBD through downregulation of NK
G2D/NKG2DLs/DAP10/NF-κB pathway. These results suggest that N KG2D may be a potential target for the treatment of neonatal H I
BD.
422
Effect of diet supplemented with functional amino acids and polyphenols on gut health in broilers
subjected to a corticosterone-induced stress
By: Yvon, Sophie; Beaumont, Martin; Dayonnet, Alix; Eutamene, Helene; Lambert, William; Tondereau, Valerie; Chalvon-Demersay,
Tristan; Belloir, Pauline; Paes, Charlotte
To address the overuse of antimicrobials in poultry produc tion, new functional feed ingredients, i.e. ingredients with benefits
beyond meeting basic nutritional requirements, can play a crucial role thanks to their prophy lactic effects. This study evaluated the
effects of the supplementation of arginine, threonine and glutamine together with grape polyph enols on the gut integrity and
functionality of broilers facing a stress condition. 108 straight- run newly hatched Ross PM3 chicks were kept until 35 days and were
allocated to 3 treatments. Broilers in the control group were raised in standard condit ions. In exptl. groups, birds were admini
stered with corticosterone in drinking water (C ORT groups) to impair the global health of the animal and were fed a well- balanced
diet supplemented or not with a mix of functional amino acids together with grape extracts (1 g/kg of diet- CORT + M IX group). Gut
permeability was significantly increased by cortico sterone in non-supplemented birds. This corticos terone-induced stress effect was
alleviated in the CORT + M IX group. M IX supplementation attenuated the reduction of crypt depth induced by corticos terone. Mucin
2 and TN F-α gene expression was upregulated in the CORT + M IX group compared to the C ORT group. Caecal microbiota
remained similar between the groups. These findings indicate that a balanced diet supplemented with functional AA and polyph
enols can help to restore broiler intestinal barrier after a stress exposure.
Keywords: corticosterone diet supplement amino acid polyphenol gut health broiler

423
ApoL6 associates with lipid droplets and disrupts Perilipin1-HSL interaction to inhibit lipolysis
By: Wang, Yuhui; Nguyen, Hai P.; Xue, Pengya ; Xie, Ying; Yi, Danielle; Lin, Frances; Dinh, Jennie ; Viscarra, Jose A.; Ibe, Nnejiuwa
U.; Duncan, Robin E. ; et al
Adipose tissue stores triacylglycerol (TAG) in lipid droplets (LD) and release fatty acids upon lipolysis during energy shortage. We
identify ApoL6 as a LD-associated protein mainly found in adipose tissue, specif ically in adipocytes. ApoL6 expression is low during
fasting but induced upon feeding. ApoL6 knockdown results in smaller L D with lower TAG content in adipocytes, while ApoL6
overexpression causes larger LD with higher T AG content. We show that the Apo L6 affects adipocytes through inhibition of
lipolysis. While ApoL6, Perilipin 1 (Plin1), and HSL can form a complex on L D, C-terminal ApoL6 directly interacts with N- terminal
Plin1 to prevent Plin1 binding to HSL, to inhibit lipolysis. Thus, Apo L6 ablation decreases white adipose tissue mass, protecting mice
from diet-induced obesity, while ApoL6 overexpression in adipose brings obesity and insulin resist ance, making ApoL6 a potential
future target against obesity and diabetes.
Keywords: Apol6 lipid droplet perilipin1 lipolysis insulin resistance diabetes mellitus
424
Structure-based development of 3,5-dihydroxybenzoyl-hydrazineylidene as tyrosinase inhibitor; in

vitro and in silico study
By: Bagheri, Azzam; Moradi, Shahram; Iraji, Aida; Mahdavi, Mohammad

Abstract: A series of new analogs of 3,5-dihydroxybenzoyl-hydrazineylidene conjugated to different methoxyphenyl triazole (11a-n)
synthesized using click reaction. The structures of all synthe sized compounds were characterized by FTIR, 1H, 13 C-NMR spectro
scopy, and CHO anal. The tyrosinase inhibitory potential of the synthe sized compounds was studied. The newly synthe sized
scaffolds were found to illustrate the variable degree of the inhibitory profile, and the most potent analog of this series was that
one bearing 4-methoxyphenyl moiety, and exhibited an I C50 value of 55.39 ± 4.93 μ M. The kinetic study of the most potent
derivative reveals a competitive mode of inhibition . Next, mol. docking studies were performed to understand the potent inhibi
tor′s binding mode within the enzyme′s binding site. Mol. dynamics simula tions were accomplished to further investigate the orient
ation and binding interaction over time and the stability of the 11m- tyrosinase complex.

425
RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via
hijacking YY1 binding
By: Lin, Ying; Wu, Yun; Zhang, Qiangzu; Tu, Xunwei; Chen, Sufang; Pan, Junfan; Xu, Nengluan; Lin, Ming; She, Peiwei; Niu, Gang; et al
Abstract: Background: Ceramide metabolism is crucial in the progress of brain metastasis (B M). However, it remains unexplored
whether targeting ceramide metabolism may arrest BM. Methods: RNA sequencing was applied to screen different genes in primary
and metastatic foci and whole-exome sequencing (WES) to seek crucial abnormal pathway in B M + and B M-patients. Cellular arrays
were applied to analyze the permeability of blood-brain barrier (BBB) and the activation or inhibition of pathway. Database and Co-
Immunoprecipitation (Co-IP) assay were adopted to verify the protein- protein interaction. Xenograft and zebrafish model were
further employed to verify the cellular results. Results: RNA sequencing and W ES reported the involv ement of RPTOR and ceramide
metabolism in BM progress. R PTOR was significantly upregulated in BM foci and increased the permea bility of BBB, while RPTOR
deficiency attenuated the cell invasiveness and protected extrace llular matrix. Exogenous R PTOR boosted the S PHK2/S1P/STAT3
cascades by binding YY1, in which YY1 bound to the regions of S PHK2 promoter (at - 353 ∼ -365 nt), further promoting the expression
of SPHK2. The latter was rescued by Y Y1 RNAi. Xenograft and zebrafish model showed that R PTOR blockade suppressed B M of non-
small cell lung cancer (N SCLC) and impaired the S PHK2/S1P/STAT3 pathway. Conclusion: RPTOR is a key driver gene in the brain
metastasis of lung cancer, which signifies that RPTOR blockade may serve as a promising therap eutic candidate for clin. applic ation.
Keywords: Brain metastasis; Non-small cell lung cancer; R PTOR; S1P; SPHK2
426
Low dose cadmium exposure regulates miR-381-ANO1 interaction in airway epithelial cells
By: Singh, Pooja; Li, Fu Jun; Dsouza, Kevin; Stephens, Crystal T.; Zheng, Huaxiu; Kumar, Abhishek; Dransfield, Mark T.; Antony, Veena
B.
Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death worldwide. Cigarette smoke which has approx. 2-
3μg of Cadmium (Cd) per cigarette contri butes to the environmental exposure and development and severity of C OPD. With the
lack of a cadmium elimination mechanism in humans, the contri bution of cadmium induced stress to lung epithelial cells remains
unclear. Studies on cadmium responsive miRNAs suggest regulation of target genes with an emphasis on the critical role of mi RNA-
mRNA interaction for cellular homeostasis. Mir-381, the target miRNA in this study is neg. regulated by cadmium in airway epithelial
cells. miR-381 is reported to also regulate A NO1 (Anoctamin 1) expression neg. and in this study low dose cadmium exposure to
airway epithelial cells was observed to upregulate ANO1 mRNA expression via mir-381 inhibition . ANO1 which is a Ca2+-activated
chloride channel has multiple effects on cellular functions such as proliferation, mucus hypersecretion and fibroblast differen tiation
in inflamed airways in chronic respiratory diseases. In vitro studies with cadmium at a high concent ration range of 100- 500μM is
reported to activate chloride channel, ANO1. The secretory epithelial cells are regulated by chloride channels like C FTR, ANO1 and S
LC26A9. We examined "ever" smokers with C OPD (n = 13) lung tissue sections compared to "never" smoker without C OPD (n = 9).
We found that "ever" smokers with COPD had higher ANO1 expression. Using mir- 381 mimic to inhibit ANO1, we demonstrate here
that ANO1 expression is significantly (p < 0.001) downreg ulated in COPD derived airway epithelial cells exposed to cadmium.
Exposure to environmental cadmium contributes significantly to ANO1 expression.
Keywords: human airway epithelium chronic obstructive pulmonary disease cadmium microRNA

427
Multipronged regulation of autophagy and apoptosis: emerging role of TRIM proteins
By: Ahsan, Nuzhat ; Shariq, Mohd; Surolia, Avadhesha; Raj, Reshmi; Khan, Mohammad Firoz; Kumar, Pramod
Abstract: TRIM proteins are characterized by their conserved N- terminal RING, B-box, and coiled-coil domains. These proteins are
efficient regulators of autophagy, apoptosis, and innate immune responses and confer immunity against viruses and bacteria. TRI
Ms function as receptors or scaffold proteins that target substrates for autophagy- mediated degradation Most TRIMs interact with
the BECN1-ULK1 complex to form T RIMosomes, thereby efficiently targeting substrates to autophagosomes. They regulate the
functions of ATG proteins through phys. interactions or ubiquitination. TRIMs affect the lipidation of M AP1LC3B1 to form MAP1LC3
B2, which is a prerequisite for phagophore and autopha gosome formation. In addition, they regulate M TOR kinase and T FEB,
thereby regulating the expression of ATG genes. TRIM proteins are efficient regulators of apoptosis and are crucial for regulating
cell proliferation and tumor formation. Many T RIM proteins regulate intrinsic and extrinsic apoptosis via the cell surface receptors T
GFBR2, TNFRSF1A, and FAS. Mitochondria modulate the anti- and proapo ptotic functions of BCL2, BAX, BAK1, and CYCS. These
proteins use a multipronged approach to regulate the intrinsic and extrinsic apoptotic pathways, culmin ating in coordinated
activation or inhibition of the initiator and executor C ASPs. Furthermore, TRIMs can have a dual effect in determ ining cell fate and
are therefore crucial for cellular homeostasis. In this review, we discuss mechanistic insights into the role of T RIM proteins in
regulating autophagy and apoptosis, which can be used to better understand cellular physiol. These findings can be used to develop
therapeutic interventions to prevent or treat multiple genetic and infectious diseases. Graphical Abstract: [graphic not available: see
fulltext]
Keywords: Apoptosis; Autophagosome; Autophagy; Autophagy receptor; BECN1; E3-Ub ligase; T P53; TRIM proteins; ULK1; Ubiquit
ination
428
Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis
By: Zhang, Yun; Du, Lijun; Wang, Chenxi; Jiang, Zhangsheng; Duan, Qingchi; Li, Yiping; Xie, Zhijun; He, Zhixing; Sun, Yi ; Huang, Lin;
et al
Abstract: Systemic lupus erythematosus (SLE), a severe autoimmune disorder, is characterized by systemic inflammatory response,
autoantibody accumulation and damage to organs. The dysregu lation of double-neg. (DN) T cells is considered as a crucial
commander during SLE. Neddylation, a signif icant type of protein post-translational modification (PTM), has been well-proved to
regulate T cell-mediated immune response. However, the function of neddyl ation in SLE is still unknown. Here, we reported that
neddylation inactivation with MLN4924, a specific inhibitor of N EDD8-activating enzyme E1 (N AE1), or genetic abrogation of Ube2m
in T cells decreased DN T cell accumu lation and attenuated murine lupus develo pment. Further investi gations revealed that inacti
vation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in D N T cells, contri buting to the apoptosis
of the accumulated DN T cells in lupus mice. Then double knockout (K O) lupus-prone mice (Ube2m -/- Bim-/- lpr) were generated and
results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progre
ssion. Our findings identified that neddyl ation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus
progression. Clin., we also found that in S LE patients, the proportion of DN T cells was raised and their apoptosis was reduced.
Moreover, compared to healthy groups, SLE patients exhibited decreased Bim levels and elevated Cullin1 neddyl ation levels.
Meantime, the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from S LE patients. Altogether, our
findings provide the direct evidence about the function of neddylation during lupus, suggesting a promising therap eutic approach
for this disease.

429
Fermentation of waste water from agar processing with Bacillus subtilis by metabolomic analysis
By: Wu, Yanyan; Duan, Boyan; Lin, Qiaoyan; Liang, Yingying; Du, Xiping; Zheng, Mingjing; Zhu, Yanbing; Jiang, Zedong; Li, Qingbiao;
Ni, Hui; et al
Fungal infection has become a major threat to crop loss and affects food safety. The waste water from agar processing industries
extraction has a number of active substances, which could be further transformed by microor ganisms to synthesize antifungal
active substances. In this study, Bacillus subtilis was used to ferment the waste water from agar processing industries extraction to
analyze the antifungal activity of the fermentation broth on Alternaria alternata and Alternaria spp. Results showed that 25% of the
fermentation broth was the most effective in inhibited A. alternata and Alternaria spp., with fungal inhibition rates of 99.9% and
96.1%, resp., and a min. inhibitory concentration (MIC) was 0.156μg/mL. Metabolomic anal. showed that flavonoid polyph enols such
as coniferyl aldehyde, glycycoumarin, glycitin, and procya nidin A1 may enhance the inhibitory activity against the two pathogenic
fungal strains. Kyoto Encyclopedia of Genes and Genomes (K EGG) anal. showed that polyphenols involved in the biosyn thesis
pathways of isoflavonoid and phenylpropanoid were upregulated after fermen tation The laser confocal microscopy analyses and
cell conductivity showed that the cytoplasm of fungi treated with fermen tation broth was destroyed. This study provides a research
basis for the development of new natural antifungal agents and rational use of seaweed agar waste.
Keywords: Bacillus subtilis waste water agar processing metabolomic analysis; Alternaria alternata; Alternaria spp.; Antifungal
activity; Bacillus subtilis; Seaweed waste water
430
Green and environmentally friendly synthesis of silver nanoparticles with antibacterial properties
from some medicinal plants
By: Asefian, Samira; Ghavam, Mansureh

BMC Biotechnology (2024), 24(1), 5 | Language: English, Database: CAplus and MEDLINE
Abstract: Recently there have been a variety of methods to synthesize silver nanoparticles, among which the biosynthesis method is
more noticeable due to features like being eco-friendly, simple, and cost- efficient. The present study aims for the green synthesis of
silver nanoparticles from the extract of the three plants A. wilhelmsi, M. chamom illa, and C. longa; moreover, it pledges to measure
the antibacterial activity against some variants causing a skin rash. The morphol. and size of the synthe sized silver nanoparticles
were evaluated by UV.vis, XRD, SEM, and FTIR analyses. Then results showed a color alteration from light yellow to dark brown and
the formation of silver nanoparticles. The absorption peak with the wavelength of approx. 450 nm resulting from the Spectroph
otometry anal. confirmed the synthesis of silver nanoparticles. The presence of strong and wide peaks in F TIR indicated the
presence of OH groups. The SEM results showed that most synthe sized nanoparticles had a spherical angular structure and their
size was about 10 to 20 nm. The highest inhibition power was demonstrated by silver nanoparticles synthesized from the extract
combined from all three species against Gram-pos. bacteria Staphylococcus aureus and Staphylococcus epidermidis (23 mm) which
had a performance far more powerful than the extract Thus, it can be understood that the nanopar ticles synthesized from these
three species can act as potential environment-friendly alternatives to inhibit some variations causing skin disorders; an issue that
calls for further clin. studies.
Keywords: Anti-microbial activity; Extract; Green synthesis; Nanotechnology; Wound healing

431
Synthesis, characterization, Hirshfeld surface analysis, antioxidant and selective β-glucuronidase

inhibitory studies of transition metal complexes of hydrazide based Schiff base ligand
By: Farzia; Rehman, Sadia; Ikram, Muhammad; Khan, Adnan; Khan, Rizwan; Sinnokrot, Mutasem Omar; Khan, Momin; AlAsmari,
Abdullah F.; Alasmari, Fawaz; Alharbi, Metab
Abstract: The synthesis of N′-[(4-hydroxy-3-methoxyphenyl)methylidene] 2-aminobenzohydrazide (H-AHMB) was performed by

condensing O-vanillin with 2-aminobenzohydrazide and was characterized by FTIR, high resolution ESI(+) mass spectral anal., 1H and
13 C-NMR. The compound H-AHMB was crystallized in orthorhombic Pbca space group and studied for single crystal diffra ction anal.
Hirshfeld surface anal. was also carried out for identifying short interat. interactions. The major interactions H...H, O...H and C... H
cover the Hirshfeld surface of H-AHMB. The metal complexes [M(AHMB)n] where M = Co (II), Ni(II), Cu(II) and Zn(II) were prepared
from metal chlorides and H-AHMB ligand. The bonding was unambigously assigned using FTIR and UV/vis anal. The synthesized
ligand H-AHMB and its metal complexes were studied for β- glucuronidase enzyme inhibition . Surprisingly the metal complexes
were found more active than the parent ligand and even the standard drug. Zn-AHMB shown IC50 = 17.3 ± 0.68 μ M compared to I
C50 = 45.75 ± 2.16 μ M shown by D-saccharic acid-1,4-lactone used as standard The better activity by Zn- AHMB implying zinc based
metallodrug for the treatment of diseases associated with β- glucuronidase enzyme. The DPPH radical scavenging activities were
also studied for all the synthesized compounds The Co- AHMB complex with IC50 = 98.2 ± 1.78 μ M was the only candidate to
scavenge the DPPH free radicals.
432
Coculture of bacterial levans and evaluation of its anti-cancer activity against hepatocellular carcinoma
cell lines
By: Wahab, Walaa A. Abdel; Shafey, Heba I.; Mahrous, Karima F.; Esawy, Mona A.; Saleh, Shireen A. A.
Abstract: This research represents a novel study to assess how coculture affects levan yield, structure, bioactivities, and mol. weight
Among the 16 honey isolates, four bacterial strains recorded the highest levan yield. The Plackett-Burman design showed that the
coculture (M) of isolates G2 and K2 had the maximum levan yield (52 g/L) and the effective factors were sucrose, incubation time,
and sugarcane bagasse. The CCD showed that the most proper concent rations for maximum levan yield (81 g/L) : were 130 g/L of
sucrose and 6 g/f of sugarcane bagasse. Levan′s backbone was characterized, and the mol. weight was determined G2 and K2
isolates were identified based on 16 sRNA as Bacillus megaterium strain YM1C10 and Rhizobium sp. G6- 1. M levan had promising
antioxidant activity (99.66%), slowed the migration activity to a great extent, and recorded 70.70% inhibition against the hepatob
lastoma cell line (HepG2) at 1000 μg/mL. Gene expression anal. in liver cancer cell lines (He PG2) revealed that M levan decreased
the expression of CCL20), 2GRB2, and CCR6) genes and was superior to Doxo. While increasing the expression of the I L4R and IL-10
genes. The DNA damage values were significantly increased (P < 0.01) in treated liver cancer cell lines with levan M and Doxo. The
results referred to the importance of each of the hydroxyl and carboxyl groups and the mol. weight in levans bioactivities.

433
A novel complement C3 inhibitor CP40-KK protects against experimental pulmonary arterial

hypertension via an inflammasome NLRP3 associated pathway
By: Dai, Lei; Chen, Yu; Wu, Jinhua; He, Zhen; Zhang, Yueqi; Zhang, Wenjun; Xie, Yang; Zeng, Hesong ; Zhong, Xiaodan
Abstract: Background: Pulmonary arterial hypert ension (PAH) is a severe cardiopulmonary disease characterized by complement
dependent and proinflammatory activation of macrophages. However, effective treatment for complement activation in P AH is
lacking. We aimed to explore the effect and mechanism of CP40-KK (a newly identified analog of selective complement C3 inhibitor
CP40) in the PAH model. Methods: We used western blotting, immunohis tochem., and immunofluorescence staining of lung tissues
from the monocrotaline (MCT)-induced rat PAH model to study macrophage infiltration, NLPR3 inflammasome activation, and
proinflammatory cytokines (IL-1β and IL-18) release. Surface plasmon resonance (S PR), ELISA, and CH50 assays were used to test
the affinity between CP40-KK and rat/human complement C3. C P40-KK group rats only received C P40-KK (2 mg/kg) by s.c. injection
at day 15 to day 28 continuously. Results: C3a was signifi cantly upregulated in the plasma of M CT-treated rats. S PR, ELISA, and CH50
assays revealed that CP40-KK displayed similar affinity binding to human and rat complement C3. Pharmacol. inhibition of
complement C3 cleavage (CP40-KK) could ameliorate M CT-induced NLRP3 inflammasome activity, pulmonary vascular remode ling,
and right ventricular hypertrophy. Mechanistically, increased proliferation of pulmonary arterial smooth muscle cells is closely
associated with macrophage infiltration, NLPR3 inflammasome activation, and proinflammatory cytokines (IL-1β and IL-18) release.
Besides, C3a enhanced IL-1β activity in macrophages and promoted pulmonary arterial smooth muscle cell prolife ration in vitro.
Conclusion: Our findings suggest that C P40-KK treatment was protective in the M CT-induced rat PAH model, which might serve as a
therapeutic option for P AH.
Keywords: CP40-KK; Complement C3; N LRP3; Proinflammatory cytokine; Pulmonary arterial hypert ension
434
The clarithromycin-binding proteins NIPSNAP1 and 2 regulate cytokine production through

mitochondrial quality control
By: Yamamoto, Soh; Ogasawara, Noriko; Mitsuhashi, Yukari; Takano, Kenichi; Yokota, Shin-ichi
Abstract: The mechanism underlying the anti-inflammatory effect of macrolide antibi otics, such as clarithromycin (CAM), remains to
be clarified. The CAM-binding proteins 4-nitrophenylphosphatase domain and non-neuronal synaptosomal associated protein 25 (S
NAP25)-like protein homolog (N IPSNAP) 1 and 2 are involved in the immune response and mitocho ndrial homeostasis. However,
the axis between CAM-NIPSNAP-mitochondria and Toll- like receptor (TLR) and their mol. mechanisms remain unknown. In this
study, we sought to elucidate the relationship between mitochondrial homeostasis mediated by N IPSNAP1 and 2 and the
immunomodulatory effect of C AM. NIPSNAP1 or 2 knockdown (KD) by RNA interference impaired TLR4-mediated interleukin-8 (IL-8)
production Similar impairment was observed upon treatment with mitochondrial function inhibitors. However, IL-8 secretion was
not impaired in NIPSNAP1 and 2 individual knockout (KO) and double K O (DKO) cells. Moreover, the oxygen consum ption rate (OC
R) in mitochondria measured using a flex analyzer was signifi cantly reduced in N IPSNAP1 or 2 KD cells, but not in D KO cells. CAM
also dose-dependently reduced the OCR. These results indicate that C AM suppresses the I L-8 production via the mitochondrial
quality control regulated by temporary functional inhibition of NIPSNAP1 and 2. Our findings provide new insight into the
mechanisms underlying cytokine production, including the TLR-mitochondria axis, and the immunomo dulatory effects of macrol
ides.

435
Transcriptomic and physiological analysis of the response of Spirodela polyrrhiza to sodium

nitroprusside
By: Zhang, Yamei; Jia, Rong; Hui, Tanyue; Hu, Yue; Wang, Wenjing; Wang, Yi; Wang, Yong; Zhu, Yerong; Yang, Lin; Xiang, Beibei
Abstract: Background: Spirodela polyrrhiza is a simple floating aquatic plant with great potential in synthetic biol. Sodium nitropr
usside (SNP) stimulates plant develo pment and increases the biomass and flavonoid content in some plants. However, the mol.
mechanism of SNP action is still unclear. Results: To determine the effect of S NP on growth and metabolic flux in S. polyrr hiza, the
plants were treated with different concentrations of SNP. Our results showed an inhibition of growth, an increase in starch, soluble
protein, and flavonoid contents, and enhanced antioxidant enzyme activity in plants after 0.025 m M SNP treatment. Differentially
expressed transcripts were analyzed in S. polyrrhiza after 0.025 m M SNP treatment. A total of 2776 differe ntially expressed genes
(1425 upregulated and 1351 downreg ulated) were identified. The expression of some genes related to flavonoid biosyn thesis and N
O biosynthesis was upregulated, while the expression of some photosynthesis-related genes was downregulated. Moreover, SNP
stress also significantly influenced the expression of transcription factors (TFs), such as ERF, BHLH, NAC, and WRKY TFs. Conclu
sions: Taken together, these findings provide novel insights into the mechanisms of underlying the S NP stress response in S.
polyrrhiza and show that the metabolic flux of fixed CO2 is redirected into the starch synthesis and flavonoid biosyn thesis pathways
after SNP treatment.
Keywords: Metabolic flux; Sodium nitroprusside; Spirodela polyrr hiza; Synthetic biology

436
Extracellular vesicles involved in growth regulation and metabolic modulation in Haematococcus

pluvialis
By: Hu, Qunju; Hu, Zhangli; Yan, Xiaojun; Lu, Jun; Wang, Chaogang
Abstract: Background: Microalgae-derived extracellular vesicles (E Vs), which transfer their cargos to the extrace llular environment
to affect recipient cells, play important roles in microalgal growth and environmental adaptation. And, they are also considered as
sustainable and renewable biores ources of delivery nanocarrier for bioactive mols. and/or artificial drug mols. However, their mol.
composition and functions remain poorly unders tood. Results: In this study, isolation, character ization, and functional verification
of Haematococcus pluvialis-derived EVs (HpEVs) were performed. The results indicated that Hp EVs with typical E V morphol. and
size were secreted by H. pluvialis cells during the whole period of growth and accumulated in the culture medium. Cellular uptake
of HpEVs by H. pluvialis was confirmed, and their roles in regulation of growth and various physiol. processes of the recipient cells
were also characterized. The short-term inhibition of HpEV secretion results in the accumulation of functional cellular components
of HpEVs, thereby altering the biol. response of these cells at the mol. level. Meanwhile, contin uously inhibiting the secretion of HpE
Vs neg. influenced growth, and fatty acid and astaxa nthin accumulation in H. pluvialis. Small R NA high-throughput sequencing was
further performed to determine the miRNA cargoes and compelling details in Hp EVs in depth. Comparative anal. revealed
commonalities and differences in mi RNA species and expression levels in three stages of Hp EVs. A total of 163 mature mi RNAs
were identified with a few unique miRNAs reveal the highest expression levels, and mi RNA expression profile of the HpEVs
exhibited a clear stage-specific pattern. Moreover, a total of 12 differe ntially expressed miRNAs were identified and their target
genes were classified to cell cycle control, lipid transport and metabolism, secondary metabolites biosynthesis and so on. Conclu
sion: It was therefore proposed that cargos of Hp EVs, including miRNA constituents, were suggested potential roles in modulate cell
physiol. state of H. pluvialis. To summarize, this work uncovers the intercellular communication and metabolism regulation
functions of HpEVs.
Keywords: Extracellular vesicles; Functional analysis; Haematococcus pluvialis; Metabolite biosynthesis; microRNA

437
The senescent mesothelial matrix accentuates colonization by ovarian cancer cells
By: Thapa, Bharat Vivan; Banerjee, Mallar; Glimm, Tilmann; Saini, Deepak K.; Bhat, Ramray
Abstract: Ovarian cancer is amongst the most morbid of gynecol. malignancies due to its diagnosis at an advanced stage, a transco
elomic mode of metastasis, and rapid transition to chemothe rapeutic resistance. Like all other maligna ncies, the progression of
ovarian cancer may be interpreted as an emergent outcome of the conflict between metasta sizing cancer cells and the natural
defense mounted by microenvironmental barriers to such migration. Here, we asked whether senescence in coelom- lining mesoth
elia, brought about by drug exposure, affects their intera ction with disseminated ovarian cancer cells. We observed that cancer cells
adhered faster on senescent human and murine mesothelial monolayers than on non-senescent controls. Time- lapse epifluor
escence microscopy showed that mesoth elial cells were cleared by a host of cancer cells that surrounded the former, even under
sub-confluent conditions. A multiscale computational model predicted that such colocalized mesothelial clearance under sub-
confluence requires greater adhesion between cancer cells and senescent mesoth elia. Consistent with the prediction, we observed
that senescent mesothelia expressed an extracellular matrix with higher levels of fibron ectin, laminins and hyaluronan than non-
senescent controls. On senescent matrix, cancer cells adhered more effici ently, spread better, and moved faster and persist ently,
aiding the spread of cancer. Inhibition assays using R GD cyclopeptides suggested the adhesion was predominantly contributed by
fibronectin and laminin. These findings led us to propose that the senesc ence-associated matrisomal phenotype of peritoneal
barriers enhances the colonization of invading ovarian cancer cells contri buting to the metastatic burden associated with the
disease.
Keywords: Chemotherapy; Extracellular matrix; Mesothelia; Multiscale modeling; Ovarian cancer; Senescence
438
Anti-staphylococcal activity of soilless cultivated cannabis across the whole vegetation cycle under
various nutritional treatments in relation to cannabinoid content
By: Malikova, Lucie; Malik, Matej; Pavlik, Jan; Ulman, Milos; Pechouckova, Eva; Skrivan, Milos; Kokoska, Ladislav; Tlustos, Pavel
Abstract: Antibiotic resistance in staphylococcal strains and its impact on public health and agricu lture are global problems. The
development of new anti-staphylococcal agents is an effective strategy for addressing the increasing incidence of bacterial resist
ance. In this study, ethanolic extracts of Cannabis sativa L. made from plant parts harvested during the whole vegetation cycle
under various nutritional treatments were assessed for in vitro anti- staphylococcal effects. The results showed that all the cannabis
extracts tested exhibited a certain degree of growth inhibition against bacterial strains of Staphyl ococcus aureus, including antibi
otic-resistant and antibiotic-sensitive forms. The highest antibac terial activity of the extracts was observed from the 5th to the 13th
week of plant growth across all the nutritional treatments tested, with min. inhibitory concent rations ranging from 32 to 64 μg/m L.
Using HPLC, Δ9-tetrahydrocannabinolic acid (T HCA) was identified as the most abundant cannab inoid in the ethanolic extracts A
homolog of THCA, tetrahydrocannabivarinic acid (THCVA), reduced bacterial growth by 74%. These findings suggest that the
cannabis extracts tested in this study can be used for the development of new anti-staphylococcal compounds with improved
efficacy.

439
The Temozolomide-Doxorubicin paradox in Glioblastoma in vitro-in silico preclinical drug-screening
By: Oraiopoulou, Mariam-Eleni; Tzamali, Eleftheria; Psycharakis, Stylianos E.; Tzedakis, Georgios; Makatounakis, Takis; Manolitsi,
Katina; Drakos, Elias; Vakis, Antonis F.; Zacharakis, Giannis; Papamatheakis, Joseph; et al
Abstract: Adjuvant Temozolomide is considered the front-line Glioblastoma chemotherapeutic treatment; yet not all patients
respond. Latest trends in clin. trials usually refer to Doxorubicin; yet it can lead to severe side- effects if administered in high doses.
While Glioblastoma prognosis remains poor, little is known about the combin ation of the two chemotherapeutics. Patient-derived
spheroids were generated and treated with a range of Temozolomide/Doxorubicin concentrations either as monotherapy or in
combination. Optical microscopy was used to monitor the growth pattern and cell death. Based on the monoth erapy experiments,
we developed a probabilistic math. framework in order to describe the drug-induced effect at the single-cell level and simulate drug
doses in combination assuming probabilistic independence. Doxorubicin was found to be effective in doses even four orders of
magnitude less than Temozolomide in monotherapy. The combination therapy doses tested in vitro were able to lead to irreve rsible
growth inhibition at doses where monoth erapy resulted in relapse. In our simula tions, we assumed both drugs are antimitotic;
Temozolomide has a growth- arrest effect, while Doxorubicin is able to cumulatively cause necrosis. Interes tingly, under no mechan
istic synergy assumption, the in silico predictions underestimate the in vitro results. In silico models allow the explor ation of a
variety of potential underlying hypotheses. The simulated-biol. discrepancy at certain doses indicates a supra- additive response
when both drugs are combined. Our results suggest a Temozolomide-Doxorubicin dual chemotherapeutic scheme to both disable
proliferation and increase cytotoxicity against Glioblastoma.
Keywords: Brain cancer; Computational models; Doxoru bicin; Preclinical drug-screening; Temozolomide
440
In vitro influence of PEG functionalized ZnO-CuO nanocomposites on bacterial growth
By: Jayanetti, Madara; Thambiliyagodage, Charitha; Liyanaarachchi, Heshan; Ekanayake, Geethma; Mendis, Amavin; Usgodaarachchi,
Leshan
Abstract: Polyethyleneglycol-coated biocompatible CuO-ZnO nanocomposites were fabricated hydrothermally varying Zn:Cu ratios
as 1:1, 2:1, and 1:2, and their antibacterial activity was determined through the well diffusion method against the Gram-neg. Escher
ichia coli, Pseudo monas aeruginosa, Klebsiella pneumoniae, and the Gram-pos. Staphylococcus aureus. The min. inhibitory concent
ration and the min. bacter icidal concentration values of the synthesized samples were determined Subsequently, the time synergy
kill assay was performed to elucidate the nature of the overall inhibitory effect against the aforementioned bacterial species. The
mean zone of inhibition values for all four samples are presented. The inhibitory effect increased with increasing concent ration of
the nanocomposite (20, 40 and 60 mg/m L) on all the bacterial species except for S. aureus. According to the M BC/MIC ratio, Zn O
was found to be bacteriostatic for E. coli and P. aerugi nosa, and bacter icidal for S. aureus and K. pneumo niae. Zn:Cu 2:1 was bacter
icidal on all bacterial species. A bacteri ostatic effect was observed on E. coli and P. aeruginosa in the presence of Zn: Cu 1:1 whereas,
it showed a bactericidal effect on S. aureus and K. pneumo niae. Zn:Cu 1:2 exhibited a bacteri ostatic effect on E. coli while a bacter
icidal effect was observed for E. coli, P. aerugi nosa, and K. pneumoniae. The metal oxide nanocom posites were found to be more
sensitive towards the Gram-pos. strain than the Gram-neg. strains. Further, all the nanocom posites possess anti-oxidant activity as
shown by the DPPH assay.

441
High-throughput screening assay for PARP-HPF1 interaction inhibitors to affect DNA damage repair
By: Dhakar, Saurabh S.; Galera-Prat, Albert; Lehtio, Lari

Abstract: ADP-ribosyltransferases PARP1 and PARP2 play a major role in D NA repair mechanism by detecting the D NA damage and
inducing poly-ADP-ribosylation dependent chromatin relaxation and recruitment of repair proteins. Catalytic PARP inhibitors are
used as anticancer drugs especially in the case of tumors arising from sensitizing mutations. Recently, a study showed that Histone
PARylation Factor (HPF1) forms a joint active site with P ARP1/2. The interaction of HPF1 with PARP1/2 alters the modification site
from Aspartate/Glutamate to Serine, which has been shown to be a key A DP-ribosylation event in the context of D NA damage.
Therefore, disruption of PARP1/2-HPF1 interaction could be an alternative strategy for drug develo pment to block the PARP1/2
activity. In this study, we describe a FRET based high-throughput screening assay to screen inhibitor libraries against P ARP-HPF1
interaction. We optimized the conditions for F RET signal and verified the intera ction by competing the FRET pair in multiple ways.
The assay is robust and easy to automate. Validatory screening showed the robust performance of the assay, and we discovered
two compounds Dimethylacrylshikonin and Alkannin, with μ M inhibition potency against PARP1/2-HPF1 interaction. The assay will
facilitate the discovery of inhibitors against HPF1-PARP1/2 complex and to develop potent ially new effective anticancer agents.
442
The androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell
phenotype in breast cancer
By: Hosseinzadeh, Leila; Kikhtyak, Zoya; Laven-Law, Geraldine; Pederson, Stephen M.; Puiu, Caroline G.; D′Santos, Clive S.; Lim,
Elgene; Carroll, Jason S.; Tilley, Wayne D.; Dwyer, Amy R.; et al
Genome Biology (2024), 25(1), 44 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: The androgen receptor (A R) is a tumor suppressor in estrogen receptor (E R) pos. breast cancer, a role
sustained in some ER neg. breast cancers. Key factors dictating A R genomic activity in a breast context are largely unknown. Herein,
we employ an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-
regulatory proteins in ER pos. and neg. models of breast cancer to gain new insight into mechanisms of A R signaling in this disease.
Results: The DNA-binding factor GATA3 is identified and validated as a novel A R interacting protein in breast cancer cells irresp. of E
R status. AR activation by the natural ligand 5α- dihydrotestosterone (DHT) increases nuclear A R-GATA3 interactions, resulting in A R-
dependent enrichment of GATA3 chromatin binding at a subset of genomic loci. Silencing G ATA3 reduces but does not prevent A R
DNA binding and transactivation of genes associated with A R/GATA3 co-occupied loci, indicating a co- regulatory role for GATA3 in A
R signaling. DHT-induced AR/GATA3 binding coincides with upregu lation of luminal differen tiation genes, including E HF and KDM4B,
established master regulators of a breast epithelial cell lineage. These findings are validated in a patient- derived xenograft model of
breast cancer. Interaction between AR and GATA3 is also associated with A R-mediated growth inhibition in ER pos. and ER neg.
breast cancer. Conclusions: AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differen tiation in breast
cancer regardless of ER status. This interaction facilitates the tumor suppressor function of A R and mechanis tically explains why A R
expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer.
Keywords: Androgen receptor; Breast; GATA3; Luminal lineage

443
Cell-permeable PI3 kinase competitive peptide inhibits KIT mutant mediated tumorigenesis of
gastrointestinal stromal tumor (GIST)
By: Jiang, Zongying; Guo, Yue; Shi, Jun; Zhang, Shaoting; Zhang, Liangying; Wang, Yapeng; Li, Guofu; Bai, Ru; Zhao, Hui; Sun, Jianmin
Abstract: Background: Mutations in the receptor tyrosine kinase K IT are the main cause of gastroin testinal stromal tumor (GIST),
and the KIT mutants mediated P I3 kinase activation plays a key role in the tumorig enesis of GIST. In this study, we aimed to block P
I3 kinase activation by cell- permeable peptide and invest igate its possible applic ation in the treatment of GIST. Methods and results:
We designed cell-permeable peptides based on the binding domain of P I3 kinase subunit p85 to K IT or PI3 kinase subunit p110,
resp., in order to compete for the binding between p85 and KIT or p110 and therefore inhibit the activation of P I3 kinases mediated
by KIT. The results showed that the peptide can penetrate the cells, and inhibit the activation of P I3 kinases, leading to reduced cell
survival and cell proliferation mediated by K IT mutants in vitro. Treatment of mice carrying germline K IT/V558A mutation, which can
develop GIST, with the peptide that can compete for the binding between p85 and p110, led to reduced tumorig enesis of GIST. The
peptide can further enhance the inhibition of the tumor growth by imatinib which is used as the first line targeted therapy of G IST.
Conclusions: Our results showed that cell- permeable PI3 kinase competitive peptide can inhibit K IT-mediated PI3 kinase activation
and tumorigenesis of GIST, providing a rationale to further test the peptide in the treatment of G IST and even other tumors with
over-activation of PI3 kinases.
Keywords: Competitive peptide; GIST; KIT; PI3 kinase

444
TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer
progression
By: Zhang, Yu; Huang, Zhenlin; Li, Keqiang; Xie, Guoqing; Feng, Yuankang; Wang, Zihao; Li, Ningyang; Liu, Ruoyang; Ding, Yinghui;
Wang, Jun; et al
Abstract: Background: As a novel necrosis manner, ferrop tosis has been increasingly reported to play a role in tumor progre ssion
and treatment, however, the specific mechanisms underlying its development in prostate cancer remain unclear. Growing evidence
showed that peroxisome plays a key role in ferroptosis. Herein, we identified a novel mechanism for the involv ement of ferroptosis
in prostate cancer progression, which may provide a new strategy for clin. treatment of prostate cancer. Methods: Label- Free Mass
spectrometry was used to screen and identify candidate proteins after ferrop tosis inducer-ML210 treatment. Immunohistochem.
was undertaken to explore the protein expression of AGPS in prostate cancer tissues compared with normal tissues. Co-
immunoprecipitation and GST pull-down were used to identify the directly binding of A GPS to MDM2 in vivo and in vitro. C CK8
assay and colony formation assay were used to illustrate the key role of AGPS in the progression of prostate cancer in vitro. The
xenograft model was established to verify the key role of A GPS in the progression of prostate cancer in vivo. Results: A GPS protein
expression was downregulated in prostate cancer tissues compared with normal tissues from the first affiliated hospital of
Zhengzhou University dataset. Lower expression was correlated with poorer overall survival of patients compared to those with
high expression of AGPS. In addition, AGPS can promote ferrop tosis by modulating the function of peroxi some-resulting in the
lower survival of prostate cancer cells. Furthermore, it was shown that AGPS can be ubiquitinated and degraded by the E3 ligase- MD
M2 through the proteasomal pathway. Meanwhile, kinase Trk A can promote the combin ation of AGPS and M DM2 by phosphor
ylating AGPS at Y451 site. It was verified that kinase Trk A inhibitor-Larotrectinib can increase the suscept ibility of prostate cancer
cells to ferroptosis, which leads to the inhibition of prostate cancer proliferation to a great extent in vitro and in vivo. Conclu sion:
Based on these findings, we proposed the combination of ferroptosis inducer and TrkA inhibitor to synergistically exert anti-tumor
effects, which may provide a new strategy for the clin. treatment of prostate cancer.
Keywords: AGPS; Ferroptosis; MDM2; Prostate cancer; TrkA

445
GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression
By: Kang, Hong Soon; Grimm, Sara A.; Liao, Xiao-Hui; Jetten, Anton M.
Abstract: Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothy roidism (CH). In this study, we
demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid develo pment, a time at which GLIS3 target genes, such
as Slc5a5 (Nis), become expressed. This, together with observ ations showing that ubiquitous Glis3KO mice do not display major
changes in prenatal thyroid gland morphol., indicated that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid
dysgenesis. Anal. of GLIS3 in postnatal thyroid suggested a link between G LIS3 protein expression and blood T SH levels. This was
supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constit utively active PKA
enhanced GLIS3 protein stability and transcri ptional activity, indicating that GLIS3 activity is regulated at least in part by T SH/TSHR-
mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3
target gene expression, including several thyroid hormone (T H) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine
diet (LID) when blood T SH levels are highly elevated. Like T H biosynthetic genes, the expression of cell cycle genes is suppressed in
ubiquitous Glis3KO mice fed a L ID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not
repressed, in contrast to TH biosynthetic genes. This indicated that the inhibition of cell cycle genes in ubiquitous Glis3 KO mice is
dependent on changes in gene expression in GLIS3 target tissues other than the thyroid.
Keywords: GLIS3; Hypothyroidism; PKA; TSH signaling; Thyroid development; Thyroid follicular cell prolife ration; Thyroid hormone
biosynthesis

446
High molecular/low acetylated chitosans reduce adhesion of Campylobacter jejuni to host cells by
blocking JlpA
By: Kreling, Vanessa; Falcone, Franco H.; Herrmann, Fabian; Kemper, Leon; Amiteye, Daniel; Cord-Landwehr, Stefan; Kehrenberg,
Corinna; Moerschbacher, Bruno M.; Hensel, Andreas
Abstract: Infections caused by Campylobacter spp. are a major cause of severe enteritis worldwide. Multifa ctorial prevention
strategies are necessary to reduce the prevalence of Campylobacter. In particular, antiadhesive strategies with specific inhibitors of
early host-pathogen interaction are promising approaches to reduce the bacterial load. An in vitro flow cytometric adhesion assay
was established to study the influence of carbohy drates on the adhesion of C. jejuni to Caco- 2 cells. Chitosans with a high d.p. and
low degree of acetylation were identified as potent antiadhesive compounds, exerting significant reduction of C. jejuni adhesion to
Caco-2 cells at non-toxic concentrations Antiadhesive and also anti-invasive effects were verified by confocal laser scanning micros
copy. For target identification, C. jejuni adhesins Flp A and JlpA were expressed in Escherichia coli ArcticExpress, and the influence of
chitosan on binding to fibronectin and HSP90α, resp., was investigated. While no effects on FlpA binding were found, a strong
inhibition of JlpA-HSP90α binding was observed To simulate real- life conditions, chicken meat was inoculated with C. jejuni, treated
with antiadhesive chitosan, and the bacterial load was quantified. A strong reduction of C. jejuni load was observed Atomic force
microscopy revealed morphol. changes of C. jejuni after 2 h of chitosan treatment, indicating disturbance of the cell wall and sacculi
formation by electrostatic interaction of pos. charged chitosan with the neg. charged cell surface. In conclu sion, our data indicate
promising antiadhesive and anti-invasive potential of high mol. weight, strongly de- acetylated chitosans for reducing C. jejuni load
in livestock and food production Key points: • Antiadhesive effects of chitosan with high DP/low DA against C. jejuni to host cells •
Specific targeting of JlpA/Hsp90α interaction by chitosan • Meat treatment with chitosan reduces C. jejuni load
Keywords: Adhesion; Atomic force microscopy; Campylobacter jejuni; Chitosan; Jlp A; Sacculus

447
TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative
inflammatory breast cancer
By: Lynce, Filipa; Stevens, Laura E.; Li, Zheqi; Brock, Jane E.; Gulvady, Anushree; Huang, Ying; Nakhlis, Faina; Patel, Ashka; Force,
Jeremy M.; Haddad, Tufia C.; et al
Abstract: Background: Patients with inflam matory breast cancer (I BC) have overall poor clin. outcomes, with triple- neg. IBC (TN-IBC)
being associated with the worst survival, warranting the investigation of novel therapies. Preclin. studies implied that ruxoli tinib (RU
X), a JAK1/2 inhibitor, may be an effective therapy for T N-IBC. Methods: We conducted a randomized phase I I study with nested
window-of-opportunity in TN-IBC. Treatment-naive patients received a 7- day run-in of RUX alone or RUX plus paclitaxel (P AC). After
the run-in, those who received R UX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 wk; those
who had received RUX + PAC continued treatment for 12 wk. All patients subseq uently received 4 cycles of doxoru bicin plus
cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre- run-in) and after run-in therapy.
Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunost aining, and a subset was also analyzed by R NA-seq. The
primary endpoint was the percent of pSTAT3-pos. pre-run-in tumors that became p STAT3-neg. Secondary endpoints included
pathol. complete response (pCR). Results: Overall, 23 patients were enrolled, of whom 21 completed preope rative therapy. Two
patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post- run-in biopsies of RUX-treated samples, while
sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to R UX alone. Both treatments decreased G Z
MB+ T cells implying immune suppre ssion. RUX alone effectively inhibited JAK/STAT3 signaling but its combin ation with PAC led to
incomplete inhibition . The immune suppre ssive effects of RUX alone and in combin ation may negate its growth inhibitory effects
on cancer cells. Conclusion: In summary, the use of RUX in TN-IBC was associated with a decrease in p STAT3 levels despite lack of
clin. benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further
evaluation of JAK2/STAT3 signaling as a cancer therap eutic target. Trial registr ation: www.clinicaltrials.gov, NCT02876302. Registered
23 August 2016.
Keywords: Inflammatory breast cancer; Neoadj uvant; Paclitaxel; Ruxolitinib; Triple negative

448
Targeting tumor-stromal interactions in triple-negative breast cancer using a human vascularized

micro-tumor model
By: Hachey, Stephanie J.; Hatch, Christopher J.; Gaebler, Daniela; Mocherla, Aneela; Nee, Kevin; Kessenbrock, Kai; Hughes,
Christopher C. W.
Abstract: Triple-neg. breast cancer (T NBC) is highly aggressive with limited available treatm ents. Stromal cells in the tumor
microenvironment (TME) are crucial in TNBC progression; however, underst anding the mol. basis of stromal cell activation and
tumor-stromal crosstalk in T NBC is limited. To invest igate therapeutic targets in the T NBC stromal niche, we used an advanced
human in vitro microphysiol. system called the vascularized micro-tumor (VMT). Using single-cell RNA sequencing, we revealed that
normal breast tissue stromal cells activate neoplastic signaling pathways in the TNBC TME. By comparing interactions in VMTs with
clin. data, we identified therapeutic targets at the tumor- stromal interface with potential clin. signifi cance. Combining treatments
targeting Tie2 signaling with paclitaxel resulted in vessel normalization and increased efficacy of paclitaxel in the T NBC VMT. Dual
inhibition of HER3 and Akt also showed efficacy against T NBC. These data demons trate the potential of inducing a favorable T ME
as a targeted therapeutic approach in T NBC.
Keywords: Microphysiologic system; Triple-negative breast cancer; Tumor microenv ironment
449
Discovery of psoralen as a quorum sensing inhibitor suppresses Pseudomonas aeruginosa virulence
By: Wen, Fulong; Wu, Yi; Yuan, Yang; Yang, Xiting; Ran, Qiman; Gan, Xiongyao; Guo, Yidong; Wang, Xinrong; Chu, Yiwen; Zhao, Kelei
Abstract: Pseudomonas aeruginosa is a common opportu nistic pathogen with growing resistance and presents heightened
treatment challenges. Quorum sensing (QS) is a cell-to-cell communication system that contributes to the production of a variety of
virulence factors and is also related to biofilm formation of P. aeruginosa. Compared to traditional antibiotics which kill bacteria
directly, the anti-virulence strategy by targeting Q S is a promising strategy for combating pseudo monal infections. In this study, the
QS inhibition potential of the compounds derived from the Tradit ional Chinese Medicines was evaluated by using in silico, in vitro,
and in vivo analyses. The results showed that psoralen, a natural furocoumarin compound derived from Psoralea coryli folia L., was
capable of simultaneously inhibiting the three main Q S regulators, LasR, RhlR, and PqsR of P. aeruginosa. Psoralen had no bacter
icidal activity but could widely inhibit the production of extrace llular proteases, pyocyanin, and biofilm, and the cell motilities of the
model and clin. P. aeruginosa strains. RNA-sequencing and quant. PCR analyses further demons trated that a majority of Q S-
activated genes in P. aeruginosa were suppressed by psoralen. The suppleme ntation of psoralen could protect Caenorh abditis
elegans from P. aeruginosa challenge, especially for the hypervirulent strain PA14. Moreover, psoralen showed synerg istic antibac
terial effects with polymyxin B, levofloxacin, and kanamycin. In conclusions, this study identifies the anti- QS and antibiofilm effects
of psoralen against P. aeruginosa strains and sheds light on the discovery of anti-pseudomonal drugs among Traditional Chinese
Medicines. Key points: • Psoralen derived from Psoralea corylifolia L. inhibits the virulence- related phenotypes of P. aeruginosa. •
Psoralen simultaneously targets the three core regulators of P. aeruginosa Q S system and inhibits the expression of a large part of
downstream genes. • Psoralen protects C. elegans from P. aeruginosa challenge and enhances the susceptibility of P. aeruginosa to
antibiotics.
Keywords: Drug combination; Functional profiling; Pseudo monas aeruginosa; Psoralen; Quorum sensing inhibitor; Tradit ional
Chinese Medicine

450
Microbial host engineering for sustainable isobutanol production from renewable resources
By: Nawab, Said; Zhang, YaFei; Ullah, Muhammad Wajid; Lodhi, Adil Farooq; Shah, Syed Bilal; Rahman, Mujeeb Ur; Yong, Yang-Chun
Abstract: Due to the limited resources and environmental problems associated with fossil fuels, there is a growing interest in
utilizing renewable resources for the production of biofuels through microbial fermentation Isobutanol is a promising biofuel that
could potentially replace gasoline. However, its production efficiency is currently limited by the use of naturally isolated microorg
anisms. These naturally isolated microor ganisms often encounter problems such as a limited range of substr ates, low tolerance to
solvents or inhibitors, feedback inhibition , and an imbalanced redox state. This makes it difficult to improve their production
efficiency through traditional process optimization methods. Fortunately, recent advancements in genetic engineering technologies
have made it possible to enhance microbial hosts for the increased production of isobutanol from renewable resources. This review
provides a summary of the strategies and synthetic biol. approaches that have been employed in the past few years to improve
naturally isolated or non-natural microbial hosts for the enhanced production of isobutanol by utilizing different renewable
resources. Furthermore, it also discusses the challenges that are faced by engineered microbial hosts and presents future perspe
ctives to enhancing isobutanol production Key points: • Promising potential of isobutanol to replace gasoline • Engine ering of native
and non-native microbial host for isobutanol production • Challenges and opportu nities for enhanced isobutanol production
Keywords: Biofuel production; Genetic engineering; Isobutanol; Microbial hosts; Synthetic pathway
451
MiR-320a upregulation contributes to the effectiveness of pemetrexed by inhibiting the growth and
invasion of human lung cancer cell line (Calu-6)
By: Ghorbani Alvanegh, Akbar; Arpanaei, Ayyoob; Esmaeili Gouvarchin Ghaleh, Hadi; Mohammad Ganji, Shahla
Abstract: Background: Lung cancer is a common and deadly disease. Chemot herapy is the most common treatment, which inhibits
cancer cell growth. Pemetrexed (PMX) is often used with other drugs. Environ mental stress can affect regulatory non- coding RNAs
such as MicroRNAs that modify gene expres sion. This study invest igates the effect of PMX on the hsa-miR-320a-3p expression in
the Calu-6 lung cancer cell line. Methods and result: Calu- 6 cells were cultured in an incubator with 37 °C, 5% C O2, and 98%
humidity. The MTT test was performed to determine the concent ration of PMX required to inhibit 50% of cell growth. To examine
growth inhibition and apoptosis, release of lactate dehydro genase (LDH), cell assays and caspase 3 and 7 enzyme activity were
used. Finally, mol. studies were conducted to compare the expression of hsa-miR-320a-3p and genes including V DAC1, DHFR, STAT3,
BAX and BCL2 before and after therapy. Results: According to a study, it has been observed that P MX therapy significantly increases
LDH release after 24 h. The study found that P MX′s IC50 on Calu-6 is 8.870 μ M. In addition, the treated sample showed higher
expression of hsa-miR-320a-3p and BAX, while the expression of VDAC1, STAT3, DHFR and BCL2 decreased compared to the control
sample. Conclusion: According to the findings of the current research, hsa- miR-320a-3p seems to have the potential to play an
important role in the development of novel approaches to the treatment of lung cancer.
Keywords: Calu-6; Hsa-miR-320a-3p; Lung cancer; Pemetrexed

452
4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) alleviates lung injury by inhibiting SIRT6-HIF-

1α signaling pathway activation through the upregulation of miR-212-5p expression
By: Ai, Li; Li, Ran; Cao, Yu; Liu, Zhijuan; Niu, Xiaoqun; Li, Yongxia
Abstract: Objective: Obstructive sleep apnea is closely related to oxidative stress. 4- hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl
(Tempol) can scavenge reactive oxygen species (ROS) and ameliorate oxidative damage in the body. The mechanism by which
Tempol alleviates chronic intermittent hypoxia-induced lung injury has rarely been reported. This study aimed to confirm the mol.
mechanism by which Tempol alleviates lung injury. Methods: The levels of miR-212-5p and Sirtuin 6 (S IRT6) in injured lungs were
analyzed using bioinformatics. In vitro, intermittent hypoxia (IH) treatment induced hypoxia in BEAS-2B cells and we established a
model of chronic intermittent hypoxia (CIH) in mouse using a programmed hypoxia chamber. We used H E staining to observe the
morphol. of lung tissue, and the changes in lung fibers were observed by Masson staining. The levels of inflammatory factors in
mouse serum were detected by ELISA, and the levels of the oxidative stress indicators G SH, MDA, SOD and ROS were detected
using com. available kits. Moreover, a real-time qPCR assay was used to detect mi R-212-5p expression, and Western blotting was
used to detect the levels of SIRT6, HIF-1α and apoptosis-related proteins. CCK-8 was used to detect cell prolife ration. Subsequently,
we used flow cytometry to detect cell apoptosis. Dual-luciferase gene reporters determine the on- target binding relationship of miR-
212-5p and S IRT6. Results: SIRT6 was highly expressed in C IH-induced lung injury, as shown by bioinformatics anal.; however, mi R-
212-5p expression was decreased. Tempol promoted mi R-212-5p expression, and the levels of S IRT6 and HIF-1α were inhibited. In
BEAS-2B cells, Tempol also increased proliferation, inhibited apoptosis and inhibited oxidative stress in B EAS-2B cells under IH
conditions. In BEAS-2B cells, these effects of Tempol were reversed after transf ection with an miR-212-5p inhibitor. mi R-212-5p
targeted and neg. regulated the level of SIRT6 and overexpression of SIRT6 effectively reversed the enhanced influence of the mi R-
212-5p mimic on Tempol′s antiox idant activity. Tempol effectively ameliorated lung injury in C IH mice and inhibited collagen
deposition and inflammatory cell infiltr ation. Likewise, the therapeutic effect of Tempol could be effect ively reversed by interference
with the miR-212-5p inhibitor. Conclu sion: Inhibition of the SIRT6-HIF-1α signaling pathway could promote the effect of Tempol by
upregulating the level of mi R-212-5p, thereby alleviating the occurrence of lung injury and providing a new underlying target for the
treatment of lung injury.
Keywords: HIF-1α; Lung injury; Obstructive sleep apnea; SIRT6; Tempol; miR-212-5p

453
Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis
and radiotherapy resistance through JNK pathway
By: Tao, Jinqiu; Xue, Cailin; Cao, Meng; Ye, Jiahui; Sun, Yulu; Chen, Hao; Guan, Yinan; Zhang, Wenjie; Zhang, Weijie; Yao, Yongzhong
Abstract: Background: Despite radiotherapy ability to significantly improve treatment outcomes and survival in triple- neg. breast
cancer (TNBC) patients, acquired resistance to radiotherapy poses a serious clin. challenge. Protein disulfide isomerase exists in
endoplasmic reticulum and plays an important role in promoting protein folding and posttranslational modification. However, little
is known about the role of protein disulfide isomerase family member 4 (PDIA4) in TNBC, especially in the context of radiot herapy
resistance. Methods: We detected the presence of P DIA4 in TNBC tissues and paracan cerous tissues, then examined the prolife
ration and apoptosis of T NBC cells with/without radiotherapy. As part of the validation process, xenograft tumor mouse model was
used. Mass spectrometry and western blot anal. were used to identify P DIA4-mediated mol. signaling pathway. Results: Based on
paired clin. specimens of TNBC patients, we found that P DIA4 expression was significantly higher in tumor tissues compared to
adjacent normal tissues. In vitro, PDIA4 knockdown not only increased apoptosis of tumor cells with/w ithout radiotherapy, but also
decreased the ability of proliferation. In contrast, overexpression of PDIA4 induced the opposite effects on apoptosis and prolife
ration. According to Co- IP/MS results, PDIA4 prevented Tax1 binding protein 1 (T AX1BP1) degradation by binding to T AX1BP1, which
inhibited c-Jun N-terminal kinase (JNK) activation. Moreover, PDIA4 knockdown suppressed tumor growth xenograft model in vivo,
which was accompanied by an increase in apoptosis and promoted tumor growth inhibition after radiotherapy. Conclusions: The
results of this study indicate that PDIA4 is an oncoprotein that promotes TNBC progression, and targeted therapy may represent a
new and effective anti-tumor strategy, especially for patients with radiot herapy resistance.
Keywords: Apoptosis; PDIA4; Radiation resistance; TAXBP1 JNK; TNBC
454
Apatinib weakens proliferation, migration, invasion, and angiogenesis of thyroid cancer cells through
downregulating pyruvate kinase M2
By: Yang, Xia; Li, Wenhong; Han, Xiaoying; Wang, Jiao; Dai, Jianjian; Ye, Xin; Meng, Min
Abstract: Thyroid cancer (TC) is the most frequent malignancy of the endocrine system. Apatinib, as an anti- angiogenic agent, has
been applied in the therapy of several cancers. However, the function and mechanism of Apatinib in TC have not been clearly elucid
ated. After processing with Apatinib alone or combined P KM2 overexpression plasmids, cell proliferation, migration, and invasion
were analyzed by EdU staining, CCK-8, wound healing, and Transwell. Meanwhile. H UVECs were incubated with the condit ioned
medium prepared from cell culture medium, and tube formation and VEGFR2 expression in HUVECs were examined using tube
formation and immunofluorescence (IF) assays. Besides, we established a nude mouse xenograft model by lentiv irus-mediated PK
M2 shRNAs, and tested the growth of tumors; the pathol. structure was analyzed with H&E staining. And the expres sions of N-
cadherin, Vimentin, E-cadherin, PKM2, VEGFA, VEGFR2, and Ki67 were determined by immunohi stochem. or Western blot. Apatinib
could prominently suppress proliferation, migration, invasion, and H UVEC tube formation in S W579 and TPC-1 cells. Besides, we
discovered that Apatinib had a significant inhibitory role on the expression of pyruvate kinase M2 (P KM2) in TC cells. And PKM2
overexpression also could notably reverse Apatinib- mediated inhibition of TC progression. Moreover, PKM2 shRNAs were applied
to TC xenografts, resulting in signif icant reduction in tumor volume and suppre ssion of angiogenesis-related protein expression. In
summary, Apatinib has a regulatory role in TC progression, and Apatinib can block cancer cell angiog enesis by downregulating PK
M2. This will provide a theor. basis for therapy of T C.

455
Elucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis

antibiotics Mycoplanecins
By: Fu, Chengzhang; Liu, Yunkun; Walt, Christine; Rasheed, Sari; Bader, Chantal D.; Lukat, Peer; Neuber, Markus; Haeckl, F. P. Jake;
Blankenfeldt, Wulf; Kalinina, Olga V.; et al
Abstract: DNA polymerase III sliding clamp (Dna N) was recently validated as a new anti- tuberculosis target employing griselimycins.
Three (2 S,4 R)-4-methylproline moieties of methylgri selimycin play significant roles in target binding and metabolic stability. Here,
we identify the mycoplanecin biosynthetic gene cluster by genome mining using bait genes from the 4- methylproline pathway. We
isolate and structurally elucidate four mycoplanecins comprising scarce homo-amino acids and 4-alkylprolines. Evaluating mycopl
anecin E against Mycobac terium tuberculosis surprisingly reveals an excitingly low min. inhibition concentration at 83 ng/mL, thus
outcompeting griselimycin by approx. 24- fold. We show that mycopla necins bind DnaN with nanomolar affinity and provide a co-
crystal structure of mycoplanecin A-bound DnaN. Addnl., we reconstitute the biosyntheses of the unusual L-homoleucine, L-
homonorleucine, and (2 S,4 R)-4-ethylproline building blocks by charact erizing in vitro the full set of eight enzymes involved. The
biosynthetic study, bioactivity evaluation, and drug target validation of mycopla necins pave the way for their further develo pment
to tackle multidrug-resistant mycobacterial infections.
456
Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated
killing
By: Zhou, Yabo ; Wang, Dianheng; Zhou, Li; Zhou, Nannan; Wang, Zhenfeng; Chen, Jie; Pang, Ruiyang; Fu, Haixia; Huang, Qiusha;
Dong, Fang; et al
Abstract: Mech. force contributes to perforin pore formation at immune synapses, thus facili tating the cytotoxic T lymphocytes (CTL)
-mediated killing of tumor cells in a unidire ctional fashion. How such mech. cues affect C TL evasion of perforin-mediated autolysis
remains unclear. Here we show that activated CTLs use their softness to evade perforin- mediated autolysis, which, however, is
shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via Z AP70-mediated YAP
Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, C TLs are more
resistant to YAP inhibitors than malignant T cells, potent ially due to the higher expression of the drug-resistant transporter, MDR1,
in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares C TLs, thus allowing CTLs to cytolyze malignant
cells without autolysis. Our findings thus hint a mech. force-based immunotherapeutic strategy against T cell leukemia.

457
Combinatorial targeting of telomerase and DNA-PK induces synergistic apoptotic effects against Pre-B
acute lymphoblastic leukemia cells
By: Katoueezadeh, Maryam; Maleki, Parisa; Torabizadeh, Seyedeh Atekeh; Farsinejad, Alireza; Khalilabadi, Roohollah Mirzaee;
Valandani, Hajar Mardani; Nurain, Ismaila Olanrewaju; Ashoub, Muhammad Hossein; Fatemi, Ahmad
Abstract: Background: Due to the high demand for novel approaches for leukemia- targeted therapy, this study invest igates the
impact of DNA-PK inhibitor NU7441 on the sensitivity of pre-B ALL cells to the telomerase inhibitor M ST-312. Methods: The study
involved NALM-6 cells treated with M ST-312 and NU7441, assessing their viability and metabolic activity using trypan blue and M TT
assays. The study also evaluated apoptosis, gene expression changes, and DNA damage using flow cytometry, q RT-PCR, and micron
ucleus assays. The binding energy of M ST-312 in the active site of telomerase was calculated using mol. docking. Results: The
study′s findings revealed a synergistic decline in both cell viability and metabolic activity in N ALM-6 cells when exposed to the
combined treatment of MST-312 and NU7441, and this decrease occurred without any adverse effects on healthy P BMC cells.
Furthermore, the combination treatment exhibited a signifi cantly higher induction of apoptosis than treatment with M ST-312 alone,
as observed through flow cytometry assay. qRT-PCR anal. revealed that this enhanced apoptosis was associated with a notable
downregulation of Bcl-2 expression and an upregulation of Bax gene expres sion. Moreover, the combination therapy decreased
expression levels of hTERT and c-Myc genes. The micronucleus assay indicated that the combin ation treatment increased DNA
damage in NALM-6 cells. Also, a good confor mation between M ST-312 and the active site of telomerase was revealed by docking
data. Conclusions: The study suggests that simult aneous inhibition of telomerase and D NA-PK in pre- B ALL presents a novel
targeted therapy approach.
Keywords: DNA-PK; MST-312; NU7441; Pre-B ALL; Telomerase
458
HuR promotes castration-resistant prostate cancer progression by altering ERK5 activation via
posttranscriptional regulation of BCAT1
By: You, Hang; Song, Guojing; Xu, Zhizhen; Chen, Saipeng; Shen, Wenhao; Liu, Heting; Deng, Bingqian; Li, Jun; Huang, Gang
Abstract: Background: Castration-resistant prostate cancer (C RPC) is refractory to hormone treatment, and the underlying
mechanism has not been fully elucidated. This study aimed to clarify the role and mechanism of Human antigen R (Hu R) as a therap
eutic target for C RPC progression. Methods: HuR was knocked out by Cas9 or inhibited by the Hu R-specific inhibitor KH-3 in CRPC
cell lines and in a mouse xenograft model. The effects of HuR inhibition on tumor cell behaviors and signal transd uction were
examined by proliferation, transwell, and tumor xenograft assays. Posttransc riptional regulation of B CAT1 by Hu R was determined
by half-life and R IP assays. Results: HuR knockout attenuated the proliferation, migration, and invasion of PC3 and DU145 cells in
vitro and inhibited tumor progression in vivo. Moreover, B CAT1 was a direct target gene of Hu R and mediated the oncogenic effect
of HuR on CRPC. Mechanistically, HuR directly interacted with B CAT1 mRNA and upregulated BCAT1 expression by increasing the
stability and translation of BCAT1, which activated ERK5 signalling. Addnl., the HuR-specific inhibitor KH-3 attenuated CRPC progre
ssion by disrupting the Hu R-BCAT1 interaction. Conclusions: We confirmed that the Hu R/BCAT1 axis plays a crucial role in C RPC
progression and suggest that inhibiting the Hu R/BCAT1 axis is a promising therap eutic approach for suppre ssing CRPC progre
ssion. Graphical Abstract: [graphic not available: see fulltext]
Keywords: Branched-chain amino transferase 1; Castra tion-resistant prostate cancer; E RK5; Human antigen R; KH-3

459
Biosynthesis of Bt-Ag 2O nanoparticles using Bacillus thuringiensis and their pesticidal and
antimicrobial activities
By: Ge, Jiajia; Hu, Jianzhong; Cui, Sufen; Wang, Yirong; Xu, Caijiayi; Liu, Wenzhuo
Abstract: Nanosilver oxide exhibits strong antibacterial and photocatalytic properties and has shown great applic ation potential in
food packaging, biochem. fields, and other fields involving diseases and pest control. In this study, Ag 2O nanoparticles were synthe
sized using Bacillus thuringiensis (Bt-Ag 2O NPs). The physicochem. characteristics of the Bt- Ag 2O NPs were analyzed by U V-vis
spectroscopy, Fourier transform I R spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscope (S EM), inductively
coupled plasma emission spectrometry (ICP), high-resolution transmission electron microscopy (HR-TEM), and zeta potential. The
phis-chem. characterization revealed that the Bt-Ag 2O NPs are in spherical shape with the small particle size (18.24 nm) , high crystal
linity, well disper sity, and stability. The biopest icidal and antifungal effects of Bt- Ag 2O NPs were tested against Tribolium
castaneum, Aspergillus flavus, and Penici llium chrysogenum. The survival, growth, and reprod uction of tested pests and molds were
significantly inhibited by Bt- Ag 2O NPs in a dose-dependent manner. Bt-Ag 2O NPs showed higher pesticidal activities against T.
castaneum than Bt and com. Ag 2O NPs. The LC50 values of Bt, Ag 2O NPs, and Bt- Ag 2O NPs were 0.139%, 0.072%, and 0.06% on day
14, resp. The Bt-Ag 2O NPs also showed well antifungal activities against A. flavus and P. chryso genum, while it resulted a small
inhibition zone than com. Ag 2O NPs did. In addition, A. flavus showed much more sensitive to Bt- Ag 2O NP treatments, compared to
P. chrysogenum. Our results revealed that Bt- Ag 2O NPs synthesized using B. thuring iensis could act as pesticides and antifungal
agents in stored-product fields. Key points: • Bt-Ag 2O NPs could be synthesized using Bacillus thuringiensis (Bt). • The N Ps showed a
high degree of crystallinity, spherical shape, and small particle size. • The N Ps also showed excellent insecticidal and antifungal
activity.
Keywords: Ag2O NPs; Antifungal activity; Bacillus thuring iensis; Biosynthesis; Insecticidal activity

460
The synergism of cytosolic acidosis and reduced NAD +/NADH ratio is responsible for lactic acidosis-
induced vascular smooth muscle cell impairment in sepsis
By: Terpe, Philipp; Ruhs, Stefanie ; Dubourg, Virginie; Bucher, Michael; Gekle, Michael
Abstract: Background: During sepsis, serve vascular dysfun ctions lead to life-threatening multiple organ failure, due to vascular
smooth muscle cells (VSMC) impairments, resulting in vasoplegia, hypotension and hypoperfusion. In addition, septic patients have
an altered cell metabolism that leads to lactic acidosis. Septic patients suffering from lactic acidosis have a high risk of mortality. In
addition, septic survivors are at risk of secondary vascular disease. The underlying mechanisms of whether and how lactic acidosis
leads to the changes in VSMCs is not well unders tood. The aim of this study was to comprehe nsively investigate the effect of lactic
acidosis on VSMCs and addnl. compare the effects with those induced by pure acidosis and sodium lactate. Methods: Primary
human aortic smooth muscle cells (HAoSMCs) were treated for 48 h with lactic acidosis (L A_pH 6.8), hydrochloric acid (HCl_pH 6.8),
sodium lactate (Na+-lactate_pH 7.4) and the resp. controls (ctrl._p H 7.4; hyperosmolarity control: mannitol_pH 7.4) and compara
tively analyzed for changes in (i) transcr iptome, (ii) energy metabo lism, and (iii) phenotype. Results: Both types of acidosis led to
comparable and sustained intracellular acidification without affecting cell viability. R NA sequencing and detailed transcr iptome
anal. revealed more significant changes for lactic acidosis than for hydroc hloric acidosis, with lactate being almost ineffective,
suggesting qual. and quant. synergism of acidosis and lactate. Bioinformatic predictions in energy metabolism and phenotype were
confirmed exptl. Lactic acidosis resulted in strong inhibition of glycolysis, glutaminolysis, and altered mitochondrial respiration
which reduced cellular ATP content, likely due to increased TXNIP expression and altered NAD+/NADH ratio. Hydrochloric acidosis
induced significantly smaller effects without changing the N AD+/NADH ratio, with the ATP content remaining constant These
metabolic changes led to osteo-/chondrogenic/senescent transdifferentiation of VSMCs, with the effect being more pronounced in
lactic acidosis than in pure acidosis. Conclusions: Overall, lactic acidosis exerted a much stronger effect on energy metabolism than
pure acidosis, whereas lactate had almost no effect, reflecting the qual. and quant. synergism of acidosis and lactate. As a conseq
uence, lactic acidosis may lead to acute functional impair ments of VSMC, sustained perturbations of the transcriptome and cellular
dedifferentiation. Moreover, these effects may contribute to the acute and prolonged vascular pathomec hanisms in septic patients.
Keywords: Acidosis; Cellular dedifferentiation; Lactic acidosis; Metabo lism; NAD+/NADH ratio; Sepsis; Vascular calcification; Vascular
smooth muscle cells

461
A combined opposite targeting of p110δ PI3K and RhoA abrogates skin cancer
By: Tzenaki, Niki; Xenou, Lydia; Goulielmaki, Evangelia; Tsapara, Anna; Voudouri, Irene; Antoniou, Angelika; Valianatos, George;
Tzardi, Maria; De Bree, Eelco; Berdiaki, Aikaterini; et al
Abstract: Malignant melanoma is the most aggressive and deadly skin cancer with an increasing incidence worldwide whereas SCC
is the second most common non-melanoma human skin cancer with limited treatment options. Here we show that the develo
pment and metastasis of melanoma and S CC cancers can be blocked by a combined opposite targeting of Rho A and p110δ PI3K.
We found that a targeted induction of RhoA activity into tumors by deletion of p190 RhoGAP-a potent inhibitor of RhoA GTPase-in
tumor cells together with adoptive macrophages transfer from δ D910A/D910A mice in mice bearing tumors with active Rho A
abrogated growth progression of melanoma and S CC tumors. Τhe efficacy of this combined treatment is the same in tumors
lacking activating mutations in BRAF and in tumors harbouring the most frequent B RAF(V600E) mutation. Furthe rmore, the
efficiency of this combined treatment is associated with decreased ATX expression in tumor cells and tumor stroma bypassing a
pos. feedback expression of ATX induced by direct A TX pharmacol. inactivation. Together, our findings highlight the importance of
targeting cancer cells and macrophages for skin cancer therapy, emerge a reverse link between A TX and RhoA and illustrate the
benefit of p110δ PI3K inhibition as a combinatorial regimen for the treatment of skin cancers.
462
TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis
By: Hao, Xiang-lin; Lv, Yang-fan; Li, De-feng; Bai, Fu-hai; Gong, Ji; Pan, Guang-qiang; Su, Lin-xi; Wang, Ya-li; Fu, Wan-lei; Liu, Bo; et al
Abstract: Background: Tandem C2 domains, nuclear (T C2N) is a C2 domain- containing protein that belongs to the carboxyl- terminal
type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previo usly, we preliminarily reported that
TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (B C) cells. Beyond that, its precise biol.
functions and detailed mol. mechanisms in BC development and progression are not fully understood. Methods: Tumor tissues of
212 BC patients were subjected to tissue microarray and further assessed the associ ations of TC2N expression with pathol.
parameters and FASN expression. The protein levels of T C2N and FASN in cell lines and tumor specimens were monitored by q RT-P
CR, WB, immunofluorescence and immunohistochem. In vitro cell assays, in vivo nude mice model was used to assess the effect of
TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target
mol. of TC2N was mined using a combin ation of transcriptomics, proteomics and lipidomics, and the underlying mechanism was
explored by WB and co-IP assays. Results: Here, we found that the expression of T C2N remarkedly silenced in metastatic and poorly
differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem- like properties of BC via inhibition of fatty
acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2 B domain
is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by
competing with neddylated PTEN for binding to F ASN in nucleus. On the other hand, cytopl asmic TC2N interacts with import
proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. Conclusions: Altogether, we demonstrate a
previously unidentified role and mechanism of T C2N in regulation of lipid metabolism and P TEN neddylation, providing a potential
therapeutic target for anticancer.
Keywords: Breast cancer; Cancer stem cell; Fatty synthesis; Metastasis; PTEN neddylation; TC2N

463
Serine/threonine kinase 36 induced epithelial-mesenchymal transition promotes docetaxel resistance

in prostate cancer
By: He, Tao; Li, Nan-Xing; Pan, Zhao-Jun; Zou, Zi-Hao; Chen, Jie-Chuan; Yu, Si-Zhe; Lv, Fa; Xie, Quan-Cheng; Zou, Jun
Abstract: To investigate the role and potential mechanism of serine/t hreonine kinase 36 (S TK36) in docetaxel resistance-prostate
cancer (PCa). The expression of S TK36 in PCa and the correlation with clinicopathol. characteristics of PCa patients were analyzed
using the data from different databases and tissue microarrays. To invest igate the role of S TK36 on cell prolife ration, invasion, and
migration, STK36 was overexpressed and silenced in DU-145 and PC-3 cell lines. Cell counting kit- 8 (CCK8) was used to test cell
proliferation. Cell invasion and migration were detected by cell wound scratch assay and trans well, resp. The expression profile of
STK36, E-Cadherin, and Vimentin was analyzed by Western blot. Cell apoptosis was detected by the T UNEL assay. STK36 expression
was upregulated in PCa tissue compared with adjacent benign P Ca tissue; it was higher in patients with advanced stages compared
with lower stages and was significantly correlated with decreased overall survival. Up- regulation of STK36 significantly promoted
the proliferation, invasion, and migration of D U-145 and PC-3 cells and compensated for the suppression caused by docetaxel
treatment in vitro. A striking apoptosis inhibition could be observed when dealing with docetaxel, although the apoptosis of D U-
145 and PC-3 cells was not affected by the S TK36 exclusive overexpression. Besides, E-Cadherin expression was restrained while the
expression levels of vimentin were all enhanced. The knockdown of STK36 reversed the above process. S TK36 up-regulation could
accelerate the biol. behavior and docetaxel resistance of PCa by epithelial-mesenchymal transition (EMT) activation. STK36 may be
potentially used as a target in P Ca resolvent with docetaxel.
464
Single cell transcriptomic representation of social dominance in prefrontal cortex and the influence of
preweaning maternal and postweaning social environment
By: Lopez, Katherine; Baker, Madelyn R.; Toth, Miklos

Social dominance encompasses winning dyadic contests and gaining priority access to resources and reprod uction Dominance is
influenced by environmental factors, particularly during early postnatal life and adoles cence. A disinhibitory medial prefrontal
cortex (mPFC) microcircuit has been implicated in the expression of dominance in the "tube test" social compet ition paradigm in
mice, but the neuroplasticity underlying dominance is not known. We previously reported that male pups raised by phys. active
(wheel-running, as opposed to sedentary) dams exhibit tube test dominance and increased reprod uctive fitness, and here we show
that social isolation from weaning also increases dominance. By using single cell transcriptomics, we tested if increased dominance
in these models is associated with a specific transcriptional profile in one or more cell-types in the mPFC. The preweaning maternal
effect, but not postweaning social isolation, caused gene expression changes in pyramidal neurons. However, both the effect of
maternal exercise and social isolation induced the coordinated downregulation of synaptic channel, receptor, and adhesion genes
in parvalbumin pos. (PV) interneurons, suggesting that development of dominance is accompanied by impaired PV interneuron-
mediated inhibition of pyramidal cells. This study may help understand environm entally induced transcriptional plasticity in the PFC
and its relationship to tube test dominance.
Keywords: social dominance prefrontal cortex weaning single cell transcriptomics

465
The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis
through tyrosine dephosphorylation
By: Nelson, Christopher B.; Rogers, Samuel; Roychoudhury, Kaushik; Tan, Yaw Sing; Atkinson, Caroline J.; Sobinoff, Alexander P. ;
Tomlinson, Christopher G.; Hsu, Anton; Lu, Robert; Dray, Eloise ; et al
Abstract: The Eyes Absent proteins (EYA1-4) are a biochem. unique group of tyrosine phosph atases known to be tumor-promoting
across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify
Polo-like kinase 1 (P LK1) as an interactor and phosphatase substrate of E YA4 and EYA1, with pY445 on PLK1 being the primary
target site. Dephosphorylation of p Y445 in the G2 phase of the cell cycle is required for centrosome matura tion, PLK1 localization to
centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Mol. dynamics
simulations support the rationale that p Y445 confers a structural impairment to P BD-substrate interactions that is relieved by E YA-
mediated dephosphorylation. Depletion of E YA4 or EYA1, or chem. inhibition of EYA phosphatase activity, dramatically reduces PL
K1 activation, causing mitotic defects and cell death. Overall, we have charact erized a phosphotyrosine signalling network governing
PLK1 and mitosis.
466
Integrated analysis of microRNA and messenger RNA expression profiles reveals functional microRNA
in infectious bovine rhinotracheitis virus-induced mitochondrial damage in Madin-Darby bovine kidney
cells
By: Ma, Yingcai; Guo, Xueping; He, Qin; Liu, Lu; Li, Zelong; Zhao, Xiaomin; Gu, Wenxi; Zhong, Qi; Li, Na; Yao, Gang; et al
BMC Genomics (2024), 25(1), 158 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Studies have confirmed that Infectious bovine rhinotra cheitis virus (IBRV) infection induces mitochondrial
damage. MicroRNAs (miRNAs) are a class of noncoding R NA mols., which are involved in various biol. processes and pathol.
changes associated with mitochondrial damage. It is currently unclear whether mi RNAs participate in IBRV-induced mitochondrial
damage in Madin-Darby bovine kidney (MDBK) cells. Results: In the present study, we used high- throughput sequencing technol.,
Gene Ontol. (GO) and Kyoto Encyclopedia of Genes and Genomes (K EGG) enrichment anal. to screen for mitochondria-related miRN
As and mRNAs (mRNAs). In total, 279 differentially expressed miRNAs and 832 differe ntially expressed mRNAs were identified in 6
h (IBRV1) vs. 24 h (IBRV2) after IBRV infection in MDBK cells. GO and KEGG enrichment anal. revealed that 42 differentially
expressed mRNAs and 348 target genes of differe ntially expressed miRNAs were correlated with mitocho ndrial damage, and the
miRNA-mitochondria-related target genes regulatory network was constr ucted to elucidate their potential regulatory relatio nships.
Among the 10 differentially expressed miRNAs, 8 showed expression patterns consistent with the high- throughput sequencing
results. Functional validation results showed that overexpression of miR-10a and mi R-182 aggravated mitocho ndrial damage, while
inhibition of miR-10a and mi R-182 alleviated mitochondrial damage. Conclusions: This study not only revealed the expression
changes of miRNAs and mRNAs in IBRV-infected MDBK cells, but also revealed possible biol. regulatory relati onship between them.
MiR-10a and mi R-182 may have the potential to be developed as biomarkers for the diagnosis and treatment of I BRV. Together,
Together, these data and analyses provide addnl. insights into the roles of miRNA and mRNA in IBRV-induced mitochondria
damage
Keywords: Infectious bovine rhinotracheitis virus (IBRV); MicroRNA (miRNA); Mitochondrial damage; miR-10a; miR-182

467
Clearance of apoptotic cells by neutrophils in inflammation and cancer
By: Ramos, Cristiano ; Oehler, Rudolf

Abstract: When a cell dies of apoptosis, it is eliminated either by neighboring cells or by attracted profes sional phagocytes. Although
it was generally believed that neutrophils also have the ability to perform efferoc ytosis, their contri bution to the clearance of
apoptotic cells was considered less important compared with macrophages. Therefore, this ability of neutro phils remained
unexplored for a long time. Over the past decade, it has been shown that during inflammation, neutrophils contribute significantly
to the clearance of apoptotic neutrophils that accumulate in large numbers at the site of tissue damage. This "neutr ophil cannib
alism" is accompanied by inhibition of pro-inflammatory activities of these cells, such as respir atory burst and formation of
neutrophil extracellular traps (N ETs). Furthermore, efferocytosing neutrophils secrete anti-inflammatory mediators and mitogens
including hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF2), vascular endothelial growth factors (VEGF), and transf
orming growth factor beta (TGFβ). Thus, efferocytosis by neutrophils is involved in resolution of inflamm ation. Recent research
indicates that it plays also a role in cancer. Many different solid tumors contain aggregates of dead tumor cells that have undergone
spontaneous apoptosis. Their extent correlates with poor clin. outcome in most cancer types. These clusters of apoptotic tumor
cells are strongly infiltrated by tumor-associated neutrophils (TANs) that acquired an anti-inflammatory and pro-resolving polari
zation state. This review summarizes the potential conseq uences discussed in the current literature. Although the picture of the role
of efferocytosis by neutrophils in inflammation and cancer is becoming clearer, many questions are still unexplored.
468
Enzymatic upcycling of wild-simulated ginseng leaves for enhancing biological activities and
compound K
By: Lim, Juho; Kim, Hayeong; Kim, Gha-hyun J.; Kim, Taeyoon; Kang, Choon Gil; Kim, Seung Wook; Kim, Doman
Abstract: Compound K (CK), a ginsenoside with high bioavailability, is present at low levels in wild- simulated ginseng leaves (W SGL).
WSGL contains the CK precursors, Rd and F2, in amounts up to 26.4 ± 0.4 and 24.1 ± 1.9 mg/g extract, resp. In this study, C K
production in WGSL reached 25.9 ± 1.0 mg/g extract following treatment with Viscozyme, Celluclast 1.5 L, Pectinex Ultra S P-L, and
their combination. The antioxidant activities indicated by oxygen radical absorbance capacity, ferric reducing antiox idant power,
and ABTS- and DPPH radical scavenging activity of enzyme-treated WSGL were enhanced 1.69-, 2.51-, 2.88-, and 1.80-fold, resp.,
compared to non-treated WSGL. Furthermore, the CK-enriched WSGL demonstrated a 1.94-fold decrease in SA-β-galactosidase
expression in human dermal fibroblasts and a 3.8- fold enhancement of inhibition of nitric oxide release in lipopolysa ccharide-
induced RAW 264.7 cells relative to non-treated WSGL. Consequently, WSGL subjected to enzymic upcycling has potential as a
functional material in the food and pharmaceutical industries.
Keywords: Anti-inflammation; Anti-senescence; Compound K; Enzymatic biotransf ormation; Minor ginsenosides; Wild-simulated
ginseng leaves

469
DDX3X interacts with SIRT7 to promote PD-L1 expression to facilitate PDAC progression
By: Zhao, Tianming ; Zhu, Hanlong; Zou, Tianhui; Zhao, Si; Zhou, Lin ; Ni, Muhan; Liu, Feng; Zhu, Hao; Dou, Xiaotan; Di, Jian; et al
Oncogenesis (2024), 13(1), 8 | Language: English, Database: CAplus and MEDLINE
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is recognized as the most aggressive and fatal malign ancy. A previous study
reported that PDAC patients who exhibit elevated levels of D DX3X have a poor prognosis and low overall survival rate. However, the
underlying mol. mechanism remains unclear. This study aimed to investigate the specific roles of DDX3X in PDAC. Multiple bioinfo
rmatics analyses were used to evaluate DDX3X expression and its potential role in P DAC. In vitro and in vivo studies were
performed to assess the effects of DDX3X on PDAC cell growth. Furthe rmore, Western blotting, quant. P CR, immunohistochem.,
immunofluorescence, mass spectrometry, coimmunoprecipitation and multiplexed immunohistochem. staining were conducted to
identify the specific regulatory mechanism in PDAC. The results verified that D DX3X expression is notably upregulated in the tumor
tissue vs. normal tissue of PDAC patients. DDX3X knockdown markedly suppressed the prolife ration, invasion and migration of PDA
C cells in vitro and inhibited tumor growth in vivo. Conver sely, overexpression of DDX3X induced the opposite effect. Further studies
supported that the DDX3X protein can associate with sirtuin 7 (S IRT7) to stimulate PDAC carcinogenesis and progression. Furthe
rmore, SIRT7 inhibition significantly impeded DDX3X-mediated tumor growth both ex vivo and in vivo. The results also revealed
that programmed death ligand 1 (PD-L1) expression is pos. correlated with DDX3X expression. These results reveal signif icant involv
ement of the DDX3X-SIRT7 axis in the initiation and advancement of PDAC and offer previously undisc overed therapeutic options
for PDAC management. [graphic not available: see fulltext]
470
Lipoxins A4 and B 4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation
By: Livne-Bar, Izhar; Maurya, Shubham; Gronert, Karsten; Sivak, Jeremy M.

Abstract: Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of
diseases. We previously reported that Lipoxins A4 and B4 (LXA4 and LXB4) have protective activities against neurodegenerative
injury. Yet, lipoxin activities and downstream signaling in neuroinflammatory processes are not well unders tood. Here, we utilized a
model of posterior uveitis induced by lipopolysaccharide endotoxin (LPS), which results in rapid retinal neuroinfl ammation primarily
characterized by activation of resident macroglia (astrocytes and Muller glia) , and microglia. Using this model, we observed that each
lipoxin reduces acute inner retinal inflammation by affecting endogenous glial responses in a cascading sequence beginning with
astrocytes and then microglia, depending on the timing of exposure; prophylactic or therapeutic. Subsequent analyses of retinal
cytokines and chemokines revealed inhibition of both C XCL9 (MIG) and CXCL10 (IP10) by each lipoxin, compared to controls,
following LPS injection. CXCL9 and CXCL10 are common ligands for the CXCR3 chemokine receptor, which is promin ently expressed
in inner retinal astrocytes and ganglion cells. We found that CXCR3 inhibition reduces LPS-induced neuroinflammation, while CXC
R3 agonism alone induces astrocyte reacti vity. Together, these data uncover a novel lipoxin- CXCR3 pathway to promote distinct
anti-inflammatory and proresoln. cascades in endogenous retinal glia.
Keywords: CXCL10; CXCL9; CXCR3; Gliosis; Inflammation resolution; Lipoxins; Neuroinflammation; Retina; Uveitis

471
Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy,
reflecting their different metabolic risk in patients
By: Pozzi, Marco ; Vantaggiato, Chiara ; Brivio, Francesca ; Orso, Genny; Bassi, Maria Teresa
Abstract: The metabolic effects induced by antipsychotics in vitro depend on their action on the traffi cking and biosynthesis of
sterols and lipids. Previous research showed that antipsychotics with different adverse effects in patients cause similar altera tions
in vitro, suggesting the low clin. usefulness of cellular studies. Moreover, the inhibition of peripheral A MPK was suggested as
potential aetiopathogenic mechanisms of olanzapine, and different effects on autophagy were reported for several antipsyc hotics.
We thus assessed, in clin.-relevant culture conditions, the aetiopathogenic mechanisms of olanzapine, risperidone and ziprasidone,
antipsychotics with resp. high, medium, low metabolic risk in patients, finding relevant differ ences among them. We highlighted
that: olanzapine impairs lysosomal function affecting autophagy and autophagosome clearance, and increasing intrace llular lipids
and sterols; ziprasidone activates AMPK increasing the autophagic flux and reducing intrace llular lipids; risperidone increases lipid
accumulation, while it does not affect lysosomal function. These in vitro differ ences align with their different impact on patients. We
also provided evidence that metformin add-on improved autophagy in olanza pine-treated cells and reduced lipid accumu lation
induced by both risperidone and olanzapine in an A MPK-dependent way; metformin also increased the production of bile acids to
eliminate cholesterol accumulations caused by olanza pine. These results have different clin. implica tions. We demonstrated that
antipsychotics with different metabolic impacts on patients actually have different mechanisms of action, thus supporting the
possibility of a person alised antipsychotic treatment. Moreover, we found that metformin can fully revert the phenotype caused by
risperidone but not the one caused by olanza pine, that still activates SREBP2.
472
The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8 + T cells
By: Liao, Xiaofeng ; Li, Wenxue ; Zhou, Hongyue; Rajendran, Barani Kumar ; Li, Ao; Ren, Jingjing ; Luan, Yi; Calderwood,
David A. ; Turk, Benjamin ; Tang, Wenwen ; et al
Abstract: CD8+ T cells play an important role in anti- tumor immunity. Better understanding of their regulation could advance cancer
immunotherapies. Here we identify, via stepwise C RISPR-based screening, that CUL5 is a neg. regulator of the core signaling
pathways of CD8+ T cells. Knocking out C UL5 in mouse C D8+ T cells significantly improves their tumor growth inhibiting ability, with
significant proteomic alterations that broadly enhance T CR and cytokine signaling and their effector functions. Chem. inhibition of
neddylation required by CUL5 activation, also enhances C D8 effector activities with CUL5 validated as a major target. Mechanis
tically, CUL5, which is upregulated by T CR stimulation, interacts with the S OCS-box-containing protein PCMTD2 and inhibits TCR and
IL2 signaling. Addnl., CTLA4 is markedly upregulated by C UL5 knockout, and its inactivation further enhances the anti-tumor effect
of CUL5 KO. These results together reveal a neg. regulatory mechanism for C D8+ T cells and have strong transla tional implications in
cancer immunotherapy.

473
Differential contribution of THIK-1 K + channels and P2X7 receptors to ATP-mediated

neuroinflammation by human microglia
By: Rifat, Ali; Ossola, Bernardino; Buerli, Roland W.; Dawson, Lee A.; Brice, Nicola L.; Rowland, Anna; Lizio, Marina; Xu, Xiao; Page,
Keith; Fidzinski, Pawel; et al
Abstract: Neuroinflammation is highly influenced by microglia, partic ularly through activation of the NLRP3 inflammasome and
subsequent release of IL-1β. Extracellular ATP is a strong activator of N LRP3 by inducing K + efflux as a key signaling event,
suggesting that K+-permeable ion channels could have high therap eutic potential. In microglia, these include A TP-gated THIK-1 K +
channels and P2X7 receptors, but their intera ctions and potential therapeutic role in the human brain are unknown. Using a novel
specific inhibitor of THIK-1 in combination with patch-clamp electrophysiol. in slices of human neocortex, we found that T HIK-1
generated the main tonic K+ conductance in microglia that sets the resting membrane potential. Extrace llular ATP stimulated K+
efflux in a concentration-dependent manner only via P2X7 and metabotropic potentiation of THIK-1. We further demons trated that
activation of P2X7 was mandatory for A TP-evoked IL-1β release, which was strongly suppressed by blocking T HIK-1. Surprisingly, THI
K-1 contributed only marginally to the total K + conductance in the presence of A TP, which was dominated by P2X7. This suggests a
previously unknown, K+-independent mechanism of T HIK-1 for NLRP3 activation. Nuclear sequencing revealed almost selective
expression of THIK-1 in human brain microglia, while P2 X7 had a much broader expres sion. Thus, inhibition of THIK-1 could be an
effective and, in contrast to P2X7, microglia-specific therapeutic strategy to contain neuroinfl ammation. Graphical Abstract: [graphic
not available: see fulltext]
Keywords: Human brain; Ion channels; Microglia; Neocortex; Neuroinflammation; Pharmacology; Purinergic signalling
474
Unveiling the therapeutic potential of thymol from Nigella sativa L. seed: selective anticancer action
against human breast cancer cells (MCF-7) through down-regulation of Cyclin D1 and proliferative cell
nuclear antigen (PCNA) expressions
By: Vahitha, V.; Lali, Growther; Prasad, Saradh; Karuppiah, Ponmurugan; Karunakaran, Gopalu; AlSalhi, Mohamad S.
Abstract: Background: Breast adenocarcinoma cells (MCF-7) are characterized by the overexp ression of apoptotic marker genes and
proliferative cell nuclear antigen (P CNA), which promote cancer cell proliferation. Thymol, derived from Nigella sativa (N S), has been
investigated for its potential anti-proliferative and anticancer proper ties, especially its ability to suppress Cyclin D1 and P CNA
expression, which are crucial in the proliferation of cancer cells. Methods: The cytotoxicity of thymol on M CF-7 cells was assessed
using 3-[4,5-dimethylthiazol-2-yl]-2,5 di-Ph tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release methods. Thymol
was tested at increasing concentrations (0-1000 μM) to evaluate its impact on M CF-7 cell growth. Addnl., Cyclin D1 and P CNA gene
expression in thymol-treated and vehicle control groups of M CF-7 were quantified using real-time Polymerase Chain Reaction (RT-q
PCR). Protein-ligand interactions were also investigated using the CB-Dock2 server. Results: Thymol significantly inhibited M CF-7 cell
growth, with a 50% inhibition observed at 200 μ M. The gene expression of Cyclin D1 and P CNA was down-regulated in the thymol-
treated group relative to the vehicle control. The exptl. results were verified through protein- ligand interaction investigations.
Conclusions: Thymol, extracted from N S, demonstrated specific cytotoxic effects on M CF-7 cells by suppressing the expression of
Cyclin D1 and PCNA, suggesting its potential as an effective drug for M CF-7. However, addnl. in vivo research is required to
ascertain its efficacy and safety in medical applications.
Keywords: Cyclin D1; Gene expression; MCF-7; MTT; Nigella sativa; Thymol

475
Hugan Qingzhi tablets attenuates endoplasmic reticulum stress in nonalcoholic fatty liver disease rats
by regulating PERK and ATF6 pathways
By: Yang, Miaoting; Yao, Xiaorui; Xia, Fan; Xiang, Shijian; Tang, Waijiao; Zhou, Benjie
Abstract: Background: Endoplasmic reticulum (ER) stress, promoting lipid metabolism disorders and steatohe patitis, contributes
significantly to the pathogenesis of nonalcoholic fatty liver disease (N AFLD). Hugan Qingzhi tablets (HQT) has a definite effect in the
clin. treatment of NAFLD patients, but its mechanism is still unclear. This study aims to invest igate the effects of HQT on ER stress in
the liver tissues of NAFLD rats and explore the underlying mechanism. Methods: The N AFLD rat model was managed with high-fat
diet (HFD) for 12wk. HQT was administrated in a daily basis to the HFD groups. Biochem. markers, pro-inflammatory cytokines, liver
histol. were assayed to evaluate HQT effects in HFD-induced NAFLD rats. Furthermore, the expression of ER stress-related signal
mols. including glucose regulating protein 78 (GRP78), protein kinase R NA-like endoplasmic reticulum kinase (P ERK), p-PERK,
eukaryotic translation initiation factor 2α (EIF2α), p-EIF2α, activating transcription factor 4 (ATF4), acetyl-CoA-carboxylase (ACC),
activating transcription factor (ATF6), and nuclear factor-kappa B-p65 (NF-κB-p65) were detected by western blot and/or q RT-PCR.
Results: The histopathol. characteristics and biochem. data indicated that H QT exhibited protective effects on HFD-induced NAFLD
rats. Furthermore, it caused significant reduction in the expression of ERS markers, such as GRP78, PERK, p-PERK, and ATF6, and
subsequently downregulated the expression of EIF2α, p-EIF2α ATF4, ACC, and NF-κB-p65. Conclusions: The results suggested that H
QT has protective effect against hepatic steatosis and inflam mation in NAFLD rats by attenu ating ER stress, and the potential
mechanism is through inhibition of PERK and A TF6 pathways.
Keywords: Chinese traditional medicine; Endoplasmic reticulum stress (E RS) pathway; Hepatoprotective effect; Hugan Qingzhi
tablets (HQT); Non-alcoholic fatty liver disease (N AFLD)
476
Progress in the clinical effects and adverse reactions of ticagrelor
By: Wei, Peng; Wang, Xiaoqing; Fu, Qiang; Cao, Bangming

Thrombosis Journal (2024), 22(1), 8 | Language: English, Database: CAplus and MEDLINE
Abstract: Background: Ticagrelor is a novel receptor antagonist that select ively binds to the P2Y12 receptor, thereby inhibiting A DP
(ADP)-mediated platelet aggregation. Compared to clopidogrel, ticagrelor has the advantages of a fast onset, potent effects, and a
reversible platelet inhibition function, which make this drug clin. suitable for treating acute coronary syndrome (A CS), especially
acute ST-segment elevation myocardial infarction (S TEMI). Objective: This review was performed to determine the basic characte
ristics, clin. effects, and adverse reactions of ticagr elor. Methods: Relevant trials and reports were obtained from the M EDLINE,
Embase, and Cochrane Library databases. Results: Ticagrelor is rapidly absorbed by the body after oral administration, exhibits
inherent activity without requiring metabolic activation, and binds reversibly to the P2Y12 receptor. Ticagrelor has been recomm
ended in ACS treatment guidelines worldwide due to its advant ageous pharmacol. properties and signif icant clin. benefits.
Ticagrelor inhibits platelet aggregation, inhibits inflammatory response, enhances adenosine function, and has cardiopr otective
effects. However, ticagrelor also causes adverse reactions such as bleeding tendency, dyspnea, ventricular pause, gout, kidney
damage, and thrombotic thrombocytopenic purpura in clin. treatment. Therefore, it is necessary to pay attention to risk assess
ments when using ticagrelor. Conclusion: Ticagrelor is a promising drug for the effective treatment of A CS. When using ticagrelor,
individualized treatment should be provided based on the specific conditions of the patients to avoid serious adverse events.
Keywords: Acute coronary syndrome; Adverse reaction; Clinical effect; Ticagrelor

477
Pathway crosstalk between the central metabolic and heme biosynthetic pathways in Phanerochaete
chrysosporium
By: Miura, Daisuke ; Tsurigami, Ryoga; Kato, Hiroyuki; Wariishi, Hiroyuki; Shimizu, Motoyuki
Abstract: A comprehensive anal. to survey heme-binding proteins produced by the white-rot fungus Phanerochaete chrysosporium
was achieved using a biotinylated heme-streptavidin beads system. Mitochondrial citrate synthase (PcCS), glyceraldehyde 3-
phosphate dehydrogenase (PcGAPDH), and 2-Cys thioredoxin peroxidase (mammalian HBP23 homolog) were identified as putative
heme-binding proteins. Among these, Pc CS and PcGAPDH were further characterized using heterologously expressed recombinant
proteins. Difference spectra of PcCS titrated with hemin exhibited an increase in the Soret absorbance at 414 nm, suggesting that
the axial ligand of the heme is a His residue. The activity of PcCS was strongly inhibited by hemin with Ki oxaloa cetate of 8.7 μ M and
Ki acetyl-CoA of 5.8 μ M. Since the final step of heme biosynthesis occurred at the mitocho ndrial inner membrane, the inhibition of
PcCS by heme is thought to be a physiol. event. The inhibitory mode of the heme was similar to that of Co A analogs, suggesting that
heme binds to PcCS at His 347 at the Ac CoA-CoA binding site, which was supported by the homol. model of Pc CS. PcGAPDH was also
inhibited by heme, with a lower concentration than that for Pc CS. This might be caused by the different location of these enzymes.
From the integration of these phenomena, it was concluded that metabolic regula tions by heme in the central metabolic and heme
synthetic pathways occurred in the mitochondria and cytosol. This novel pathway crosstalk between the central metabolic and
heme biosynthetic pathways, via a heme mol., is important in regulating the metabolic balance (heme synthesis, A TP synthesis, flux
balance of the tricarboxylic acid (T CA) cycle and cellular redox balance (N ADPH production) during fungal aromatic degrad ation Key
points: • A comprehensive survey of heme-binding proteins in P. chrysosporium was achieved. • Several heme- binding proteins
including CS and GAPDH were identified. • A novel metabolic regulation by heme in the central metabolic pathways was found.
Keywords: Basidiomycete; Heme; Heme- binding protein; Pathway crosstalk

478
Vimentin protein is a factor for decreasing breast cancer cell proliferation co-culture with human bone
marrow-derived mesenchymal stem cells pre-treated with thiazolidinedione solutions
By: Kwok, Lim Shern; Yian, Shim Siang; Ismael, Layla Qasim; Bee, Yvonne Tee Get; Harn, Gam Lay; Yin, Khoo Boon
Abstract: Background: Our previous study invest igated the levels of soluble growth factors in the condit ioned media of bone
marrow-derived mesenchymal stem cells (BMSCs) pre-treated with thiazolidinedione solutions The present study aimed to invest
igate the complex intracellular proteins extracted from B MSCs pre-treated with pioglitazone and/or rosiglitazone using proteomics.
Methods: The proliferative effect of the identified protein on M CF-7 cells that interacted non-adhesively with BMSCs pre-treated
with pioglitazone and/or rosiglitazone was evaluated using cell culture inserts and condit ioned media. The mRNA expression of
proliferation and lipid accumulation markers was also evaluated in the interacted M CF-7 cells by reverse transcr iption-quant. PCR.
Finally, the correlation between the identified protein and fibroblast growth factor 4 (F GF-4) protein in the condit ioned media of the
pre-treated BMSCs was evaluated by E LISA. Results: The present study identified vimentin as the specific protein among the
complex intracellular proteins that likely plays a role in M CF-7 cell proliferation when the breast cancer cells interacted non-
adhesively with BMSCs pre-treated with a combin ation of pioglitazone and rosiglitazone. The inhibition of this protein promoted
the proliferation of MCF-7 cells when the breast cancer cells interacted with pre- treated BMSCs. Gene expression anal. indicated
that pre-treatment of BMSCs with a combin ation of pioglitazone and rosiglitazone decreased the mRNA expression of Ki67 and
proliferating cell nuclear antigen in M CF-7 cells. The pretreatment did not induce m RNA expression of PPARγ, which is a sign of
lipid accumulation. The level of vimentin protein was also associated with the F GF-4 protein expression level in the condit ioned
media of the pre-treated BMSCs. Bioinformatics anal. revealed that vimentin regulated the expression of FGF-4 through its intera
ction with SRY-box 2 and POU class 5 homeobox 1. Conclu sions: The present study identified a novel intrace llular protein that may
represent the promising target in pre-treated BMSCs to decrease the proliferation of breast cancer M CF-7 cells for human health
and wellness.
Keywords: Cell proliferation; FGF-4; Lipid accumulation; MCF-7 cells; PPARγ; Pre-treated bone marrow-derived mesenchymal stem
cells; Thiazolidinediones; Vimentin

479
The m 6A demethylases FTO and ALKBH5 aggravate the malignant progression of nasopharyngeal
carcinoma by coregulating ARHGAP35
By: Yang, Zhiyuan; Zhang, Siyu; Xiong, Jiayan; Xia, Tian; Zhu, Rui; Miao, Mengyu; Li, Keying; Chen, Wenyue; Zhang, Lin; You, Yiwen; et
al
Abstract: N6-methyladenosine (m 6A) is an RNA modification that can be removed by demeth ylases [fat mass and obesity- associated
protein (FTO) and AlkB homolog 5 (ALKBH5)], which regulate gene expression and cell function. We show that m 6A levels and m6A
demethylase levels are altered in nasopharyngeal carcinoma (NPC) tissues vs. normal tissues. High F TO and ALKBH5 predict a poor
prognosis in NPC patients. Silencing F TO and ALKBH5 inhibited the malignant behavior of patient-derived NPC cells in a short time.
However, as time progressed, the inhibitory effect of FTO or ALKBH5 was weakened, and the cosilencing of FTO and ALKBH5
maintained a better inhibitory effect. Combined transcriptome and m 6A-seq anal. revealed a downstream target gene that was
jointly regulated by FTO and ALKBH5 in NPC, and ARHGAP35 was chosen to do further study. The synerg istic silencing of FTO and AL
KBH5 increased the methylation level on the mRNA CDS of a new transcr iption factor (ARHGAP35) and pos. regulate the protein
coding capacity and mRNA stability of A RHGAP35, thus leading to increased expression of A RHGAP35 and inhibition of the
malignant phenotype of tumor cells. Our study revealed that the growth and metastasis of NPC can be stably inhibited through
synergistic silencing of the demethylases FTO and ALKBH5, which play a pos. role in the treatment of N PC by regulating the
downstream transcript ARHGAP35 and increasing its m 6A level.

480
ANGPTL4 regulates ovarian cancer progression by activating the ERK1/2 pathway
By: Xu, Jiaqi; Wu, Fei; Zhu, Yue; Wu, Tiantian; Cao, Tianyue; Gao, Wenxin; Liu, Meng; Qian, Weifeng; Feng, Guannan; Xi, Xiaoxue; et al
Abstract: Background: Ovarian cancer (OC) has the highest mortality rate among all gynecol. maligna ncies. A hypoxic microenv
ironment is a common feature of solid tumors, including ovarian cancer, and an important driving factor of tumor cell survival and
chemo- and radiotherapy resistance. Previous research identified the hypoxia- associated gene angiopoietin-like 4 (ANGPTL4) as
both a pro-angiogenic and pro-metastatic factor in tumors. Hence, this work aimed to further elucidate the contri bution of ANGPT
L4 to OC progression. Methods: The expression of hypoxia- associated ANGPTL4 in human ovarian cancer was examined by bioinfo
rmatics anal. of TCGA and GEO datasets. The CIBERSORT tool was used to analyze the distri bution of tumor-infiltrating immune
cells in ovarian cancer cases in TCGA. The effect of A NGPTL4 silencing and overexp ression on the proliferation and migration of OVC
AR3 and A2780 O C cells was studied in vitro, using C CK-8, colony formation, and Transwell assays, and in vivo, through s.c. tumorig
enesis assays in nude mice. G O enrichment anal. and WGCNA were performed to explore biol. processes and genetic networks
associated with ANGPTL4. The results obtained were corrob orated in OC cells in vitro by western blotting. Results: Screening of
hypoxia-associated genes in O C-related TCGA and GEO datasets revealed a signif icant neg. association between ANGPTL4
expression and patient survival. Based on CIBERSORT anal., differential representation of 14 distinct tumor-infiltrating immune cell
types was detected between low- and high-risk patient groups. Silencing of A NGPTL4 inhibited OVCAR3 and A2780 cell prolife ration
and migration in vitro and reduced the growth rate of xenografted OVCAR3 cells in vivo. Based on results from W GCNA and
previous studies, western blot assays in cultured OC cells demonstrated that ANGPTL4 activates the Extracellular signal-related
kinases 1 and 2 (ERK1/2) pathway and this results in upregu lation of c-Myc, Cyclin D1, and M MP2 expression. Suggesting that the
above mechanism mediates the pro-oncogenic actions of ANGPTL4T in OC, the pro-survival effects of ANGPTL4 were largely
abolished upon inhibition of ERK1/2 signaling with P D98059. Conclusions: Our work suggests that the hypoxia- associated gene AN
GPTL4 stimulates OC progression through activation of the ERK1/2 pathway. These findings may offer a new prospect for targeted
therapies for the treatment of OC.
Keywords: ANGPTL4; ERK1/2; Ovarian cancer; Tumorigenesis
481
Cracking the code of seasonal seawater biofouling: enhanced biofouling control with quorum sensing
inhibitor-functionalized membranes
By: Chen, Chao; Yang, Yu ; Choo, Kwang-Ho ; Ng, How Yong; Takizawa, Satoshi; Hou, Li-an
npj Clean Water (2024), 7(1), 12 | Language: English, Database: CAplus
Abstract: Membrane biofouling poses an ongoing challenge in seawater reverse osmosis (SWRO) desalination. Here we delved into
the impact of seasonal variations in microbial communities on membrane biofouling and innova tively fabricated quorum sensing
inhibitors (acylase (AC) and Me anthranilate (MA))-modified membranes to combat it. Results indicated that Proteobacteria
dominated in seawater and membrane biofilm across all seasons, while other phyla varied seasonally. At the class level, the two
leading bacteria on the membrane were Gamma- and Alphaproteobacteria, constituting 14-48% and 4- 27%, resp. Genera like
Arcobacter, Vibrio, and Rhodobac teraceae were identified as keystone species that exhibited a signif icant pos. correlation with
extracellular polymeric substance (EPS) and biofilm formation, leading to a substa ntive reduction in membrane flux by 70 to 77%.
The introduction of AC and M A inhibitors on the membrane suppressed keystone bacteria Rhodobac teraceae and Arcobacter and
affected their metabolism, thereby significantly reducing EPS by 65- 69% and 55- 59%, resp., and alleviating membrane flux decline
by 30-32% and 18- 22%, resp., compared to the pristine membrane. These findings shed new light on the seasonal patterns of
membrane biofouling and provide valuable insights into anti-biofouling strategies based on Q S inhibition for collaborative biofilm
formation.

482
Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations
using the Delphi technique
By: Gallagher, Emily J. ; Moore, Heather ; Lacouture, Mario E.; Dent, Susan F.; Farooki, Azeez; Goncalves, Marcus D. ; Isaacs,
Claudine ; Johnston, Abigail; Juric, Dejan ; Quandt, Zoe; et al
npj Breast Cancer (2024), 10(1), 12 | Language: English, Database: CAplus and MEDLINE
Abstract: Hyperglycemia and rash are expected but challe nging adverse events of phosphatidylinositol-3-kinase inhibition (such as
with alpelisib). Two modified Delphi panels were conducted to provide consensus recommen dations for managing hypergl ycemia
and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1- to-9 scale; median scores and
dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is approp riate to start alpelisib in patients
with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hypergl ycemia, if they have a pre-treatment endocrinol.
consult. Recommend prophylactic metformin in patients with baseline Hb A1c 5.7% to 6.4%. Metformin is the preferred first- line
anti-hyperglycemic agent. Per the rash panel, initiate prophy lactic nonsedating H1 antihistamines in patients starting alpelisib.
Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clin. trial evidence,
these recommendations will help address gaps encoun tered in clin. practice.
483
Deletion of Aurora kinase A prevents the development of polycystic kidney disease in mice
By: Tham, Ming Shen ; Cottle, Denny L. ; Zylberberg, Allara K.; Short, Kieran M. ; Jones, Lynelle K.; Chan, Perkin; Conduit,
Sarah E. ; Dyson, Jennifer M.; Mitchell, Christina A. ; Smyth, Ian M.
Abstract: Aurora Kinase A (AURKA) promotes cell prolife ration and is overexpressed in different types of polycystic kidney disease (P
KD). To understand A URKA′s role in regulating renal cyst develo pment we conditionally deleted the gene in mouse models of
Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polypho sphate-5-phosph
atase E (Inpp5e) mutations resp. We show that while Aurka is dispen sable for collecting duct development and homeostasis, its
deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in
cyst prevention and we show that (i) AURKA and AKT phys. interact, (ii) A URKA regulates A KT activity in a kinase-independent
manner and (iii) inhibition of AKT can reduce disease severity. A KT activation also regulates Aurka expres sion, creating a feed-
forward loop driving renal cystoge nesis. We find that the AURKA kinase inhibitor Alisertib stabilizes the A URKA protein, agonizing its
cystogenic functions. These studies identify AURKA as a master regulator of renal cyst develo pment in different types of PKD, functi
oning in-part via AKT.

484
Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance
By: Lee, Hyemin ; Horbath, Amber ; Kondiparthi, Lavanya; Meena, Jitendra Kumar ; Lei, Guang ; Dasgupta, Shayani; Liu,
Xiaoguang ; Zhuang, Li; Koppula, Pranavi ; Li, Mi ; et al
Abstract: How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell
cycle arrest has a potent suppressive effect on ferrop tosis, a form of regulated cell death induced by overwh elming lipid peroxi
dation at cellular membranes. Mechanis tically, cell cycle arrest induces diacylg lycerol acyltransferase (DGAT)-dependent lipid droplet
formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylg lycerols (TAGs),
resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from T AGs to phospho
lipids and re-sensitizes arrested cells to ferroptosis. We show that some slow- cycling antimitotic drug-resistant cancer cells, such as
5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferrop tosis inducers and DGAT
inhibitors effectively suppresses the growth of 5- fluorouracil-resistant tumors by inducing ferrop tosis. Together, these results reveal
a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferrop tosis-inducing therapeutic strategy to target slow-
cycling therapy-resistant cancers.
485
Recent advance of microbial mercury methylation in the environment
By: Peng, Xuya; Yang, Yan; Yang, Shu; Li, Lei; Song, Liyan
Abstract: Methylmercury formation is mainly driven by microbial- mediated process. The mechanism of microbial mercury methyl
ation has become a crucial research topic for underst anding methylation in the environment. Pioneering studies of microbial
mercury methylation are focusing on functional strain isolation, microbial community compos ition characterization, and
mechanism elucidation in various environments. Therefore, the functional genes of microbial mercury methyl ation, global isolations
of Hg methylation strains, and their methyl ation potential were systematically analyzed, and methylators in typical environments
were extensively reviewed. The main drivers (key physic ochem. factors and microbiota) of microbial mercury methyl ation were
summarized and discussed. Though significant progress on the mechanism of the Hg microbial methyl ation has been explored in
recent decade, it is still limited in several aspects, including (1) mol. biol. techniques for identifying methylators; (2) characterization
methods for mercury methylation potential; and (3) complex environ mental properties (environ mental factors, complex commun
ities, etc.). Accordingly, strategies for studying the Hg microbial methyl ation mechanism were proposed. These strategies include
the following: (1) the development of new mol. biol. methods to charac terize methylation potential; (2) treating the environment as
a micro-ecosystem and studying them from a holistic perspe ctive to clearly understand mercury methyl ation; (3) a more reasonable
and sensitive inhibition test needs to be considered. Key points: • Global Hg microbial methyl ation is phylogenetically and functi
onally discussed. • The main drivers of microbial methyl ation are compared in various condition. • Future study of Hg microbial
methylation is proposed. Graphical Abstract: [graphic not available: see fulltext]
Keywords: Driving factors; Functional genes; Functional strains; Mercury methylation; Methylation mechanism; Methylation
potential

486
The therapeutically actionable long non-coding RNA ′T-RECS′ is essential to cancer cells′ survival in
NRAS/MAPK-driven melanoma
By: Feichtenschlager, Valentin; Chen, Linan; Zheng, Yixuan James; Ho, Wilson; Sanlorenzo, Martina; Vujic, Igor; Fewings, Eleanor; Lee,
Albert; Chen, Christopher; Callanan, Ciara; et al
Molecular Cancer (2024), 23(1), 40 | Language: English, Database: CAplus and MEDLINE
Abstract: Finding effective therapeutic targets to treat N RAS-mutated melanoma remains a challenge. Long non- coding RNAs (lncRN
As) recently emerged as essential regulators of tumorig enesis. Using a discovery approach combining exptl. models and unbiased
computational anal. complemented by validation in patient biospec imens, we identified a nuclear- enriched lncRNA (AC004540.4)
that is upregulated in N RAS/MAPK-dependent melanoma, and that we named T- RECS. Considering potential innovative treatment
strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells
and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-R
ECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hn RNPA2/B1, a pro-oncogenic
regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demons trated that systemic
treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. A SO-mediated T-
RECS inhibition represents a promising R NA-targeting approach to improve the outcome of M APK pathway-activated melanoma.
Keywords: Antisense oligonucleotides; Apoptosis; HT-KAM; MAPK-pathway; Melanoma; T-RECS; hnRNPA2/B1; lncRNA
487
Folic acid-functionalized PEGylated niosomes co-encapsulated cisplatin and doxoribicin exhibit

enhanced anticancer efficacy
By: Safari Sharafshadeh, Mona; Tafvizi, Farzaneh; Khodarahmi, Parvin; Ehtesham, Somayeh
Cancer Nanotechnology (2024), 15(1), 14 | Language: English, Database: CAplus
Abstract: The medical field is faced with the difficult task of developing a new approach to curing cancer, which is prevalent in
organs such as the breast and ovaries and has a high mortality rate. Since chemotherapy is the conventional method of treatment,
efforts are being made to improve it to help patients function better. Fortunately, with the use of nanoca rriers and their remarkable
ability to manage and direct drug delivery, progress is being made in cancer treatment. In addition, folic acid-coated nanocarriers
offer several advantages in drug delivery, including improved stability, bioavailability, targeted delivery and drug solubility These
properties make them promising tools for improving cancer treatment efficacy. This research focused on investigating the stability
of a specific niosomal formulation (consisting of Span 60 and choles terol) under different temperature conditions (4 and 25 °C) for
2 mo. In addition, the drug release rate of the formulation was evaluated. The results showed that the size and polydis persity index
increased significantly in the stability studies, but the entrapment effici ency% decreased dramat ically over time. In addition,
encapsulation of drugs in niosomal formul ations resulted in stable and slow drug release. The cytoto xicity evaluation results of
formulations containing doxorubicin and cisplatin show their signif icant inhibitory effect on both breast and ovarian cancer cell lines
(IC50 for DOX-CIS-Nio@PEG-FA formulation was 6.11 and 17.87 μg/m L for A2780 and M CF-7, resp.). Niosomes loaded with a combin
ation of two drugs were found to affect gene expression in the cancer cell lines tested. They decreased the expression of B Cl2, VEG
F, CCND1, and HER2 genes while increasing the expression of B AX gene. Flow cytometry results indicated that niosomes loaded
with doxorubicin and cisplatin increased the rate of apoptosis in both cell lines compared to a drug mixture R OS and cell cycle
arrest, confirm the significant inhibition of cancer cells and their destru ction in the presence of the synthe sized noisome formul
ation in comparison to free drugs and the combin ation of two drugs. The potential of this novel approach for delivering drugs to
cancer cells lies in the ability to combine treatments and target multiple cancers simultaneously. Such formulations allow co-
delivery of drugs to different cancer cells, thereby improving the efficacy of chemot herapy through synergistic effects between
drugs. Graphical Abstract: [graphic not available: see fulltext]

488
Identification of CD8 + T-cell exhaustion signatures for prognosis in HBV-related hepatocellular

carcinoma patients by integrated analysis of single-cell and bulk RNA-sequencing
By: Li, Jianhao; Chen, Han; Bai, Lang; Tang, Hong

Abstract: Background: HBV infection is the leading risk factor for H CC. HBV infection has been confirmed to be associated with the
exhaustion status of CD8+ T cells and immunothe rapeutic efficacy in HCC. In this study, we aimed to invest igate the prognostic value
of the CD8+ T-cell exhaustion signature and immunotherapy response in patients with H BV-related HCC. Methods: We identified
different clusters of HBV-related HCC cells by single-cell RNA sequencing (scRNA-seq) and identified C D8+ T-cell exhaustion-related
genes (TERGs) by pseudotime anal. We conducted differ ential expression anal. and LASSO Cox regression to detect genes and
construct a CD8+ T-cell exhaustion index (T EI). We next combined the T EI with other clinico pathol. factors to design a prognostic
nomogram for HCC patients. We also analyzed the difference in the T EI between the non-responder and responder groups during
anti-PD-L1 therapy. In addition, we investigated how HBV induces CD8+ T lymphocyte exhaustion through the inhibition of tyrosine
metabolism in HCC using gene set enrichment anal. and R T-qPCR. Results: A C D8+ T-cell exhaustion index (T EI) was established with
5 TERGs (EEF1E1, GAGE1, CHORDC1, IKBIP and MAGOH). An AFP level > 500 ng, vascular invasion, histol. grade (G3- G4), advanced TN
M stage and poor five- year prognosis were related to a higher T EI score, while HBV infection was related to a lower T EI score.
Among those receiving anti-PD-L1 therapy, responders had lower T EIs than non-responders did. The TEI also serves as an indepe
ndent prognostic factor for HCC, and the nomogram incorpo rating the TEI, TNM stage, and vascular invasion exhibited excellent
predictive value for the prognosis in HCC patients. R T-qPCR revealed that among the tyrosine metabo lism-associated genes, TAT
(tyrosine aminotransferase) and HGD (homogentisate 1,2 dioxygenase) were expressed at lower levels in H BV-HCC than in non-HBV
HCC. Conclusion: Generally, we established a novel TEI model by comprehe nsively analyzing the progression of CD8+ T-cell exhaus
tion, which shows promise for predicting the clin. prognosis and potential immunothe rapeutic efficacy in HBV-related HCC patients.
Keywords: CD8+ T cell exhaustion signat ures; HBV-related hepatocellular carcinoma; Immunotherapy; Prognosis
489
MiR-383 sensitizes osteosarcoma cells to bortezomib treatment via down-regulating PSMB5
By: Wang, Haifan; Bai, Chuanyi; Dang, Xiaoqian; Wang, Haoyu

Abstract: Background: Proteasome inhibition is a promising strategy for cancer therapy. Bortez omib, which primarily targets the
chymotrypsin-like activity of PSMB5, has demonstrated efficacy in various tumors. However, there is variable sensit ivity to bortez
omib, which could be attributed, in part, to variations in the expression of proteasome subunits. Methods and results: In this study,
we investigated whether miR-383 affects the expression of proteasome subunits in osteosarcoma (OS) cells, and if so, whether O S
cells display differential sensitivity to bortezomib concerning mi R-383 expression. We detected a decreased mi R-383 expression in O
S cells and tissues. Then we found a neg. correl ation between the cytotoxicity of bortezomib and the expression level of the
proteasome 20S core particle subunit β5 (P SMB5). Intriguingly, we identified P SMB5 as a direct target of mi R-383. Increased
expression of miR-383 resulted in decreased P SMB5 expression and increased sensitivity to bortezomib in O S cells. Conclu sions: In
summary, our findings present the initial comprehensive anal. of the function of miR-383 in OS. The outcomes indicate that mi R-383
may augment the anticancer effect of bortezomib through PSMB5 repression, offering a novel therapeutic approach in O S and a
fresh pathway for proteasome regulation.
Keywords: Bortezomib; MicroRNA-383; Osteosarcoma; PSMB5; Sensitivities

490
Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc
degeneration through both cell autonomous and non-autonomous mechanisms
By: Zhang, Lei; Hu, Siyuan; Xiu, Chunmei; Li, Meng; Zheng, Yixin; Zhang, Rui; Li, Bin; Chen, Jianquan
Abstract: Intervertebral disk degeneration is closely related to abnormal phenotypic changes in disk cells. However, the mechanism
by which disk cell phenotypes are maintained remains poorly understood. Here, Hedgehog-responsive cells were found to be specif
ically localized in the inner annulus fibrosus and cartila ginous endplate of postnatal disks, likely activated by Indian Hedgehog.
Global inhibition of Hedgehog signaling using a pharmacol. inhibitor or Agc1- CreERT2-mediated deletion of Smo in disk cells of
juvenile mice led to spontaneous degenerative changes in annulus fibrosus and cartila ginous endplate accompanied by aberrant
disk cell differentiation in adult mice. In contrast, Krt19- CreER-mediated deletion of Smo specifically in nucleus pulposus cells led to
healthy disks and normal disk cell phenotypes. Similarly, age-related degeneration of nucleus pulposus was accelerated by genetic
inactivation of Hedgehog signaling in all disk cells, but not in nucleus pulposus cells. Furthe rmore, inactivation of Gli2 in disk cells
resulted in partial loss of the vertebral growth plate but otherwise healthy disks, whereas deletion of Gli3 in disk cells largely
corrected disk defects caused by Smo ablation in mice. Taken together, our findings not only revealed for the first time a direct role
of Hedgehog-Gli3 signaling in mainta ining homeostasis and cell phenotypes of annuls fibrosus and cartila ginous endplate, but also
identified disk-intrinsic Hedgehog signaling as a novel non- cell-autonomous mechanism to regulate nucleus pulposus cell
phenotype and protect mice from age-dependent nucleus pulposus degeneration. Thus, targeting Hedgehog signaling may
represent a potential therapeutic strategy for the prevention and treatment of interve rtebral disk degeneration.
Keywords: Chondrocyte-like cells; Dis cell differen tiation; Gli3 repressor; Intervertebral disc homeostasis; Low back pain; Shh
signaling
491
Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence
By: Sun, Di-Yang ; Wu, Wen-Bin ; Wu, Jian-Jin ; Shi, Yu ; Xu, Jia-Jun; Ouyang, Shen-Xi; Chi, Chen ; Shi, Yi; Ji, Qing-Xin ;
Miao, Jin-Hao ; et al
Abstract: Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting
arterial remodelling and stiffness. Ferrop tosis is a novel type of regulated cell death associated with lipid oxidation Here, we show
that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular N AD+ loss, remodelling and aging. Pro-ferroptotic
signaling is triggered in senescent VSMCs and arteries of aged mice. Furthe rmore, the activation of pro-ferroptotic signaling in V SM
Cs not only induces N AD+ loss and senescence but also promotes the release of a pro- senescent secretome. Pharmacol. or genetic
inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progre ssion of
abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facili tates the nuclear-
cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coacti vator 4-ferrtin complex-
centric ferritinophagy. Finally, the activated pro- ferroptotic signaling correlates with arterial stiffness in a human proof- of-concept
study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferrop tosis in
senescence- or aging-associated cardiovascular diseases.

492
Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin

resistance by inhibiting caspase-dependent apoptosis in colorectal cancer
By: Huang, Yuting; Chan, Szehoi; Chen, Shuna; Liu, Xueqi; Li, Miao; Zheng, Liyuan; Dong, Zhaoxia; Yang, Ziyi; Liu, Zixuan; Zhou,
Disheng; et al
Abstract: Background: Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (C RC), while
the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resist ance, however,
the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the
functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC. Methods: An oxaliplatin-resistant CR
C cell line was generated, and untargeted metabo lomics anal. was conducted. The I MP dehydrogenase type II (IMPDH2) expression
in CRC cell lines was determined by quant. real- time polymerase chain reaction (qPCR) and western blotting anal. The effects of I MP
DH2 overexpression, knockdown and pharmacol. inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry anal.
of cell apoptosis in vivo and in vitro. Results: Metabolic anal. revealed that the levels of purine metabolites, especially guanosine
monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabo lites mainly
arose from the upregulation of IMPDH2 expression. Gene set enrichment anal. (GSEA) indicated high IMPDH2 expression in CRC
correlates with PURINE_Metab. and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher I MPDH2 expression were more
resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment
with oxaliplatin, whereas knockdown of I MPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the
Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (M PA) or mycophenolate
mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumor burden when combined with oxalip latin treatment.
Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal pos. regulatory
mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resens itize resistant cells to
oxaliplatin, which could be restored by the addition of G MP. Conclusions: IMPDH2 is a predictive biomarker and therap eutic target
for oxaliplatin resistance in CRC.
Keywords: Apoptosis; Colorectal cancer; IMPDH2; Oxaliplatin resistance; Purine metabo lism; β‑catenin

493
Effects of poly (ADP-ribose) polymerase inhibitor treatment on the repair process of ischemic acute
kidney injury
By: Jeon, Junseok; Lee, Kyungho; Jang, Hye Ryoun; Yang, Kyeong Eun; Lee, Cheol-Jung; Ahn, Hyeonju; Park, Woong-Yang; Lee, Jung
Eun; Kwon, Ghee Young; Kim, Yoon-Goo; et al
Abstract: Excessive activation of poly (ADP-ribose) polymerase (PARP) contributes to ischemic acute kidney injury (A KI). PARP
inhibition has been shown to be beneficial in renal ischemia- reperfusion injury (IRI) in the early phase, but its role in the repair
process remains unclear. The effects of JPI-289, a novel PARP inhibitor, during the healing phase after renal I RI were investigated. IRI
was performed on 9-wk-old male C57BL/6 mice. Saline or J PI-289 100 mg/kg was i.p. admini stered once at 24 h or addnl. at 48 h
after IRI. Hypoxic HK-2 cells were treated with J PI-289. Renal function and fibrosis extent were comparable between groups. J PI-289
treatment caused more prominent tubular atrophy and proinflammatory intrarenal leukocyte phenotypes and cytokines/
chemokines changes at 12 wk after unilateral I RI. JPI-289 treatment enhanced gene expres sions associated with collagen formation,
toll-like receptors, and the immune system in proximal tubules and endoth elial cells after IRI. JPI-289 treatment at 3 or 6 h after
hypoxia facilitated proliferation of hypoxic HK-2 cells, whereas further treatment after 24 h suppressed prolife ration. Delayed
inhibition of PARP after renal IRI did not facilitate the repair process during the early healing phase but rather may aggravate renal
tubular atrophy during the late healing phase in ischemic AKI.
494
Early endocannabinoid-mediated depolarization-induced suppression of excitation delays the

appearance of the epileptic phenotype in synapsin II knockout mice
By: Forte, Nicola; Nicois, Alessandro; Marfella, Brenda; Mavaro, Isabella; D′Angelo, Livia; Piscitelli, Fabiana; Scandurra, Anna; De
Girolamo, Paolo; Baldelli, Pietro; Benfenati, Fabio; et al
Abstract: The mechanism underlying the transition from the pre-symptomatic to the symptomatic state is a crucial aspect of
epileptogenesis. SYN2 is a member of a multigene family of synaptic vesicle phosphop roteins playing a fundam ental role in contro
lling neurotransmitter release. Human SYN2 gene mutations are associated with epilepsy and autism spectrum disorder. Mice
knocked out for synapsin II (SynII KO) are prone to epileptic seizures that appear after 2 mo of age. However, the involv ement of
the endocannabinoid system, known to regulate seizure develo pment and propagation, in the modulation of the excitatory/inh
ibitory balance in the epileptic hippoc ampal network of SynII KO mice has not been explored. In this study, we invest igated the
impact of endocannabinoids on glutamatergic and GABAergic synapses at hippocampal dentate gyrus granule cells in young pre-
symptomatic (1-2 mo old) and adult sympto matic (5-8 mo old) SynII KO mice. We observed an increase in endocann abinoid-
mediated depolarization-induced suppression of excitation in young Syn II KO mice, compared to age-matched wild-type controls. In
contrast, the endocannabinoid-mediated depolarization-induced suppression of inhibition remained unchanged in Syn II KO mice
at both ages. This selective alteration of excitatory synaptic transmission was accompanied by changes in hippocampal endocann
abinoid levels and cannabinoid receptor type 1 distri bution among glutamatergic and GABAergic synaptic terminals contacting the
granule cells of the dentate gyrus. Finally, inhibition of type-1 cannabinoid receptors in young pre- symptomatic SynII KO mice
induced seizures during a tail suspension test. Our results suggest that endocannabinoids contribute to mainta ining network
stability in a genetic mouse model of human epilepsy.
Keywords: CB1; Dentate gyrus; Endocannabinoids; Epileptogenesis

495
Ganoderma lucidum polysaccharide ameliorates cholesterol gallstone formation by modulating

cholesterol and bile acid metabolism in an FXR-dependent manner
By: Huang, Dan; Shen, Shuang; Zhuang, Qian; Ye, Xin; Qian, Yueqin; Dong, Zhixia; Wan, Xinjian
Abstract: Background: Cholesterol gallstone (CG) disease is a worldwide common disease charact erized by cholesterol supersat
uration in gallbl adder bile. Ganoderma lucidum polysaccharide (GLP) has been shown to possess various beneficial effects against
metabolic disorders. However, the role and underlying mechanism of GLP in CG formation are still unknown. This study aimed to
determine the role of GLP in ameliorating lithogenic diet (LD)-induced CG formation. Methods: Mice were fed either a normal chow
diet, a LD, or LD supplemented with GLP. Real-time quant. polymerase chain reaction (RT-qPCR) and western blotting were used to
detect the expression of genes involved in cholesterol and bile acid (BA) metabolism The BA concentrations in the ileum were
quantified by liquid chromatog.-tandem mass spectrometry (LC-MS/MS). The microbiota in cecal contents were charact erized using
16S rRNA (16S rRNA) gene sequencing. Results: GLP effectively alleviated CG formation induced by LD. Specifically, GLP reduced the
total cholesterol (TC) levels, increased the total B A levels, and decreased the choles terol saturation index (CSI) in gallbladder bile.
The protective effect of GLP was attributed to the inhibition of farnesoid X receptor (F XR) signaling, increased hepatic B A synthesis
and decreased hepatic cholesterol synthesis and secretion. G LP also altered the BA composition in the ileum, reducing FXR-
agonistic BAs and increasing F XR-antagonistic BAs, which may contribute to the inhibition of intestinal FXR signaling. Addnl., GLP
improved dysbiosis of the intestinal flora and reduced the serum levels of hydrogen sulfide (H2S), a bacterial metabolite that can
induce hepatic FXR, thereby inhibiting hepatic F XR signaling. Moreover, the protective effect of G LP against CG formation could be
reversed by both the global and gut-restricted FXR agonists. Conclu sions: Taken together, GLP ameliorates CG formation by
regulating cholesterol and BA metabolism in an FXR-dependent manner. Our study demonstrates that GLP may be a potential
strategy for the prevention against CG disease.
Keywords: Bile acids; Cholesterol; Cholesterol gallstones; Farnesoid X receptor; Ganoderma lucidum polysaccharide; Intestinal flora

496
Interplay between androgen and CXCR4 chemokine signaling in myelin repair
By: Asbelaoui, Narimene; Abi-Ghanem, Charly; Schlecht-Louf, Geraldine; Oukil, Hania; The Netherlands Brain Bank; Schumacher,
Michael; Ghoumari, Abdel Mouman
Acta Neuropathologica Communications (2024), 12(1), 18 | Language: English, Database: CAplus and MEDLINE
Abstract: In men, reduced levels of testosterone are associated with the prevalence and progre ssion of multiple sclerosis (M S), a
chronic and disabling demyelinating disorder. Testosterone has been shown to promote myelin repair. Here, we demons trate that
the cooperation between testos terone and CXCR4 signaling involving astrocytes is required for myelin regene ration after focal
demyelination produced in the ventral mouse spinal cord by the infusion of lysolec ithin. The testosterone-dependent remyelination
of axons by oligodendrocytes was accompanied by an increase in astrocytes expressing C XCR4, its ligand C XCL12 and the androgen
receptor (AR) within the demyelinated area. Depriving males of their testos terone or pharmacol. inhibition of CXCR4, with the
selective antagonist AMD3100, prevented the appearance of astrocytes expressing C XCR4, CXCL12 and AR within the demyelinated
area and the concomitant recruitment of myelin forming oligodend rocytes. Conditional genetic ablation of either CXCR4 or AR in
astrocytes also completely blocked the formation of new myelin by oligodendrocytes. Interestingly, the gain of function mutation in
CXCR4 causing WHIM syndrome allows remyeli nation to take place, even in the absence of testost erone, but its potentiating effects
remained observable. After testosterone deprivation or CXCR4 inhibition , the absence of astrocytes within the demyel inated area
led to the incursion of Schwann cells, most likely derived from spinal nerves, and the formation of peripheral nerve type myelin. In
patients with progressive MS, astrocytes expressing CXCR4 and AR surrounded myelin lesions, and their presence opposed the
incursion of Schwann cells. These results highlight a mechanism of promyelinating testosterone signaling and the importance of
normalizing its levels in combined myelin repair therapies.
Keywords: Androgen receptor; Astrocytes; Chemokine receptor; Remyelination; Schwann cells; Testos terone

497
Prunella vulgaris polysaccharide inhibits herpes simplex virus infection by blocking TLR-mediated NF-
κB activation
By: Zhong, Xuanlei; Zhang, Yibo; Yuan, Man; Xu, Lin; Luo, Xiaomei; Wu, Rong; Xi, Zhichao; Li, Yang; Xu, Hongxi
Prunella vulgaris polysaccharide extracted by hot water and 30% ethanol precipi tation (PVE30) was reported to possess potent
antiviral effects against herpes simplex virus (HSV) infection. However, its anti-HSV mechanism has not yet been fully elucid ated.
This study aimed to investigate the potential mechanisms of PVE30 against HSV infection. Antiviral activity was evaluated by a
plaque reduction assay, and the EC50 value was calculated Immunofluorescence staining and heparin bead pull- down assays
confirmed the interactions between PVE30 and viral glycopr oteins. Real-time PCR was conducted to determine the m RNA levels of
viral genes, including UL54, UL29, UL27, UL44, and US6, and the proinflammatory cytokines IL-6 and TN F-α . The protein
expression of viral proteins (ICP27, ICP8, gB, gC, and gD), the activity of the TLR-NF-κB signalling pathway, and necrop totic-
associated proteins were evaluated by Western blotting. The proportion of necrop totic cells was determined by flow cytometric
anal. The P. vulgaris polysaccharide PVE30 was shown to compete with heparan sulfate for intera ction with HSV surface glycop
rotein B and g C, thus strongly inhibiting H SV attachment to cells. In addition, PVE30 downregulated the expression of IE genes,
which subsequently downregulated the expression of E and L viral gene products, and thus effect ively restricted the yield of
progeny virus. Further investigation confirmed that PVE30 inhibited T LR2 and T LR3 signalling, leading to the effective suppre ssion of
NF-κB activation and IL-6 and TN F-α expression levels, and blocked H SV-1-induced necroptosis by reducing HSV-1-induced
phosphorylation of MLKL. Our results demonstrate that the P. vulgaris polysaccharide PVE30 is a potent anti-HSV agent that blocks
TLR-mediated NF-κB activation.
Keywords: herpes simplex virus infection Prunella vulgaris toll like receptor; necroptosis polysaccharide; Herpes simplex virus;
Necroptosis; Prunella vulgaris polysaccharide; TLR/NF-κB signalling pathway

498
Autoinducer-2 promotes the colonization of Lactobacillus rhamnosus GG to improve the intestinal

barrier function in a neonatal mouse model of antibiotic-induced intestinal dysbiosis
By: Hu, Riqiang; Yang, Ting; Ai, Qing; Shi, Yuan; Ji, Yanchun; Sun, Qian; Tong, Bei; Chen, Jie; Wang, Zhengli
Abstract: Background: Human health is seriously threatened by antibi otic-induced intestinal disorders. Herein, we aimed to
determine the effects of Autoinducer-2 (AI-2) combined with Lactobacillus rhamnosus GG (LGG) on the intestinal barrier function of
antibiotic-induced intestinal dysbiosis neonatal mice. Methods: An antibi otic-induced intestinal dysbiosis neonatal mouse model
was created using antibiotic cocktails, and the model mice were randomized into the control, AI-2, LGG, and LGG + AI-2 groups.
Intestinal short-chain fatty acids and AI-2 concentrations were detected by mass spectr ometry and chemiluminescence, resp. The
community composition of the gut microbiota was analyzed using 16 S rDNA sequencing, and biofilm thickness and bacterial
adhesion in the colon were assessed using SEM. Transcriptome RNA sequencing of intestinal tissues was performed, and the m RNA
and protein levels of HCAR2 (hydroxycarboxylic acid receptor 2) , claudin3, and claudin4 in intestinal tissues were determined using
quant. real-time reverse transcription PCR and western blotting. The levels of inflam matory factors in intestinal tissues were
evaluated using enzyme-linked immunosorbent assays (ELISAs). D-ribose, an inhibitor of AI-2, was used to treat Caco-2 cells in vitro.
Results: Compared with the control, AI-2, and LGG groups, the LGG + AI-2 group showed increased levels of intestinal A I-2 and
proportions of Firmicutes and Lacticasei bacillus, but a reduced fraction of Proteoba cteria. Specifically, the LGG + AI-2 group had
considerably more biofilms and LGG on the colon surface than those of other three groups. Meanwhile, the combin ation of AI-2 and
LGG markedly increased the concentration of butyric acid and promoted Hcar2, claudin3 and claudin4 expression levels compared
with supplementation with LGG or AI-2 alone. The ELISAs revealed a signifi cantly higher tumor necrosis factor alpha ( TN F-α) level
in the control group than in the LGG and LGG + AI-2 groups, whereas the interleukin 10 (IL-10) level was significantly higher in the L
GG + AI-2 group than in the other three groups. In vitro, D- ribose treatment dramat ically suppressed the increased levels of Hcar2,
claudin3, and claudin4 in Caco-2 cells induced by A I-2 + LGG. Conclusions: AI-2 promotes the colonization of LGG and biofilm
formation to improve intestinal barrier function in an antibiotic-induced intestinal dysbiosis neonatal mouse model.
Keywords: Antibiotics-induced intestinal flora; Autoinducer-2; Biofilm; Butyric acid; Hydroxyca rboxylic acid receptor 2; Intestinal
barrier function; Lactobacillus rhamnosus GG; Tight junctions

499
D-Cycloserine enhances the bidirectional range of NMDAR-dependent hippocampal synaptic plasticity
By: Vestring, Stefan ; Dorner, Alexandra; Scholliers, Jonas; Ehrenberger, Konstantin; Kiss, Andrea; Arenz, Luis; Theiss, Alice;
Rossner, Paul; Frase, Sibylle; Du Vinage, Catherine; et al
The partial N-methyl-D-aspartate receptor (N MDAR) agonist D- Cycloserine (DCS) has been evaluated for the treatment of a wide
variety of psychiatric disorders, including dementia, schizop hrenia, depression and for the augmentation of exposure-based
psychotherapy. Most if not all of the potential psychi atric applications of DCS target an enhancement or restitution of cognitive
functions, learning and memory. Their mol. correlate is long-term synaptic plasti city; and many forms of synaptic plasticity depend
on the activation of NMDA receptors. Here, we comprehe nsively examined the modulation of different forms of synaptic plasticity
in the hippocampus by DCS and its mechanism. We found that D CS pos. modulates NMDAR-dependent forms of long-term synaptic
plasticity (long-term synaptic potenti ation, LTP, and long-term synaptic depression, LTD) in hippocampal brain slices of juvenile rats
without affecting basal synaptic transmission. DCS binds to the D- serine/glycine binding site of the N MDAR. Pharmacol. inhibition
of this site prevented the induction of LTP, whereas agonism at the D- serine/glycine binding site augmented L TP and could functi
onally substitute for weak LTP induction paradigms. The most probable origin of endogenous D- serine are astrocytes, and its
exocytosis is regulated by astrocytic metabotropic glutamate receptors (mGluR1). Functional eradication of astrocytes, inhibition of
mGluR1 receptors and G- protein signaling in astrocytes adjacent to postsy naptic neurons prevented the induction of N MDAR-
dependent forms of LTP and LTD. Our results support the enhanc ement of a bidirectional range of N MDAR-dependent hippoc
ampal synaptic plasticity by D CS and D- serine-mediated gliotransmission. Therefore, the D-serine/glycine-binding site in N MDAR is a
major target for psychopharmacol. interventions targeting plasticity-related disorders.
Keywords: cycloserine N MDAR hippocampus synaptic plasticity

500
Current and future therapeutic strategies for high-grade gliomas leveraging the interplay between
epigenetic regulators and kinase signaling networks
By: Stitzlein, Lea M.; Adams, Jack T.; Stitzlein, Erin N.; Dudley, Richard W.; Chandra, Joya
Abstract: Targeted therapies, including small mol. inhibitors directed against aberrant kinase signaling and chromatin regulators,
are emerging treatment options for high-grade gliomas (HGG). However, when translating these inhibitors into the clinic, their
efficacy is generally limited to partial and transient responses. Recent studies in models of high-grade gliomas reveal a conver gence
of epigenetic regulators and kinase signaling networks that often cooperate to promote malignant properties and drug resistance.
This review examines the interplay between five well-characterized groups of chromatin regulators, including the histone deacet
ylase (HDAC) family, bromodomain and extraterminal (BET)-containing proteins, protein arginine methyltransferase (PRMT) family,
Enhancer of zeste homolog 2 (EZH2), and lysine-specific demethylase 1 (LSD1), and various signaling pathways essential for cancer
cell growth and progression. These specific epigenetic regulators were chosen for review due to their targeta bility via pharmacol.
intervention and clin. relevance. Several studies have demons trated improved efficacy from the dual inhibition of the epigenetic
regulators and signaling kinases. Overall, the interactions between epigenetic regulators and kinase signaling pathways are likely
influenced by several factors, including individual glioma subtypes, preexisting mutations, and overlapping/interdependent
functions of the chromatin regulators. The insights gained by underst anding how the genome and epigenome cooperate in high-
grade gliomas will guide the design of future therap eutic strategies that utilize dual inhibition with improved efficacy and overall
survival.
Keywords: Diffuse midline gliomas; Epigenetic regulators; Epigenetically directed therapy; Gliobla stoma; High-grade gliomas;
Targeted therapy
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