Professional Documents
Culture Documents
The Genus Inula
The Genus Inula
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
Review
art ic l e i nf o
a b s t r a c t
Article history:
Received 27 October 2013
Received in revised form
3 April 2014
Accepted 5 April 2014
Available online 19 April 2014
Ethnopharmacological relevance: The genus Inula comprises more than one hundred species widespread in
temperate regions of Europe and Asia. Uses of this genus as herbal medicines have been rst recorded by the
Greek and Roman ancient physicians. In the Chinese Pharmacopoeia, from the 20 Inula spp. distributed in
China, three are used as Traditional Chinese medicines, named Tumuxiang, Xuanfuhua and Jinfeicao. These
medicines are used as expectorants, antitussives, diaphoretics, antiemetics, and bactericides. Moreover, Inula
helenium L. which is mentioned in Minoan, Mycenaean, Egyptian/Assyrian pharmacotherapy and Chilandar
Medical Codex, is good to treat neoplasm, wound, freckles and dandruff. Many other Inula spp. are used in
Ayurvedic and Tibetan traditional medicinal systems for the treatment of diseases such as bronchitis,
diabetes, fever, hypertension and several types of inammation. This review is a critical evaluation of the
published data on the more relevant ethnopharmacological and medicinal uses of Inula spp. and on their
metabolites biological activities. This study allows the identication of the ethnopharmacological knowledge
of this genus and will provide insight into the emerging pharmacological applications of Inula spp. facilitating
the prioritirization of future investigations. The corroboration of the ethnopharmacological applications
described in the literature with proved biological activities of Inula spp. secondary metabolites will also be
explored.
Keywords:
Inula
Traditional medicinal plants
Sesquiterpene lactones
Cytotoxicity
Anti-inammatory
Antimicrobial
Abbreviations: A-549, human lung carcinoma cell line; ABTS, 2,20 -azinobis(3-ethylbenzothiazoline-6-sulfonic acid); AGS, human gastric carcinoma cell line; AHR, airway
hiper-responsiveness; AKT, serine/threonine-specic protein kinase; AMPK, adenosine 50 -monophosphate-activated protein kinase; ATPase, adenosine triphosphatase; B16,
murine melanoma cell line; Bcl-2, apoptosis regulator proteins encoded by the BCL2 gene; Capan-2, human pancreas adenocarcinoma cell line; CC50, 50% cytotoxic
concentration; c-FLIP, cellular FLICE (FADD-like interleukine-1-converting enzyme) inhibitory protein; COX, cyclooxygenase; COX-1, cyclooxygenase-1; COX-2,
cyclooxygenase-2; CVB3, coxsackievirus B3 enterovirus; DNA, deoxyribonucleic acid; DOX, doxorubicin; DPPH, 1,1-diphenyl-2-picrylhydrazyl radical; ED50, effective dose to
produce effect in 50% of a population; G1, astrocytoma cell line; G2/M, cell cycle checkpoint in eukaryotic organisms; GMK, green monkey kidney cell line; GSTs, glutathioneS-transferase; HCT-116, colon carcinoma cell line; HeLa, human cervix cancer cell line; HepG-2, liver hepatocellular carcinoma cell line; HIV/AIDS, human immunodeciency
virus infection/acquired immunodeciency syndrome; HIV-1, human immunodeciency virus type 1; HL-60, human promyelocytic leukemia cell line; HSP70, heat shock
protein 70; HSV-1, herpes Simplex Virus type 1; HT-29, human colon adenocarcinoma grade II cell line; IC50, inhibitory concentration for 50% of viability; ICAM-1,
intracellular adhesion molecule-1; IKK, IB kinase; IKK, IB kinase ; IL-2, Interleukin 2; iNOS, inducible nitric oxide synthase; JNK, c-jun terminal-NH2 kinase; KB, human
nasopharyngeal carcinoma; L6, rat skeletal myoblasts cell line; L929, murine aneuploid brosarcoma cell line; L929sA, murine brosarcoma cell line; L-NAME, N-nitro-Larginine methyl ester; LOVO, human colon adenocarcinoma cell line; LPS, lipopolysaccharide; LTB4, leukotriene B4; MBC, minimum bactericidal concentrations; MCF-7,
breast cancer cell line; MDA-MB-435, human breast adenocarcinoma cells; MDCK, madin-Darby canine kidney cell line; MGC-803, human gastric carcinoma cell line; MIC,
minimum inhibitory concentrations; MMP-9, matrix metalloproteinase-9; MRSA, methicillin resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus
aureus; NCI, national Cancer Institute; NF-B, nuclear factor kappa B; Nrf2, nuclear factor 2-related factor 2; OPN, osteopontin; p47phox, 47-kilodalton cytosolic subunit of
the multi-protein complex known as NADPH oxidase; PAF, platelet-activating factor; PBMCs, human peripheral blood mononuclear cells; PC-3, human prostate cancer cell
lines; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PI3K, phosphatidylinositol 3-kinase; PLA2, phospholipase A2; PMA, phorbol myristate acetate; PMNs,
polymorphonuclear leukocytes; PPAR2, peroxisome proliferator-activated receptor 2; QR, quinone reductase; RAW264, murine monocyte/macrophage line derived from
ascitic tumour induced with Abelson leukaemai virus; ROS, reactive oxygen species; SCF, stem cell factor; SGC-7901, gastric cancer cell line; SiHa, human cervix uteri cancer
cell line; SK-28, human melanoma cell line; SOD, superoxide dismutase; sPLA2, secretory phospholipase A2; STAT1, signal transducer and activator of transcription 1;
SW620, human colon carcinoma cell line; Th2, T helper cells type 2; TNFR1, tumour necrosis factor receptor 1; TNF-, tumour necrosis factor-alpha; TPA, 12-Otetradecanoylphorbol-13-acetate; Tyrp1, tyrosinase-related protein 1; U937, human monoblastic leukemia cell line; VCAM-1, vascular adhesion molecule-1; Vero, African
green monkey kidney cell line; VSMCs, vascular smooth muscle cells
n
Corresponding author. Tel.: 351234370714; fax: 351234370084.
E-mail addresses: anaseca@uac.pt (A.M.L. Seca), alicearmatu@yahoo.com (A. Grigore), diana@ua.pt (D.C.G.A. Pinto), artur.silva@ua.pt (A.M.S. Silva).
http://dx.doi.org/10.1016/j.jep.2014.04.010
0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
287
Materials and methods: The major scientic databases including ScienceDirect, Medline, Scopus and Web of
Science were queried for information on the genus Inula using various keyword combinations, more than 180
papers and patents related to the genus Inula were consulted. The International Plant Name Index was also
used to conrm the species names.
Results: Although the benets of Inula spp. are known for centuries, there are insufcient scientic studies to
certify it. Most of the patents are registered by Chinese researchers, proving the traditional use of these plants
in their country. Although a total of sixteen Inula species were reported in the literature to have
ethnopharmacological applications, the species Inula cappa (Buch.-Ham. ex D.Don) DC., Inula racemosa Hook.
f., Inula viscosa (L.) Aiton [actually the accepted name is Dittrichia viscosa (L.) Greuter], Inula helenium, Inula
britannica L. and Inula japonica Thunb. are the most frequently cited ones since their ethnopharmacological
applications are vast. They are used to treat a large spectrum of disorders, mainly respiratory, digestive,
inammatory, dermatological, cancer and microbial diseases. Fifteen Inula spp. crude extracts were investigated
and showed interesting biological activities. From these, only 7 involved extracts of the reported spp. used in
traditional medicine and 6 of these were studied to isolate the bioactive compounds. Furthermore, 90 bioactive
compounds were isolated from 16 Inula spp. The characteristic compounds of the genus, sesquiterpene
lactones, are involved in a network of biological effects, and in consequence, the majority of the experimental
studies are focused on these products, especially on their cytotoxic and anti-inammatory activities. The review
shows the chemical composition of the genus Inula and presents the pharmacological effects proved by in vitro
and in vivo experiments, namely the cytotoxic, anti-inammatory (with focus on nitric oxide, arachidonic acid
and NF-B pathways), antimicrobial, antidiabetic and insecticidal activities.
Conclusions: Although there are ca. 100 species in the genus Inula, only a few species have been investigated so
far. Eight of the sixteen Inula spp. with ethnopharmacological application had been subjected to biological
evaluations and/or phytochemical studies. Despite Inula royleana DC. and Inula obtusifolia A. Kerner are being
used in traditional medicine, as far as we are aware, these species were not subjected to phytochemical or
pharmacological studies. The biological activities exhibited by the compounds isolated from Inula spp., mainly
anti-inammatory and cytotoxic, support some of the described ethnopharmacological applications. Sesquiterpene lactone derivatives were identied as the most studied class, being britannilactone derivatives the most
active ones and present high potential as anti-inammatory drugs, although, their pharmacological effects,
doseresponse relationship and toxicological investigations to assess potential for acute or chronic adverse
effects should be further investigated. The experimental results are promising, but the precise mechanism of
action, the compound or extract toxicity, and the dose to be administrated for an optimal effect need to be
investigated. Also human trials (some preclinical studies proved to be remarkable) should be further
investigated. The genus Inula comprises species useful not only in medicine but also in other domains which
makes it a high value-added plant.
& 2014 Elsevier Ireland Ltd. All rights reserved.
Contents
1.
2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Taxonomy and botanical aspects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Ethnopharmacological uses of Inula species. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Bioactive secondary metabolites isolated from Inula spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
4.1.
Eudesmanolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
4.2.
Guaianolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
4.3.
Pseudoguaianolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
4.4.
Germacranolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
4.5.
Xanthanolides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
4.6.
Dimeric sesquiterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
4.7.
Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
4.8.
Other compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
5. Biological and pharmacological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
5.1.
Crude extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
5.2.
Pharmacological properties of the isolated compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
5.2.1.
Anti-tumour/cytotoxic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
5.2.2.
Anti-inammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
5.2.3.
Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
5.2.4.
Antidiabetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
5.2.5.
Insecticidal/larvicidal/acaricidal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
5.2.6.
Other activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
6. Toxicology of the genus Inula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
7. Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
7.1.
Unequivocal identication of the species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
7.2.
Selection of species for further studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
7.3.
Selection of compounds for further studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
288
1. Introduction
Inula, from Compositae (Asteraceae), is a large genus in the tribe
Inuleae with more than one hundred species. This genus is found
mainly in Africa, Asia (20 species are distributed in China) and in
Europe, predominantly, in the Mediterranean area. Several Inula spp.
are used in traditional medicine throughout the world, although
more common in Traditional Chinese Medicine. Therefore the genus
Inula comprises several species of reputed medicinal value. For
instance, Inula helenium L., commonly known as elecampane, Inula
racemosa Hook.f. and Inula britannica L. are frequently used in
ethnomedicine. Due to their important ethnomedicinal uses, several
Inula spp. are found in commercial herbal preparations, such as Inula
japonica Thunb. on Huang-Lian-Shang-Qing (HLSQ) tablets (Han et
al., 2010), Inula helenium on the antiulcerous drug Ventrot (Nikolaev
et al., 2006), or supplements with medical applications, for example
Pancreophyt, Relaxing Balms or Syrup of smokerss (Ghedira et al.,
2011; Nikolaev et al., 2011) and some of them are ofcially listed in
various European pharmacopoeias (Stojakowska et al., 2006;
Trendalova et al., 2010).
An increasing number of studies are being carried out on plants
of the genus Inula due to their ethnopharmacological use. These
scientic investigations involved phytochemical studies to nd the
active principle and pharmacological evaluations both to attest
their traditional applications.
Despite all the scientic studies and the widespread ethnopharmacological use of Inula spp., as far as we are aware, no
comprehensive review to document and analyse the contributions
of this genus to ethnomedicine has been carried out. In fact the
available data on its pharmacological properties remain disperse
in the middle of many other medicinal plants. So it is essential that
a systematic and critical assessment of the past work is made in
order to help the future directions of research in this eld. To ll
this gap, the present work aims to present a comprehensive and
structured state of the art on the progress of Inula spp. pharmacological studies. It will provide insight on the emerging pharmacological applications of Inula spp. highlighting the biological
activities reported for extracts and isolated secondary metabolites.
In this way an up-to-date and comprehensive information on
ethnomedicinal uses, phythochemistry, pharmacology and toxicology of the plants of the genus Inula will be described.
289
290
Rhizoma Helenii (EB 6DAB 6 Supplement, Germany), and Elecampane (Helenii rhizoma) (BHPBritish Herbal Pharmacopoeia).
In the Mediterranean area, Inula viscosa [actually the accepted
name is Dittrichia viscosa (L.) Greuter] is being used for years in folk
medicine for its anti-inammatory, antipyretic, antiseptic, antiphlogistic, balsamic, anti-scabies activities and to treat gastro-duodenal
disorders (Lauro and Rolih, 1990; Fontana et al., 2007; elik and
Aslantrk, 2010; Musthaba et al., 2011). In Greco-Arab and Islamic
traditional medicine, the roots of Inula viscosa Tayon are also used
against cough and cattarh, as an antiseptic and expectorant agent,
which loosens phlegm and supports mucus membranes (Saad and
Said, 2011). Arabs, in the holy land regards Inula viscosa as one of the
most important medicinal plants, because it heals 40 different
ailments (Palevitch and Yaniv, 1991). This is used in Moroccan folk
medicine as antihelmintic, diuretic, anti-anemic and as cataplasm for
rheumatic pain, tuberculosis, and expectorant and for the treatment
of bronchitis (Hmamouchi, 2001). In South Eastern region of Morocco, decoction of leaves and roots were used in traditional medicine
to treat hypertension (Tahraoui et al., 2007), while decocation of
leaves and owers of Inula viscosa together with Inula helenium and
Inula conyza were included in the list of medicinal plants used
traditionally to treat diabetes mellitus in Morocco (Eddouks et al.,
2007). In Jordan, traditional medicine ascribes several uses to Inula
viscosa, such as treatment of cancer (A-Yazar et al., 2011), as
antihelmintic (A-Yazar et al., 2011; Talib and Mahasneh, 2010a),
muscle relaxant (Hudaib et al., 2008; Talib and Mahasneh, 2010a),
expectorant, diuretic and also to treat bronchitis, tuberculosis,
anemia and as cataplasm for rheumatic pain. In Palestine, leaves of
Inula viscosa are used for muscle relaxation and to treat infertility
(Kaileh et al., 2007).
In some areas of Calabria (Southern Italy), decoction of Inula
viscosa roots was reported to be used in the treatment of skin
irritations of allergic origin and specically the aerial parts were
used to stop cuts haemorrhage (Passalacqua et al., 2007). Inula
viscosa is also included in the large palette of herbs used against
psoriasis (Musthaba et al., 2011).
Table 1
Bioactive compounds isolated from Inula spp. (structures illustrated in Figs. 213).
No.
Species
Parts of plant
References
Inula
Inula
Inula
Inula
Inula
Inula
Roots
Roots essential oil
Roots
Roots
Roots
Roots
Inula hupehensis
Aerial part
Inula
Inula
Inula
Inula
Aerial
Aerial
Aerial
Aerial
13
4,5-Epoxyalantolactone
Diplophyllin
5-Epoxyalantolactone
2-Hydroxyeudesma-4,11(13)-dien-12,8-olide
11,13-Dihydroalantolactone
(4S,8S,10R)-12-Hydroxy-eudesma-5(6),7(11)-dien12,8-olide
3-oxo-6-Hydroxy-eudesma-4(5),11(13)-dien-12,8olide
6-Hydroxyisoalloalantolactone
6-Hydroxy-4-epi-septuplinolide
Granilin
5,H-Eudesma-4(15),11(13)-dien-12,
8-olide (also named isoalantolactone)
1,6-O,O-Diacetylbritannilactone
14
Britannilactone
15
1-O-Acetylbritannilactone
Eudesmanolides
2
3
4
5
6
7
8
9
10
11
12
Guaianolides
16
17
helenium
helenium
helenium
racemosa
racemosa
racemosa
hupehensis
hupehensis
falconeri
japonica
Inula britannica
Inula britannica var.
chinensis
Inula britannica
Inula britannica var.
chinensis
Inula britannica
Inula britannica var.
chinensis
part
part
parts
parts
Flowers
Flowers
Qi et al. (2008)
Ra et al. (2005)
Flowers
Flowers
Qi et al. (2008)
Liu et al. (2009)
Flowers
Flowers
Qi et al. (2008)
Ra et al. (2005)
Whole parts
Whole parts
291
Table 1 (continued )
No.
Species
Parts of plant
References
18
19
20
21
Gaillardin
2-Acetoxy-inuviscolide
Inuchinenolide B
2-Acetoxy-4,6-dihydroxy-1,5H-guai-9(10),11
(13)-dien-12,8-olide
8-epi-Inuviscolide
4-epi-Isoinuviscolide
6-Hydroxyinuviscolide
4,6-Dihydroxy-1,5,7H-guaia-9(10),11(13)-dien12,8 olide
4,5-Epoxy-10,14H-1-epi-inuviscolide
Inuviscolide
Inula
Inula
Inula
Inula
hookeri
hookeri
hookeri
hupehensis
Whole parts
Whole parts
Whole parts
Aerial parts
Cheng
Cheng
Cheng
Qin et
et al. (2012)
et al. (2012)
et al. (2012)
al. (2011a)
Inula
Inula
Inula
Inula
hupehensis
hupehensis
falconeri
falconeri
Aerial
Aerial
Aerial
Aerial
Qin et
Qin et
Cheng
Cheng
al. (2011a)
al. (2011a)
et al. (2011)
et al. (2011)
22
23
24
25
26
27
Pseudoguaianolides
28
Inuchinenolide C
29
(1S,2S,5R,6S,7R,8S,10R)-6-Acetoxy-2-methoxy-4oxopseudoguai11(13)-en-12,8-olide
30
Carpesiolin
31
Graveolide (2,3-dihydroaromaticin)
32
Confertin
33
Burrodin
34
(1R,5R,6S,7R,8S,10R)-8-Hydroxy-4-oxopseudoguai-2
(3),
11-(13)-dien-12,6-olide
35
(1R,5R,6S,7S,8S,10R,11S)-6-Hydroxy-4oxopseudoguai-2(3)-en-12,
8-olide
36
(1S,5S,7R,8S,10R)-14-Acetoxy-4-oxopseudoguai-11
(13)-en-12,8-olide
37
(1S,2R,5R,6S,7S,8S,10R)-6-Hydroxy-2-methoxy-4oxopseudoguai11(13)-en-12,8-olide
38
(1S,2R,5R,6S,7S,8S,10R)-6-Hydroxy-2-ethoxy-4oxopseudoguai11(13)-en-12,8-olide
39
(1S,2R,5R,6S,7R,8S,10R)-6-Acetoxy-2-methoxy-4oxopseudoguai11(13)-en-12,8-olide
40
Britanin (also named britannin)
41
42
43
44
45
2-O-Acetyl-4-epi-pulchellin
2-Desoxy-4-epi-pulchellin
Aromaticin
8-epi-Helenalin
(1S,2R,5R,6S,7R,8S,10R)-6-Acetoxy-2-ethoxy-4oxopseudoguai11(13)-en-12,8-olide
46
Ergolide
47
2-Acetoxy-4-hydroxy-1H,10H-pseudoguai-11
(13)-en-12,8-olide
Bigelovin
48
Germacranolides
50
Epoxygermacranolide
53
54
55
56
57
Diastereomeric mixture of (30 R,40 S- and 30 S,40 R)-9(30 ,40 -epoxy-30 -methylpentanoyloxy)parthenolide
Inulasalsolide
4,5-Epoxyeupatolide
Inulacappolide
Ineupatolide
11(13)-Dehydroivaxillin
58
59
Acetyl neobritannilactone B
Eupatolide
60
61
62
9-Acetoxy-eupatolide
Isocostunolide
[1(10)E]-5-Hydroxygermacra-1(10),4(15),11-trien8,12-olide
51/52
Xanthanolides
64
6-Hydroxytomentosin
parts
parts
parts
parts
Inula falconeri
Inula viscosab
Aerial parts
Leaves
Inula hupehensis
Inula hupehensis
Aerial parts
Aerial parts
Inula
Inula
Inula
Inula
Inula
Aerial
Aerial
Aerial
Aerial
Aerial
Qin
Qin
Qin
Qin
Qin
hupehensis
hupehensis
hupehensis
hupehensis
hupehensis
parts
parts
parts
parts
parts
et
et
et
et
et
al.
al.
al.
al.
al.
(2011a)
(2011a)
(2011a)
(2011a)
(2011a)
Inula hupehensis
Aerial parts
Inula hupehensis
Aerial parts
Inula hupehensis
Aerial parts
Inula hupehensis
Aerial parts
Inula hupehensis
Aerial parts
Aerial parts
Flowers
Not identied
Aerial parts
Aerial parts
Whole parts
Whole parts
Whole parts
Inula falconeri
Inula britannica
Inula japonica
Aerial parts
Flowers
Aerial parts
Inula helianthus-aquatica
Leaves/owers
Aerial parts
Go
kbulut et al. (2012)
Aerial parts
Roots
Roots
Aerial parts
Inula
Inula
Inula
Inula
Inula
Inula
Inula
Inula
lineariifoliac
japonica
aucherianad
lineariifoliac
lineariifoliac
hookeri
hookeri
hookeri
Inula salsoloides
Inula salsoloides
Inula cappa
Inula cappa
Inula hupehensis
Inula hookeri
Inula britannica
Inula japonica
Inula britannica var.
chinensis
Inula hupehensis
Inula helenium
Inula racemosa
Inula hupehensis
Hu et al (2011)
Hu et al (2011)
Xie et al. (2007)
Wang et al. (2012)
Qin et al. (2012b)
Cheng et al. (2012)
Bai et al. (2006)
Qin et al. (2010b)
Jin et al. (2006)
292
Table 1 (continued )
No.
Species
Parts of plant
References
65
66
67
68
6-Hydroxytomentosin
Inuchinenolide A
Carabrone
4H-Tomentosin (also named 4H-xanthalongin)
Inula
Inula
Inula
Inula
Aerial parts
Aerial parts
Aerial parts
Whole plant
Qin et
Qin et
Qin et
Cheng
Inula japonica
Aerial parts
Inula japonica
Inula japonica
Inula japonica
Inula japonica
Inula japonica
Inula britannica var.
chinensis
Inula britannica var.
chinensis
Aerial
Aerial
Aerial
Aerial
Aerial
Aerial
Aerial parts
Aerial parts
Dimeric sesquiterpenes
69
Japonicone A
hupehensis
hupehensis
hupehensis
hookeri
70
71
72
73
74
75
Japonicone E
Japonicone F
Japonicone J
Neojaponicone A
Japonicone M
Inulanolide B
76
Inulanolide C
Flavonoids
77
7-O-Methylaromadendrin
Inula viscosab
78
79
80
81
82
83
84
85
Sakuranetin
3-Acetyl-7-O-methylaromadendrin
3,30 -di-O-Methylquercetin
Quercitrin
Spinacetin
Isorhamnetin
Luteolin
Nepetin (also named 6-methoxyluteolin)
Inula
Inula
Inula
Inula
Inula
Inula
Inula
Inula
Inula
viscosab
viscosab
viscosab
britannica
britannica
britannica
britannica
britannica
viscosab
Aerial parts
Aerial parts
Aerial parts
Flowers
Flowers
Flowers
Flowers
Flowers
aerial parts
Inula
Inula
Inula
Inula
Inula
viscosab
crithmoidesg
britannica
hupehensis
nervosa
Leaves
Roots
Not identied
Roots
Root
Other compounds
86
Costic acid
87
1,5-di-O-Caffeoylquinic acid
88
Lupeol
89
8-Hydroxy-9,10-diisobutyryloxythymol
90
Inulavosin
parts
parts
parts
parts
parts
parts
al. (2012b)
al. (2012b)
al. (2012b)
et al. (2012)
et
et
et
et
et
al.
al.
al.
al.
al.
(2011)
(2011)
(2011)
(2011)
(2011),
Note: Only the signicant mistakes found in names or structures were correct. Otherwise the names and structures are exactly as were found in the original publication.
a
britannica and Inula britannica var. chinensis were the main sources
of these bioactive sesquiterpene lactones (Table 1).
Concerning the Inula britannica var. chinensis, it is important
to make a clarication on its botanic classication, since the Latin
scientic name Inula britannica var. chinensis (Rupr.) Regel was
not found in the The Plant List database, although it is an
accepted name on Global Compositae Checklist database. We
found in the literature some works where a comprehensive
specimen citations is included (Jin et al., 2006), but some reports
showed contradictory data about the species studied. This issue is
particularly relevant in the case of Inula britannica and Inula
britannica var. chinensis. For example, the Latin scientic name
indicated in the abstract, results and discussion sections does not
coincide with the one indicated in the experimental part (Bai
et al., 2006; Liu et al., 2009), contributing to the confusion
between these two species. Aware that ambiguous or erroneous
use of botanical nomenclature makes impossible, for readers, to
establish relations between plant and isolated metabolites, but
also that the potential of an isolated compound does not change
by changing the taxonomy of the species and that it is almost
impossible to correct, retroactively, taxonomic failures, we keep
the reference to compounds whose bioactivity values may arouse
further investigations.
293
Guaianolides (Figs. 3 and 4) are another sesquiterpene lactonetype compounds widely distributed in the genus Inula and most
likely are responsible for their biological properties. Due to the
occurrence of guaianolide-type compounds in Inula spp. several of
the isolated derivatives were also biologically evaluated.
The number of naturally-occurring guaianolides is considerable,
although only a few plants were examined (Table 1; Fig. 4). As an
example, inuviscolide 27 presented interesting anti-inammatory
activity which is in agreement with Inula viscosa (actually the
accepted name is Dittrichia viscosa) use to treat inammations
(Abrham et al., 2010). None of the isolated metabolites were
evaluated for their antidiabetic potential whereas both Inula hupehensis and Inula viscosa are reported to be used in folk medicine to
treat diabetes (Eddouks et al., 2002; Qin et al., 2011a).
4.3. Pseudoguaianolides
4.5. Xanthanolides
4.2. Guaianolides
294
4.7. Flavonoids
Flavonoids are very important compounds displaying interesting biological properties, such as anticancer, anti-inammatory
and antioxidant activities, to mention just a few examples. Subsequently, the isolation of avonoid-type compounds from Inula spp.
is not a surprise and most likely they can be the constituents
responsible for some activities that support its use in traditional
medicine. Several avanones and avonols (Fig. 12, Table 1) were
isolated from Inula viscosa (actually the accepted name is Dittrichia
viscosa) (Hernndez et al., 2007; Zhang et al., 2010b; Talib et al.,
2012) and for some of them very interesting biological properties
were also reported, such as antitumour, antibiabetic and antiinammatory activities (Tables 3 and 4). These activities can
support the vast use of this plant in several traditional medicine
systems. Another important plant used in traditional medicine is
Inula britannica and its use can be supported by the presence of
active metabolites such as avonol and avone derivatives (Fig. 12,
Table 1) (Zhang et al., 2009, 2011; Ehrman et al., 2010; Khan et al.,
2010a).
295
296
(Zhao et al., 2006). We point out the case of Inula britannica which
was extensively studied and, in the last decade, several publications
of its pharmacological applications and/or their constituents' biological activities can be found in another review (Khan et al., 2010a).
Alternatively, the great pharmacological potential of alantolactone 1
(Fig. 1) and 5H-eudesma-4(15),11(13)-dien-12,8-olide (isoalantolactone) 12 (Fig. 2), natural sesquiterpene lactones widespread in
Inula spp., led to the publication of many works (Klochkov et al.,
2006; Marc et al., 2008; Trendalova et al., 2010; Khan et al., 2012;
Lei et al., 2012). Many other studies have been published but are
scattered, some of them are written in non-English language, so it is
difcult to have an idea of the state of the art. Besides reporting the
biological activity of an extract, it is more important to recognize the
metabolite or metabolites accountable for it.
We will focus our attention on the biological applications/
activities that somehow are related with human health. Nonetheless some other activities reported for metabolites isolated
from Inula spp. can be useful for mankind. Examples are the
biological potential as plant growth regulators of alantolactone
1 (Fig. 1), isoalantolactone 12 (Fig. 2) and several synthetic
derivatives (Hussain et al., 2011), the potent allelochemical
activity of 3-caffeoxyl-1,8-dihydroxyeudesm-4(15)-ene 91
(Fig. 14) (Khan et al., 2010b) and the antialgal activity of
sesquiterpenes isolated from Inula helenium (Cantrell et al.,
2007). Compounds isolated from Inula spp. are effective also in
plant protection by inhibiting several pathogens or pests. For
instance, inuloxins A 92, C 93 and D 94 (Fig. 14), isolated from
Inula viscosa, are active in two parasitic plant species, i.e. crenate
broomrape (Orobanche crenata) and eld dodder (Cuscuta campestris), causing up to 100% inhibition of the seed germination
(Andol et al., 2013). We call attention to the fact that, in this
work, the Inula sp. is erroneously described as Inula viscosa
when actually the accepted name is Dittrichia viscosa (L.)
Greuter. The article also failed in other essential aspects, namely
the indication of the authors associated with the Latin scientic
name, the voucher specimen number and the botanist responsible for identication. Particularly regrettable is the fact that
Andol' group did not take into account the recommendations
made by Cheng et al. (2012) in the good practice of reviewing
and publishing studies on herbal medicine.
The oily paste extracts of Inula viscosa leaves [major compounds tomentosin 63 (Fig. 9) and costic acid 86 (Fig. 13)] is
effective in controlling downy mildew caused by Plasmopara
viticola in detached leaf tissues of grapes in growth chambers
(Cohen et al., 2006), but it is also used for other fungicidal
preparations against foliar diseases caused by pathogens belonging to the families Oomycetes, Ascomycetes and Basidiomycetes
(Wang et al., 2004).
297
Fig. 11. Structures of dimeric sesquiterpene lactones isolated from Inula spp..
genera containing at least one but less than three plants active
constituents against leukemia cell line tested by NCI (Cragg et al.,
2006). This is also an incentive to evaluate the antitumor and/or
298
Table 2
In vitro and in vivo studies carried out on the bioactivity of Inula spp. extracts.
Plant part
Biological activity
evaluated
Tested material
Inula viscosaa
Petroleum ether, dichloromethane,
Leaves
Abortifacient and
methanol and aqueous extracts
anti-implantation
(in vivo)
Leaves
Cytotoxicity (in vitro) Metanolic extract
Leaves
Antibacterial
(in vitro)
Ethanolic extract
Leaves
Anti-hypertensive
(in vivo)
Aqueous extract
Leaves
Dichloromethane/methanol (1:1)
Leaves
Cytotoxic and
genotoxic (in vitro)
Aqueous extract
Aqueous extract
Flowers
Flowers
Antimicrobial
(in vitro)
Inula britannica
Whole
Acaricidal
plant
Not
Anti-melanogenic
identied (in vitro)
Inula britannica var. chinensis
Not
Antioxidant
identied
Inula japonica
Aerial parts Anti-inammatory
(in vitro)
Flowers
Anti-asthmatic
(in vivo)
Ethanolic extract
Inula cuspidatad
Leaves
Anti-inammatory
(in vivo)
Merghoub et al.
(2009)
Oskay et al.
(2009)
Kattouf et al.
(2009)
Kaileh et al.
(2007)
elik and
Aslantrk
(2010)
Zeggwagh et al.
(2006)
Sassi et al.
(2008)
A-Yazar et al.
(2011), Talib
and Mahasneh
(2010b)
Talib and
The most active extract showed lower activity against Salmonella
typhimurium, Methicillin resistant Staphylococcus aureus and Bacillus Mahasneh
(2010a)
cereus (MIC 125250 mg/mL to the extracts and 410 mg/mL to
tetracycline and penicillin G
Duan et al.
(2011)
Yamashita et al.
(2010)
Ethanolic extract
Inula ensifoliac
Cytotoxic (in vitro)
Flowers/
fruits,
leaves
and roots
References
Flowers
Inula auriculatab
Stem
Antifeedant
Results
Wang et al.
(2006)
Park et al.
(2011)
Lu et al. (2012)
Shan et al.
(2006)
Cha et al.
(2006)
Methanolic extract
Pavela (2010)
The Leptinotarsa decemlineata larvae was very sensitive to the
extract (ED50 0.2 g/cm2) while Spodoptera littoralis had neglectable
2
sensitivity (feeding deterrence index 6.3% at 500 g/cm )
The chloroform extract from owers/fruits showed highest tumour Rthy et al.
cell-inhibitory activity against HeLa (IC50 2.68 g/mL) (cisplatin IC50 (2007)
3.73 mg/mL; doxorubicin IC50 0.089 mg/mL)
Thapliyal et al.
(2011)
299
Table 2 (continued )
Plant part
Biological activity
evaluated
Inula confertiora
Leaves
Antiviral (in vitro)
Inula montbretiana
Antimicrobial
Leaves,
(in vitro)
owers
and stem
Inula falconeri
Aerial parts Allelopathic and
antifungal
Inula crithmoidese
Aerial parts Immunomodulatory
(in vitro)
Roots,
shoots
and
owers
Allelopathic
Tested material
Results
The inuenza A and HSV-1 virus were inhibited by the extract (IC50 Gebre-Mariam
et al. (2006)
6.50 and 96.9 mg/mL, respectively) while the extract was well
tolerated by the host cells of virus HeLa, MDCK and GMK
(CC50 4150 mg/mL). The extract is inactive against CVB3
Aqueous extract
Ethanolic extract
Essential oils
Roots
Roots
Antistaphylococcal
(in vitro)
Inula racemosa
Roots
Anti-atherogenic
(in vivo)
Roots
Cardioprotective
(in vivo)
Roots
Antiasthmatic
(in vivo)
Roots
Antiasthmatic
(in vitro and in vivo)
Kunduhoglu
et al. (2011)
Hexane, chloroform, ethyl acetate, n-butanol The hexane fraction presented 100% inhibitory effect to germination Khan et al.
of lettuce seeds and hexane subfraction demonstrated 13.3 mm of (2010c)
and water fractions of the methanolic
inhibition zone at 5 mg/disc against Alternaria alternata and
extract
Rhizoctonia
Roots
Not
Antibacterial
identied (in vitro)
References
Aqueous extracts
Attard and
Cuschieri
(2009)
Abdel-Wahhab
et al. (2008)
Abu-Dahab and
A (2007)
Omezzine et al.
(2011)
Guinoiseau
et al. (2010)
The ethanol extract decreased total cholesterol, triglycerides, lowdensity lipoprotein cholesterol and the atherogenic index, and
increased high-density lipoprotein cholesterol compared with the
positive control group. The hexane extract elevated plasma HDL-C
levels
50% and 70% Hydromethanolic extracts
The extracts showed cardioprotective effect from myocardial
ischemic-reperfusion and isoproterenol-induced myocardial injuries
by supressing the oxidative stress and improving haemodynamic
and ventricular contractile function
Hydroethanolic extract
Protection against induced mast cell degranulation (single dose)
was similar to that of disodium cromoglycate while the seven days
drug treatment showed greater protection than disodium
cromoglycate intraperitoneal
Petroleum ether, ethanol and water extracts The highest inhibition of histamine induced contractions (55.4%)
was observed to petroleum ether extract at a dose of 4 mg/mL, and
Urban et al.
(2008)
O'Shea et al.
(2009)
Wojcikowski
et al. (2009)
Dorn et al.
(2006)
Alexenizer
and Dorn
(2007)
StojanoviRadi et al.
(2012)
Stanojevi
et al. (2010)
Mangathayaru
et al. (2009)
Ojha et al.
(2010), Ojha
et al. (2011)
Srivastava et al.
(1999), Ismail
(2010)
Vadnere et al.
(2009)
300
Table 2 (continued )
Plant part
Roots
Roots
Biological activity
evaluated
Tested material
Results
References
Inula oculus-christig
Not
Amoebicidal
identied (in vitro)
Aqueous extract
Degerli et al.
(2012)
Table 3
Cytotoxic compounds isolated from Inula spp.
Cell line
Compounds
References
B16F10
MK-1
T47D
PA-I
OVCAR
DU-145
DUPro-I
DUPro-I
MCF-7
MCF-7
MCF-7
MCF-7
Malme-3 M
HeLa
HeLa
HeLa
K-562
KB
Jurkat T
AGS
HL-60
HL-60
HCT-116
44 (Fig. 6)
1 (Fig. 1), 4 (Fig. 2)
48 (Fig. 6)
55 (Fig. 8)
55 (Fig. 8)
55 (Fig. 8)
46 (Fig. 6)
58 (Fig. 8)
56 (Fig. 8)
46, 48 (Fig. 6)
50 (Fig. 8)
HCT-15
HepG-2
HepG-2
HepG-2
PC-3
PC-3
MGC-803
MGC-803
44 (Fig. 6)
40 (Fig. 6)
61 (Fig. 8)
43, 44, 45, 48, (Fig. 6); 57 (Fig. 8)
16 (Fig. 4), 43, 44, 45, 48 (Fig. 6)
30 (Fig. 6)
43, 44, 48, (Fig. 6)
16, 17, 18, 19, 20 (Fig. 4),
30, 31, 45, 46 (Fig. 6), 68 (Fig. 10)
48 (Fig. 6)
40 (Fig. 6)
12 (Fig. 2)
69 (Fig. 11)
69 (Fig. 11)
69 (Fig. 11)
69 (Fig. 11)
61 /Fig. 8)
61 (Fig. 8)
U-937
A-549
A-549
A-549
LOVO
CEM
MDA-MB-435
A-2058
HT-29
8.7 mM
2.2 mg/mL
2.0 mg/mL
2.54.1 mM (DOX 0.2 mM)
1.32.9 mM (DOX 0.3 mM)
8.7 mM (DOX 0.3 mM)
1.01.4 mM (DOX 0.3 mM)
6.510.1 mM (DOX 0.3 mM)
0.47 M
3.5 mg/mL
8.1 mM (Taxol 0.006 mM)
1.620 mg/mL
0.256 mg/mL
0.001 mg/mL
0.198 mg/mL
3.20 mg/mL
5.0 mg/mL
301
Table 4
Isolated compounds of Inula spp. with inhibitory activity against NO production in LPS-stimulated RAW264.7 cells.
Compound
References
1 (Fig. 1)
5 (Fig. 2)
8 (Fig. 2)
9 (Fig. 2)
10 (Fig. 2)
11 (Fig. 2)
20 (Fig. 4)
21 (Fig. 4)
22 (Fig. 4)
23 (Fig. 4)
24 (Fig. 4)
25 (Fig. 4)
26 (Fig. 4)
28 (Fig. 6)
29 (Fig. 6)
30 (Fig. 6)
31 (Fig. 6)
32 (Fig. 6)
33 (Fig. 6)
34 (Fig. 6)
35 (Fig. 6)
36 (Fig. 6)
37 (Fig. 6)
38 (Fig. 6)
39 (Fig. 6)
40 (Fig. 6)
41 (Fig. 6)
42 (Fig. 6)
43 (Fig. 6)
44 (Fig. 6)
46 (Fig. 6)
46 (Fig. 6)
46 (Fig. 6)
47 (Fig. 6)
48 (Fig. 6)
48 (Fig. 6),
49 (Fig. 7)
53 (Fig. 8)
54 (Fig. 8)
59 (Fig. 8)
59 (Fig. 8)
60 (Fig. 8)
62 (Fig. 8)
63 (Fig. 9)
64 (Fig. 10)
65 (Fig. 10)
66 (Fig. 10)
67 (Fig. 10)
70 (Fig. 11)
71 (Fig. 11)
72 (Fig. 11)
73 (Fig. 11)
74 (Fig. 11)
75 (Fig. 11)
76 (Fig. 11)
cytotoxic activity of Inula spp. secondary metabolites. Sesquiterpene lactones constitute a major and diverse group of biologically
active Inula compounds that possess antitumor activity (Huo et al.,
2008, Rthy et al., 2007, Park and Kim, 1998). A great number of
compounds isolated from Inula spp. were tested in vitro against
more than forty tumour cell lines, being the most frequently cited
HeLa, MCF-7, A-549, HepG-2 and HL-60 cell lines. However, the
vast majority of compounds tested are inactive or with IC50 valus
higher than 5 g/mL or 10 M. These values are much higher than
those obtained for the antitumour/cytotoxic commercial drugs like
doxorubicin (DOX), daunorubicin, among others. So these type of
compounds are not interesting as potential anticancer drugs and
we choose not include them in this review. Thus, only the
302
against tumor cell lines from colon LOVO, breast MDA-MB-435 and
particularly against lymphoblastic leukemia cells CEM. However,
for such low IC50 values to be taken seriously, they should be
accompanied by the respective associated error, the value of IC50
for a reference drug obtained under the same conditions, besides
the selectivity index. On the other hand, taking into account that
there are several types of CEM tumor cell line, it would be
interesting to know more details about the cell line used in this
work; d) nepetin 85 (Fig. 12), which is not a sesquiterpene lactone,
exhibits an IC50 slightly higher than the criterion applied (5 mg/mL)
but, in our literature survey, it was the only compound that
besides the IC50 value of both compound and positive control,
the authors also tested its selectivity (Table 3).
It should be noted that the rst studies on the cytotoxicity of
britannilactone 14 (Fig. 2), the major component of Inula britannica, plant used in traditional medicine as anti-tumor agent, and
its derivative 1-O-acetylbritannilactone 15 (Fig. 2), showed lower
activity (IC50 Z10 M). Nevertheless, several studies described
their cytotoxicity and anticancer mechanism, the synthesis of
several derivatives and their cytotoxic evaluation, being some of
them much more actives, were also reported (Liu et al., 2004,
2005; Ra et al., 2005; Bai et al., 2006; Qi et al., 2008). In fact,
these studies are signicant and allowed important conclusions;
C-6 substitution and the substituent group structure are very
important for the level of cytotoxic activity. Another remarkable
study, as in the previous case, only possible when several compounds with similar structures are available, showed that pseudoguaianolides 33 and 34 (Fig. 6) exhibited much stronger
cytotoxicities against PC-3, MGC-803, HeLa and HepG2 cell lines
than 30, 31 and 46 (Fig. 6), suggesting that the ,-unsaturated
cyclopentenones is probably the active group of pseudoguaianolides sesquiterpene lactones.
1,6-O,O-Diacetylbritannilactone 13 (Fig. 2) is the most studied
and active britannilactone derivative. Compound 13 is capable of
inducing Bcl-2 phosphorylation and G2/M cell cycle arrest in BRKp53 cell line similarly to paclitaxel, an anticancer commercial drug
of natural origin (Ra et al., 2005). On the other hand, activation of
caspase-3, -8, and -9 and increasing release of cytochrome c from
mitochondria into cytosolic fraction were detected in HL-60 cells
treated with 1,6-O,O-diacetylbritannilactone 13 (Fig. 2) (Pan et al.,
2007). Furthermore, the production of ROS, activation of MAPK
and JNK signalling pathways may also play an important role in
1,6-O,O-diacetylbritannilactone 13 (Fig. 2) induced apoptosis (Pan
et al., 2007).
Bigelovin 48 (Fig. 6) was tested against several tumor cell lines
and the results showed that it strongly inhibits the growth of
cancer cells like SGC-7901, B-16, 293-T, and K-562 with
IC50 o3 mM (the exact value was not indicated by the author),
with emphasis on the activity against U937 cell line (IC50 0.47 M,
see Table 3) (Zeng et al., 2009). This strong activity encouraged the
study of its anticancer mechanism that involves induction of
apoptosis and cell cycle arrest at G0/G1 phase (Zeng et al.,
2009). It is a pity that in this study the authors did not used any
commercial drug as a positive control neither the compound 48
(Fig. 6) was tested against non-tumor cell lines.
The effect of a mixture of compounds known as helenin [40%
alantolactone 1 (Fig. 1) and 60% isoalantolactone 12 (Fig. 2)] in the
growth of human lymphoblastoid Raji cells seems to exceeded that of
Fig. 14. Structures of some important bioactive compounds isolated from Inula spp..
303
304
305
306
7. Concluding remarks
This review summarizes the existing ethnopharmacological
uses of medicinal plants of the genus Inula and the research
carried out on its phythochemistry and toxicology. The data
provided herein conrm some of the ethnomedicinal uses, by
biological evaluations of both extracts and isolated secondary
metabolites. It should be emphasized that most of the evaluations
were conducted in vitro, but some were done also in vivo, however
many studies reported in the literature were ignored because they
do not follow the minimum quality criteria adopted. Despite all
inaccuracies found in the literature, this review conrms the
importance of the genus Inula as a source of medicines for
humans. Nevertheless, much remains to be done. We have made
the best effort to summarise the information available and we
used gures and tables to help the analysis. We think this
information can assist researchers in the selection of species that
should be further studied. But, in order to benet from the
potential medicinal properties of this genus, the following future
directions and/or suggestions are recommended.
7.1. Unequivocal identication of the species
Various problems arising from ambiguous identication of
botanical species were detected in this literature review, even in
recent cited works. For example Inula britannica can mean either
the species Inula britannica L. (accepted botanic name), Inula
britannica var. chinensis (Liu et al., 2009) or a Latin specic name
created by the authors as in Song et al. (2002). In some studies, it
appears referred as Inula britannica syn. Inula japonica (Merten
et al., 2011) and also as Inula britannica L. subsp. japonica Kitam.
(Kobayashi et al., 2002) which is not in accordance with The Plant
List database. Moreover, Inula britannica var. japonica is a synonym of Inula japonica Thunb. not a variety of Inula britannica L.
We also found several works where was not possible to identify
the plant part studied (see Table 2, works involving Inula britannica and Inula japonica). It is very important to unequivocally
identify the species and the part of the plant used.
In an era in which good practice in reviewing and publishing
studies on herbal medicine are published and intensely discussed
at least since 2012, we suggest a more proactive approach by all
researchers in medicinal plants, to a rigorous assessment of the
taxonomic nomenclature and the reading of Chan et al. (2012) and
Rivera et al. (2014) are suggested.
7.2. Selection of species for further studies
From the widespread Inula spp. only 16 are claimed to be used
in folk medicine, mainly in Asia. Out of this number, only 7 had
their pharmacological potential validated by in vitro or in vivo
different bioassays. However, in almost all the cases the claimed
medicinal properties were not evaluated and as far as we are
aware no clinical trials have been done.
A bird's eye view on the reviewed literature indicates a gap in
scientic studies that corroborate the pharmacological properties
illustrated by the ethnomedicinal use of Inula royleana and Inula
obtusifolia. So these species should undoubtedly be the focus of
future research.
Biologically active metabolites were isolated from 16 Inula spp.
(Table 1) and extracts, with acceptable results, of 14 Inula spp.
(Table 2) were biologicaly assayed. The combined analysis of the
information of Tables 1 and 2 shows that 7 Inula spp. whose
extracts were biologically evaluated were not subjected to phytochemical studies. From these, Inula oculus-christi and Inula ensifolia
can be highlighted as species for future phytochemical studies,
because their extracts showed very interesting activities. We call
attention to the fact that, currently, the accepted name for Inula
graveolens (L.) Desf. is Dittrichia graveolens (L.) Greuter (based on
The Plant List database), which does not detract its pharmacological potential but its study will be in the framework of
Dittrichia spp..
Acknowledgements
Thanks are due to the University of Aveiro, Fundao para a
Cincia e a Tecnologia (FCT, Portugal), the European Union, QREN,
FEDER, COMPETE, for funding the Organic Chemistry Research
Unit (QOPNA) (project PEst-C/QUI/UI0062/2013; FCOMP-01-0124FEDER-037296). The work was also supported by a grant of
UEFISCDI, Romania, PN-II-PT-PCCA-2 no. 134/2012.
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