The Genus Inula

Journal of Ethnopharmacology 154 (2014) 286310
Contents lists available at ScienceDirect
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
Review
The genus Inula and their metabolites: From ethnopharmacological

to medicinal uses
Ana M.L. Seca a,b, Alice Grigore c, Diana C.G.A. Pinto b, Artur M.S. Silva b,n
a
DCTD, University of Azores, 9501-801 Ponta Delgada, Portugal

Chemistry Department & QOPNA, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal
c
Department of Pharmaceutical Biotechnologies, National Institute of Chemical-Pharmaceutical R&D, 112 Vitan Av., Bucharest, Romania
b
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.
A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310
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.
2. Taxonomy and botanical aspects

More than 590 plants are reported as belonging to the genus
Inula but only 112 correspond to an accepted name (The Plant List
database) and this should encourage a reection. The huge number
of doubtful/ratings reclassications resulting in many names that
are synonyms and/or unresolved do not help the research in this
area. An example is Inula cappa (Buch.-Ham. ex D.Don)
DC., one of the most studied species and used in Chinese folk
medicine. Although, in several articles the authors indicate that
plants were identied by experts and deposited in herbaria (Wu et
al., 2010; Wang et al., 2012), the species still appears as unresolved in The Plant List database, due to the fact that data sources
did not contain sufcient evidence. We would like to emphasize an
emblematic case of reclassication and its extend in time. Taxonomic revision of the genus Dittrichia showed that Inula viscosa (L.)
Aiton is a synonym of the accepted name Dittrichia viscosa (L.)
Greuter (Brullo and de Marco, 2000) and this taxonomic change is
conrmed in the online The Plant List database. Although in our
literature survey Inula viscosa is one of the most studied species,
with a high number of citations relative to ethnomedicinal applications and pharmacological studies and not being in question the
ethnomedicinal value of the species, we call attention, in particular,
to the chemotaxonomic implications that the genus change can

cause (but this is not the issue on this review). Also noteworthy is
the fact that Inula viscosa name continue appearing in publications
even after the accepted taxonomic change (for example Kattouf et
al., 2009; Talib et al., 2012; Andol et al., 2013). This situation is a
clear reex of the long timeline that mediates the change in
taxonomic classication of species and their effective adoption by
the scientic community. We believe that, at this point, it is more
useful to the future readers that all the works published using the
name Inula viscosa will be mention here even though the species
has been reassign.
Following recent recommendations (Chan et al., 2012; Rivera
et al., 2014), special care was placed in the citation of the botanic
species listed in this paper. The rst time that one Inula sp. is cited in
this review it is identied by its accepted Latin scientic name plus
author (conrmed in the online database The Plant List). However
taking into account the length of the manuscript, it was decided
to omit the authors' names when the species name is repeated.
When considered relevant, synonym botanical names are given in
brackets.
Also a careful analysis of the literature reviewed revealed that
frequently the species botanical name mentioned does not correspond to a currently accepted name (The Plant List database).
This lack of scientic accurateness is of particular concern, mainly
because it is also found in recent publications. Given the difculty
to retroactively clarify the correct name of the species studied, we
choose to keep the names given by the authors in their work and
highlighted the cases where we found inaccuracies.
With respect to botanical aspects, the Inula spp. may be annuals,
biennals {Inula conyza (Griess) DC. [syn. Aster conyzae Griess., Aster
pubescens Moench, Conyza squarrosa L., Conyza vulgaris Lam., Erigeron
squarrosus Clairv., Inula squarrosa (L.) Bernh., Inula vulgaris (Lam.)
Trevis., Jacobaea conzyae (Griess.) Merino]}, perennials (Inula racemosa,
Inula helenium, Inula britannica), herbs (Inula helenium) or shrubs
(Inula arbuscula Del.) that vary greatly in size, from small species with
a few centimeters tall to enormous perennials over 3 m tall. Their
stems are well developed, often branched, rarely simple. Leaves are
herbaceous, membranous, alternate, simple, and generally sessile. The
genus Inula is characterized by solitary terminal capitula, or several,
arranged in corymbs or cymes, heterogamous radiate, disciform or
homogamous discoid. Receptacle is epaleate and smooth. The plants
carry involucral bracts 37 seriate, imbricate, outer herbaceous, inner
usually rigid and narrow. Marginal orets are female, ligulate-miniligulate, 2-3-toothed or hermaphrodite, tubular, 5-toothed. Central
orets are hermaphrodite, tubular, 5-toothed, styles with acute
sweeping hairs not reaching to the furcation. Pappus bristles are 12
seriate, persistent, numerous (2052), barbellate (Abid and Qaiser,
2002). Cypselae are subterete, above non attenuate, usually thick
walled and ribbed. The diverse morphology of cypselae has often led
the workers to describe new species and even new genera. The genus
Inula is splitted into two distinct groups, as these groups fall apart
from each other. Group A is characterized by having relatively
primitive characters, the presence of larger and usually glabrous
cypselae (Inula racemosa). Group B is characterized by having species
with relatively advance characters such as smaller and pubescent
cypselae (Inula orientalis Lam., Inula clarkei (Hook.f.) R.R. Stewart, Inula
obtusifolia A. Kerner, Inula britannica, Inula acuminata Royle ex DC.,
Inula falconeri Hook.f.) (Dawar, 1998).
3. Ethnopharmacological uses of Inula species

World Health Organization reports indicate that around eighty
percent of the global population still relies on botanical drugs and
several herbal medicines have advanced to clinical use in modern
times. In fact, the therapeutic power of plants is as old as mankind.
More than 2000 plants were listed in the traditional (Herbal/

Alternative) systems of medicine and some of them belong to the
genus Inula. Ethnopharmacological studies are very important as
they point out plants that should be subjected to phytochemical
studies.
In the last years, several papers have described relevant information on the applications of plants in traditional medicine. However,
the pharmacological and chemical data about Inula spp. is disperse in
the middle of many other medicinal plants. In the Chinese Pharmacopoeia, out of over 20 species distributed in China, three traditional
Chinese medicines used as expectorants, antitussives, diaphoretics,
antiemetics, and bactericides, are originated from ve Inula plants:
Xuan Fu Hua (Flos InulaeInula britannica/Inula japonica), Jin Fei Cao
(Herba InulaeInula japonica/Inula linariifolia Turcz.), Tu Mu Xiang
(Radix InulaeInula helenium/Inula racemosa). In Chinese folk medicine, Inula hupehensis (Ling) Ling (syn. Inula helianthus-aquatilis
subsp. hupehensis Ling) is used to cure bronchitis, diabetes and
intestinal ulcers (Qin et al., 2011a).
The whole aerial parts and the roots of Inula cappa have been
traditionally used for treating rheumatoid arthritis, malaria, dysentery and hepatitis (Wang et al., 2012). Actually, roots of Inula
cappa are one of the components of Ya-Jiao-Ha-Dun San, a famous
formula of medicines used by Dai people against fever, abdominal
distention and menoxenia (Zou et al., 2008). The leaves juice of
this species is used by the indigenous communities of Mizoram, a
Sub-Himalayan region of India, to treat jaundice (Sharma et al.,
2012). There are also other reports supporting the use of this
species in Chinese folk medicine to treat rheumatism, laryngotracheitis and abdominal pain (Zou et al., 2008; Wu et al., 2010).
Inula royleana D.C. (syn. Corvisartia indica Lindl., Inula stoliczkai
C.B. Clarke), a plant occurring in Nandiar Khuwarr catchment,
District BattagramPakistan, is also used in traditional medicine,
especially against hypertension (Haq et al., 2011).
Inula obtusifolia (syn. Inula thomsonii C.B. Clarke), Inula racemosa and Inula royleana, common Inula spp. in Ladakh, are known
to present various properties, such as antihelmintic, antiseptic,
expectorant, diuretic, hypotensive activities and stimulant of the
peristaltic movements (Grimaud, 2009). In the Tibetan traditional
medicine, Inula obtusifolia (the whole plant) is used to treat several
symptoms, such as gastrointestinal and larynx infections, and also
for rheumatoid arthritis (Grimaud, 2009).
In Ayurvedic medicine, Inula racemosa (syn. Inula royleana C.B.
Clarke) is used mainly as an expectorant and bronchodilator, but also
to treat tuberculosis and topically in the treatment of skin diseases
(Shishodia et al., 2008). This plant is known as Puskara in Ayurvedic
Pharmacopoeia and as pushkarmool by Indian people. The root
powder of the plant is indicated for the treatment of asthma-like
conditions by Ayurvedic practitioners in India (Vadnere et al., 2009),
to reduce cholesterol, to support healthy circulation, to treat angina
and dyspnea (Mahmood et al., 2010) and to ensure healthy heart
functions (Miller, 1998; Sharma et al., 2007; Mangathayaru et al.,
2009). It is also used for the management of diabetes (Chaturvedi et
al., 1995; Krishnaraju et al., 2005). On the other hand, in the Chinese
folk medicine, Inula racemosa, known as manu, has been used for
long time to regulate the function of the stomach, alleviate pain and
as antimicrobial agent (Xu and Shi, 2011). Inula racemosa is also cited
as an aphrodisiac plant (Goetz, 2006).
Inula salsoloides (Turc.) Ostenf. [syn. Conyza salsoloides Turcz.,
Inula ammophila Bunge ex DC., Inula ammophila var. salsoloides
(Turcz.) Turcz., Inula schugnanica C.Winkl., Iphiona radiata Benth.]
widespread in West and North of China is used, before owering,
to treat fevers and diuresis (Hu et al., 2011). Conversely, Inula
nervosa Wall. ex DC. (syn. Aster macilentus Vaniot, Aster vellereus
Franch., Inula asperrima Edgew., Inula esquirolii H. Lv., Inula nitida
Edgew., Inula venosa Hand.-Mazz.), found in the Southwestern
region of China, is used in Chinese folk medicine to treat
289
stomachache and relieving rheumatism (Yan et al., 2010). Another

species used in China as a traditional medicinal plant is Inula
helianthus-aquatica C.Y. Wu, mainly used in folk herbal medicine of
Yunnan province to treat some cancers, such as esophageal,
gastric, colon, breast, gum and brain cancers (Zeng et al., 2009).
Inula confertiora A. Rich. is used in Ethiopia to treat skin diseases
of viral origin, wounds and eczematous lesions (Messele, 2004).
The Inula sp. with more reports on its use in traditional
medicine is Inula helenium [syn. Aster helenium (L.) Scop., Aster
ofcinalis All., Corvisartia helenium (L.) Mrat, Helenium grandiorum Gilib.], also known as elecampane. It is famous for its
successful use as a medication by Prophet Job who had chronic
sore boils (Al-Gammal, 1998). Hippocrates described it as a good
and effective cure for chronic skin eruptions and itch. In the
Middle Ages, an elecampane-based wine called Potio Sancti Pauli
(potion St. Paul) was considered for a panacea of head, lung or
stomach diseases, as well as a protection against the plague.
Elecampane is also reputed to relieve all kinds of pains, especially
those arising from chills and animal bites. In traditional medicine,
elecampane was and still is used in different forms to cure of many
diseases (Al-Gammal, 1998). For instance, the medicinal use of its
aerial parts is described in The Chilandar Medical Codex (a large
collection of medical manuscripts from the 12th to 15th centuries)
and consists in an unguent (the herb is cooked in olive oil and
wine) that is applied onto wounds or freckles and also suppress
dandruff (Jaric et al., 2011).
In Hungarian folk medicine, essential oil of Inula helenium is
used to treat respiratory and digestive diseases (Babulka, 2011).
In a 2011 review, it was indicated that both root and ower of Inula
helenium are used to treat emphysema, bronchitis and bronchial
asthma (Ram et al., 2011) and this constitutes one of the few
examples where the aerial parts of this plant seemed to be used,
because almost all the examples indicate the use of roots.
The roots of Inula helenium have been used in the folk medicine
against a variety of ailments, including asthma, cough, bronchitis,
lung disorders, tuberculosis, indigestion, chronic enterogastritis,
infectious and helminthic diseases (Grimaud, 2009; Huo et al.,
2010), as balm for dermatitis, darters and herpes (Grimaud, 2009).
It is also mentioned in the Oral Instruction Tantra for the treatment of
dark phlegm and other disorders (Gyatso and Hakim, 2010).
In Prokletije Mountains (Montenegro) the roots of Inula helenium
(elecampane) are used in the bath to treat psoriasis (Menkovic et al.,
2011), and in BosniaHerzegovina, where the species is a wild plant,
tea made from its roots is used to regulate the menstruation (SaricKundalic et al., 2010). Roots and rhizome of Inula helenium have been
used in the Azerbaijan traditional medicine to treat pediatric
diseases, such as gastrointestinal, gastric and small bowel diseases,
common cold and bronchitis, and as antihelminthic and antitussive
agents (Ibadullayeva et al., 2010).
Currently, it is possible to claim for the root and the rhizome of
Inula helenium (as infusion, powder, wine, syrup) the following
therapeutic indications: (i) antiseptic in exanthema, bacterial and
fungal dermatitis; (ii) antipruritic in dry patches; (iii) to facilitate
urinary and digestive functions; (iv) to treat symptomatic cough
and bronchitis; (v) to treat failure by the dyspeptic hepatobiliary
or biliary dyskinesia; (vi) as an adjunct in the ght against
hyperglycemia and obesity (Ghedira et al., 2011).
We did not considered here a few reports which do not indicate
the part of the plant used (examples Zhao et al., 2006; Aljancic et
al., 2008). This is a serious failure of the authors of these works,
since the indication of the plant part used is considered of vital
information in any herbal medicines research and also essential
for the herbal quality validation (Chan et al., 2012).
The herbal product Inulae radix consists in dried roots of Inula
helenium or Inula racemosa, and is present in the European pharmacopoeias as: Aune (PF XFrance), Radix Helenii (Ned 5Netherlands),
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).
Finally, there are reports on traditional uses of Inula britannica

[syn. Aster britannicus All., Aster orientalis S.G. Gmel., Conyza britannica (L.) Moris ex Rupr., Inula britannica var. tymiensis Kudo, Inula
dichotoma Zuccagni, Inula serrata Gilib., Inula tymiensis Kudo], a wild
plant growing in Europe, North America and Eastern Asia, including
China and Korea, also known as British yellowhead or meadow
eabane. It is used in traditional Chinese and Kampo Medicines for
the treatment of various diseases (Khan et al., 2010a), especially
asthma, chronic bronchitis, and acute pleurisy (Nam et al., 2009). It
has been used combined with other plants as a remedy for nausea,
hiccup and excessive sputum (Khan et al., 2010a).
Inula japonica [syn. Inula britannica var. japonica (Thunb.)
Franch. & Sav., Inula britannica subsp. japonica (Thunb.) Kitam.,
Inula britannica var. vulgaris Franch. & Sav., Inula repanda Turcz.,
Inula yosezatoana Makino, Limbarda japonica (Thunb.) Raf.], mainly
distributed in Northern China is indicated, in the Chinese Pharmacopoeia (actually its aerial parts), to treat furunculosis, cough,
digestive disorders, bronchitis, and inammation (Gong et al.,
2011). The owers from this plant are used to treat digestive
disorders, bronchitis and inammation (Park et al., 2011).
In traditional Chinese Medicine, the owers of Inula britannica/
Inula japonica are used to treat digestive disorders, bronchitis and
inammation, bacterial and viral infections (including hepatitis),
as well as some tumours (Liu et al., 2004; Zhao et al., 2006).
4. Bioactive secondary metabolites isolated from Inula spp.

Exhaustive phytochemical studies of Inula spp. have reported
not only the isolation of new secondary metabolites but as well as
their biological activities. Detailed extensive phytochemical investigations are necessary to understand the pharmacological activity
of these species, namely to quantify and/or validate them but also
to comprehend their mechanism of action. Herein we will indicate
the name and structure of metabolites, and the part of plant from
which they were isolated. These data are listed in Table 1 and in
Table 1
Bioactive compounds isolated from Inula spp. (structures illustrated in Figs. 213).
No.
Compound class and name
Species
Parts of plant
References
Inula
Inula
Inula
Inula
Inula
Inula
Roots
Roots essential oil
Roots
Roots
Roots
Roots
Jiang et al. (2011)

Stojanovi-Radi et al. (2012)
Konishi et al. (2002), Im et al. (2007)
Zhang et al. (2012a)
Inula hupehensis
Aerial part
Qin et al. (2012b)
Inula
Inula
Inula
Inula
Aerial
Aerial
Aerial
Aerial
Qin et al. (2012b)

Qin et al. (2012b)
Cheng et al. (2011)
Wang et al. (2007)
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
chinensis
Inula britannica
chinensis
5,6-Epoxy-2-acetoxy-4-hydroxy-1,7-guaia-11 Inula hookeria

(13)-en-12,8-olide
14-Acetoxy-1,5,7H-4-hydroxy-guai-9(10),11(13)- Inula hookeri
dien-12,8-olide
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
Cheng et al. (2012)
Whole parts
Cheng et al. (2012)
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
Cheng et al. (2011)

Rozenblat et al. (2008)
Inula hupehensis
Inula hupehensis
Aerial parts
Aerial parts
Qin et al. (2011a)

Qin et al. (2011a)
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
Qin et al. (2011a)
Inula hupehensis
Aerial parts
Qin et al. (2011a)
Inula hupehensis
Aerial parts
Qin et al. (2011a)
Inula hupehensis
Aerial parts
Qin et al. (2011a)
Inula hupehensis
Aerial parts
Qin et al. (2011a)
Aerial parts
Flowers
Not identied
Aerial parts
Aerial parts
Whole parts
Whole parts
Whole parts
Nie et al. (2010),

Lu et al. (2012)
Moghadam et al. (2012)
Nie et al. (2010)
Nie et al. (2010)
Cheng et al. (2012)
Cheng et al. (2012)
Cheng et al. (2012)
Inula falconeri
Inula britannica
Inula japonica
Aerial parts
Flowers
Aerial parts
Cheng et al. (2011)

Park and Kim (1998)
Qin et al. (2010b)
Inula helianthus-aquatica
Leaves/owers
Zeng et al. (2009)
Inula verbascifolia subsp.

methaneae
Inula montbretianaf
Aerial parts
Zhao et al. (2006), Chin et al. (2009)
Aerial parts (with

owers)
Aerial parts
Aerial parts
Whole plant
Aerial plant
Aerial plant
Whole plant
Flowers
Aerial parts
Aerial parts
Go
kbulut et al. (2012)
Aerial parts
Roots
Roots
Qin et al. (2012b)

Chen et al. (2007)
Aerial parts
Qin et al. (2012b)
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
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
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
chinensis
chinensis
Aerial
Aerial
Aerial
Aerial
Aerial
Aerial
Qin et al. (2009),

Zhan et al. (2011), Hu et al. (2012)
Qin et al. (2010a), Zhan et al. (2011)
Qin et al. (2011b), Zhan et al. (2011)
Zhan et al. (2011), Qin et al. (2011b))
Jin et al. (2006)
Aerial parts
Jin et al. (2006)
Aerial parts
Zhang et al. (2010b),

Hernndez et al. (2007)
Talib et al. (2012)
Zhang et al. (2009), Zhang
Khan et al. (2010a)
Talib et al. (2012)
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),
Cohen et al. (2006)

Aboul-Ela et al. (2012a, 2012b)
Duan et al. (2011)
Zhao et al. (2010)
Fujita et al. (2009), Yoshida et al. (1995)
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
Inula hookeri C.B.Clarke.

Actually the accepted name is Dittrichia viscosa (L.) Greuter.
We believe that this is a writing error. The correct is Inula linariifolia Turcz..
d
Inula aucheriana DC..
e
Actually the accepted name is Inula methanaea Hausskn..
f
Inula montbretiana DC..
g
Actually the accepted name is.Limbarda crithmoides (L.) Dumort..
b
c
Fig. 1. Basic structure of eudesmanolides and of alantolactone 1.
Figs. 213 and although the phytochemistry studies of genus Inula

is vast, we choose to present here only the active compounds
found after the review of Zhao et al. (2006) and highlight others
that are important or were not fully presented in the referred
manuscript..
4.1. Eudesmanolides
The literature survey indicates that the sesquiterpene lactones
eudesmanolides (Figs. 1 and 2) are the major group of secondary
metabolites found in the genus Inula and several authors proposed
that the pharmacological effects of Inula spp. can be associated
with the wide range of biological properties displayed by these
sesquiterpenes, including anticancer, anti-inammatory and antibacterial activities (Ghantous et al., 2010; Orono et al., 2012).
Extracts of Inula helenium, Inula racemosa, Inula hupehensis, Inula
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
Fig. 2. Structures of eudesmanolide derivatives isolated from Inula spp..
Fig. 3. Basic structure of guaianolides.
Alantolactone 1 (Fig. 1) is the most known eudesmanolide

derivative found in several Inula spp. and is considered the main
compound responsible for the Inula spp. allergic contact dermatitis.
One of the most prominent eudesmanolides is 1-O-acetylbritannilactone 15, which can be associated with the Traditional
Chinese Medicine use of Inula britannica var. chinensis and Inula
japonica to treat inammation (Geng et al., 2007; Park et al., 2011).
In fact its anti-inammatory action is well studied as will be
demonstrated and discussed later.
isolated from the ethanolic fraction of petroleum ether extract of

Inula helianthus-aquatica leaves and owers, that strongly inhibits
the growth of several cancer cell lines with IC50 values lower than
2 M (Zeng et al., 2009). These results strongly support the use of
Inula helianthus-aquatica in folk herbal medicine of Yunnan
province to treat gastric cancer (Zeng et al., 2009).
4.4. Germacranolides
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).
Parthenolide 49 (Fig. 7) is the most noticeable germacranolide

sesquiterpene lactone, due to its high cytotoxicity and the fact that
is currently under clinical trials as anticancer agent (Orono et al.,
2012).
Other germacranolide derivatives (Fig. 8), isolated from Inula
spp., showed potential as health promoters as it will be discussed
in a subsequent section. For example, epoxygermacranolide 50 can
be used against human cancer cell lines HCT-116 (Harvala et al.,
2002; Chin et al., 2009), and acetyl neobritannilactone B 58
induces cell apoptosis in human cancer cell line AGS (Bai et al.,
2006). Several other derivatives found in medicinal plants showed
moderate biological activities which are not noticeable but can be
used as models to obtain more active ones. As examples, one can
refer neobritannilactone B which is active against HeLa cell line
(Bai et al., 2006) and 9-(3-hydroxy-3-methylpentanoyloxy)
parthenolide active against colon HCT-116 (Harvala et al., 2002).
From the plants that afforded these germacranolides, only Inula
britannica is reported to be used in traditional medicine to treat
tumours (Zhao et al., 2006; Geng et al., 2007). On the other hand,
eupatolide 59 and 4,5-epoxyeupatolide 54 are derivatives that
can be related with the plant traditional use due to the fact that
they presented interesting anti-inammatory activities (Qin et al.,
2010b; Hu et al., 2011).
4.3. Pseudoguaianolides
4.5. Xanthanolides
Pseudoguaianolides (Figs. 5 and 6) are structurally very similar

to the previously mentioned guaianolides (the difference is the
methyl group at C-4 instead of C-5) and are also widely distributed
in the genus Inula.
The ethanolic extract of Inula hupehensis aerial parts yielded a
great number of pseudoguaianolide derivatives and some of them,
such as inuchinenolide C 28 and (1S,2S,5R,6S,7R,8S,10R)-6-acetoxy-2-methoxy-4-oxopseudoguai-11(13)-en-12,8-olide 29 (Fig. 6),
showed potent inhibitory activity against LPS-induced NO production in the RAW 264.7 macrophages (Qin et al., 2011a). These
ndings are an important support for the traditional use of this
species. Another interesting example is bigelovin 48 (Fig. 6),
Xanthanolides (Figs. 9 and 10) are sesquiterpene-type lactones,

which biogenetically can be formed from the guaiane skeleton by
ring opening at C-4/C-5 and are common in Inula spp.. A review on
xanthane sesquiterpenoids covering the literature up to the end of
2009 has described several xanthanolides from Inula spp. (Vasas
and Hohmann, 2011). Tomentosin (also known as xanthalongin)
63 (Fig. 9) is one of the most common derivative in Inula spp..
Not many bioactive xanthanolides were reported recently, but
some tomentosin derivatives, isolated from the medicinal plant
Inula hupehensis, showed inhibitory activity against LPS-induced
NO production in RAW 264.7 macrophages very close to the
positive control aminoguanidine (Qin et al., 2012b).
4.2. Guaianolides
294
Fig. 4. Structures of guaianolides isolated from Inula spp..
4.8. Other compounds
Fig. 5. Basic structure of pseudoguaianolides.
4.6. Dimeric sesquiterpenes

The isolation of dimeric sesquiterpene lactones (Fig. 11) is
recent and predominantly from Inula japonica (Qin et al., 2009,
2010a, 2011b; Zhan et al., 2011; Hu et al., 2012), being named
japonicones or neojaponicones (6974, Table 1). Qin et al. (2012a)
reported the isolation, structure elucidation and antiinammatory activity evaluation of several rare unsymmetrical
dimeric sesquiterpene lactones from Inula lineariifolia Turcz. An
important remark is the fact that this Inula sp. is not reported in
the databases consulted (The Plant List and Global Compositae
Checklist). It is our perception that it was a writing error and the
species used was Inula linariifolia Turcz.; but unfortunately the
same error is found in other publication from the same research
group (Nie et al., 2010). The structures of the reported compounds
are very interesting but their anti-inammatory activity is moderate. Some similar compounds, also recently isolated, showed
promising antitumour and anti-inamatory activity as it will be
described in Tables 3 and 4.
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).
In addition to all the above mentioned classes of compounds,

several other secondary metabolites were isolated from Inula spp..
For instance, extracts of Inula crithmoides allowed the isolation of a
quinic acid derivative 87 (Aboul-Ela et al., 2012a, 2012b) while a
thymol derivative 89 was isolated from Inula hupehensis roots
(Zhao et al., 2010) and lastly inulavosin 90 was isolated from Inula
nervosa (Yoshida et al., 1995) (Fig. 13, Table 1).
5. Biological and pharmacological activities

In the ancient times, plants were the only available medicine
(Tobyn et al., 2011). Nowadays products of plants are frequently
considered less poisonous and having fewer side effects than
synthetic drugs, and consequently still widely used by the population to treat several diseases. Extracts of Inula spp., used experimentally or in the popular medicine, can act by different ways to
control or inhibit symptoms of health problems. Herein these
extracts will be reviewed to show their bioactivities. In our manuscript we consider the description of the literature reports on each
Inula spp. extract activity and the bioactivities already proved for
the pure isolated secondary metabolites. On the rst glance at the
literature, we conclude that there is a huge lack of critical spirit in
analysing the results of the biological activity evaluations of both
extracts and pure isolated secondary metabolites. In fact, we found
many different criteria used by the authors and often the good
practices are not taken into account, we highligtht this and
comment it through the text. Many works were not cited here
nor can be used as a starting point for future investigations due to
the lack of proper information about the species used and/or part of
the plant extracted and/or concentrationeffect paradigm. Gertsch
(2009) discussed some points of these situations and pointed out in
his paper How scientic is the science in Ethnopharmacology?
several of the problems we found in the literature which challenging our selection. However, we consider that the genus Inula
deserves this literature survey and our effort.
5.1. Crude extracts
Several extracts of Inula spp. commonly used to treat health
problems were evaluated to ensure its traditional use. Table 2
summarizes the reported biological evaluations and our selection
was made considering: (a) the most active extracts; (b) the more
polar extracts (traditional medicine mainly uses aqueous and
alcoholic preparations); (c) the good practices leading to unambiguous identication of Inula spp., the repeatability of the
295
Fig. 6. Structures of pseudoguaianolides isolated from Inula spp..
Fig. 7. Structure of parthenolide structure 49.
experimental procedure, and the validation of the results. Some

studies that do not t these criteria are also presented in Table 2
but their inclusion will be discussed later on. It is important to
highlight that some of the cited literature is written in non-English
language and in some cases the results herein presented are based
on the English abstract (Cha et al., 2006; Lee et al., 2009; Duan et
al., 2011; Thapliyal et al., 2011), fact that limited the presentation
of more detailed results.
A careful analysis of the above mentioned data (Table 2) and
other not showed allowed some crucial considerations. It is, in our
opinion, acceptable to publish data where the values of bioactivity
reveal a product without pharmacological and/or commercial
potential, if they will contribute to the redirection of future
research. However we think that the authors should be more
critical when they are discussing and/or evaluating their results.
For example, almost all substances exhibit antioxidant effects
depending on the concentration tested and the exhibition of lower
IC50 values is not enough to conrm a powerful antioxidant
activity. The authors should use a good reference for antioxidant
activity (which must have current medicinal or food application,
depending on the purpose for which it is intended the evaluation)
and carefully compare the obtained results. When these conditions
are not fullled, which occurred for example in the antioxidant
evaluations of Inula cappa roots (Kalola and Shah, 2006) and Inula
verbascifolia (Willd.) Hausskn. (Jukic et al., 2012), it is impossible to
considerer the work as a valuable contribution for the scientic
community.
In the case of anticancer activity, the American National Cancer
Institute assigns a signicant cytotoxic effect of promising anticancer products for future bioguided studies if IC50 value is lower
than 30 g/mL. This criterion should be taken into account by the
authors when they are discussing their results. For instance,
statements like could be considered as potential sources of
anticancer compounds when the IC50 value is higher than
54 g/mL (Merghoub et al., 2009) or show tumoricidal effect
when the IC50 value is higher than 200 g/mL (Mazzio and
Soliman, 2009) are unacceptable. Even compounds having an

IC50 value lower than 30 g/mL should be referred as having
potential (meaning that other studies are required) anticancer
activity. Another important issue is the use of positive (and
negative) control in the evaluations. In order to indicate that some
extract is better, it is imperative to compare it with known active
compounds. Sadly, several authors do not use a positive control
and others do not indicate the positive control IC50 value and in
doing so they reduce the impact of the obtained results (GebreMariam et al., 2006; Wang et al., 2006; Kaileh et al., 2007; AbuDahab and A, 2007; Merghoub et al., 2009; Mazzio and Soliman,
2009, Oskay et al., 2009; Talib and Mahasneh, 2010b; Khan et al.,
2010c; Jukic et al., 2012).
In assessing the anticancer potential of any mixture and/or pure
compound, the selectivity index (SI IC50 non-tumor cells/IC50 tumor
cells) is essential. Our literature survey, which is summarized in
Table 2, showed that many authors do not take that into consideration.
Unfortunately, a signicant number of authors do not indicate in
their work statistic parameters that are essential to the results
credibility.
Some very interesting works do not indicate the part of the
plant analysed. In some cases we suspect that this could be due to
the fact that the results were published in a non-English journal,
and, consequently, the information could be hindered (Cha et al.,
2006; Lee et al., 2009), but in other cases the authors do not give
any indication of the plant part used (Stanojevi et al., 2010;
Yamashita et al., 2010; Degerli et al., 2012).
From the point of view of the biological activity of extracts
versus ethnopharmacological applications we are pleased to make
some remarks. The traditional use of Inula viscosa to induce
abortion was conrmed by the antifertility characteristic of its
aqueous extract reported by Al-Dissi et al. (2001). Talib and
Mahasneh (2010a) found that Inula viscosa owers extracts present also antimicrobial activity and their careful research led to
nd its low toxicity towards normal human cells (Vero cell line
IC50 202.43 73.70 g/mL).
Lu et al. (2012) proposed that britanin 40 (Fig. 6) and tomentosin 63 (Fig. 9), the major compounds identied from the owers
extract of Inula japonica by HPLC, are responsible for the extract
antiallergic activity (Table 2).
The chloroform extract of Inula ensifolia owers and fruits was
strongly active against HeLa and with some selectivity for dividing
cell populations (difference of antiproliferative and cytotoxic value
296
Fig. 8. Structures of germacranolides isolated from Inula spp..
Fig. 9. Basic structure of xanthanolidse and tomentosin 63.
436%) (Rthy et al., 2007). These results indicate that Inula

ensifolia extracts can be the source of high value antitumor agents,
although ethnopharmacological applications for this Inula sp. were
not reported.
Gebre-Mariam et al. (2006) work is a rationale justication to
the traditional use of Inula confertiora extracts to treat dermatological disorders, such as herpes and fungal infections caused by
Tinea capitis and Tinea corporis.
The Inula racemosa roots extract was carefully studied and their
anti-atherogenic and cardioprotective effect in rats, before and after
experimental myocardial infarction was demonstrated (Mahmood
et al., 2010). These results support the traditional medicinal use of
Inula racemosa as cardioprotective and anti-obesity agent (Singh
et al., 1990).
The above referred activities (Table 2), from which we highlighted a few, prove that Inula spp. seem to have a signicant effect
when used in traditional medicine, in the treatment of several
diseases, but they also demonstrate that more experiments should
be carried out and it is crucial that the unequivocal identication
of the responsible secondary metabolites should be done. It should
be pointed that from the classical phytotherapeutical and pharmacological point of view, the use of plant extract decreases the
frequency of side effects and potentiates the synergistic or at least
the additive effects.
5.2. Pharmacological properties of the isolated compounds
The search for the active principles present in the plant extracts
is in most cases associated to the scientic knowledge but it
should become a validation of the traditional herbal use.
The review elaborated by Zhao et al. (2006) reported the
secondary metabolites and their biological activities (e.g. antiproliferative and bactericidal) from Inula spp. and also the strong interest
of the scientic community in sesquiterpene lactones, the major
secondary metabolites found in this genus. Furthermore, some
structure/activity relationships were also discussed. For instance,
the 11,13-dehydrolactone moiety is crucial for the antiproliferative
activity of alantolactone 1 (Fig. 1) derivatives. The presence of
electrophilic sites, e.g. other unsaturations or epoxide functions,
together with a moderate-to-high lipophilicity, seems to enhance
the in vitro antimycobacterial activitiy of sesquiterpene lactones
(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. 10. Structures of xanthanolides isolated from Inula spp..
Fig. 11. Structures of dimeric sesquiterpene lactones isolated from Inula spp..
Fig. 12. Structures of avonoid compounds isolated from Inula spp..
Fig. 13. Structures of other metabolites isolated from Inula spp..
5.2.1. Anti-tumour/cytotoxic activity

The genus Inula comprise several species used in traditional
medicine to treat cancer diseases and it is included in the list of
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
Cytotoxic (in vitro)
Dichloromethane/methanol (1:1)
Leaves
Cytotoxic and
genotoxic (in vitro)
Aqueous extract
Aerial parts Hypoglycaemic and

hypolipidemic
(in vivo)
Aerial parts Antiherpetic
(in vitro)
Aqueous extract
Hexane, acetone and methanol extracts
Flowers
Cytotoxicity (in vitro) Several fractions and sub fractions of 95%

hydroethanolic extract
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
Petroleum ether extract

Ethanolic extract
Inula cuspidatad
Leaves
Anti-inammatory
(in vivo)
The aqueous extract exhibited potent anti-implantation, mid-term Al-Dissi et al.,

abortion and luteolytic effects in pregnant rats but not acute toxicity 2001
Growth inhibitory effect against SiHa and HeLa cell lines
respectively harbouring HPV16 and HPV18 (IC50 54 and 60 mg/mL,
respectively)
The multi-drug resistant clinical isolates and reference bacteria
were tested and the most susceptible organism was the clinical
bacteria Pseudomonas aeruginosa (MIC 8.0 mg/mL)
This extract prevents signicantly the development of hypertension
induced by L-NAME and showed a dose-dependent negative
inotropic effect in cardiac muscle
The extrat showed weak cytotoxicity against L929sA cell line (IC50
600 754 mg/mL)
In Allium cepa test, extract (at 10 mg/mL) induced the cell death,
ghost cells, cells with membrane damage, binucleated cells,
chromosomal aberrations and micronuclei (MNC) formations
The tested extract, at a dose of 20 mg/kg showed hypoglycaemic
activity by reducing blood glucose levels, without effect on plasma
insulin but not affect the total cholesterol and triglycerides levels
Acetone extract was the most active (low activity) against HSV-1
(47.4 7 1.5% of inhibition at 500 mg/mL of extract; acyclovir
100.4 7 0.2% of inhibition at 5 mg/mL)
10% aqueous methanol fraction of ethanolic extract was active and
selective against MCF-7 (IC50 15.78 70.59 mg/mL, SI 5) and induces
the cell death by apoptosis
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
The extrat was active against Tetranychus cinnabarinus with a

mortality of 92% at the concentration of 2 mg/mL
The extract acts as moderate HSP70 inducer, with a safe induction
index (SI) of 80 (SI-cell viability (%) at a concentration that doubles
the expression of HSP70)
Duan et al.
(2011)
Yamashita et al.
(2010)
The water fraction showed the strongest antioxidant activity by

Lee et al. (2009)
DPPH (IC50 20.7 g/mL) and ABTS methods (IC50 39.4 g/mL) and it
protects the cells from H2O2-induced damage (increasing cell
survival by 35.077.0% at a concentration range of 62.5250 g/mL
and decrease intracellular ROS of 3439%)
60% Hydroethanolic extract
The extract exhibited a weak NO-production inhibitory activity but a

histamine-release inhibition of 86% at 0.1 mg/mL was obtained
The extract inhibited the OVA-induced airway inammation by
reducing the leukocyte inltration, AHR, Th2 cytokines, IgE level
and mucus hypersecretation
The extract modulates eicosanoids generation and degranulation
through the suppression of SCF-mediated signalling pathways
The hypolipidemic effect of the extract in alloxan-diabetic mice was
demonstrated. The anti-hyperglycemic effect was better than
metformin and gliclazide used as positive controls
The diethyl ether fraction showed the highest cytotoxic activity
against HT-29 cell line, but also showed activity against SW620,
HeLa and MCF-7 cells
Ethanolic extract
Anti-allergic (in vitro Ethanolic extract

and in vivo)
Aqueous extract
Flowers
Antidiabetic and
hypolipidemic
(in vivo)
Not
Acetone and ethanolic extrat and diethyl
identied
ether fraction of the ethanolic extract
Inula ensifoliac
Flowers/
fruits,
leaves
and roots
References
Hexane, petroleum ether, chloroform, ethyl

acetate and water fraction from 70%
hydromethanolic extract
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 )
Hexane, chloroform, hydromethanolic and

water extracts
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)
Petroleum ether, chloroform, acetone,

methanol and water extracts
The maximum anti-inammatory effect was observed in water

extract followed by petroleum ether extract
Thapliyal et al.
(2011)
299
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)
Aerial parts Anti-mutagenic

(in vivo)
Inula graveolensf
Flowers
Roots,
shoots
and
owers
Allelopathic
Aerial parts Antibacterial

(in vitro)
Inula helenium
Anthelmintic
Rhizomes
and roots (in vitro)
Rhizomes
Antistaphylococcal
and roots (in vitro)
Roots
Tested material
Results
80% Hydromethanolic extract
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
Ethanol, acetone and diethyl ether extracts

of each plant parts
Weak but broad activity against a wide range of microorganisms,

being the ethanol extracts of leaves and stem the most effective
mainly against Bacillus subtilis, Staphylococcus aureus, Escherichia
coli and Candida albicans (MIC value of 250500 g/mL to the
extracts, 2.550 g/mL to gentamicin and 1.25 g/mL nystatin)
Petroleum ether, chloroform, ethanol, 50%

hydroethanol and water
Aqueous extract
Ethanolic extract
Aqueous extracts and sequential hexane,

chloroform, and methanol extracts of each
plant parts
Essential oils

Ethyl acetate, methanolic and 50%
hydromethanolic extracts
Roots
Insecticidal (in vitro) Acetone/methanol (2:1)
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
Acetone/methanol 2:1 (v/v)
Hydrodistilled essential oil
Aqueous extracts
Hexane and ethanol extracts
The extracts caused no signicant lymphocyte activation or

pronounced blastogenesis when compared with
phytohaemagglutinin (PHA). The petroleum ether extract was the
most toxic (cytotoxicity 59.622 7 6.177% to the extract and
25.058 7 5.059 to PHA)
Treatment with extract counteracts the ochratoxin A-induced
oxidative stress prevents the liver and kidney injury by protecting
against the mutagenic and clastogenic effets
The extract showed strong antiproliferative (IC50 3.83 mg/mL) and
cytotoxic activity (IC50 5.83 mg/mL) against MCF-7 cell line while it is
not toxic against A549 and HL60 cells at 50 mg/mL
Only shoot and ower extracts (especially the chloroform extracts),
at 6 mg/mL reduced the germination index in Lactuca sativa,
Raphanus sativus, Peganum harmala and Silybum marianum L. Flower
aqueous extracts, in soil, decreased the seedlings length more than
shoot extract
The essential oil showed a MIC of 5 mg/mL and, destructively,
affects the integrity of the plasmatic membrane and the cell wall of
the Staphylococcus aureus
Attard and
Cuschieri
(2009)
Abdel-Wahhab
et al. (2008)
Abu-Dahab and
A (2007)
Omezzine et al.
(2011)
Guinoiseau
et al. (2010)
The effect against infective third-stage larvae of Trichostrongylus

colubriformis was higher than with the synthetic anthelmintic Zentel
The extract presents bactericidal activity against MRSA and MSSA
Staphylococcus aureus isolates (MBC 0.99.0 mg/mL)
Methanol and hydromethanolic extracts showed value as therapeutic
agents in renal brosis due to the apoptotic effect on NRK49F cells
without adversely affecting epithelial cells NRK52E
Remarkable highly selective antineoplastic activity (SI 4 100) against
HT-29, MCF-7, Capan-2 and G1 with no mutagenic activity
Efcient insecticide against Oncopeltus fasciatus causing severe
reduction of fecundity, shortening of antennae and proboscis in a high
percentage (75% of insects) and strong antifeedant effect
Potent but no fast bactericidal activity against Staphylococcus aureus
(MIC 13.00 g/mL, MBC 26.00 g/mL), with increased membrane
permeability
The extract showed antibacterial activity (MIC 10 mg/mL) with
synergistic action with sodium nitrite (MIC 2.5 mg/mL) against Bacillus
subtilis and Pseudomonas uorescens
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
Plant part
Roots
Roots
Biological activity
evaluated
Tested material
Results
References
the same extract signicantly reduced (23.8%) milk-induced

eosinophilia in mice at a dose of 50 mg/kg
Antidiabetic (in vivo) Methanolic extract
Chronic treatment with extract produced signicant reduction in
Ajani et al.
blood sugar level in alloxan induced hyperglycemia status than in (2009)
alone alloxan treated animals. The body weight, food intake, water
intake and urine output were signicantly reversed to normal by
extract treatment
Pal et al. (2010)
95% Ethanolic extract and its n-hexane,
The n-hexane fraction was the most active (IC50 from 10.25 to
chloroform, n-butanol and aqueous fractions 17.89 mg/mL) for any of the cell line tested (Colo-205, SW-620, IGROV-1, OVCAR-5, DU-145, PC-3, A-549, Hop-62, SK-n-SH, SF-295, HL60). It induces apoptosis in HL-60 by caspase activation, but it did
not exert any cytotoxic effect on PBMC (IC50 4 100 mg/mL)
Inula oculus-christig
Not
Amoebicidal
identied (in vitro)
Aqueous extract
Strong amoebicidal effect on the Acanthamoeba castellanii

(trophozoites and cysts) (at the concentration 32.00 mg/mL no
viable trophozoites were detected in 24 h of experiment but only
25.3% of the total cysts were killed effectively)
Degerli et al.
(2012)
Actually the accepted name is Dittrichia viscosa (L.) Greuter).

Inula auriculata Boiss. & Balansa.
c
Inula ensifolia L..
d
Inula cuspidata (Wall. ex DC.) C.B.Clarke.
e
Actually the accepted name is Limbarda crithmoides (L.) Dumort..
f
Inula graveolens (L.) Desf. Actually the accepted name is Dittrichia graveolens (L.) Greuter.
g
Inula oculus-christi L.
b
Table 3
Cytotoxic compounds isolated from Inula spp.
Cell line
Compounds
IC50 values (IC50 to positive control)
References
B16F10
MK-1
T47D
PA-I
OVCAR
DU-145
DUPro-I
DUPro-I
MCF-7
MCF-7
MCF-7
MCF-7
1 (Fig. 1), 4 (Fig. 2)

1 (Fig. 1), 4 (Fig. 2)
13 (Fig. 2)
13 (Fig. 2)
13 (Fig. 2)
13 (Fig. 2)
13 (Fig. 2)
15 (Fig. 2)
13 (Fig. 2)
15 (Fig. 2)
44 (Fig. 6)
85 (Fig. 12)
Konishi et al. (2002)

Ra et al. (2005)
Ra et al. (2005)
Ra et al. (2005)
Ra et al. (2005)
Ra et al. (2005)
Ra et al. (2005)
Ra et al. (2005)
Ra et al. (2005)
Park and Kim (1998)
Talib et al. (2012)
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)
3.64.7 mM (5-Fluorouracil 1.1 mM)

6.9 mM (5-Fluorouracil 19.2 mM)
7.50 mM
8.00 mM
10.00 mM
10.00 mM
5.00 mM
10.00 mM
5.00 mM
10.00 mM
9.1 mM
5.87 mg/mL (Vincristine sulfate
10.03 mg/mL, SI 417)
8.3 mM
6.56.9 mM (5-Fluorouracil 12.3 mM)
5.5 mM (DOX 0.4 mM)
1.2 M
3.8 M
5.3 M
3.56 mM
5.4 mM
1.50 M (DOX 0.059 M)
2.75.6 mM (DOX 0.15 M)
0.39 g/mL (Daunorubicin 0.28 g/mL)
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)
Park and Kim (1998)

Cheng et al. (2012)
Xie et al. (2007)
Xie et al. (2007)
Xie et al. (2007)
Song et al. (2005)
Bai et al. (2006)
Wang et al. (2012)
Park and Kim (1998)
Harvala et al. (2002),
Chin et al. (2009)
Park and Kim (1998)
Chen et al. (2007)
Cheng et al. (2012)
Cheng et al. (2012)
Cheng et al. (2012)
Cheng et al. (2012)
Cheng et al. (2012)
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
Zeng et al. (2009)

Zhang et al. (2012b)
Qin et al. (2009)
Qin et al. (2009)
Qin et al. (2009)
Qin et al. (2009)
Chen et al. (2007)
Chen et al. (2007)
301
Table 4
Isolated compounds of Inula spp. with inhibitory activity against NO production in LPS-stimulated RAW264.7 cells.
Compound
Inhibition value (IC50)
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)
7.39 M, [aminoguanidine (IC50 9.12 M)]

0.29 M [aminoguanidine (IC50 0.20 M)]
0.69 M, [L-N6-(1-iminoethyl)lysine (IC50 3.49 M)]
0.46 M, [L-N6-(1-iminoethyl)lysine (IC50 3.49 M)]
2.45 mM
0.013 g/mL, [aminoguanidine (IC50 114.900 g/mL)]
0.010 g/mL, [aminoguanidine (IC50 114.900 g/mL)]
2.39 M, [parthenolide (IC50 2.45 M)]
20.8 g/mL [aminoguanidine (IC50 48.7 g/mL)]
4.5 g/mL
12.0 g/mL
1.59 mM, [parthenolide (IC50 2.45 M)]
1.52 mM, [parthenolide (IC50 2.45 M)]

Qin et al. (2012b)
Qin et al. (2012b)
Qin et al. (2012b)
Cheng et al. (2011)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Cheng et al. (2011)
Cheng et al. (2011)
Cheng et al. (2011)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Nie et al. (2010)
Nie et al. (2010)
Nie et al. (2010)
Qin et al. (2011a)
Qin et al. (2011a)
Qin et al. (2011a)
Cheng et al. (2011)
Lee et al. (2002)
Qin et al. (2010b)
Lee et al. (2002)
Qin et al. (2011a)
Jin et al. (2006)
Hu et al. (2011)
Hu et al. (2011)
Qin et al. (2010b)
Jin et al. (2006)
Qin et al. (2012b)
Qin et al. (2012b)
Qin et al. (2012b)
Qin et al. (2012b)
Qin et al. (2012b)
Qin et al. (2012b)
Qin et al. (2010a)
Qin et al. (2010a)
Qin et al. (2010a)
Qin et al. (2011b)
Qin et al. (2011b)
Jin et al. (2006)
Jin et al. (2006)
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
compounds with IC50 lower than 5 g/mL or 10 M are presented

on Table 3, where we also include information about the IC50 of
the compound used in the study as a positive control, whenever
such information is available.
The results showed in Table 3, point up that; (a) the epoxygermacranolide 50 (Fig. 8) exhibited an IC50 value comparable
with that of the pharmaceutical drug daunorubicin, albeit this is
not a reference drug for the treatment of colon cancer;
(b) bigelovin 48 (Fig. 6) is the 4th most active compound from
Table 3, with IC50 against leukemia cell line U-937 lower than
0.5 mM; (c) japonicone A 69 (Fig. 11) is the most cytotoxic
compound so far isolated from a Inula spp.. According to Qin
et al. (2009) this compound is more active than DOX (doxorubicin)
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
the commercial drugs cyclophosphamide and uorouracil, and being

close to the activity of methotrexate (Spiridonov et al., 2005). These
results look very promising but may require conrmation since the
authors do not indicate the IC50 values, and the composition and
purity of the helenin was not conveniently checked.
It is interesting to note that most of the studies on the anticancer
mechanism of Inula compounds are related with those presenting
moderate activity and not with the most active ones. Based on these
studies, we concluded that the antiproliferative effect of the major
compounds was due to the induction of apoptosis by different ways:
(a) via inhibition of the NF-B signalling pathway. For example,
ergolide 46 (Fig. 6) against Jurkat T cells (Song et al., 2005) and
inuviscolide 27 (Fig. 4) against melanoma SK-28 cells (Rozenblat et
al., 2008); (b) by causing DNA damage. For example alantolactone 1
(Fig. 2) against HepG-2 (Lei et al., 2012), tomentosin 63 (Fig. 9) and
inuviscolide 27 (Fig. 4) against human melanoma cell lines, by DNA
alkylation which activates the kinases ATM/R and cause a G2-M
arrest (Rozenblat et al., 2008); (c) via decreasing the level of survivin,
a member of the inhibitor of apoptosis protein (IAP) family, by
caspase activation, poly ADP ribose polymerase cleavage, and cytochrome c release. For example 1,6-O,O-diacetylbritannilactone 13
(Fig. 2) against HL-60 cells (Pan et al., 2007) and alantolactone 1
(Fig. 1) against U87 cells (Khan et al., 2012). In this last study, the
toxicity and cross bloodbrain barrier capacity of the alantolactone 1
were evaluated in vivo.
The cancer chemopreventive mechanisms do not involve only
antiproliferative effect but also the antimutagenic effect, as in the
case of alantolactone 1 (Fig. 1) and 5-epoxyalantolactone 4 (Fig. 2)
which involves the induction of phase 2 detoxifying and antioxidant enzymes, like quinone reductase (QR) and glutathione Stransferase (GST), mediated by Nrf2-ARE pathway (Im et al., 2007;
Seo et al., 2008).
5.2.2. Anti-inammatory activity
Inula compounds are capable to modulate the enzyme activities of
arachidonic acid (AA) metabolizing enzymes, such as phospholipase
A2 (PLA2), cyclooxygenase (COX), and lipoxygenase (LOX) and the
nitric oxide (NO) producing enzyme, nitric oxide synthase (NOS).
An inhibition of these enzymes reduces the production of AA,
prostaglandins (PG), leukotrienes (LT), and NO, crucial mediators
of inammation.
5.2.2.1. NO inhibition. One of the most studied models of antiinammatory activity evaluation focuses on the inhibitory effect of
Inula isolated compounds against NO production in LPSstimulated RAW264.7 cells (Table 4).
Compounds 7072 exhibit much higher activity than the aminoguanidine used as positive control (Table 4), the IC50 values units are
different, but we decided to report the values indicated by the authors
(Qin et al., 2010a). It should also be mentioned that these three
compounds were not cytotoxicity towards RAW264.7 cells and we
should emphasise this type of evaluations are rare in the literature.
The same criteria was adopted with compounds 73 and 74, where the
authors indicate that they signicantly inhibit LPS-induced NO production in RAW264.7 (using aminoguanidine as a positive control),
but if we convert the unit used in the manuscript for those more
commonly found (M) only compound 73 full our criteria.
Fig. 14. Structures of some important bioactive compounds isolated from Inula spp..
From the analysis of Table 4 it is possible to conclude that

sesquiterpene lactones are very good inhibitors of NO production
in LPS-stimulated RAW264.7 cells. Some structure/activity relationship claimed by several authors can be inferred. For instance, the
lower inhibitory activity of -methyl--lactones suggests that a methylene--lactone moiety is crucial for the compounds activity
(Cheng et al., 2011). The acetylation of hydroxyl groups usually tends
to increase lipophilicities resulting in a better penetration through
cell membranes and enhanced inhibitory effects on NO production,
also the presence of a hydroxyl group at C-2 or C-6 pseudoguaianolides reveals to be of pivotal importance for the inhibitory effects (Qin
et al., 2011a). Several studies showed that the -methylene--lactone
and the propenoic methyl ester chain can be the key chemical
characteristic responsible for the anti-inammatory activity (Qin et
al., 2010b). Accordingly to Cheng et al. (2011) the presence of orientation of 14-CH3 might increase the inhibitory effects of
xanthanolide derivatives. These conclusions are based on the IC50
values between 10-epi-4H-tomentosin 95 (Fig. 15) and 4H-tomentosin 68 (Fig. 10), although these compounds are less active than the
positive control they used as models.
Not often the isolated compounds are also evaluated for their
toxicity, so it is valuable that Qin et al. (2011a) have done it and
found that none of the compounds 2023, 2839, 43, 44, 46 and
48 exhibited signicant cytotoxicity against RAW 264.7 macrophages at their effective concentrations for the inhibition of NO
production. These results provide also a potential explanation for
the use of Inula hupehensis as a Chinese herbal medicine in the
treatment of inammatory diseases, and they may be potentially
useful in developing of new anti-inammatory agents.
Another medicinal plant used to treat inammatory diseases is
Inula britannica var. chinensis and to provide a scientic explanation for its use Jin et al. (2006) examined the effect of its secondary
metabolites on the NO production in LPS-stimulated RAW264.7
cells. The authors used a more active positive control, the parthenolide 49 (Fig. 7), and found that eupatolide 59 IC50 was similar to
the one obtained for the positive control but in the cases of
inulanolides B 75 and C 76 the values were lower (see IC50 value
on Table 4). There are no signicant results to clarify the structureactivity relationship but it seems that the presence of a guaianolide moiety enhances the activity. It is expected that very soon
more information will be available to conrm these data, considering that new dimeric sesquiterpene lactones are still being
found and tested (Zhu et al., 2013).
Britanin 40 (Fig. 6) is another compound that is able to inhibit
the nitric oxide (NO) and prostaglandin E2 (PGE 2) production,
along with the expression of inducible NO synthase (iNOS) and
cyclooxygenase (COX)-2 in lipopolysaccharide (LPS)-stimulated
RAW264.7 cells. In addition, britanin 40 reduce the release of
pro-inammatory cytokines, such as TNF-, IL-1, and IL-6.
Furthermore, the phosphorylations of MAP kinases (p38 and
JNK) in LPS-stimulated RAW 264.7 cells were also suppressed by
britanin 40. Moreover, britanin 40 inhibit the NF-B activation
induced by LPS, which was associated with the abrogation of IB
degradation and subsequent decreases in nuclear p65 levels (Park
et al., 2012). The activity of britanin 40 (Fig. 6) conrms the antiinammatory ethnopharmacological application of Inula japonica.
5.2.2.2. Inuence on arachidonic acid pathway. Another route of

counteracting inammatory process implies the arachidonic acid
pathway. Several experimental methods were developed and Inula
isolated compounds were tested. One of the most interesting works
is that of Hernndez et al. (2007) on the in vivo and in vitro
evaluation of anti-inammatory activity, of several secondary
metabolites isolated from Inula viscosa, which give a scientic proof
of the ethnopharmacological application of this species. Some
303
compounds proved to be effective against the phospholipase A2

(PLA2)-induced paw oedema, being the most relevant results
obtained with 7-O-methylaromadendrin 77 (Fig. 12) (ID50 8 mg/kg)
and sakuranetin 78 (Fig. 12) (ID50 18 mg/kg). In the case of 12-Otetradecanoylphorbol 13-acetate (TPA)-induced ear oedema the
authors found out that 3-acetyl-7-O-methylaromadendrin 79 (ID50
185 g/ear) and sakuranetin 78 (ID50 205 g/ear) were the most
potent ones (Hernandez et al., 2007). In the case of TPA-induced ear
oedema the authors indicate the result obtained with the
indomethacin (ID50 125 g/ear), a known drug, whereas with the
PLA2-induced paw oedema they indicate that cyproheptadine was
used as control although they do not indicate the obtained result
with this known active compound. In the in vitro evaluation using
leukotriene B4 (LTB4) generation in intact cells it was found that
3-acetyl-7-O-methylaromadendrin 79 (Fig. 12) (IC50 15 M) and
sakuranetin 78 (Fig. 12) (IC50 9 M) were the most effective
compounds, being sakuranetin better than the active compound
used apigenin with an IC50 value of 14 M (Hernandez et al., 2007).
Inuviscolide 27 (Fig. 4) is an interesting sesquiterpenoid whose
inhibitory effect in some enzymes related to leukocyte exocytosis
(elastase) and to the turnover of lipid mediators, such as PLA2 and
COX, was evaluated (Mez et al., 2007). The results showed that
inuviscolide 27 (Fig. 4) inhibits signicantly the release of human
leukocyte elastase, showing a 70% inhibition after 2 min, with an
IC50 value of 80.5 mM against sPLA2 from bee venom and also
inhibits cyclooxygenase-1 (COX-1) at 50 mM (40%). Furthermore, it
reduces the skin leukocyte inltration in a murine model of
induced dermatitis (Mez et al., 2007). Later on, inuviscolide 27
(Fig. 4) together with tomentosin 63 (Fig. 9) were tested in vitro to
evaluate their effect on the secretion of pro-inammatory cytokines from PBMCs upon stimulation with LPS or PMA (Abrham
et al., 2010). The results showed that both compounds cause a
decrease in the production of IL-2, IL-1, IFN and a reduction in
the protein level of both the transcription factor component
p65/RelA of NF-B and STAT1 (Abrham et al., 2010).
Zhang et al. (2010a) evaluated another interesting effect, the
inhibitory activity against the release of -glucuronidase from rat
PMNs (polymorphonuclear leukocytes) induced by PAF (plateletactivating factor), and showed that 11,13-dihydroalantolactone
6 and (4S,8S,10R)-12-hydroxy-eudesma-5(6),7(11)-dien-12,8-olide
7 (Fig. 2), identied in the species Inula racemosa used in the
treatment of asthma-like conditions, presented potent anti-PAF
effect (inhibitory ratios 65.4% and 80.5% at concentration of 10 mM,
respectively).
5.2.2.3. Inuence on transcription factors/gene expression. The
cellular action mechanisms of Inula compounds for modulating
gene expression have been also actively studied. Lee et al. (2010a)
identied that eupatolide 59 (Fig. 8) inhibited the production of
NO and PGE2 as well as iNOS and COX-2 protein expression in LPSstimulated RAW 264.7 cells. Eupatolide 59 (Fig. 8) also inhibited
AKT phosphorylation and Akt by LY294002, a specic PI3K
inhibitor, down-regulated c-FLIP expression in MCF-7 cells (Lee
et al., 2010b).
Suppression of NF-kB activation by ergolide 46 (Fig. 6) might be
attributed to the inhibition of nuclear translocation of NF-kB,
resulted from blockade of IkB degradation and the direct modication of active NF-kB (Whan et al., 2001). It was also showed
that it suppresses the DNA binding activity of NF-kB and nuclear
translocation of NF-kB p65 subunit, leading to the inhibition of NF-
Fig. 15. Structure of 10-epi-4H-tomentosin 95.
304
kB-dependent gene transcription in TPA-stimulated HeLa cells.

Other results suggested that ergolide 46 (Fig. 6) suppresses NF-kB
activation through the inhibition of PKC-IKK activity, providing
insight for PKC as a molecular target for anti-inammatory drugs
(Chun et al., 2007; Jae et al., 2007).
Recently, japonicone A 69 (Fig. 11) was reported as an interesting lead compound for the development of novel antiinammatory remedies, due to the fact that it can directly bind
to TNF-, modulating its biological activity (inhibiting selectively
its binding to TNFR1, blocking effectively TNFR1-mediated signalling in TNF--stimulated cells, and antagonizing its proinammatory activity in vivo without impairing the host antiviral immunity)
(Hu et al., 2012).
The new sesquiterpenoid dimers bearing a norbornene moiety,
inulanolides B 75 and C 76 (Fig. 11) along with eupatolide 59 (Fig. 8)
exhibited potent inhibitory activity on the LPS-induced NF-B
activation (IC50 value of 0.49, 0.48 and 1.54 mM, respectively; parthenolide was used as positive control IC50 2.97 mM) (Jin et al., 2006).
These results provided a scientic explanation for the use of Inula
britannica var. chinensis in Asia to treat inammatory diseases. In
addition, bigelovin 48 (Fig. 6), also found in this plant, is known to
inhibits monocyte adhesion to TNF--stimulated endothelial cells by
the inhibition of VCAM-1, ICAM-1, and E-selectin expression on the
surface of endothelial cells (Nam et al., 2009).
1,6-O,O-Diacetylbritannilactone 13, britannilactone 14 and 1-Oacetylbritannilactone 15 (Fig. 2) are members of the 1,10-secoeudesmanolide family of sesquiterpene lactones, which have been
considered as anti-inammatory agents (Liu et al., 2009; Merten et
al., 2011). There are evidences that 1,6-O,O-diacetylbritannilactone
13 (Fig. 2) signicantly inhibited the phosphorylation of IKK and
is the one that exhibits the highest anti-inammatory effect of the
three compounds above mentioned (Liu et al., 2009). The effects of
1,6-O,O-diacetylbritannilactone 13 (Fig. 2) on activation of
endothelial cells and its interaction with macrophages treated
with LPS were also investigated (Li et al., 2008; Yin and Tang,
2011) and it was found that it inhibited the adhesion between
endothelial cells and macrophages by decreasing expression of
VCAM-1, OPN, MMP-9 and tenascin-c (Li et al., 2008).
The most studied compound of this 1,10-seco-eudesmanolide
family of sesquiterpene lactones was 1-O-acetylbritannilactone 15
(Fig. 2). In 2007 was proved its anti-inammatory action in VSMCs
stimulated by LPS at multiple levels (Liu et al., 2007). The
modulation of COX-2 activity by 1-O-acetylbritannilactone 15
(Fig. 2) may contribute to the anti-inammatory effects in VSMCs,
via mechanisms that are likely to involve obstruction of NF-B
activation and direct modication of active NF-B (Liu et al., 2007,
2008; Khan et al., 2010a). It is also recognised that 1-O-acetylbritannilactone 15 (Fig. 2) inhibits the expression of inammationassociated genes by blocking the activation of kinase-, an inhibitor of NF-B and by suppressing the degradation of NF-B-
inhibitors (Khan et al., 2010a, Liu et al., 2008). Subsequently, Liu
et al. (2011a) claried the effects of 1-O-acetylbritannilactone 15
(Fig. 2) on VSMC proliferation and apoptosis and demonstrated
that it inhibited PDGF (platelet-derived growth factor) induced
DNA synthesis and proliferation in cultured VSMC. In addition, 1O-acetylbritannilactone 15 (Fig. 2) also induced apoptosis in
proliferative VSMCs, that was a benecial means to eliminate
excessively proliferative cells and it offered protection to the
vessels against restenosis induced by artery injury (Liu et al.,
2011a). The same group found that 1-O-acetylbritannilactone 15
(Fig. 2) could reduce celecoxib dose (the rst selective COX-2
inhibitor approved by the U.S. Food and Drug Administration)
(Liu et al., 2011b). As a nal point, last year it was observed that 1O-acetylbritannilactone 15 (Fig. 2) also protects rats from overtraining (ES) induced kidney injury by inhibiting renal cell apoptosis, suppressing oxidative-stress generation and inhibiting
inammation by decreasing TNF- and NF-B expression (Wu

et al., 2012).
Besides sesquiterpene lactones, avonoids also play an important role in exerting anti-inammatory effects; for instance, the
mixture of 45.5% quercitrin 81, 4.33% spinacetin 82, 1.85% isorhamnetin 83, 25.85% luteolin 84, 12.96% 6-methoxyluteolin 85
(Fig. 12), extracted from Inula britannica, inhibits neointimal
formation induced by balloon injury (Zhang et al., 2009). In fact,
total avonoid extract reduces O2 generation via augmenting
SOD activity and decreasing p47phox expression (Zhang et al.,
2009). Recently, the same authors demonstrated that this mixture
is capable of attenuating the oxidative stress generation and the
subsequent inammation response via preventing the overexpression and activation of p47phox and the increased TNF-
secretion in VSMCs in vitro (Zhang et al., 2011).
5.2.3. Antimicrobial activity

5.2.3.1. Antiviral. The major component of Inula crithmoides roots
extract, 1,5-di-O-caffeoylquinic acid 87 (Fig. 13), is a potent HIV-1
integrase inhibitor and currently is involved in an undergoing
evaluation as a promising novel HIV therapeutic agent (Yang et al.,
2005; Bhuwan et al., 2011). Furthermore, the Chinese scientists
have initiated the clinical evaluation of this compound to treat
HIV/AIDS and hepatitis B (Bhuwan et al., 2011).
5.2.3.2. Antifungal. Tomentosin 63 (Fig. 9) antifungal activity was
proved several years ago in an in vitro assay against Microsporum canis,
Microsporum gypseum and Trichophyton mentagrophytes at 1 mg/mL
concentration (Cafarchia et al., 2001). More recently it was proved to
be effective in controlling downy mildew caused by the fungi Plasmopara viticola in detached leaf tissues of grapes (Cohen et al., 2006),
some other compounds such as costic acid 86 (Fig. 3), alantolactone 1
(Fig. 1) and isoalantolactone 12 (Fig. 3) was also observed inhibitory
activity of this fungi (Grimaud, 2009). For isoalantolactone 12 (Fig. 2) it
was earlier established the inhibition of the human pathogenic fungi
Aspergillus avus, Aspergillus niger, Geotrichum candidum, Candida
tropicalis and Candida albicans at concentrations of 50, 50, 25, 25
and 25 g/mL, respectively (Tan et al., 1998).
Finally, the antifungal activity of thymol derivatives revealed that
8-hydroxy-9,10-diisobutyryloxythymol 89 (Fig. 13) displayed moderate inhibitory activity against Rhizoctonia solani, Phytophthora melonis
and Peronophythora litchi (Zhao et al., 2010).
5.2.3.3. Antibacterial. The antibacterial activity was the most
investigated antimicrobial activity, although some studies were not
performed in pure compounds but in mixtures. Alantolactone 1
(Fig. 1) is the most assayed pure compound and it is very active
against Pseudomonas aeruginosa and Bacillus cereus (near to streptomycin used as positive control) and moderately active against Shigella
dysenteriae, suggesting its use in bacillary dysenteries, although its
exact mode of action remains unclear (Lokhande et al., 2007). 4,5Epoxyalantolactone 2 (Fig. 1) is more active (MIC 15.5 mg/mL) than
ampicillin (MIC 25.0 mg/mL) against Bacillus cereus (Jiang et al., 2011).
Recently, alantolactone 1 (Fig. 1) together with diplophyllin 3 and
isoalantolactone 12 (Fig. 2) were identied as the antistaphylococcal
active constituents of the essential oils from Inula helenium roots
(Stojanovi-Radi et al., 2012). The authors performed a structure/
activity relationship study and suggested that the eudesmane core
olenic bonds alongside with the ,-methylene-lactone ring are
essential structural features for antimicrobial activity against
Staphylococcus aureus. Furthermore the conformational analysis
showed differences that inuence the optimal interaction of
lactone moiety with the binding region of the target biomolecules,
and can explain the higher antistaphylococcal activity of diplophyllin
3 (Fig. 2).
Another study showed that isoalantolactone 12 (Fig. 2) can inhibit

the expression of -toxin in Staphylococcus aureus at very low
concentrations (Qiu et al., 2011), whereas 8-hydroxy-9,10-diisobutyryloxythymol 89 (Fig. 13) displays moderate antibacterial activity
against Staphylococcus aureus and Escherichia coli (Zhao et al., 2010).
Quercetin derivatives were also examined for their antimicrobial
activity and it was found that 3,30 -di-O-methylquercetin 80 (Fig. 12)
was effective in inducing damage in bacteria cell walls and cytoplasmic membranes inhibiting Bacillus cereus (MIC of 62.5 mg/mL)
and Salmonella typhimurium (MIC of 125 mg/mL) (Talib et al., 2012).
The antimicrobial activity of tomentosin 63 (Fig. 9), isolated from
Inula viscosa, alantolactone 1 (Fig. 1) and isoalantolactone 12 (Fig. 2),
isolated from Inula racemosa, and 4,5-epoxyalantolactone 2 (Fig. 2),
isolated from Inula helenium, corroborate the antiseptic and antimicrobial function of these species in traditional medicine.
5.2.3.4. Antiprotozoal. Some germacranolide derivatives were
evaluated for their toxicity against Trypanosoma brucei
rhodesiense and Plasmodium falciparum (Go
kbulut et al., 2012),
being found that the diastereomeric mixture of (30 R,40 S- and
30 S,40 R)-9-(30 ,40 -epoxy-30 -methylpentanoyloxy)parthenolide 51
and 52 (Fig. 8) was active (IC50 0.26 g/mL) against Trypanosoma
brucei rhodesiense (IC50 0.003 g/mL to melarsoprol used as
positive control), with low cytotoxicity against mammalian
control cells L6 (IC50 2.33 g/mL).
5.2.4. Antidiabetic
A study on Inula viscosa extracts allowed the isolation of the
avanone 7-O-methylaromadendrin 77 (Fig. 12), which was evaluated as potential antidiabetic agent (Zhang et al., 2010b). The
study showed that 7-O-methylaromadendrin 77 (Fig. 12) might
stimulate glucose uptake by increasing both gene and protein level
of PPAR2 and improve insulin resistance by reactivation of
insulin-mediated phosphorylation of PI3K and AMPK, concluding
that this avanone can be a potential candidate for the management of type 2 diabetes mellitus (Zhang et al., 2010b). These
results support the traditional application of Inula viscosa in
Marocco, to treat diabetes.
5.2.5. Insecticidal/larvicidal/acaricidal
It is well known that the yellow fever mosquito Aedes aegypti
cause serious health problems, therefore the evaluation of larvicidal activity against this mosquito is common. The eudesmanolides
alantolactone 1 (Fig. 1) and isoalantolactone 12 (Fig. 2) showed the
highest larvicidal activity against rst instar larvae of Aedes aegypti
(Cantrell et al., 2010). Alantolactone 1 (Fig. 1) was also signicantly
toxic against Aedes albopictus (Konishi et al., 2008).
Other compounds, such as lupeol 88 (Fig. 13), revealed in vitro
acaricidal activity against the carmine spider mite Tetranychus
cinnabarinus. The effects of lupeol 88 (Fig. 13) in the activity of
GSTs, Ca2 -ATPase, SOD and protein content of Tetranychus
cinnabarinus were assayed and a statistical analysis revealed that
the main enzyme activity of the mites was changed by lupeol 88
(Fig. 13) (Duan et al., 2011).
5.2.6. Other activities
Various pharmacological activities have been established for
Inula spp. secondary metabolites, such as antidepressant (Yu et al.,
2006), hepatoprotective (Aboul-Ela et al., 2012a) and antioxidant
(Danino et al., 2009; Zhang et al., 2011) activities, just to mention a
few examples, but the main problem of these reports is the lack of
references usage or statistical studies and sometimes the authors
start from an active fraction and afterwards identify the secondary
metabolites, but do not conrm their bioactivities. All these
aspects make the reported results unreliable, reason why our
305
option was to discuss the most trustworthily ones. One example

that can be focused here is the work on the anti-melagenic activity
evaluation of inulavosin 90 (Fig. 13), that proved its potential as a
melanogenesis inhibitor reducing the melanin content without
affecting either the enzymatic activity or the transcription of
tyrosinase or Tyrp1 in B16 melanoma cells. Thus, inulavosin 90
(Fig. 13) inhibits melanogenesis as a result of mistargeting of
tyrosinase to lysosomes (Fujita et al., 2009).
6. Toxicology of the genus Inula

Plants of the genus Inula are traditionally used to treat several
diseases but they are also known as being harmful, especially to
cause dermatitis. The potential toxicity of the genus Inula has not
been well addressed but some studies point to several toxic effects
that cannot be overlooked. Apparently Inula helenium, is the Inula
sp. causes more dermatitis by contact (Paulsen, 2002; Ventura et
al., 2006; Aalto-Korte et al., 2007; Aberer, 2008), but no epidemiological data are available for this species. External use of Inula
helenium is therefore associated with the greatest risk not only of
contact dermatitis, but also more widespread immunological
responses such as erythema multiforme-like eruptions (Paulsen,
2002). This allergic contact dermatitis caused by exposure to
plants is common with Compositae family (Paulsen, 2002;
Aberer, 2008), and appears clinically as acute or chronic dermatitis
of exposed sites. In the case of Inula spp. there are evidences that
the presence of sesquiterpenoid lactones, such as alantolactone 1
(Fig. 1) and isoalantolactone 12 (Fig. 2), are responsible for the
allergic contact dermatitis (Marc et al., 2008). This result is in
agreement with Stampf et al. (1978) that showed isoalantolactone
12 (Fig. 2) as a sensitizer which cross-reacts with alantolactone,
but in contradiction with the conclusion of Blasi et al. (1992) that
isoalantolactone did not show any sensitizing capacity in the
murine model studied.
On the other hand, the safety of Inula racemosa roots was
conrmed by Srivastava et al. (1999) showing that the hydroethanolic extract was not toxic in rats (LD50 2100 mg/kg by intraperitoneal route). This extract seems to be very safe for use in clinical
situations, though further evaluation for chronic toxicity is required.
elik and Aslantrk (2010) showed that aqueous extract of
Inula viscosa leaf induced cytogenetic alterations leading to cell
death in root tips of Allium cepa. Thus, although Inula viscosa has
benecial effects in medicine, it can cause serious problems and
damage on cells when used improperly.
One important issue is the fact that sesquiterpenoid lactones,
the most representative class of compounds identied on Inula
spp. were never thoroughly evaluated for their toxicological
prole. A recent review was focused on this topic (Amorim et al.,
2013) and concluded that with increasing the medicinal use of
these compounds, further studies of their toxic potential are
needed, especially those focusing on the structural determinants
of genotoxicity and embryotoxicity. The wide range of biological
activities attributed and/or demonstrated for these natural metabolites are well known, as demonstrated in the present work, and
underlie their therapeutic potential. However, the toxicological
prole of these compounds must be thoroughly characterized,
since sesquiterpenoid lactones-containing plants have long been
known to induce a contact dermatitis in exposed farm workers,
and also to cause several toxic syndromes in farm animals.
It is evident, from our literature survey, that several important
toxicological studies were not done or yet published, for instance
teratogenicity and carcinogenicity of the plant extracts, were not
reported and obviously are essential. A myriad of conventional, in
silico, in vitro and in vivo methods, based on omics technologies,
to predict the genotoxicity, teratogenicity and nephrotoxicity of
306
herbal medicinal products were reviewed recently (Ouedraogo

et al., 2012).
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..
7.3. Selection of compounds for further studies

Several of the medicinal uses can be elucidated by the presence
of active metabolites in the species, but further studies must be
performed, for instance -lactones are considered as antimalarial
pharmacophore groups and may become lead compounds in the
development of new drugs against malaria. In our literature survey
only one example of a bioassay against Plasmodium falciparum was
found and it seems petty taking into account that sesquiterpene
lactones, one of the main classes of secondary metabolites
detected in this genus are -lactone derivatives.
Although the studies on anti-tumour and anti-inammatory
activities suggest that secondary metabolites isolated from Inula
spp. can be important new anti-tumour and anti-inammatory
drugs or lead compounds for developing new ones, we conclude
that the overwhelming majority of the cited compounds exhibit
high IC50 values (mM) when compared, for example, with the
successful anticancer therapeutic agents' paclitaxel (nM).
Additionally, the four skeletal types of sesquiterpene lactones,
eudesmanolides, guaianolides pseudoguainolides and germacranolides, which have been detected in Inula spp. and have received
considerable attention because of their ecological functions,
biological activity and taxonomic signicance, are the main
anti-tumour active compounds. Unfortunately, the vast literature
consulted showed as well that, in almost all the published
studies, there were no evaluations against non-tumor cells and
consequently no selectivity index (SI) calculations. It is known
that one criterion for a drug to be considered good is that it
should not exhibit signicant undesirable side-effects on normal
cells. The use of a positive control is a crucial point often
overlooked by researchers moreover the use of a commercial
drug with effective action in the same type of cancer cell lines is
highly recommended.
Sesquiterpene lactones are once more the most active compounds found in anti-inammatory studies, in this case the 1,10seco-eudesmanolide type-compound, 1-O-acetylbritannilactone
15, can be highlighted as the most studied one. It is vital that
some of the biologically active secondary metabolites will be
subjected to in vivo studies; the in vitro herein described are
important as a rst evaluation but now the most active require
further studies to validate or ascertain their medicinal potentials.
The pharmacological potential of Inula spp. was validated by
different bioassays and led to the isolation of different bioactive
secondary metabolites, from which sesquiterpene lactones can be
considered as characteristic chemical markers of Inula spp. having
an important role for various bioactivities. Nevertheless, since
toxicity may be dependent on the applied dose and route of
administration it is imperative that comprehensive toxicological
evaluation of extracts and/or isolated compounds must be done.
Also clinical trials should be performed to further validate the use
of Inula spp. in the traditional medicine and promote them as a
safe and effective tool in the treatment of several diseases.
In conclusion, special attention should be paid to the genus
Inula to validate and ascertain its ethnomedicinal value.
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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Journal of Ethnopharmacology 154 (2014) 286310

Contents lists available at ScienceDirect

The genus Inula and their metabolites: From ethnopharmacological

DCTD, University of Azores, 9501-801 Ponta Delgada, Portugal

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

2. Taxonomy and botanical aspects

to the chemotaxonomic implications that the genus change can

3. Ethnopharmacological uses of Inula species

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

More than 2000 plants were listed in the traditional (Herbal/

stomachache and relieving rheumatism (Yan et al., 2010). Another

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

Finally, there are reports on traditional uses of Inula britannica

4. Bioactive secondary metabolites isolated from Inula spp.

Compound class and name

Jiang et al. (2011)

Qin et al. (2012b)

Qin et al. (2012b)

5,6-Epoxy-2-acetoxy-4-hydroxy-1,7-guaia-11 Inula hookeria

Cheng et al. (2012)

Cheng et al. (2012)

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

Compound class and name

Cheng et al. (2011)

Qin et al. (2011a)

Qin et al. (2011a)

Qin et al. (2011a)

Qin et al. (2011a)

Qin et al. (2011a)

Qin et al. (2011a)

Nie et al. (2010),

Cheng et al. (2011)

Zeng et al. (2009)

Inula verbascifolia subsp.

Zhao et al. (2006), Chin et al. (2009)

Aerial parts (with

Qin et al. (2012b)

Qin et al. (2012b)

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

Compound class and name

Qin et al. (2009),

Jin et al. (2006)

Zhang et al. (2010b),

Cohen et al. (2006)

Inula hookeri C.B.Clarke.

Fig. 1. Basic structure of eudesmanolides and of alantolactone 1.

Figs. 213 and although the phytochemistry studies of genus Inula

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

Fig. 2. Structures of eudesmanolide derivatives isolated from Inula spp..

Fig. 3. Basic structure of guaianolides.

Alantolactone 1 (Fig. 1) is the most known eudesmanolide

isolated from the ethanolic fraction of petroleum ether extract of

Parthenolide 49 (Fig. 7) is the most noticeable germacranolide

Pseudoguaianolides (Figs. 5 and 6) are structurally very similar

Xanthanolides (Figs. 9 and 10) are sesquiterpene-type lactones,

A.M.L. Seca et al. / Journal of Ethnopharmacology 154 (2014) 286310

Fig. 4. Structures of guaianolides isolated from Inula spp..

4.8. Other compounds

Fig. 5. Basic structure of pseudoguaianolides.

4.6. Dimeric sesquiterpenes

In addition to all the above mentioned classes of compounds,

5. Biological and pharmacological activities