Next Article in Journal
Synthesis, Spectral and Thermal Studies of New Rutin Vanadyl Complexes
Previous Article in Journal
Allelochemical, Eudesmane-Type Sesquiterpenoids from Inula falconeri
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 15
Issue 3
10.3390/molecules15031562
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Secondary Metabolites from Inula britannica L. and Their Biological Activities

by
Abdul Latif Khan
1,2,
Javid Hussain
2,
Muhammad Hamayun
1,
Syed Abdullah Gilani
4,
Shabir Ahmad
2,
Gauhar Rehman
3,
Yoon-Ha Kim
1,
Sang-Mo Kang
1 and
In-Jung Lee
1,*
1
School of Applied Biosciences, Kyungpook National University, Korea
2
Department of Chemistry, Kohat University of Science & Technology, Kohat, Pakistan
3
Department of Genetic Engineering, School of Life Sciences & Biotechnology, Kyungpook National University, Korea
4
Department of Biotechnology, Kohat University of Science & Technology, Kohat, Pakistan
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(3), 1562-1577; https://doi.org/10.3390/molecules15031562
Submission received: 4 January 2010 / Revised: 25 January 2010 / Accepted: 28 January 2010 / Published: 10 March 2010
Browse Figures
Versions Notes

Abstract

:
Inula britannica L., family Asteraceae, is used in traditional Chinese and Kampo Medicines for various diseases. Flowers or the aerial parts are a rich source of secondary metabolites. These consist mainly of terpenoids (sesquiterpene lactones and dimmers, diterpenes and triterpenoids) and flavonoids. The isolated compounds have shown diverse biological activities: anticancer, antioxidant, anti-inflammatory, neuroprotective and hepatoprotective activities. This review provides information on isolated bioactive phytochemicals and pharmacological potentials of I. britannica.

Graphical Abstract

1. Introduction

The genus Inula (Asteraceae) is known for diverse biological activities, i.e., anticancer, antibacterial, hepaprotective, cytotoxic, and anti-inflammatory properties [1]. It comprises about 100 species distributed in Asia, Europe and Africa [2]. Inula britannica (Figure 1) is an important plant species used in Traditional Chinese Medicine (TCM) and Kampo Medicines. Along with Inula japonica, it is known as ‘Xuan Fu Hua’ in TCM. It is also known as British yellowhead or meadow fleabane.
Molecules 15 01562 g001 550
Figure 1. Inula britannica (courtesy Mr. Ivan Bilek, Nature photo).
Figure 1. Inula britannica (courtesy Mr. Ivan Bilek, Nature photo).
Molecules 15 01562 g001
I. britannica is an erect biennial or perennial plant and is species of eutropic and disturbed grassland [3]. It is 15 to 75 cm tall and its stem is covered with oppressed hairs or without hairs. The flowers of the plant are bright yellow, standing alone or in clusters of 2–3 [4]. A common configuration of the plant is to have a mother plant surrounded by 8 to 10 satellite plants connected by rhizomes [2]. The plant prefers sandy loamy and clayey soil [5].
More than 80% of the marginal communities rely, one way or the other, on various medicinal plants for curing diseases using traditional knowledge [6]. I. britannica, in combination with other plants, is used for nausea, hiccups and excessive sputum [7]. Its flowers are used for treatment of intestinal diseases, bronchitis and inflammation [8,9,10,11]. In TCM, a decoction of aerial parts or flowers is used for asthma, and as an expectorant [12,13,14]. The flowers are used as antibacterial, carminative, diuretic, laxative, stomachic, tonic rapid-healer, for hepatitis and tumors [9,13,14]. Being such an important medicinal plant, scientists have examined various aspects of the plant. In the present review, we focus on the biologically active secondary metabolites and their potential pharmacological roles.

1.1. Perspective Secondary Metabolites

Various chemical constituents have been isolated from I. britannica and reported (Table 1). These include steroids, terpenoids (sesquiterpene lactones, diterpenes and triterpenoids), phenolics and flavonoids. The literature shows that almost 102 compounds have been isolated and purified from this plant [15]. Most of the reported compounds are from the flowers or aerial parts of the plant. Due to the richness of its chemical constituents in aerial parts or flowers, the roots have been largely neglected so far. In the present review, only bioactive metabolites purified from I. britannica and their biological potential are discussed. Major bioactive secondary metabolites and their biological effect have been summarized in Table 2.
Table
Table 1. Reported chemical constituents from I. britannica.
Table 1. Reported chemical constituents from I. britannica.
Chemical compound(s)Part/FractionReference(s)
Bisdesacetylbritannin; dihydrodihydrobritannin; acetyldihydrobritannin; bisdesacetyldihydrobritannin; methyl ester of 2α,6α-diacetoxy-4β-hydroxy-7α(H),8,10β(H)-pseudoguai-8,12-olidylmethylenethioacetic acid and methyl ester of 2α,6α-diacetoxy-4β-hydroxy-7α(H),8,10β(H)-13-methylpseudoguai-8,12-olidylmethylenethioacetic acidDerivatives/synthesis [16, 17, 18, 19]
2-O-Alkyloxime-3-phenyl)-propionyl-1-O-acetylbritannilactone estersDerivatives/Synthesis [20]
Britannilide, oxobritannilactone, eremobritanilinFlowers /Ethyl acetate [21, 22]
Pulchellin CFlowers/Acetone [23]
Inuchinenolides A, B, and C, tomentosin, ivalin, 4-epi-isoinuviscolide, gaillardin Aerial / Ethyl acetate [24]
4α,5β-Epoxyeupatolide; 4α,5β-epoxydesacetylovatifolin; 5α-hydroxydehydroleucodin; 14-hydroxy-2-oxoguaia-1(10),3-dien-5α,11βH-12,6α-olide and 2-oxo-8α,10β,dihydroxyguai-3-en-1-α,6β,11βH-12,6-olideFlowers [26]
Salicylic, p-hydroxybenzoic, protacatechuic, vanillic, syringic, p-hydroxyphenylacetic, p-coumaric, caffeic, and ferulic acidsAerial parts [28]
2,3,4,5-Tetrahydro-1-benzooxepin-3-ol, Essential oils [29]
Kaurane glycosides- Inulosides A and BFlowers/Butanol [30, 72]
Triterpene fatty acid esters, 3β,16β–dihydroxylupeol 3-palmitate 3β,16β-dihydroxylupeol 3-myristate, 6-hydroxykaempferol 3-sulfate; epi-friedelinol, β -amyrin palmitate, olean-13(18)-en 3-acetate, sitosteryl 3-glucoside; quercetin 3-sulfateAerial parts [31]
Britanlins A, B, C, D Dried flower/Ethanol extract [75]
Table
Table 2. Summary of biologically active compounds from I. britannica.
Table 2. Summary of biologically active compounds from I. britannica.
CompoundPlant partExtract/FractionYieldActivityStandardRef
1-O-Acetylbritannilactone (2)Flower 95% EtOH 1.1 gCytotoxic, apopotic, inflammationStreptomycin [3,25,57,58]
1,6-O,O-diacetylbritannilactone (3)32 mg
6α-O-(2-methylbutyryl)-britannilactone (11)63 mg
Neobritannilactone A (9)15 mg
Neobritannilactone B (10)102 mg
Inulanolides A (5)Aerial partEtOAc9 mgInflammation Nm [37]
Inulanolides B (6)31 mg
Inulanolides C (7)89 mg
Inulanolides D (8)37 mg
Ergolide (4)Flowers80% MeOH110 mgInflammation iNOS, NF-KB, IKB, COX-2Nm [35]
Taraxasteryl acetate (13)Aerial partCHCl339 mgHepato--protectiveNm [38]
Patuletin (14)Flowers80% MeOH70 mgAntioxidant, Garlic acid/DPPH [4,39]
Axillarin (18)60 mg
Nepitrin (21)60 mg
Quercetin (27)Flowers95% EtOH1.2 gAntioxidant, balloon injury, cytotoxicDPPH [43,73]
Spinacetin (28)75 mg
Diosmetin (24)32 mg
Nm = Not mentioned.

1.1.1. Sesquiterpenes

Britannin (1) was the first compound purified from the ethanolic fraction of aerial parts of I. britannica. It led to the isolation and synthesis of physiologically active compounds [16] (Table 1). Among sesquiterpenes, the most significant are 1-O-acetylbritannilactone (OABL) (2) and 1,6-O,O-diacetylbritannilactone (OODABL) (3). These were purified from the chloroform fraction of flowers using advanced chromatographic and spectroscopic techniques [25,32]. These have been reported to work against oxidative stress and are cytotoxic [33]. OODABL has one α,β unsaturated sesquiterpene lactone and two acetyl moieties, while OABL has one acetyl group [34]. Acetyl groups at positions 1 and 6 in OODABL have been found to be more cytotoxic in human leukemia cell-60 compared to OABL [34] (Figure 2).
Cytotoxicity-guided isolation resulted in identification of 4α,6α-dihydroxyeudesman-8 β,12-olide, ergolide, 8-epi-helenalin, and bigelovin from the flowers of I. britannica [35]. The presence of exo-methylene group in ergolide has made it more reactive thus presenting higher biological activity. Ergolide (4) inhibits inducible nitric oxide synthase and cyclo-oxygenase-2 expression in RAW 264.7 macrophages through inactivation of NF-KB [36] (Figure 2).
A bioassay guided isolation from ethyl acetate fraction of aerial parts of I. britannica resulted in exploration of four new sesquiterpene dimmers bearing a norbornene moiety, inulanolide A (5) B (6) C (7) and D (8) and three known sesquiterpenes [37,80]. Inulanolide B and D have exhibited potent inhibitory effect on the LPS-induced NF-KB activation [37].
From air dried powdered flowers of I. britannica, three new sesquiterpenes - neobritannilactone A (9), neobritannilactone B (10), acetyl neobritannilactone B (11) and 6β-O-(2-methylbutyryl)britannilactone (12) along with known compounds i.e., britannilactone, 1-O-acetylbritannilactone (2) and 1, 6-O,O-diacetylbritannilactone (3) - were obtained and identified using 1D, and 2D NMR [3,25].
Molecules 15 01562 g002 550
Figure 2. Bioactive metabolites isolated from I. britannica.
Figure 2. Bioactive metabolites isolated from I. britannica.
Molecules 15 01562 g002

1.1.2. Triterpenoids

Three triterpenoids [taraxasteryl acetate (13), β-amyrin and lupeol] and three steroids (β-resasterol and stigmasterol and ψ-taraxasterol) were purified from the chloroform fraction of the aerial parts of the plant [27] (Figure 3). Besides that, two new triterpenoids fatty acid esters, 3β,16β dihydroxylupeol 3-palmitate and 3β,16β-dihydroxylupeol-3-myristate were also isolated [31]. Taraxasteryl acetate has been found very effective in preventing activity against acute hepatic failure induced by PA and LPS in a concentration dependent manner [38].
Molecules 15 01562 g003 550
Figure 3. Bioactive terpenoids from I. britannica.
Figure 3. Bioactive terpenoids from I. britannica.
Molecules 15 01562 g003
Molecules 15 01562 g004 550
Figure 4. Flavonoids from I. britannica.
Figure 4. Flavonoids from I. britannica.
Molecules 15 01562 g004

1.1.3. Flavonoids

Flavonoids were isolated from the butanol fraction of I. britannica (Figure 4). These include patuletin (14), luteolin, patulitrin, patuletin 7-O-(6''-isovaleryl)glucoside (15), patuletin 7-O-(6''-isobutyryl) glucoside (16), patuletin 7-O- [6''-(2-methylbutyryl)] glucoside (17), nepetin (18), nepitrin (19), kaempferol 3- glucoside (20), axillarin (21), hispiduline-7-glucoside (22), and isorhamnetin 3-glucoside (23) [4,39]. From butanol fraction of the flowers, four flavonoids: 4,5,7-trihydroxy-3,6-dimethylflavone-7-O-β-D-glucopyranoside, isohamnetin-3-O-β-D-glucopyranoside, rhamnetin-3-O-β-D-glucopyranoside and kaemferol-3-O-β-D-glucopyranoside were identified [30]. These flavonoids play a vital role in enzyme inhibition, are antioxidant and posses cytotoxic activities [40,41,42].
In continuation to the exploration of chemical constituents from its aerial parts, eight more flavonones were identified: (i) luteolin; (ii) diosmetin (24); (iii) chrysoeriol (25); (iv) kaempferol (26); (v) quercetin (27); (vi) 6-hydroxyluteolin-6-meether; (vii) spinacetin (28); and (viii) eupatin (29) [43].

2. Pharmacological Significance

2.1. Antioxidant Activity

There is a delicate balance between generation and destruction of oxidant agents. These may be beneficial or deleterious to the organism [44,45,46]. Under physiological conditions, the level of reactive oxygen species is maintained low by the activity of antioxidative systems that include secondary plant metabolites and scavenging enzymes [45,47]. Many in vitro studies indicate that compounds like sesquiterpenes, flavonoids, coumarins and phenolic acids can have substantial antioxidant activity [48,49]. Flavonoids have been extensively studied for antioxidant activities [50].
As for the flavonoids, various flavonones like patuletin, luteolin, patuletin 7-O-(6''-isovaleryl) glucoside, patuletin 7-O-(6''-isobutyryl) glucoside, patuletin 7-O- [6''-(2-methylbutyryl)] glucoside, nepetin, nepitrin, kaempferol 3-glucoside, axillarin, hispiduline 7-glucoside, and isorhamnetin 3-glucoside were evaluated for antioxidant activity using DPPH assay [39]. According to results, the IC50 values of luteoline, patuletin 7-O-(6''-isovaleryl) glucoside and patuletin 7-O-(6''-isobutyryl) glucoside were 11.7, 10.6 and 11.2 µg/mL respectively while the positive control (garlic acid) had an IC50 value of 3.7 µg/mL [39].
Besides the aforementioned flavonoids, luteolin, diosmetin, chrysoeriol, kaempferol, quercetin, 6-hydroxyluteolin-6-methyl ether, spinacetin, and eupatin were also explored for their efficiency towards oxidative stress [43]. The antioxidant assay (using DPPH) revealed that luteolin, diosmetin, chrysoeriol, kaempferol, quercetin, 6-hydroxyluteolin-6-methyl ether, spinacetin and eupatin showed 85.6, 55.4, 53.6, 61.0, 85.4, 86.3, 85.4, and 84.9% activity, respectively [50]. Looking at findings of various studies, there is still a need to fix the pathway and overall enzymatic behavior of these molecules under biotic and abiotic stresses, both at plant and animal levels.

2.2. Anti-Cancer Activities

Natural products are now considered as the most important source of curing various mortal diseases. I. britannica, like many other plant species e.g., Rhazya stricta [51], Annona coriacea, A. glabbra, etc. [52], Teucrium royleanum [53] and many other plants and their products [54], has been found to display anticancerous activity. I. britannica is also reported to be used against tumor in TCM [15]. Looking at the indigenous uses of plant, two sesquiterpeniods, OABL (2) and OODABL (3) were isolated, which induced phosphorylation of BCl-2 (anti-apoptotic protein) in breast, ovary and prostate cancer cell line. Phosphorylation of BCl-2 was important for OODABL induced cytotoxicity [33,55,56].
OODABL has also been found inducing Bcl-2 phosphorylation in MCF-7 cells (cell lines for breast cancer) [57]. Various concentrations (1.25, 12.5, 25. 50 and 100 µM) of OODABL resulted with IC50 value of 12.5 µM in MCF-7 cells. Similarly OABL was also tested while using dose of 0.3 nM, 3 nM, 30 nM, 300 nM, 3 µM, and 30 µM in MCF-7 cells that showed that OABL has lesser cell viability with an IC50 of 200 µM. To clarify the role and function of OODABL and OABL in cytotoxicity, various cell lines (e.g., PA-1, DU-145, NCI-H-60 and NIH 3T3) were tested in different concentrations. Ho et al. have suggested in their patent that it can be used for prevention and treatment of cancer. Still there is a need for further clinical trials to prove the role of OODABL and OABL [57]. Besides that, mechanism of its role and function needs to be convoluted.
Some of the recent studies indicate that OODABL can also induce the occurrence of apoptosis in human leukemia cells (HLC) [58]. To know its effect in different concentrations, cells were treated with britannilactone (BL), OABL, and OODBL. Results indicated that BL had less ability of apoptosis in HL-60 cells. OABL has induced apoptosis with 50 and 100 µM, while the percentages of apoptotic cells were 20.13 and 40.2%. OODABL was more potent inducer of apoptosis in HL-60 cells with 20.04, 20.51, 49.86, 58.76, and 64.23% of apoptotic cells with 5, 10, 25, 50, and 100 lM OODABL, respectively [58]. The study also suggested that OODABL had an acetyl group in position 1 and 6 that is cytotoxic in HL-60 cells than OABL. Detailed mechanism has been reported that proves that OODABL is helpful in in-vitro anticancer activities [58].
Besides OABL and OODABL, other sesquiterpenes lactones isolated from I. britannica have also been tested for cytotoxic activities. The effects against various cell lines (COLO 205, HT 29, human AGS gastric carcinoma cell lines (CCRC 60102) were tested for 6β-O-(2-methylbutyryl) britannilactone, neobritannilactone A, B and acetyl neobritannilactone B. Neobritannilactone B and acetyl neobritannilactone B appeared to be more potent apoptosis-inducing agents than neobritannilactone A and 6β-O-(2-methylbutyryl) britannilactone for COLO 205, HT-29, AGS, and HL-60 cells. The percentages of apoptotic COLO 205, HT-29, HL-60, and AGS cells were 41.62 and 76.87%; 66.54 and 69.70%; 77.57 and 95.17%; and 11.78 and 9.89% after 24 h of incubation with neobritannilactone B and acetyl neobritannilactone B (25 µM), respectively [3].

2.3. Neuroprotective Activities

Neuroprotection is the term used to describe prevention or delay of pathological neuronal loss in diseases of the central nervous system [59,60]. Efforts have been made to overcome these neuronological diseases. I. britannica being used in TCM for such purpose motivated phytochemists and pharmacologists to know the neuroprotective potential of its chemical constituents. Neuroprotective activities were evaluated by monitoring the viability of primary cultures of rat cortical cells from oxidative stress induced by glutamate in DPPH and MTT assays. Subjecting patuletin (14), nepetin (18) and axillarin (21) for these assays, concentration gradient of 1, 10 and 50 µM was used. According to results, protective effect of patuletin (14), nepetin (18) and axillarin (21) was 51.8, 49.8 and 60.6% after pre-treatment and 70.7, 57.9 and 55.4% by post-treatment, using 50 µM concentrations on cell viability of the cultures. However, the optimal doze of control and glutamate-insulted was 1.335% and 0.938%, respectively [4].

2.4. Anti-Inflammatory Activities

Inflammation is regarded as a dynamic process that elicits in response to microbial infections, mechanical injuries and burns. This process involves changes in blood flow and increased vascular permeability, destruction of tissue via inflammatory mediators, such as prostaglandins (PGs) leukotriene platelet activating factors induced by phosphliphase A2, cyclooxygenase (COXs) and lipoxygenases [61]. Classical example for treating inflammation is sesquiterpenes lactones from I. britannica to inhibit NO synthesis [62]. iNOS and COX-2 expression, and NF-κB activation have been used as biomarkers for the screening of anti-inflammatory activity. OABL inhibit iNOS and COX-2, responsible for suppression of NO and PGE2 synthesis in RAW 264 macrophage [34]. A concentration of 10 μmol/L of OABL has inhibited the production of NO and PGE2 in LPS/IFN-γ -stimulated RAW 264.7 macrophages while adopting western blot analysis, electrophoretic mobility shift assay and MTT assay [34].
OABL has also been explored to know the effect on neointimal hyperplasia after balloon injury and its mechanism of action in rats (Sprague-Dawley). A concentration of 26 mg/kg of OABL and polyglycol (control) was used daily from 3 days before injury to 2 weeks after balloon injury. OABL showed significant reduction in neointimal formation. Activity ratio of OABL and control was 1.94 and 0.84, respectively. These findings suggest that OABL is a potential inhibitor of neointimal formation because it blocks injury-induced NF-KB activation, and may have beneficial effects in reducing the risk of restenosis after angioplasty [63]. Results of another study on OODABL show that acetyl moieties add to the lipophilicity, and consequently enhance cellular penetration so that OODABL possess the most anti-inflammatory effect and may be a potent lead structure for the development of therapeutic and cytokine-suppressing remedies suitable for the treatment of various inflammatory diseases [73,74]. Similarly, Inulanolides B and D exhibited potent inhibitory effect on the LPS-induced NF-KB activation [37]. In another study, higher doze of total flavonoid extracts (mainly quercetin, luteolin, 6-methoxyluteolin, spinacetin and isorhamnetin) of aerial parts of the plant inhibited the neointimal hyperplasia induced by balloon injury [73].
Ergolide markedly decreased the production of prostaglandin E (2) (PGE2) in cell-free extract of LPS/IFN-gamma-stimulated RAW 264.7 macrophages in a concentration-dependent manner, without alteration of the catalytic activity of COX-2 itself. These results demonstrate that suppression of NF-KB activation by ergolide might be attributed to the inhibition of nuclear translocation of NF-KB resulting from degradation of IKB and the direct modification of active NF-KB. This lead to suppression of the expression of iNOS and COX-2 that play important roles in inflammatory signaling pathway [64]. It has also been classified as cyclooxygenase inhibitor for COX-2 [65].
In TCM, I. britannica is used in asthma, as a warming expectorant and for phlegm removal. As for asthma, it is inflammatory disease of airways and flavonoids have been reported to strengthen the connective tissues by reducing histamine levels [78]. Certain flavonoids like luteoline and quercetin have been reported to play a lead role in alleviating bronchoconstriction and hyperreactivity i.e., anti-asthma [77,79,80]. In case of I. britannica, although a little or no focus at molecular/clinical level for anti-asthma have been found but the aforementioned purified chemical constituents from the plant have been reported elsewhere for the same purpose, thus supporting the traditional use in TCM.

2.5. Hepatoprotective Affect

Relying on the traditional Kampo uses of I. britannica, experiment have been conducted on the survival rate of mice with acute hepatic failure provided by lipopolysaccharide (LPS) and propionibacterium acnes (PA) [66]. High dosage of lipolized supernatant fluid of I. britannica reduces the acute hepatic failure; thus increasing the survival rate. Using Gardenia fruit and Caesalpinia wood (already reported as hepatoprotective) as positive controls, supernatant of I. britannica was administered intraperitoneally at a dose of 4 mg/mouse/day to each group for 3 consecutive days before injecting LPS. Results showed that survival rate was 100% after 20 hours for I. britannica compared with 37.5% for the control group [67]. The study has also evaluated the production of spleen Th-cytokine and reported that IFNγ+ IL-4- cells significantly increased in 24 h after LPS however, the group of mice receiving I. britannica showed insignificant change [67]. In conclusion, in vitro tests recommend that I. britannica inhibit Th1 differentiation and induce Th2 differentiation by suppressing the production of macrophage IL-12 and promoting the production of IL-10. This in-turn restrains the immunology of hepatic injury by affecting the balance between Th1 and Th2 [67].
The bioassay guided isolation of taraxasteryl acetate from I. britannica (13) showed potent preventive activity against acute hepatic failure induced by PA and LPS in a dose-dependent manner that is in compliance with aforementioned study on extract. It was also observed that deacetylation and modification of olefinic bonds significantly decreased the anti-hepatitis activity of taraxasteryl acetate. Taraxasteryl acetate also inhibited the increment of plasma transaminase on acute hepatic failure induced by carbon tetrachloride (CCl4) or D-galactosamine. From a histological study, it appeared that degeneration and necrosis, which were observed in the liver induced by CCl4 mice, were not found in the liver cells from taraxasteryl acetate-treated mice. These results indicate that taraxasteryl acetate shows preventive effects on experimental hepatitis caused by either immunologically-induced injuries or hepatotoxic chemicals [38].

2.6. Enzyme Inhibition Activities

Many studies on animals and humans have reported the significant role of glutathione in antioxidant protection of lungs. In humans, glutathione concentrations in epithelial lining fluid are normally much higher than in blood. They have also been reported to be higher in epithelial lining fluid of smokers and patients with chronic obstructive pulmonary disease. The reported anti-oxidative flavonoids were tested against catalase, glutathione reductase and glutathione-peroxidase (GSH-px) [4]. Patuletin, nepetin, and axillarin showed significant decrease in glutathione induced by glutamate, which is associated with the oxidative stress by reducing the restrained glutathione. Patuletin resulted in 36.8, 14.6 and 11.9 µM consumed/min/mg protein compared with control 41.5, 18.1 and 13.2 µM consumed/min/mg proteins against Catalase, GSH-px and GSSG-R enzymes; Other compounds had lesser values compared to patuletin. This result showed non-simulative effect of flavonoids on the synthesis of glutathione. Furthermore, the oxidation of GSH induced by excess glutamate was counteracted by patuletin while the synthesis of GSH remained unaffected [4].
Glutathione is found higher in concentration in duodenum. The detoxifying capability of glutathione is related to the fact that glutathione regulates the action of glutathione-peroxidases and glutathione-transferases. A direct relationship has also been observed between glutathione concentration and mucosal damage or between glutathione-related enzymes present in various pathological conditions of gastrointestinal tract (from esophagus to rectum) [76].
Role of reported compounds (patuletin, nepetin, and axillarin) from I. britannica still needs to be studied under various physiological and pathological conditions in experimental animals and at a later stage, on man through clinical studies.

3. Conclusions

I. britannica alone or in combination with other plant species has widely been used for various diseases in TCM and Kampo Medicine. Indigenous uses of the plant created curiosity among scientists to isolate responsible bioactive constituents. Pursuing this, perspective metabolites were isolated from the plant. Most of the isolation work has been done on flowers and aerial parts of the plant, however, no information could be found on isolation of chemical constituents from roots. Mostly chloroform, ethyl acetate, or butanol fractions were used in isolation work. Limited work has however been done on the water fractions and saponins of the plant. Total syntheses of OABL and OODABL and some derivatives are available. In case of pharmacological investigations, results are obtained using animals’ cells by in vitro or in vivo experimentation. Several studies have elaborated the role of isolated compounds against various malfunctions at cellular and physiological levels. However, broader clinical trials on patients have yet to be performed.
Biosynthetic pathways of various phytochemicals, isolated (especially OABL and OODABL) from the plant, need to be elaborated so that a variety of physiological and pathological effects may be understood. Other sesquiterpenes, which are biologically screened and observed potent, are ignored for their possible significant effect in inflammation and carcinoma. Although isolated sesquiterpenes from I. britannica had been observed for anti-inflammatory and anticancer activities but antioxidant activities of purified sesquiterpenes were not found – which are widely reported as potent antioxidant too [68,69,70,71].
Metabolic pathways for important metabolites should be elaborated along with exploration of secondary metabolite synthesis in I. britannica. Studies should be planned so as to explore the allelopathic behavior of the plant. Studies explaining the ecological interactions with other species, wider distribution among various countries, production, trade and economic perspectives, and ethnobotany should be undertaken. Additional studies should be done to evaluate the genetic resources of the plant for variation in growth, morphology and yield-related characteristics which, in turn, can be used to identify high-yielding populations suitable for agronomical and plant breeding programs. Besides the ethnopharmacological recipes in TCM and Kampo Medicine, less or no work has been documented on the indigenous use of I. britannica by various marginal communities of world. Since, it has been reported to be an invasive weed species in various areas (including some US states) efforts are underway for its eradication. In doing so, conservational and medicinal importance of the plant has to be kept in mind.

Acknowledgment

The authors are thankful to the financial support provided by Gyengsangbuk-do Medical Crop Cluster and Brain Korea 21 Project, funded by Republic of Korea.
  • Samples Availability: Samples not available

References and Notes

  1. Zhao, Y.M.; Zhang, M.L.; Shi, Q.W.; Kiyota, H. Chemical constituents of plants from the genus. Inula. J. Chem. Biod. 2006, 3, 371–384. [Google Scholar] [CrossRef]
  2. Ali, S.I.; Qaiser, M.; Abid, R. Flora of Pakistan – Astereaceae; University of Karachi, Karachi Printing Press: Karachi, Pakistan, 1992; Volume 210, p. 71. [Google Scholar]
  3. Mullar, S. Diversity of Management practices required to ensure conservation of rare and locally threatened plant species in grasslands: A case study at regional scale Lorraine, France. Biod. Cons. 2002, 11, 1173–1184. [Google Scholar] [CrossRef]
  4. Dawar, R. Biosystematics of Genus Inula from Pakistan and Kashmir; Department of Botany, University of Karachi: Karachi, Pakistan, 1998; pp. 99–100. [Google Scholar]
  5. Chevallier, A. The Encyclopaedia of Medicinal Plants; Dorling Kindersley: London, UK, 1996; p. 301. [Google Scholar]
  6. Latif, A.; Shinwari, Z.K.; Hussain, J.; Murtaza, S. NTFPs: An alternative to forest logging in Miandam and Sulatanr Valley, Swat. Lyonia 2006, 11, 15–21. [Google Scholar]
  7. Clapham, A.R.; Tutin, T.G.; Warburg, E.F. Flora of the British Isles; Cambridge University Press: London, UK, 1962; pp. 174–175. [Google Scholar]
  8. Song, Q.H.; Kobayashi, T.; Hong, T.; Cyong, J.C. Effects of Inula britannica on the production of antibodies and cytokines and on T cell differentiation in C57BL/6 mice immunized by ovalbumin. Am. J. Chin. Med. 2002, 30, 297–305. [Google Scholar] [CrossRef]
  9. Bai, N.; Lai, C.S.; He, K.; Zhou, Z.; Zhang, L.; Quan, Z.; Zhu, N.; Zheng, Q.; Pan, M.H.; Ho, C.T. Sesquiterpene lactones from Inula britannica and their cytotoxic and apoptotic effects on human cancer cell lines. J. Nat. Prod. 2006, 69, 531–535. [Google Scholar] [CrossRef]
  10. Kim, S.R.; Park, M.J.; Lee, M.K.; Sung, S.H.; Park, E.J.; Kim, J.; Kim, S.Y.; Oh, T.H.; Markelonis, G.J.; Kim, Y.C. Flavonoids of Inula britannica protect cultured cortical cells from necrotic cell death induced by glutamate. Free Rad. Biol. Med. 2002, 32, 596–604. [Google Scholar] [CrossRef]
  11. Kobayashi, T.; Song, Q.H.; Hong, T.; Kitamura, H.; Cyong, J.C. Preventative effects of the flowers of Inula britannica on autoimmune diabetes in C57BL/KsJ mice induced by multiple low doses of streptozotocin. Phytoth. Res. 2002, 16, 377–382. [Google Scholar] [CrossRef]
  12. Duke, J.A.; Ayensu, E.S. Medicinal Plants of China; Reference Publications. Inc: Algonac, MI, USA, 1985; p. 311. [Google Scholar]
  13. Zemlinskii, S.E. Medicinal Plants of the USSR (in Russian); Meditsina Publishers: Moscow, Russia, 1958; p. 109. [Google Scholar]
  14. Bown, D. Encyclopedia of Herbs and Their Uses; Dorling Kindersley Limited: London, UK, 1995; p. 293. [Google Scholar]
  15. Khan, A.L.; Gilani, S.A.; Fujii, Y. Watanabe K.N. Monograph on Inula britannica L.; Mimatsu Corporation: Tokyo, Japan, 2008; p. 21. [Google Scholar]
  16. Chugnov, P.V.; Sheichenko, V.I.; Ban'kovskii, A.I.; Rybalko, K.S. Structure of britannin, a sesquiterpene lactone from Inula britannica. Khim. Prirod. Soed. 1971, 7, 276–280. [Google Scholar]
  17. Artemova, N.P.; Nikitina, L.E.; Yushkov, D.A.; Shigabutdinova, O.G.; Plemenkov, V.V.; Klochkov, V.V.; Khairutdinov, B.I. Synthesis of S-containing derivatives of the sesquiterpene lactone britanin. Chem. Nat. Comp. 2005, 41, 45–47. [Google Scholar] [CrossRef]
  18. Ustinov, A.K.; Klochkov, S.G.; Tkachenko, S.E. Oxidation of Britannin. Chem. Heterocyc.Comp. 2000, 36, 7. [Google Scholar]
  19. Rybalko, K.S.; Sheichenko, V.I.; Maslova, G.A.; Kiseleva, E.Y.; Gubanov, I.A. Britannin, a lactone from Inula britannica. Khim. Prirod. Soed. 1968, 4, 251–252. [Google Scholar]
  20. Liu, S.; Liu, H.; Yan, W.; Zhang, L.; Bai, N.; Ho, C.T. Design, synthesis, and anti-tumor activity of (2-O-alkyloxime-3-phenyl)-propionyl-1-O-acetylbritannilactone esters. Bioorg. Med. Chem. 2005, 13, 2783–2789. [Google Scholar] [CrossRef]
  21. Bai, N.; Zhou, B.N.; Zhang, L.; Sang, S.; He, K.; Zheng, Q.Y. Three new sesquiterpene lactones from Inula britannica. In Oriental Foods and Herbs: Chemistry and Health Effects; Ho, C.T., Lin, J.K., Zheng, Q.Y, Eds.; American Chemical Society Symposium Series: Washington, DC, USA, 2003; pp. 271–278. [Google Scholar]
  22. Chun, J.K.; Seo, D.W.; Ahn, S.H.; Park, J.H.; You, J.S.; Lee, C.H.; Lee, J.C.; Kim, Y.K.; Han, J.W. Suppression of the NF-kappaB signaling pathway by ergolide, sesquiterpene lactone, in HeLa cells. J. Pharm. Pharmacol. 2007, 59, 561–566. [Google Scholar]
  23. Serkerov, S.V.; Mir-Babaev, N.F. Pulchellin C from Inula britannica. Khim. Prirod. Soed. 1988, 6, 879–880. [Google Scholar]
  24. Ito, K.; Iida, T. Seven sesquiterpene lactones from Inula britannica var. chinensis. Phytochemistry 1981, 20, 271–273. [Google Scholar]
  25. Zhou, B.; Bai, N.; Lin, L.; Cordell, G.A. Sesquiterpene lactones from Inula britannica. Phytochemistry 1993, 34, 249–52. [Google Scholar]
  26. Qi, J.; Fu, Y.; Shi, X.; Wu, Y.; Wang, Y.; Zhang, D.; Shi, Q. Sesquiterpene lactones and their anti-tumor activity from the flowers of Inula britannica. Lett. Drug Des. Discov. 2008, 5, 433–436. [Google Scholar] [CrossRef]
  27. Wu, Y.; Yunzhi, W.; Zha, J.; Yang, S.; Shi, X.; Zhang, D. Separation and structure identification of triterpenes and steroids in Inula britannica L. Zhong Cao Yao 2006, 37, 666–668. [Google Scholar]
  28. Krolikowska, M.; Wolbis, M. Polyphenolic compounds in Inula britannica. Acta Polon. Pharm. 1981, 38, 107–114. [Google Scholar]
  29. Zha, J.; Fu, Y.; Wu, Y.; Guo, C.; Zhang, D.; Wang, Y. Study of chemical constituents of the essential oil from Inula britannica L. by GC-MS. Zhong Yao Cai 2005, 28, 466–468. [Google Scholar]
  30. Shao, Y.; Bai, N.; Zhou, B. Kaurane glycosides from Inula britannica. Phytochemistry 1996, 42, 783–786. [Google Scholar] [CrossRef]
  31. Oksuz, S.; Topcu, G. Triterpene fatty acid esters and flavonoids from Inula britannica. Phytochemistry 1987, 26, 3082–3084. [Google Scholar] [CrossRef]
  32. Wang, W.N.; Wang, Y.Z.; Zhang, D. Study on RP-HPLC determination of 1-O-acetylbritannilactone in Inula britannica L. Chin. J. Pharm. Anal. 2005, 25, 205–207. [Google Scholar]
  33. Rafi, M.; Bai, N.; Ho, C.T.; Rosen, R.T.; White, E.; Perez, D.; Dipaola, R.S. A sesquiterpenelactone from Inula britannica induces anti-tumor effects dependent on Bcl-2 phosphorylation. Antican. Res. 2005, 25, 313–318. [Google Scholar]
  34. Han, M.; Wen, J.; Zheng, B.; Zhang, D. Acetylbritannilatone suppresses NO and PGE2 synthesis in RAW 264.7 macrophages through the inhibition of iNOS and COX-2 gene expression. Life Sci. 2004, 75, 675–684. [Google Scholar]
  35. Park, E.J.; Kim, J. Cytotoxic sesquiterpene lactones from Inula britannica. Planta Med. 1998, 64, 752–754. [Google Scholar] [CrossRef]
  36. Han, J.W.; Lee, B.G.; Kim, Y.K.; Yoon, J.W.; Jin, H.K.; Hong, S.; Lee, H.Y.; Lee, K.R.; Lee, H.W. Ergolide, sesquiterpene lactone from Inula britannica, inhibits inducible nitric oxide synthase and cyclo-oxygenase-2 expression in RAW 264.7 macrophages through the inactivation of NF-kB. Brit. J. Pharm. 2001, 133, 503–512. [Google Scholar]
  37. Jin, H.Z.; Lee, D.; Lee, J.H.; Lee, K.; Hong, Y.S.; Choung, D.H.; Kim, Y.H.; Lee, J.J. New sesquiterpene dimers from Inula britannica inhibit NF-kappaB activation and NO and TNF-alpha production in LPS-stimulated RAW264. 7 cells. Planta Med. 2005, 72, 40–45. [Google Scholar]
  38. Iijima, K.; Kiyohara, H.; Tanaka, M.; Matsumoto, T.; Cyong, J.C.; Yamada, H. Preventive effect of taraxasteryl acetate from Inula britannica subsp. japonica on experimental hepatitis in vivo. Planta Med. 1995, 61, 50–53. [Google Scholar] [CrossRef]
  39. Park, E.J.; Kim, Y.; Kim, J. Acylated flavonol glycosides from the flower of Inula britannica. J. Nat. Prod. 2000, 63, 34–36. [Google Scholar] [CrossRef]
  40. Orhan, I.; Kupeli, E.; Terzioglu, S.; Yesilada, E. Bioassay-guided isolation of kaempferol-3-O-B-d-galactoside with anti-inflammatory and antinociceptive activity from the aerial part of Calluna vulgaris L. J. Ethnopharm. 2007, 114, 32–37. [Google Scholar]
  41. Nazari, A.S.; Dias, S.A.; Da-Costa, W.F.; Bersani-Amado, C.A.; Vidotti, G.J.; De-Souza, M.C.; Sarragiotto, M.H. Anti-inflammatory and antioxidant activities of Randia hebecarpa and major constituents. Pharm. Bio. 2006, 44, 7–9. [Google Scholar] [CrossRef]
  42. Middleton, E. Flavonoids in the Living System; Plenum Press: New York, USA, 1998; p. 181. [Google Scholar]
  43. Bai, N.; Zhou, Z.; Zhu, N.; Zhang, L.; Quan, Z.; He, K.; Zheng, Q.Y.; Ho, C. Antioxidant flavonoids from the flower of Inula britannica. J. Food Lip. 2005, 12, 141–149. [Google Scholar] [CrossRef]
  44. Maffei, M.E.; Mitho, A.; Boland, W. Insects feeding on plants: Rapid signals and responses preceding the induction of phytochemical release. Phytochemistry 2007, 68, 2946–2959. [Google Scholar] [CrossRef]
  45. Foyer, C. H.; Noctor, G. Oxidant and antioxidant signalling in plants: A re-evaluation of the concept of oxidative stress in a physiological context. Plant Cell Environ. 2005, 28, 1056–1071. [Google Scholar] [CrossRef]
  46. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.D.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 2007, 39, 44–84. [Google Scholar] [CrossRef]
  47. Pandhair, V.; Sekhon, B.S. Reactive oxygen species and antioxidants in plants: An overview. J. Plant Biochem. Biotechnol. 2006, 15, 71–78. [Google Scholar]
  48. Duthie, G.; Crosier, A. Plant-derived phenolic antioxidants. Opin. Clin. Nutr. Metab. Care 2000, 3, 447–451. [Google Scholar] [CrossRef]
  49. Khan, A.L.; Khan, H.; Hussain, J.; Adnan, M.; Hussain, I.; Khan, T.; Rehman, A. Sesquiterpenes: A potent antioxidants-A review. Pak. J. Sci. Ind. Res. 2008, 51, 343–350. [Google Scholar]
  50. Lotito, S.B.; Frei, B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: Cause, consequence, or epiphenomenon? Free Radic. Biol. Med. 2006, 41, 1727–1746. [Google Scholar]
  51. Bai, N.; Ho, C.T.; Zhou, Z. Phytochemicals from Inula britannica and their scavenging effects on 2,2-diphenyl-1-picryhydrazyl radicals. In Proceedings of the Abstracts of 219th ACS National Meeting, San Francisco, USA, 26−30 March 2000; p. 89.
  52. Kim, J.; Park, E.J. Cytotoxic candidates from natural resources. Med. Chem. Antican. Ag. 2002, 2, 485–537. [Google Scholar] [CrossRef]
  53. Gilani, S.A.; Kikuchi, A.; Shinwari, Z.K.; Khattak, Z.I.; Watanabe, K.N. Phytochemical, pharmalogical and ethnobotanical uses of Rhazya stricta (D.). Phytoth. Res. 2007, 21, 301–307. [Google Scholar]
  54. Graham, J.G.; Quinn, M.L.; Fabricant, D.S.; Farnsworth, N.R. Plants used against cancer-an extension of the work of Jonathan Hartwell. J. Ethnopham. 2004, 73, 347–377. [Google Scholar]
  55. Rafi, M.; Bai, N.; Rosen, R.T.; Dipaola, R.S.; Ho, C.T. Cytotoxic and Bcl-2 phosphorylating molecules from a Chinese medicinal flower Inula britannica. In 224th ACS National Meeting, Boston, MA, United States, 18–22 August 2002.
  56. Rafi, M.; Bai, N.; Ho, C.T.; Rosen, R.T.; Ghai, G.; Perez, D.; White, E.; Dipaola, R.S. Britannilactone, a novel derivative isolated from Inula britannica is cytotoxic through the phosphorylation of Bcl-2 at a Paclitaxel phosphorylation site. In 221st ACS National Meeting, San Diego, CA, US, April 1–5, 2001.
  57. Ho, C.T.; Rafi, M.; Bai, N.; Dipaola, R.S.; Ghai, G.; Rosen, R.T. Inducing cell apoptosis and treating cancer using 1-O-acetylbritannilactone or 1,6-O,O-diacetylbritannilactone. US Pat. No. 6,627,623, 2003. [Google Scholar]
  58. Pan, M.H.; Chiou, Y.; Cheng, A.C.; Bai, N.; Lo, C.Y.; Tan, D.; Ho, C.T. Involvement of MAPK, Bcl-2 family, cytochrome-c, and caspases in induction of apoptosis by 1,6-O,O-diacetylbritannilactone in human leukemia cells. Mol. Nut. Food Res. 2007, 51, 229–238. [Google Scholar]
  59. Wang, S.; Wang, D.S.; Wang, R. Neuroprotective activities of enzymatically hydrolyzed peptides from porcine hide gelatin. Int. J. Clin. Exp. Med. 2008, 1, 283–293. [Google Scholar]
  60. Kajta, M. Apoptosis in the central nervous system: Mechanisms and protective strategies. Pol. J. Pharmacol. 2004, 56, 689–700. [Google Scholar]
  61. Hinz, B.; Brune, K. Cyclooxygenase – 2 - 10 years later. J. Pharm. Experim. Therap. 2002, 300, 367–375. [Google Scholar] [CrossRef]
  62. Wiart, C. Ethnophamacology of Medicinal Plants Asia and the Pacific; Hunama Press: Totowa, NJ, USA, 2007; pp. 31–33. [Google Scholar]
  63. Liu, B.; Han, M.; Wen, J.K. Acetylbritannilactone inhibits neointimal hyperplasia after balloon injury of rat artery by suppressing NF-kB Activation. J. Pharm. Experim. Therap. 2008, 324, 292–298. [Google Scholar]
  64. Song, Y.J.; Lee, D.Y.; Kim, S.N.; Lee, K.R.; Lee, H.W.; Han, J.W.; Kang, D.W.; Lee, H.Y.; Kim, Y.K. Apoptotic potential of sesquiterpene lactone ergolide through the inhibition of NF-kappaB signaling pathway. J. Pharm. Pharmacol. 2005, 57, 1591–1597. [Google Scholar]
  65. Dahanukar, S.A.; Kulkarni, R.A.; Rege, N.N. Pharmacology of medicinal plants and natural products. Ind. J. Pharmacol. 2000, 32, 81–118. [Google Scholar]
  66. Je, K.H.; Han, A.; Lee, H.T.; Mar, W.; Seo, E.K. The inhibitory principle of lipopolysaccharide-induced nitric oxide production from Inula britannica var. chinensis. Arch. Pharm. Res. 2004, 27, 83–85. [Google Scholar] [CrossRef]
  67. Song, Q.H.; Kobayashi, T.; Iijima, K.; Hong, T.; Cyong, J.C. Hepatoprotective effects of Inula britannica on hepatic injury in mice. Phytoth. Res. 2006, 14, 180–186. [Google Scholar]
  68. Serkerov, S.V.; Mir-Babaev, N.F. Pulchellin C from Inula britannica. Khim. Prirod. Soed. 1998, 6, 879–880. [Google Scholar]
  69. Fatope, O.; Nair, R.S.; Marwah, R.G.; Al-Nadhiri, H.S.H. New sesquiterpenes from Pluchea arabica. J. Nat. Prod. 2004, 67, 1925–1928. [Google Scholar]
  70. Rosa, A.; Deiana, M.; Atzeri, A.; Corona, G.; Incani, A.; Melis, M.P.; Appendino, G.; Dess, M.A. Evaluation of the antioxidant and cytotoxic activity of arzanol, a prenylated α-pyrone-phloroglucinol etherodimer from Helichrysum italicum subsp. Microphyllum. Chem-Biol. Inter. 2007, 165, 117–126. [Google Scholar]
  71. Klika, K.D.; Demirci, B.; Salminen, J.P.; Ovcharenko, V.V.; Vuorela, S.; Baser, H.C.; Pihlaja, K. New, sesquiterpenoid-type bicyclic compounds from the buds of Betula pubescens-ring-contracted products of β-caryophyllene? Eur. J. Org. Chem. 2004, 2627–2635. [Google Scholar]
  72. Shao, Y.; Bai, N.; Zhou, B. Inuloside A and B, two new diterpene glycosides from Inula britannica L. var chinensis. Chin. Chem. Lett. 1994, 5, 757–760. [Google Scholar]
  73. Zhang, H.; Wen, J.; Wang, Y.; Zheng, B.; Han, M. Flavonoids from Inula britannica L. inhibits injury-induced neointimal hyperplasia through suppressing oxidative stress generation. FASEB J. 2009, 23, 229. [Google Scholar]
  74. Liu, Y.; Wen, J.; Wo, Y.; Zhang, J.; Zheng, B.; Zhang, D.; Han, M. 1,6-O,O-diacetylbritannilactones inhibits IκB kinase β-dependent NF-κB activation. Phytomedicine 2009, 16, 156–160. [Google Scholar]
  75. Yang, J.; Liu, L.; Shi, Y. Britanlins A–D, four novel sesquiterpenoids from Inula britannica. Tetrahed. Lett. 2009, 50, 6315–6317. [Google Scholar] [CrossRef]
  76. Loguercio, C.; Di Pierro, M. The role of glutathione in the gastrointestinal tract: A review. Ital. J. Gastroenterol. Hepatol. 1999, 31, 401–407. [Google Scholar]
  77. Zhang, L. Oral Chinese medicinal composition for treating asthma, and its preparation method (in Chinese). Faming Zhuanli Shenqing Gongkai Shuomingshu 2007, 14. [Google Scholar]
  78. Rankin, J.A.; Kaliner, M.; Reynolds, H.Y. Histamine levels in bronchoalveolar lavage from patients with astma, sarcoidosis, and idiopathic pulmonary fibrosis. J. Allergy. Clin. Immunol. 1987, 79, 371–377. [Google Scholar] [CrossRef]
  79. Das, M.; Ram, A.; Ghosh, B. Luteolin alleviates bronchoconstriction and airway hyperreactivity in ovalbumin sensitized mice. Inflamm. Res. 2003, 52, 101–106. [Google Scholar] [CrossRef]
  80. Park, H.; Lee, C.; Jung, I.; Lee, J.; Jeong, Y.; Chang, J.; Chun, S.; Kim, M.; Choi, I.; Ahn, S.; Shin, Y.; Yeom, S.; Park, Y. Quercetin regulates Th1/Th2 balance in a murine model of asthma. Inter. Immunopharm. 2009, 3, 261–267. [Google Scholar]

Share and Cite

MDPI and ACS Style

Khan, A.L.; Hussain, J.; Hamayun, M.; Gilani, S.A.; Ahmad, S.; Rehman, G.; Kim, Y.-H.; Kang, S.-M.; Lee, I.-J. Secondary Metabolites from Inula britannica L. and Their Biological Activities. Molecules 2010, 15, 1562-1577. https://doi.org/10.3390/molecules15031562

AMA Style

Khan AL, Hussain J, Hamayun M, Gilani SA, Ahmad S, Rehman G, Kim Y-H, Kang S-M, Lee I-J. Secondary Metabolites from Inula britannica L. and Their Biological Activities. Molecules. 2010; 15(3):1562-1577. https://doi.org/10.3390/molecules15031562

Chicago/Turabian Style

Khan, Abdul Latif, Javid Hussain, Muhammad Hamayun, Syed Abdullah Gilani, Shabir Ahmad, Gauhar Rehman, Yoon-Ha Kim, Sang-Mo Kang, and In-Jung Lee. 2010. "Secondary Metabolites from Inula britannica L. and Their Biological Activities" Molecules 15, no. 3: 1562-1577. https://doi.org/10.3390/molecules15031562

Article Metrics

Back to TopTop