Elecampane

Background & General Info

Elecampane, or Inula helenium, is a perennial herbaceous plant that is widely distributed, and sometimes cultivated, along the rivers and streams, woodland margins, and lower and middle belts of mountains of Europe, East Asia (predominantly in some regions of China), and Mediterranean region but has become broadly naturalized in North America. Elecampane botanically belongs to the family Asteraceae and is referred to by other common names such as horse-heal and elfdock. The species name of elecampane, helenium, derives from Helen of Troy, from whose fallen tears this plant had sprung up according to mythology. ^[1]

Elecampane - Botany

Elecampane is a fairly rigid herb, the erect stem of which reaches a height of 0.5 to 2.5 meters and holds elongate to ovate stem leaves that become sessile toward the top. The lower elliptic, irregularly shallow-dentate leaves of the plants are arranged alternately, are around 50 cm long and 10 to 20 cm wide, and are densely hairy on the abaxial side. Elecampane blooms from June to August, giving rise to an almost hundred of characteristically thin golden yellow ray flowers and 9–11-mm-long disc flowers, and, in due course, bears brown quadrangular achenes (or fruits) from August to September. Its root is thick, branching, and mucilaginous and possesses a warm bitter taste and camphoraceous odor. ^[2]

Elecampane - History & Traditional Use

The genus Inula, to which elecampane is a member of, numbers to a hundred species across temperate regions of Europe and Asia, where they are typically used as expectorants, antitussives, diaphoretics, antiemetics, and bactericides. The earliest account of the ethnopharmacological uses of this genus goes back to the glorious era of ancient Greeks and Romans. The Chinese Pharmacopoeia mentions three out of the 20 Inula species widespread in China as traditional Chinese medicines, namely, Tumuxiang, Xuanfuhua, and Jinfeicao, and in Ayurvedic and Tibetan traditional medicinal systems, several other Inula species are good for bronchitis, diabetes, fever, hypertension, and inflammation. ^[3]

Elecampane is celebrated as a medication used successfully by Prophet Job for his chronic sore boils. Hippocrates described it as a good and effective cure for chronic skin eruptions and itch; it is also presumed to alleviate pain, especially that due to chills, and animal bites and is used in traditional medicine as cure for many diseases. ^[4] Avicenna, the most significant and influential Persian philosopher in the Islamic tradition, considered elecampane as a tonic with the ability to invigorate and strengthen the heart. ^[2] Moreover, Minoan, Mycenaean, Egyptian, and Assyrian pharmacotherapy texts and Chilandar Medical Codex, which is said to be most important and preserved medieval Serbian manuscript, declare elecampane as a superb herbal treatment of neoplasm, wound, freckles, and dandruff. ^[3]

As a vegetable, the relatively bitter and aromatic leaves of elecampane can be cooked, while the roots can be candied and eaten as a sweet delicacy. A blue dye can also be secured when the bruised and macerated roots of elecampane are mixed with ashes and whortleberries; approximately 2% of a camphor-scented elecampane essential oil can be acquired from the roots, which can be used as a flavoring and medicine. ^[5]

Elecampane - Herbal Uses

Alantolactone, an active principle of the dry roots of elecampane, holds various beneficial uses, including being an insect repellent and an antibacterial, antidiuretic, analgesic, and anticancer agent. ^[6] Elecampane roots are medicinally valued as remedies for a vast spectrum of disorders, such as asthma, abdominal distention, vomiting, diarrhea, and lung disorders, and are broadly used as a diuretic, diaphoretic, expectorant, insect repellent, and anthelmintic agent. ^[7] In a mixture with honey, elecampane can be used as an expectorant, and a decoction and syrup from its rhizomes can function as a diuretic and an aid for menstruation. An elecampane ointment or water infusion is a good remedy for eczema and scabies, while a tincture from its roots in vodka can be drunk as treatment of gastritis, stomach and duodenal ulcers, tuberculosis, nervous disorders, goiters, heat ailments, and hypertension or can be used as an alternative expectorant to manage chronic respiratory diseases such as tracheitis, pulmonary tuberculosis, and bronchitis. ^[2]

In certain areas in Europe, elecampane roots are traditionally employed as a diaphoretic, diuretic, and expectorant agent; in Japan, however, the roots are used as a fragrance agent in home medicines, whereas the Chinese value the roots of elecampane as a preservative and remedy for tuberculotic enterorrhea, chronic enterogastritis, and bronchitis. The Native Americans prepare decoctions and infusions from the roots of elecampane to treat lung disorders, especially tuberculosis. ^[8]

Elecampane - Constituents / Active Components

Chemical analysis conducted by different studies has expressed the existence of several bioactive compounds in the rhizomes and roots of elecampane, including inulin (up to 44%), essential oil with eudesmanes (up to 5%), sesquiterpene lactones (principally alantolactone and isoalantolactone), thymol derivatives, terpenes, and sterols. ^[9] Employing a fast and sensitive high-performance liquid chromatographic technique, Wang, Zhao, Zhang, and Shi (2015) had simultaneously determined chlorogenic acid, caffeic acid, alantolactone, and isoalantolactone in elecampane. With detection examined at 225 nm, the recovery of chlorogenic acid, caffeic acid, alantolactone, and isoalantolactone ranged from 95.6 to 107.7%, 95.4 to 104.2%, 95.8 to 100.8%, and 96.5 to 102.3%, respectively. It is worthy to note that chlorogenic acid and caffeic acid exert diverse pharmacological activities, including antioxidant, antimicrobial, antiobesity, anti-inflammatory, antinociceptive, and antipyretic activities. ^[7]

Stojakowska, Malarz, and Kisiel (2004) isolated two thymol derivatives from an ethanol extract of elecampane lyophilized roots fractionated using column chromatography and thin layer chromatography techniques. These main secondary metabolites were 10-isobutyryloxy-8,9-epoxy-thymol isobutyrate and 10-isobutyryloxy-6-methoxy-8,9-epoxy-thymol isobutyrate, which were identified by spectral methods. ^[10] Konishi et al. (2002), on the other hand, detected seven sesquiterpenes from the hexane-soluble fraction of elecampane root methanol extract: 4β,5α-epoxy-1(10),11(13)-germacradiene-8,12-olide (a germacrane), igalane (an elemane), and alantolactone, isoalantolactone, 11α,13-dihydroalantolactone, 11α,13-dihydro-isoalantolactone, and 5-epoxyalantolactone (which are eudesmanes). ^[8]

Elecampane - Medicinal / Scientific Research

A broad range of modern pharmacological studies and biological evaluations have underlined the antibacterial, antitumor, antiproliferative, anti-inflammatory, and antistressor properties possessed by elecampane extracts, leading to their emerging pharmacological applications. ^[7]

Antioxidant:

A 2003 Russian study highlighted the antistressor and antioxidant properties of preparations obtained from the underground parts of elecampane, or “elfwort,” in mice. Such elecampane preparations have been found to exert a protective effect as regards internal organs, blood, carbohydrate metabolism, and lipid peroxidation process. ^[11] The methanol extract of elecampane had been demonstrated as well to potentially trigger detoxifying enzymes such as quinine reductase and glutathione S-transferase. In the study of Lim et al. (2007), a hexane fraction of elecampane demonstrated the highest dose-dependent inducing activity for quinine reductase, as evidenced by a significant increase of quinine reductase activity in the liver, kidney, small intestine, and stomach of mice intraperitoneally injected with elecampane hexane fraction, which can be attributed to sesquiterpenes. Mediation on the antioxidant response element has been suggested as the mechanism of action in the induction of phase II detoxifying enzymes, as indicated by its potential to stimulate the reporter activity. The study screened seven compounds isolated from the extract, but only alantolactone, isoalantolactone, and 5-alpha-epoxyalantolactone notably induced quinine reductase activity in both Hepa1c1c7 and BPRc1 cells, hinting their potential value as chemopreventive agents. ^[12]

Seo et al. (2009) further supported these findings by providing their own study results of elecampane-derived isoalantolactone dose-dependently stimulating quinine reductase in both Hepa1c1c7 cells and BPRc1 cells lacking the arylhydrocarbon receptor translocator. Their study evaluated the detoxifying enzyme-inducing potential of isoalantolactone, which dose-dependently induces other phase 2 detoxifying enzymes such as glutathione S-transferase, glutathione reductase, gamma-glutamylcysteine synthetase, and heme oxygenase-1, in cultured cells. Isoalantolactone has also been found to cause a proportionate increase in luciferase activity in reporter assay where HepG2-C8 cells were used and to stimulate the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2). These findings irrefutably raise the notion of isoalantolactone as a candidate for chemoprevention that performs the role of potent phase 2 enzyme inducer by inducing the buildup of Nrf2 in the nucleus. ^[13]

Anticancer:

A 2006 research program demonstrated the remarkable antineoplastic activity of botanical extracts acquired from elecampane roots, as proven by MTT assay where elecampane extract showed highly selective toxicity against four different tumor cell lines, namely, HT-29, MCF-7, Capan-2, and G1, but much lower toxicity against healthy human peripheral blood lymphocytes from two donors. An electron microscopy in order to examine the extract-induced death of tumor cells revealed a notable similarity of morphological alterations in the four tumor cell lines, such as patchy chromatin condensations, cytoplasmic vesiculation, swelling, and rupture of mitochondria. The morphology of cellular breakdown was more on necrotic death than apoptotic cell death, which was supported by the failure to mark early apoptotic events by Annexin V. Such cell death with necrotic-like morphology from potent compounds is exceptionally valuable in cases where cancerous cells have gained resistance to apoptosis. Conclusively, the cytotoxicity exhibited by elecampane extract was over 100 times higher in the tumor cell lines than in the peripheral blood lymphocytes. ^[14] Konishi et al. (2002) revealed the same high inhibitory activity of the methanol extract of elecampane roots against the growth of three tumor cell lines—MK-1, HeLa, and B16F10 cell lines—and, additionally, in vitro antiproliferative activities of the isolated elecampane sesquiterpene lactones against the aforementioned three cells. ^[8]

The results from a Turkish investigative work reinforce the claim of elecampane as a natural source of antioxidants and anticancer agents. Using 3'-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays, the study looked into the antioxidant, antiproliferative, and cytotoxic activities of aqueous extract acquired from the aerial parts of elecampane against human U-87 MG glioma cell line after 48 hours of exposure to treatment. At high concentrations tested, particularly at 200 µg/mL, the aqueous extracts exhibited significant antiproliferative and cytotoxic actions without causing oxidative stress. ^[15]

According of a very recent study published in the June 2016 issue of Oncology Letters, alantolactone, which can be acquired from the dry roots of elecampane, triggers the apoptosis of human cervical cancer cells via reactive oxygen species (ROS) generation, glutathione depletion, and inhibition of the Bcl-2/Bax signaling pathway. Alantolactone treatment at variable doses of 0, 10, 20, 30, 40, 50, and 60 µM on HeLa cells for half a day significantly suppressed the cancer cells dose-dependently. Furthermore, the cells treated with 30 µM of alantolactone for 0, 3, 6, and 12 hours displayed discernible induction of apoptosis, and at the same treatment dose and time, a considerable induction of ROS generation and an inhibition of glutathione production in HeLa cells were observed upon treatment of alantolactone in a dose-dependent manner, which also clearly suppressed the Bcl-2/Bax signaling pathway in HeLa cells. ^[6] Among the eight sesquiterpene lactones isolated from elecampane roots in the study of Li et al. (2012), isoalantolactone and santamarine displayed excellent inhibitory action against the growth of gynecologic cancer cell lines, but did not exert any toxic effect on human embryonic lung fibroblast cells in vitro. Though weakly, other identified lactones also suppressed the growth of the cell lines (IC50 ≤ 100 μM). In addition, the isolated isoalantolactone significantly inhibited the tumor growth of S180 tumor-bearing mice. ^[16]

Anti-inflammatory:

A 2013 Korean study determined the inflammation-reducing effect of elecampane ethanol extract in lipopolysaccharide-activated RAW 264.7 cells and CLP-induced septic mice via induction of heme oxygenase-1 (HO-1) through p38 MAPK/Nrf2 signaling pathway. By extension, the study pointed out the potential usefulness of elecampane in the management of sepsis. During inflammation, HO-1 negatively regulates high mobility group box 1 (HMGB1), which serves as a vital mediator in the inflammatory pathogenesis and whose expression, as revealed by the study, is time-dependently and concentration-dependently induced by the ethanol extract of elecampane. The extract significantly inhibited the activity of NF-κB luciferase, the phosphorylation of IκBα in lipopolysaccharide-activated cells, and the expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-alpha-activated human umbilical vein endothelial cells. HO-1 induction by elecampane extract was suppressed by SB203580, but not by SP600125, PD98059, and LY294002. A reduction of any increase in blood HMGB1, ALT, AST, BUN, and creatinine levels and any decrease in macrophage infiltrate in the liver of septic mice was observed after the administration of the extract. ^[17]

Prior to a lipopolysaccharide treatment, a pretreatment of elecampane extract, at doses of 20, 40, 80, and 100 μg/mL, was observed to dose-dependently suppress the overproduction of nitric oxide (p < 0.001) and was associated with the downregulation of expression of inducible nitric oxide synthase (iNOS). Furthermore, at doses of 40 and 80 μg/mL, elecampane extract significantly prevented any elevation in interukin-6 level (p < 0.01) caused by lipopolysaccharide in BV-2 cells. Such are the study findings from a 2016 research published in Tropical Journal of Pharmaceutical Research; these draw attention to the in vitro antioxidant and anti-neuroinflammatory activities of elecampane extract against lipopolysaccharide-induced nitric oxide production by primary microglial cells. Elecampane’s antioxidant activity might find applications in the prevention and management of neurodegenerative conditions related to neuroinflammatory processes and oxidative stress. ^[18]

Antibacterial:

By employing drop test and microbroth dilution methods, O'Shea, Lucey, and Cotter (2009) confirmed the bactericidal activity of elecampane extract against 200 clinically significant methicillin-resistant and methicillin-sensitive Staphylococcus aureus isolates. Elecampane extract, as the findings demonstrated, was 100% effective against all staphylococci tested, with 93% of isolates falling within the ++ and +++ groups and with a minimum bactericidal concentration of 0.9–9.0 mg/mL. The extract’s potent antistaphylococcal action was equally effective against antibiotic-resistant and antibiotic-sensitive strains, suggesting utility in the prevention of staphylococcal infection and carriage without the concern for antibiotic resistance. ^[19]

Another scientific investigation that demonstrated the antimicrobial property of elecampane is the study of Diguță et al. (2014), who qualitatively screened the in vitro antimicrobial activities of dried elecampane roots from a Romanian indigenous cultivar. As revealed by the drop-diffusion test method, which measures the inhibition zones, ethanol extracts (50% and 70% v/v) obtained from the powdered dried roots of a Romanian elecampane cultivar exhibited significant antimicrobial activity against five pathogenic bacteria, namely, Bacillus subtilis, Bacillus cereus, Enterococcus faecalis, Escherichia coli, and Staphylococcus aureus, and three fungal species, namely, Candida albicans, Candida parapsilosis, and Candida lipolytica. On these dermatophytic candidal species, the inhibitory effects of 50% and 70% elecampane extracts were very alike; moderate antifungal activity against C. albicans and good activity against C. parapsilosis and C. lipolytica were observed. ^[9] These study findings are in accord with those reported by Deriu et al. (2008), who substantiated the antimicrobial activity of elecampane root essential oil against some Gram-positive and Gram-negative bacteria and Candida species. ^[20]

An early bioassay-guided study by Cantrell et al. (1999) identified antimycobacterial eudesmanolides from the chromatographic fractions of elecampane root extracts, which have been demonstrated to display significant antibacterial action against Mycobacterium tuberculosis. When tested in a radiorespirometric bioassay for antimycobacterial activity, the eudesmanolides alantolactone and isoalantolactone showed a minimum inhibitory concentration (MIC) of 32 μg/mL, whereas 5-alpha-epoxyalantolactone and encelin had MICs of 8 and 16 μg/mL. ^[21]

Neuroprotective:

Oxidative stress has been implicated in numerous studies to contribute to neurological diseases; with it comes an overproduction of ROS, which triggers damage to important biomolecules, such as lipids, proteins, and DNA, and causes an oxidative burst of intracellular signaling cascades that eventually lead to cell death. Phenolic compounds known to be components of elecampane have been observed to scavenge free radicals and in turn prevent neurodegenerative diseases. Wang, Zhao, Zhang, and Guo (2015) reported the neuroprotection conferred by total phenolic compounds from elecampane extract against the oxidative stress induced by hydrogen peroxide in SH-SY5Y cells. The high DPPH and hydroxyl radical scavenging activities of total phenolic compounds from elecampane extract were concentration-dependent such that a DPPH free radical clearance rate of 41.1–79.3% was reached when total phenolic compound concentration was 0.5 to 5 μg/ml and likewise a 26.2–60.1% hydroxyl radical clearance rate was achieved when the concentration was 0.5–5 μg/ml. In this study, elecampane extract’s total phenolic compounds reversed the considerably harmful effects induced by hydrogen peroxide, such as loss of cell viability, increment of apoptosis, formation of ROS, reduction of superoxide dismutase activity, decrease in mitochondrial membrane potential, and decrease in adenosine triphosphate production. There was an observed suppression of any increase in ROS and decrease of SOD activity by 0.5–5 μg/mL of elecampane phenolic compounds. This study credited the neuroprotective effect of elecampane’s phenolic compounds to their effective blockade of ROS production and enhancement of mitochondrial function. ^[22]

The recent work of Sowndhararajan et al. (2016) explored the effect of inhalation of essential oil from elecampane roots on electroencephalographic (EEG) activity of the human brain. Evaluated in twenty healthy individuals, the inhalation of elecampane essential oil resulted in significant changes in measured EEG power spectrum values, which were recorded using QEEG-8 system from eight ground electrodes. The results showed a decrease in absolute theta (all the regions except T3), beta (Fp1), mid-beta (P4), and relative theta (Fp1, Fp2, F3, and F4) waves and a significant increase in the ratios of SMR to theta (Fp1 and P4) and SMR–mid-beta to theta (Fp1) during essential oil inhalation. Such changes in EEG values may improve brain alertness, thus implying the potential worth of inhalation of elecampane essential oil in the management of psychophysiological disorders. ^[23]

Tuberculosis:

A traditionally used herbal mixture for tuberculosis entails the boiling of horehound, spikenard, and elecampane in water, to which a half pint of honey and a large amount of alum are added. One tablespoon of this mixture is to be orally consumed thrice daily; however, it should be commented that no scientifically acquired data proves the efficacy and, most importantly, safety of such mixture. ^[24]

Case records of Von Unruh (1915) specified the use of two flowering plant species, Echinacea angustifolia and Inula helenium, and their compounds in the treatment of tuberculosis. The compounds, at a dose of 3–5 cubic centimeters, were intramuscularly injected on alternate sides into the gluteal muscles, either daily or as frequently as tolerated. In tuberculosis treatment, elecampane is said to control night sweats, increase and then decrease expectoration, encourage secretion from the gastrointestinal tract, and exhibit a direct toxic effect on the tubercle bacilli. In the case of a 23-year-old American female patient confined to bed because of constant fever that lasted for two weeks, persistent cough, copious mucopurulent expectoration, exhaustion, and night sweats for two months, daily injection of Echinacea and Inula compounds and oral drops of Inula (20 drops every 3 hours) appeared to have eventually improved the condition of the patient, who upon treatment showed diminishing fever and gradually declining temperature since beginning of treatment, absence of night sweats at the 7th day of treatment, reduced cough and expectoration, and disintegrated bacilli in the sputum. A 20-year-old American male patient manifesting characteristically tuberculous sputum, severe cough, profuse mucopurulent expectoration, and fine crackling rales over the right apex was injected with the same previously mentioned intervention and displayed decreased coughing, less expectoration, weight improvement, and, around 3 months later, albumin-negative sputum that is free from tubercle bacilli. Von Unruh (1915) claimed the nonexistence of any general or local toxic reactions as a result of herbal intervention. ^[25]

Elecampane - Contraindications, Interactions, And Safety

Sensitive individuals with a history of allergic reactions should best avoid elecampane use. In a new patch test series consisting of 29 plant extracts and 16 purified plant allergens, elecampane has been found to cause sensitization, as indicated by retesting, and should be patch-tested at a lower concentration, preferably 0.1%. Patients should report any late flare-up patch test reactions to gain more information concerning active sensitization. ^[26] Elecampane can potentially interfere with blood sugar and pressure control in the treatment of diabetes mellitus and high blood pressure. ^[5]

References:

[1] M. Howard, Traditional Folk Remedies: A Comprehensive Herbal, 1987. https://trove.nla.gov.au/work/12649874?q&versionId=14944689

[2] S. W. Eisenman, D. E. Zaurov and L. Struwe, Medicinal Plants of Central Asia: Uzbekistan and Kyrgyzstan, London: Springer, 2013. https://www.gbv.de/dms/bs/toc/729201937.pdf

[3] A. Seca, A. Grigore, D. Pinto and A. Silva, "The genus Inula and their metabolites: from ethnopharmacological to medicinal uses," Journal of Ethnopharmacology, vol. 154, no. 2, p. 286–310, 2014. https://www.ncbi.nlm.nih.gov/pubmed/24754913

[4] S. Al-Gammal, "Elecampane and Job's disease," Bulletin of the Indian Institute of History of Medicine, vol. 28, no. 1, p. 7–11, 1998. https://www.ncbi.nlm.nih.gov/pubmed/12587579

[5] "Inula helenium - L.," Plants For A Future. https://www.pfaf.org/User/Plant.aspx?LatinName=Inula+helenium

[6] Y. Jiang, H. Xu and J. Wang, "Alantolactone induces apoptosis of human cervical cancer cells via reactive oxygen species generation, glutathione depletion and inhibition of the Bcl-2/Bax signaling pathway," Oncology Letters, vol. 11, no. 6, p. 4203–4207, 2016. https://www.ncbi.nlm.nih.gov/pubmed/27313767

[7] J. Wang, Y.-M. Zhao, M.-L. Zhang and Q.-W. Shi, "Simultaneous determination of chlorogenic acid, caffeic acid, alantolactone and isoalantolactone in Inula helenium by HPLC," Journal of Chromatographic Science, vol. 53, no. 4, p. 526–530, 2015. https://www.ncbi.nlm.nih.gov/pubmed/24996657

[8] T. Konishi, Y. Shimada, T. Nagao, H. Okabe and T. Konoshima, "Antiproliferative sesquiterpene lactones from the roots of Inula helenium," Biological and Pharmaceutical Bulletin, vol. 25, no. 10, p. 1370–1372, 2002. https://www.ncbi.nlm.nih.gov/pubmed/12392098

[9] C. Diguţă, C. Cornea, L. Ioniţă, F. Matei, et al., "Studies on antimicrobial activity of Inula helenium L Romanian cultivar," Romanian Biotechnological Letters, vol. 19, no. 5, p. 9699–9704, 2014. https://www.researchgate.net/publication/286576700

[10] A. Stojakowska, J. Malarz and W. Kisiel, "Thymol derivatives from a root culture of Inula helenium," Zeitschrift für Naturforschung C, vol. 59, no. 7–8, p. 606–608, 2004. https://www.researchgate.net/publication/7923803

[11] I. Nesterova, K. Zelenskaia, T. Vetoshkina, S. Aksinenko, A. Gorbacheva and N. Gorbatykh, "Mechanisms of antistressor activity of Inula helenium preparations," Eksperimental'naia I Klinicheskaia Farmakologiia, vol. 66, no. 4, p. 63–65, 2003.

[12] S. Lim, J. Kim, H. Lim, et al., "Induction of detoxifying enzyme by sesquiterpenes present in Inula helenium," Journal of Medicinal Food, vol. 10, no. 3, p. 503–510, 2007. https://www.ncbi.nlm.nih.gov/pubmed/17887945

[13] G. Seo, J. Park, H. Kim, et al., "Isoalantolactone from Inula helenium caused Nrf2-mediated induction of detoxifying enzymes," Journal of Medicinal Food, vol. 12, no. 5, p. 1038–1045, 2009. https://www.ncbi.nlm.nih.gov/pubmed/19857067

[14] D. Dorn, M. Alexenizer, J. Hengstler and A. Dorn, "Tumor cell specific toxicity of Inula helenium extracts," Phytotherapy Research, vol. 20, no. 11, p. 970–980, 2006. https://www.ncbi.nlm.nih.gov/pubmed/16912983

[15] K. Koc, O. Ozdemir, A. Ozdemir, U. Dogru and H. Turkez, "Antioxidant and anticancer activities of extract of Inula helenium (L.) in human U-87 MG glioblastoma cell line," Journal of Cancer Research and Therapeutics, 2016. https://www.cancerjournal.net/preprintarticle.asp?id=187289;type=0

[16] Y. Li, Z. Ni, M. Zhu, M. Dong, S. Wang, Q. Shi, M. Zhang, Y. Wang, C. Huo, H. Kiyota and B. Cong, "Antitumour activities of sesquiterpene lactones from Inula helenium and Inula japonica," Zeitschrift für Naturforschung C, vol. 67, no. 7–8, p. 375–380, 2012. https://www.ncbi.nlm.nih.gov/pubmed/23016276

[17] E. Park, Y. Kim, S. Park, H. Kim, J. Lee, D.-U. Lee and K. Chang, "Induction of HO-1 through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice," Food and Chemical Toxicology, vol. 55, p. 386–395, 2013. https://www.ncbi.nlm.nih.gov/pubmed/23298677

[18] S.-G. Lee and H. Kang, "Anti-neuroinflammatory effects of ethanol extract of Inula helenium L (Compositae)," Tropical Journal of Pharmaceutical Research, vol. 15, no. 3, 2016. https://www.tjpr.org/admin/12389900798187/2016_15_3_13.pdf

[19] S. O'Shea, B. Lucey and L. Cotter, "In vitro activity of Inula helenium against clinical Staphylococcus aureus strains including MRSA," British Journal of Biomedical Science, vol. 66, no. 4, p. 186–189, 2009. https://www.ncbi.nlm.nih.gov/pubmed/20095126

[20] A. Deriu, S. Zanetti, L. Sechi, B. Marongiu, A. Piras, S. Porcedda and E. Tuveri, "Antimicrobial activity of Inula helenium L. essential oil against Gram-positive and Gram-negative bacteria and Candida spp.," International Journal of Antimicrobial Agents, vol. 31, no. 6, p. 588–590, 2008. https://www.ijaaonline.com/article/S0924-8579(08)00084-8/abstract

[21] C. Cantrell, L. Abate, F. Fronczek, S. Franzblau, L. Quijano and N. Fischer, "Antimycobacterial eudesmanolides from Inula helenium and Rudbeckia subtomentosa," Planta Medica, vol. 65, no. 4, p. 351–355, 1999. https://www.ncbi.nlm.nih.gov/pubmed/10364842

[22] J. Wang, Y. Zhao, B. Zhang and C. Guo, "Protective effect of total phenolic compounds from Inula helenium on hydrogen peroxide-induced oxidative stress in SH-SY5Y cells," Indian Journal of Pharmaceutical Sciences, vol. 77, no. 2, p. 163–169, 2015. https://www.ncbi.nlm.nih.gov/pubmed/26009648

[23] K. Sowndhararajan, H. Cho, B. Yu, J. Song and S. Kim, "Effect of inhalation of essential oil from Inula helenium L. root on electroencephalographic (EEG) activity of the human brain," European Journal of Integrative Medicine, vol. 8, no. 4, p. 453–457, 2016. https://www.researchgate.net/publication/292344189

[24] "Tuberculosis," in Hoosier Home Remedies, West Lafayette, Indiana: Purdue University Press, 1985, p. 166. https://books.google.com.ph/books?id=FJr7U_hsRrsC&redir_esc=y

[25] V. Von Unruh, "Echinacea angustifolia and Inula helenium in the treatment of tuberculosis," National Eclectic Medical Association Quarterly, vol. 7, no. 1, 1915. https://www.henriettes-herb.com/eclectic/journals/nemaq1915/01-ech-inula-tbc.html

[26] L. Kanerva, T. Estlander, K. Tarvainen and R. Jolanki, "Active sensitization caused by elecampane (Inula helenium)," American Journal of Contact Dermatitis, vol. 5, no. 1, 1994. https://www.mysciencework.com/publication/show/8dfd5e7236a1e472f57cfdfba044d414

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