[1]
Seaman FC. Sesquiterpene lactones as taxonomic characters in the Asteraceae. Bot Rev 1982; 48: 121-594.
[2]
Berges C, Fuchs D, Opelz G, Daniel V, Naujokat C. Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms. Mol Immunol 2009; 46: 2892-901.
[3]
Zwicker P, Schultze N, Niehs S, et al. Differential effects of Helenalin, an anti-inflammatory sesquiterpene lactone, on the proteome, metabolome and the oxidative stress response in several immune cell types. Toxicol In Vitro 2017; 40: 45-54.
[4]
Ghasemali S, Nejati-Koshki K, Akbarzadeh A, et al. Inhibitory effects of β-cyclodextrin-helenalin complexes on H-TERT gene expression in the T47D breast cancer cell line-results of real time quantitative PCR. Asian Pac J Cancer Prev 2013; 14: 6949-53.
[5]
Hoffmann R, Von Schwarzenberg K, López-Antón N, et al. Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-κB and promoting reactive oxygen species generation. Biochem Pharmacol 2011; 82: 453-63.
[6]
Kim SH, Oh SM, Kim TS. Induction of human leukemia HL-60 cell differentiation via a PKC/ERK pathway by helenalin, a pseudoguainolidesesquiterpene lactone. Eur J Pharmacol 2005; 511: 89-97.
[7]
Boulanger D, Brouillette E, Jaspar F, et al. Helenalin reduces Staphylococcus aureus infection in vitro and in vivo. Vet Microbiol 2007; 119: 330-8.
[8]
Boulogne I, Petit P, Ozier-Lafontaine H, Desfontaines L, Loranger-Merciris G. Insecticidal and antifungal chemicals produced by plants: A review. Environ Chem Lett 2012; 10: 325-47.
[9]
Schmidt TJ, Nour AM, Khalid SA, Kaiser M, Brun R. Quantitative structure‒antiprotozoal activity relationships of sesquiterpene lactones. Molecules 2009; 14: 2062-76.
[10]
Picman AK. Biological activities of sesquiterpene lactones. Biochem Syst Ecol 1986; 14: 255-81.
[11]
Yu F, Utsumi R. Diversity, regulation, and genetic manipulation of plant mono- and sesquiterpenoid biosynthesis. Cell Mol Life Sci 2009; 66: 3043-52.
[12]
Zhang S, Won YK, Ong CN, Shen HM. Anti-cancer potential of sesquiterpene lactones: Bioactivity and molecular mechanisms. Curr Med Chem Anticancer Agents 2005; 5: 239-49.
[13]
Janecka A, Wyrębska A, Gach K, Fichna J, Janecki T. Natural and synthetic α-methylenelactones and α-methylenelactams with anticancer potential. Drug Discov Today 2012; 17: 561-72.
[14]
Ding XC, Beck HP, Raso G. Plasmodium sensitivity to artemisinins: Magic bullets hit elusive targets. Trends Parasitol 2011; 27: 73-81.
[15]
Denmeade SR, Isaacs JT. The SERCA pump as a therapeutic target: making a “smart bomb” for prostate cancer. Cancer Biol Ther 2005; 4: 14-22.
[16]
Christensen SB, Skytte DM, Denmeade SR, et al. A Trojan horse in drug development: Targeting of thapsigargins towards prostate cancer cells. Anticancer Agents Med Chem 2009; 9: 276-94.
[17]
Guzman ML, Rossi RM, Karnischky L, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005; 105: 4163-9.
[18]
Guzman ML, Rossi RM, Neelakantan S, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 2007; 110: 4427-35.
[19]
Perry NB, Burgess EJ, Guitián MAR, et al. Sesquiterpene lactones in Arnica montana: Helenalin and dihydrohelenalinchemotypes in Spain. Planta Med 2009; 75: 660-6.
[20]
Leven W, Willuhn G. Sesquiterpene lactones from Arnica chamissonis less.: VI. Identification and quantitative determination by high-performance liquid and gas chromatography. J Chromatogr A 1987; 410: 329-42.
[21]
Kos O, Lindenmeyer MT, Tubaro A, Sosa S, Merfort I. New sesquiterpene lactones from Arnica tincture prepared from fresh flowerheads of Arnica montana. Planta Med 2005; 71: 1044-52.
[22]
Iannitti T, Morales-Medina JC, Bellavite P, Rottigni V, Palmieri B. Effectiveness and safety of Arnica montana in post-surgical setting, pain and inflammation. Am J Ther 2016; 23: e184-97.
[23]
Lee KH, Furukawa H, Huang ES. Antitumor agents. 3. Synthesis and cytotoxic activity of helenalin amine adducts and related derivatives. J Med Chem 1972; 15: 609-11.
[24]
Zhang Z, Xu L, Cheung HY. The inhibitory effect of helenalin on telomerase activity is attributed to the alkylation of the CYS445 residue: Evidence from QM/MM simulations. J Mol Graph Model 2014; 51: 97-103.
[25]
Schmidt TJ, Brun R, Willuhn G, Khalid SA. Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones. Planta Med 2002; 68: 750-1.
[26]
Schmidt TJ, Lyß G, Pahl HL, Merfort I. Helenanolide type sesquiterpene lactones. Part 5: The role of glutathione addition under physiological conditions. Bioorg Med Chem 1999; 7: 2849-55.
[27]
Büchele B, Zugmaier W, Lunov O, Syrovets T, Merfort I, Simmet T. Surface plasmon resonance analysis of nuclear factor-κB protein interactions with the sesquiterpene lactone helenalin. Anal Biochem 2010; 401: 30-7.
[28]
Lee KH, Ibuka T, Mar EC, Hall IH. Anti-tumor agents. 31. Helenalin sym-dimethylethylenediamine reaction products and related derivatives. J Med Chem 1978; 21: 698-701.
[29]
Grippo AA, Hall IH, Kiyokawa H, Muraoka O, Shen YC, Lee KH. The cytotoxicity of helenalin, its mono and difunctional esters, and related sesquiterpene lactones in murine and human tumor cells. Drug Des Discov 1992; 8: 191-20.
[30]
Heilmann J, Wasescha MR, Schmidt TJ. The influence of glutathione and cysteine levels on the cytotoxicity of helenanolide type sesquiterpene lactones against KB cells. Bioorg Med Chem 2001; 9: 2189-94.
[31]
Lee KH, Kim SH, Furukawa H, Piantadosi C, Huang ES. Antitumor agents. 11. Synthesis and cytotox activity of epoxides of helenalin related derivatives. J Med Chem 1975; 18: 59-63.
[32]
Klaas CA, Wagner G, Laufer S, et al. Studies on the anti-inflammatory activity of phytopharmaceuticals prepared from Arnica flowers. Planta Med 2002; 68: 385-91.
[33]
Siedle B, Gustavsson L, Johansson S, et al. The effect of sesquiterpene lactones on the release of human neutrophil elastase. Biochem Pharmacol 2003; 65: 897-903.
[34]
Schröder H, Lösche W, Strobach H, et al. Helenalin and 11 alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways. Thromb Res 1990; 57: 839-45.
[35]
Tornhamre S, Schmidt TJ, Näsman-Glaser B, Ericsson I, Lindgren JÅ. Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C4 synthase in human blood cells. Biochem Pharmacol 2001; 62: 903-11.
[36]
Hall IH, Lee KH, Starenes CO, et al. Anti‐inflammatory activity of sesquiterpene lactones and related compounds. J Pharm Sci 1979; 68: 537-42.
[37]
Lyss G, Schmidt TJ, Merfort I, Pahl HL. Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica, selectively inhibits transcription factor NF-κB. Biol Chem 1997; 378: 951-62.
[38]
Chadwick M, Trewin H, Gawthrop F, Wagstaff C. Sesquiterpenoids lactones: benefits to plants and people. Int J Mol Sci 2013; 14: 12780-805.
[39]
Merfort I. Perspectives on sesquiterpene lactones in inflammation and cancer. Curr Drug Targets 2011; 12: 1560-73.
[40]
Lee KH, Meck R, Piantadosi C, Huang ES. Antitumor agents. 4. Cytotoxicity and in vivo activity of helenalin esters and related derivatives. J Med Chem 1973; 16: 299-301.
[41]
González ML, Joray MB, Laiolo J, et al. Cytotoxic activity of extracts from plants of central argentina on sensitive and multidrug-resistant leukemia cells: Isolation of an active principle from Gaillardia megapotamica. Evid Based Complement Alternat Med 2018; 2018: 9185935.
[43]
Jimenez-Ortiz V, Brengio SD, Giordano O, et al. The trypanocidal effect of sesquiterpene lactones helenalin and mexicanin on cultured epimastigotes. J Parasitol 2005; 91: 170-4.
[44]
Jimenez V, Kemmerling U, Paredes R, Maya JD, Sosa MA, Galanti N. Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: A new therapeutic target? Phytomedicin 2014; 21: 1411-8.
[45]
Wulsten IF, Costa-Silva TA, Mesquita JT, et al. Investigation of the anti-leishmania (Leishmania) infantum activity of some natural sesquiterpene lactones. Mol 2017; 22: 685.
[46]
Barrera PA, Jimenez-Ortiz V, Tonn C, Giordano O, Galanti N, Sosa MA. Natural sesquiterpene lactones are active against Leishmania mexicana. J Parasitol 2008; 94: 1143-9.
[47]
François G, Passreiter CM. Pseudoguaianolide sesquiterpene lactones with high activities against the human malaria parasite Plasmodium falciparum. Phytother Res 2004; 18: 184-6.
[48]
Rozas-Muñoz E, Lepoittevin JP, Pujol RM, Giménez-Arnau A. Allergic contact dermatitis to plants: Understanding the chemistry will help our diagnostic approach. Actas Dermosifiliogr 2012; 103(6): 456-77.
[49]
Freudenberg MA, Esser PR, Jakob T, Galanos C, Martin SF. Innate and adaptive immune responses in contact dermatitis: Analogy with infections. G Ital Dermatol Venereol 2009; 144: 173-85.
[50]
Martin SF, Merfort I, Thierse HJ. Interactions of chemicals and metal ions with proteins and role for immune responses. Mini Rev Med Chem 2006; 6: 247-55.
[51]
Hausen BM. Arnica allergy. Hautarzt 1980; 31: 10-7.
[52]
Warshaw EM, Zug KA. Sesquiterpene lactone allergy. Am J Contact Dermat 1996; 7: 1-23.
[53]
Schlede E, Aberer W, Fuchs T, et al. Chemical substances and contact allergy-244 substances ranked according to allergenic potency. Toxicology 2003; 193: 219-59.
[54]
Rios JL, Bas E, Recio MC. Effects of natural products on contact dermatitis. Curr Med Chem Anti Inflamm Anti Allergy Agents 2005; 4: 65-80.
[55]
Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86.
[56]
Xia Y, Shen S, Verma IM. NF-κB, an active player in human cancers. Cancer Immunol Res 2014; 2: 823-30.
[57]
Gilmore TD. Introduction to NF-κB: Players, pathways, perspectives. Oncogene 2006; 25: 6680.
[58]
Gloire G, Legrand-Poels S, Piette J. NF-κB activation by reactive oxygen species: Fifteen years later. Biochem Pharmacol 2006; 72: 1493-505.
[59]
DiDonato JA, Mercurio F, Karin M. NF‐κB and the link between inflammation and cancer. Immunol Rev 2012; 246: 379-400.
[60]
Yamamoto M, Horie R, Takeiri M, Kozawa I, Umezawa K. Inactivation of NF-kappaB components by covalent binding of (-)-dehydroxymethylepoxyquinomicin to specific cysteine residues. J Med Chem 2008; 51: 5780-8.
[61]
Rüngeler P, Castro V, Mora G, et al. Inhibition of transcription factor NF-kappaB by sesquiterpene lactones: A proposed molecular mechanism of action. Bioorg Med Chem 1999; 7: 2343-52.
[62]
Lim CB, Fu PY, Ky N, et al. NF-κB p65 repression by the sesquiterpene lactone, Helenalin, contributes to the induction of autophagy cell death. BMC Complement Altern Med 2012; 12: 93.
[63]
Lyß G, Knorre A, Schmidt TJ, Pahl HL, Merfort I. The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-κB by directly targeting p65. J Biol Chem 1998; 273: 33508-16.
[64]
García-Piñeres AJ, Castro V, Mora G, et al. Cysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J Biol Chem 2001; 276: 39713-20.
[65]
Widen J. Design and Synthesis of Natural Product-Inspired, Cysteine Reactive Probes toward Inhibition of Transcription Factors and Target Identification Studies. PhD thesis. University of Minnesota January.
[66]
Widen JC, Kempema AM, Baur JW, et al. Helenalin Analogues Targeting NF‐κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles. ChemMedChem 2018; 13: 303-11.
[67]
Cong YS, Wright WE, Shay JW. Human telomerase and its regulation. Microbiol Mol Biol Rev 2002; 66: 407-25.
[68]
Huang PR, Yeh YM, Wang TCV. Potent inhibition of human telomerase by helenalin. Cancer Lett 2005; 227: 169-74.
[69]
Kordi S, Zarghami N, Akbarzadeh A, et al. A comparison of the inhibitory effect of nano-encapsulated helenalin and free helenalin on telomerase gene expression in the breast cancer cell line, by real-time PCR. Artif Cells Nanomed Biotechnol 2016; 44: 695-703.
[70]
Thorburn A. Apoptosis and autophagy: Regulatory connections between two supposedly different processes. Apptosis 2008; 13: 1-9.
[71]
Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 2008; 9: 47.
[72]
Zhivotovsky B, Orrenius S. Cell death mechanisms: Cross-talk and role in disease. Exp Cell Res 2010; 316: 1374-83.
[73]
Dirsch VM, Stuppner H, Vollmar AM. Cytotoxic sesquiterpene lactones mediate their death-inducing effect in leukemia T cells by triggering apoptosis. Planta Med 2001; 67: 557-9.
[74]
Jang JH, Iqbal T, Min KJ, et al. Helenalin-induced apoptosis is dependent on production of reactive oxygen species and independent of induction of endoplasmic reticulum stress in renal cell carcinoma. Toxicol In Vitro 2013; 27: 588-96.
[75]
Chapman DE, Roberts GB, Reynolds DJ, et al. Acute toxicity of helenalin in BDF1 mice. Fundam Appl Toxicol 1988; 10: 302-12.
[76]
Chapman DE, Holbrook DJ, Chaney SG, Hall IH, Kuo-Hsiung L. In vivo and in vitro effects of helenalin on mouse hepatic microsomal cytochrome P450. Biochem Pharmacol 1991; 41: 229-35.
[77]
Merrill JC, Kim HL, Safe S, Murray CA, Hayes MA. Role of glutathione in the toxicity of the sesquiterpene lactones hymenoxon and helenalin. J Toxicol Environ Health 1988; 23: 159-69.
[78]
Anderson AC, Kim HL. Depletion and resynthesis of tissue thiols by helenalin and tenulin. Drug Chem Toxicol 1986; 9: 75-81.
[79]
Witzel DA, Ivie W, Dollahite JW. Mammalian toxicity of helenalin, the toxic principle of Helenium microcephalum CD (smallhead sneezeweed). Am J Vet Res 1976; 37: 859-61.
[80]
Beekman AC, Woerdenbag HJ, van Uden W, et al. Structure− cytotoxicity relationships of some helenanolide-type sesquiterpene lactones. J Nat Prod 1997; 60: 252-7.
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