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<ref> K. H. Lee et al., "Sesquiterpene antitumor agents: inhibitors of cellular metabolism," Science, vol. 196, no. 4289, pp. 533-536, 1977. </ref><ref>] H. Schröder et al., "Helenalin and 11 alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways," Thrombosis Research, vol. 57, no. 6, pp. 839-845, 1990. </ref>. The dose used varied per study. There is currently no in vivo evidence regarding the anti-inflammatory and anti-tumor response of Helenalin.
<ref> K. H. Lee et al., "Sesquiterpene antitumor agents: inhibitors of cellular metabolism," Science, vol. 196, no. 4289, pp. 533-536, 1977. </ref><ref>] H. Schröder et al., "Helenalin and 11 alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways," Thrombosis Research, vol. 57, no. 6, pp. 839-845, 1990. </ref>. The dose used varied per study. There is currently no in vivo evidence regarding the anti-inflammatory and anti-tumor response of Helenalin.
The efficacy of Helenalin for treatment of pain and swilling, when applied topically, is not supported by the current available evidence at doses at 10% or lower. For doses higher that 10%, more research is required whether those remain safe and are more efficient than the current available medications<ref> N. Brito, P. Knipschild and J. Doreste-Alonso, "Systematic review on the efficacy of Topical Arnica montana for the treatment of pain, swelling and bruises," Journal of Musculoskeletal Pain, vol. 22, no. 2, pp. 216-223, 2014</ref>
The efficacy of Helenalin for treatment of pain and swilling, when applied topically, is not supported by the current available evidence at doses at 10% or lower. For doses higher that 10%, more research is required whether those remain safe and are more efficient than the current available medications<ref> N. Brito, P. Knipschild and J. Doreste-Alonso, "Systematic review on the efficacy of Topical Arnica montana for the treatment of pain, swelling and bruises," Journal of Musculoskeletal Pain, vol. 22, no. 2, pp. 216-223, 2014</ref>

=== Application ===
In former time, plant extracts containing Helenalin were used as a herbal medicine for the treatment sprains, blood clots, muscle strain and rheumatic complaints<ref> C. Berges et al., "Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms," Molecular Immunology, vol. 46, no. 15, pp. 2892-2901, 2009. </ref>. Currently Helenalin is used topically as an homeopathic medicine in the form of gels and and microemulsions. To this day, Helenalin has not been FDA approved for medical application<ref> "U.S. National Library of Medicine," [Online]. Available: https://clinicaltrials.gov/ct2/results?cond=&term=arnica+montana&cntry=&state=&city=&dist=. [Accessed 8 March 2018].</ref>. However, since in vitro studies showed anti-inflammatory and anti-tumor properties of this compound, it may be used for medical application in the future<ref> C. Berges et al., "Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms," Molecular Immunology, vol. 46, no. 15, pp. 2892-2901, 2009. </ref>

==Pharmacology==
==Pharmacology==
{{see also|Arnica montana#Medicinal use}}
{{see also|Arnica montana#Medicinal use}}

Revision as of 15:25, 26 March 2018

Helenalin
Names
IUPAC name
(3aS,4S,4aR,7aR,8R,9aR)-4-Hydroxy-4a,8-dimethyl-3-methylidene-3,3a,4,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
UNII
  • InChI=1S/C15H18O4/c1-7-6-10-12(8(2)14(18)19-10)13(17)15(3)9(7)4-5-11(15)16/h4-5,7,9-10,12-13,17H,2,6H2,1,3H3/t7-,9+,10-,12-,13+,15+/m1/s1 ☒N
    Key: ZVLOPMNVFLSSAA-XEPQRQSNSA-N ☒N
  • InChI=1/C15H18O4/c1-7-6-10-12(8(2)14(18)19-10)13(17)15(3)9(7)4-5-11(15)16/h4-5,7,9-10,12-13,17H,2,6H2,1,3H3/t7-,9+,10-,12-,13+,15+/m1/s1
    Key: ZVLOPMNVFLSSAA-XEPQRQSNBI
  • O=C/2O[C@@H]3C[C@H]([C@@H]1/C=C\C(=O)[C@@]1(C)[C@@H](O)[C@@H]3C\2=C)C
Properties
C15H18O4
Molar mass 262.305 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Helenalin, or(±)-4-Hydroxy-4a,8-dimethyl-3,3a,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione, is a sesquiterpene lactone which can be found in several European plants like Arnica Montana and Arnica chamissonic foliosa. It is generally considered that Helenalin is responsible for the toxicity of the Arnica spp. Nevertheless, in a wide variety of studies, it was demonstrated that Helenalin may contain anti-inflammatory and anti-tumor effects. These effects are the result of Helenalin's capacity to inhibit activity of certain enzymes and important functional proteins. For this reason the compound may have a potential to be applicated in medical world][1][2]

Structure and reactivity

Helenalin belongs to the group of sesquiterpene lactones which can be characterized by the lactone ring. Beside this ring, the structure of Helenalin has two reactive groups α-methylene-γ-butyrolactone and a cyclopentenone group that can undergo a Michael addition[3] [4] The double bound in the carbonyle group that can andergo a micheal addition with a thiol group, also called sulfhydryl groups. Therefore Helenalin can interact with proteins by covalent binding to the thiol groups of cysteine containing proteins like glutathione. This effect can can disrupt the molecule's function [5] Addition reaction can occur because thiol is a strong nucleophile and has al long pair of electrons [6]

Available forms

Besides Helenalin's natural structure, there are several derivates within the same sesquiterpene lactone group; pseudoguaianolides. Most of these derivates have a natural origin like the compound dihydrohelenalin, but there are some semi-synthetic ones made like 2b-(S-glutathionyle)-2,3-dihydrohelenalin[7][8] Other derivates are 11a,13-dihydrohelenalin acetate,2,3-dehydrohelenalin and 6-O-isobutyrylhelenalin. The difference between helenalin its derivates is the miolecular conformation, which essects the lipophilicity and the accessibility of the Micheal addition sites. The poorer accessibility results in a lower compounds toxicity. Anotehr possibility is that a derivats misses one of the reactive groups like the cyclopentenone group, which may couse a lower toxicity as well. In general most derivates are considered to be more toxic than Helenalin itself. Among these derivates with [9]the shortest ester groups are most likely to contain a higher toxicity


Mechanism of action

A main target of Helenalin is the p65 subunit(also called RelA)of the transcription factor NF-kβ. It can interact with the Cys38 of RelA by a Michael addition reaction with the thiol group of this Cystein. Thereby both α-methylene-γ-butyrolactone and cyclopentene of Helenalin can react with this cysteine[10]. It was also found that Helenalin can inhibit human telomerase, a ribonucleoprotein complex, by Michael addition. In this case both reactive groups of Helenalin also interact with the thiol group of the cysteine and inhibit the telomerase enzyme activity[11]. At least it was found that Helenalin inhibits the formation of leukotrienes in human blood cells by inhibiting LTC4 synthase activity. Helenalin reacts with its cyclopentenone ring to the thiol group of the synthase[12]

Metabolism

Helenalin inhibit the cytochrome P450 enzyme by its thiol groups, this results in inhibition of the mixed-function oxidase system.These groups are important for the Helenalin cytoxicity. Glutathione levels, which contains sulfhydryl groups, in cells are reduced whereas the toxicity of Helenalin increases. Compounds like glutathione may protect the cells from Helenalin toxicity. It was also seen that Helenalin increase CPK and LDH activities in serum and that it inhibits multiple enzymes of the liver in triglyceride synthesis. Therfore it could decrease cholesterol levels[13]


Efficacy

Helenalin and some of its derevatives showed to be poten anti-inflammatory and anti-tumor agents in vitro. These studies suggested that the inhibition potency of Helenalin on platet leukotriene C4 synthase, telomerase activity and transcription factor NF-kB significantly contributes to its anti-inflammatory and anti-tumor activity[14][15][16] [17][18]. The dose used varied per study. There is currently no in vivo evidence regarding the anti-inflammatory and anti-tumor response of Helenalin. The efficacy of Helenalin for treatment of pain and swilling, when applied topically, is not supported by the current available evidence at doses at 10% or lower. For doses higher that 10%, more research is required whether those remain safe and are more efficient than the current available medications[19]

Application

In former time, plant extracts containing Helenalin were used as a herbal medicine for the treatment sprains, blood clots, muscle strain and rheumatic complaints[20]. Currently Helenalin is used topically as an homeopathic medicine in the form of gels and and microemulsions. To this day, Helenalin has not been FDA approved for medical application[21]. However, since in vitro studies showed anti-inflammatory and anti-tumor properties of this compound, it may be used for medical application in the future[22]

Pharmacology

See also: Arnica montana § Medicinal use

Helenalin has a variety of observed effects in vitro including anti-inflammatory and antitumor activities.[23] Helenalin has been shown to selectively inhibit the transcription factor NF-κB, which plays a key role in regulating immune response, through a unique mechanism.[24] In vitro, it is also a potent, selective inhibitor of human telomerase[25]—which may partially account for its antitumor effects—has anti-trypanosomal activity,[26][27] and is toxic to Plasmodium falciparum.[28]

Animal and in vitro studies have also suggested that helenalin can reduce the growth of Staphylococcus aureus and reduce the severity of S. aureus infection.[29]

References

  1. '^ N.B perry et al.sesquiterpene lactones in arnica montana: Helenalin and Dihydrohelenalin chemotypes in spain ,planta medica ,vol 75, no. 6, pp.660-666, 2009
  2. ^ s. Tornhamre et al., Inhibitory effect of helenalin and related compounds on 5-lipoxygenase and leukotriene C4 synthase in human blood cells, Biochemical pharmacology, vol.62,no. 7, pp.903-911, 2001
  3. ^ J. C. Widen et al., Helenalin Analogues Tergeting NF-kB p65: Thiol Reactivity and Cellular potency studies of Varied Electrophiles, ChemMedchem, vol. 13, no. 4,pp.303-311, 2018.
  4. ^ P. Zwicker 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, Toxicology in Vitro, vol . 40, pp. 45 -54, 2017.,
  5. ^ S. Tornhamre et al., Inhibitory effects of Helenalin and related compounds 5-lipoxygenase ansd leukotriene C4 synthase in human blood cells ,Biochemical pharmacology, vo;. 62, no.7,pp.903-911, 2001
  6. ^ L.B. Poole,The basics of thiols and systeines in redox biology and chemistry, Free Radical Biology and Medicine, vol. 80,pp. 148-157, 2015
  7. ^ N.B. perry et al., Sesquiterpene Lactones in Arnica montana:Helenalin and Dihydrohelenalin Chemotypes in Spain ,Planta Medica, vol.75, no. 6,pp.660-666, 2009
  8. ^ S.Tornhamre et al., Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotrein C4 synthase in human blood cells,Biochemical Pharmacology, vol.62,no.7,pp.903-911, 2001.
  9. ^ A.C. Beekman et al.,Structure -Cytotoxicity Relationships of some Helenalin-Type Sesquiterpene Lactones,Journal of Natural Products, vol.60, no .3,pp.252-257, 1997
  10. ^ J.C.Widen et al.,Helenalin analogues Targeting NF-kB p65:Thiol reactivity and cellular potency studies of varied Electrophiles,ChemMedChem, vol.13,no 2,pp.303-311,2018
  11. ^ P.-R. Huang, y.-M.Yeh and T.-C.V. Wang,potent inhibition of human telomerase by helenalin,Cancer Letters, vol.227, no.2,pp.169-174,2005
  12. ^ S.Tornhamre et al.,Inhibitory effects of helenalin and related compound on 5-lipoxygenase and leukotriene C4 synthase in human blood cells,Biochemical Pharmacology, vol.62, no.7,pp.903-911, 2001
  13. ^ D. E. Chapman et al., "Acute toxicity of Helenalin in BDF1 Mice," Fundamental and Applied Toxicology, vol. 10, no. 2, pp. 302-312, 1988.
  14. ^ S. Tornhamre et al., "Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C4 synthase in human blood cells," Biochemical Pharmacology, vol. 62, no. 7, pp. 903-911, 2001.
  15. ^ P.-R. Huang, Y.-M. Yeh and T.-C. V. Wang, "Potent inhibition of human telomerase by helenalin," Cancer Letters, vol. 227, no. 2, pp. 169-174, 2005.
  16. ^ I. H. Hall et al., "Mode of action of sesquiterpene lactones as anti-inflammatory agents," Journal of Pharmaceutical Sciences, vol. 69, no. 5, pp. 537-543, 1980.
  17. ^ K. H. Lee et al., "Sesquiterpene antitumor agents: inhibitors of cellular metabolism," Science, vol. 196, no. 4289, pp. 533-536, 1977.
  18. ^ ] H. Schröder et al., "Helenalin and 11 alpha,13-dihydrohelenalin, two constituents from Arnica montana L., inhibit human platelet function via thiol-dependent pathways," Thrombosis Research, vol. 57, no. 6, pp. 839-845, 1990.
  19. ^ N. Brito, P. Knipschild and J. Doreste-Alonso, "Systematic review on the efficacy of Topical Arnica montana for the treatment of pain, swelling and bruises," Journal of Musculoskeletal Pain, vol. 22, no. 2, pp. 216-223, 2014
  20. ^ C. Berges et al., "Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms," Molecular Immunology, vol. 46, no. 15, pp. 2892-2901, 2009.
  21. ^ "U.S. National Library of Medicine," [Online]. Available: https://clinicaltrials.gov/ct2/results?cond=&term=arnica+montana&cntry=&state=&city=&dist=. [Accessed 8 March 2018].
  22. ^ C. Berges et al., "Helenalin suppresses essential immune functions of activated CD4+ T cells by multiple mechanisms," Molecular Immunology, vol. 46, no. 15, pp. 2892-2901, 2009.
  23. ^ Powis G, Gallegos A, Abraham RT, Ashendel CL, Zalkow LH, Grindey GB, Bonjouklian R; Gallegos; Abraham; Ashendel; Zalkow; Grindey; Bonjouklian (1994). "Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues". Cancer Chemother. Pharmacol. 34 (4): 344–350. doi:10.1007/BF00686043. PMID 8033301.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I; Knorre; Schmidt; Pahl; Merfort (1998). "The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65". J Biol Chem. 273 (50): 33508–16. doi:10.1074/jbc.273.50.33508. PMID 9837931.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  25. ^ Huang PR, Yeh YM, Wang TC; Yeh; Wang (2005). "Potent inhibition of human telomerase by helenalin". Cancer Lett. 227 (2): 169–74. doi:10.1016/j.canlet.2004.11.045. PMID 16112419.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Jimenez-Ortiz V, Brengio SD, Giordano O (2005). "The trypanocidal effect of sesquiterpene lactones helenalin and mexicanin on cultured epimastigotes". J Parasitol. 91 (1): 170–4. doi:10.1645/GE-3373. PMID 15856894. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  27. ^ Schmidt TJ, Brun R, Willuhn G, Khalid SA; Brun; Willuhn; Khalid (2002). "Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones". Planta Med. 68 (8): 750–1. doi:10.1055/s-2002-33799. PMID 12221603.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ François G, Passreiter CM; Passreiter (2004). "Pseudoguaianolide sesquiterpene lactones with high activities against the human malaria parasite Plasmodium falciparum". Phytother Res. 18 (2): 184–6. doi:10.1002/ptr.1376. PMID 15022176.
  29. ^ Boulanger D, Brouillette E, Jaspar F (2007). "Helenalin reduces Staphylococcus aureus infection in vitro and in vivo". Vet Microbiol. 119 (2–4): 330–8. doi:10.1016/j.vetmic.2006.08.020. PMID 17010538. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
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