Celastrol Explained

Celastrol (tripterine) is a chemical compound isolated from the root extracts of Tripterygium wilfordii (Thunder god vine) and Tripterygium regelii (Regel's threewingnut). Celastrol is a pentacyclic and belongs to the family of quinone methides. In mice, celastrol is an NR4A1 agonist that alleviates inflammation and induces autophagy.[1] Also in mice, celastrol increase expression of IL1R1, which is the receptor for the cytokine interleukin-1 (IL-1). IL1R1 knock-out mice exposed to celastrol exhibit no leptin-sensitizing or anti-obesity effect.[2]

In in vitro and in vivo animal experiments, celastrol exhibits antibacterial,[3] antioxidant,[4] anti-inflammatory,[5] [6] anticancer,[7] [8] [9] [10] [11] and insecticidal [12] activities. It has been shown to have obesity-controlling effects in mice by inhibiting negative regulators of leptin.[13] [14] [15] Celastrol has also shown to possess (by inhibition of NF-κB in the hypothalamus[16]) anti-diabetic effects on diabetic nephropathy and improve whole-body insulin resistance.[17]

Celastrol inhibits IKK-NF-κB signaling via multiple molecular targets: direct inhibition of IKKα and β kinases, inactivation of CDC37 and p23, which are HSP90 chaperone proteins, inhibition of proteasome function and activation of HSF1, which triggers the heat shock response. The available evidence indicates that celastrol bonds covalently to the thiol groups of cysteine residues in its molecular targets.[18]

Celastrol also has demonstrated in vitro inhibitory effects against the carbapenemase of CRE Klebsiella pneumoniae, in combination with thymol, a monoterpene.[19]

Notes and References

  1. Zhang L, Wang Q, Liu W, Liu F, Ji A, Li Y . The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases . J Diabetes Res . 2018 . 9363461 . 2018 . 30013988 . 6022324 . 10.1155/2018/9363461 . free .
  2. Feng X, Guan D, Auen T, Choi JW, Salazar Hernández MA, Lee J, Chun H, Faruk F, Kaplun E, Herbert Z, Copps KD, Ozcan U . 6 . IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects . Nature Medicine . 25 . 4 . 575–582 . April 2019 . 30833749 . 10.1038/s41591-019-0358-x . 7158951 .
  3. Padilla-Montaño N, de León Guerra L, Moujir L . Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources . Foods . 10 . 3 . March 2021 . 591 . 33799720 . 7998816 . 10.3390/foods10030591 . free .
  4. Allison AC, Cacabelos R, Lombardi VR, Alvarez XA, Vigo C . Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease . Progress in Neuro-Psychopharmacology & Biological Psychiatry . 25 . 7 . 1341–57 . October 2001 . 11513350 . 10.1016/S0278-5846(01)00192-0 . 21569585 .
  5. Kim DH, Shin EK, Kim YH, Lee BW, Jun JG, Park JH, Kim JK . Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii . European Journal of Clinical Investigation . 39 . 9 . 819–27 . September 2009 . 19549173 . 10.1111/j.1365-2362.2009.02186.x . 205291261 .
  6. Venkatesha SH, Yu H, Rajaiah R, Tong L, Moudgil KD . Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses . The Journal of Biological Chemistry . 286 . 17 . 15138–46 . April 2011 . 21402700 . 3083183 . 10.1074/jbc.M111.226365 . free .
  7. Metselaar DS, Meel MH, Benedict B, Waranecki P, Koster J, ((Kaspers GJL)), Hulleman E . Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin . EBioMedicine . 50 . 81–92 . November 2019 . 31735550 . 6921187. 10.1016/j.ebiom.2019.10.062 . free .
  8. Lee JH, Choi KJ, Seo WD, Jang SY, Kim M, Lee BW, Kim JY, Kang S, Park KH, Lee YS, Bae S . 6 . Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90 . International Journal of Molecular Medicine . 27 . 3 . 441–6 . March 2011 . 21249311 . 10.3892/ijmm.2011.601 . free .
  9. Tiedemann RE, Schmidt J, Keats JJ, Shi CX, Zhu YX, Palmer SE, Mao X, Schimmer AD, Stewart AK . 6 . Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo . Blood . 113 . 17 . 4027–37 . April 2009 . 19096011 . 3952546 . 10.1182/blood-2008-09-179796 .
  10. Zhu H, Liu XW, Cai TY, Cao J, Tu CX, Lu W, He QJ, Yang B . 6 . Celastrol acts as a potent antimetastatic agent targeting beta1 integrin and inhibiting cell-extracellular matrix adhesion, in part via the p38 mitogen-activated protein kinase pathway . The Journal of Pharmacology and Experimental Therapeutics . 334 . 2 . 489–99 . August 2010 . 20472666 . 10.1124/jpet.110.165654 . 25854329 .
  11. Byun JY, Kim MJ, Eum DY, Yoon CH, Seo WD, Park KH, Hyun JW, Lee YS, Lee JS, Yoon MY, Lee SJ . 6 . Reactive oxygen species-dependent activation of Bax and poly(ADP-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid pristimerin in human cervical cancer cells . Molecular Pharmacology . 76 . 4 . 734–44 . October 2009 . 19574249 . 10.1124/mol.109.056259 . 6541041 .
  12. Avilla J, Teixidò A, Velázquez C, Alvarenga N, Ferro E, Canela R . Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone methides against codling moth, Cydia pomonella (L.) (Lepidoptera: tortricidae) . Journal of Agricultural and Food Chemistry . 48 . 1 . 88–92 . January 2000 . 10637057 . 10.1021/jf990008w .
  13. Kyriakou E, Schmidt S, Dodd GT, et al. Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. J Med Chem. 2018;61(24):11144-11157. doi:10.1021/acs.jmedchem.8b01224
  14. Pfuhlmann K, Schriever SC, Baumann P, Kabra DG, Harrison L, Mazibuko-Mbeje SE, Contreras RE, Kyriakou E, Simonds SE, Tiganis T, Cowley MA, Woods SC, Jastroch M, Clemmensen C, De Angelis M, Schramm KW, Sattler M, Messias AC, Tschöp MH, Pfluger PT . 6 . Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1 . Diabetes . 67 . 11 . 2456–2465 . November 2018 . 30158241 . 10.2337/db18-0146 . free .
  15. Liu J, Lee J, Salazar Hernandez MA, Mazitschek R, Ozcan U . Treatment of obesity with celastrol . Cell . 161 . 5 . 999–1011 . May 2015 . 26000480 . 4768733 . 10.1016/j.cell.2015.05.011 .
  16. Lee JH, Koo TH, Yoon H, Jung HS, Jin HZ, Lee K, Lee JJ . 2006 . Inhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid . Biochemical Pharmacology . 72 . 10. 1311–1321 . 10.1016/j.bcp.2006.08.014 . 16984800 .
  17. Kim JE, Lee MH, Nam DH, Song HK, Kang YS, Lee JE, Kim HW, Cha JJ, Hyun YY, Han SY, Han KH, Han JY, Cha DR . 6 . Celastrol, an NF-κB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice . PLOS ONE . 8 . 4 . e62068 . 2013 . 23637966 . 3637455 . 10.1371/journal.pone.0062068 . 2013PLoSO...862068K . free .
  18. Salminen A, Lehtonen M, Paimela T, Kaarniranta K . Celastrol: Molecular targets of Thunder God Vine . Biochem Biophys Res Commun . 394 . 3 . 439–42 . April 2010 . 20226165 . 10.1016/j.bbrc.2010.03.050 .
  19. In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates. Abdel-Halim MS, Askoura M, Mansour B, Yahya G, El-Ganiny AM. The Journal of Antibiotics. 27 September 2022. 75. 679–690. 10.1038/s41429-022-00566-y. free. 9640353.

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