title: Celastrol prevents circulatory failure via induction of heme oxygenase-1 and heat shock protein 70 in endotoxemic rats.
abstract: BACKGROUND
  Celastrol, a quinone methide extracted from the root of Tripterygium wilfordii Hook, possesses anti-oxidant and anti-inflammatory effects. Tripterygium wilfordii Hook is officially listed in the Chinese Pharmacopoeia and is used traditionally against rheumatoid arthritis, ankylosing spondylitis, and cancer. Furthermore, the circulatory protective effect of celastrol on an in vivo animal model of sepsis was investigated.
  
  
  OBJECTIVE
  Sepsis is a systemic inflammatory disorder that increases tissue oxidative stress and leads to multiple organ injury. We evaluated the beneficial effects of celastrol on multiple organ failure induced by lipopolysaccharide (LPS) in rats.
  
  
  METHODS
  Celastrol (0.5 and 1.0 mg/kg, i.v.) was administered to anaesthetized rats 2 h before and 30 min after LPS challenge (10 mg/kg, i.v.). Eight hours later, cardiac and aortic protein expressions related to inflammatory responses, superoxide anion production, and reduced glutathione (GSH) level were measured.
  
  
  RESULTS
  Treatment with celastrol prevented circulatory failure (bradycardia and hypotension) 8h after LPS challenge. The plasma levels of ALT, LDH, TNF-α, and nitric oxide metabolites increased markedly during sepsis, which significantly reduced after celastrol treatments. Celastrol attenuated iNOS, TNF-α, NF-κB phospho-p65 expression, superoxide anion production, and caspase 3 activity in the cardiovascular system, all of which were markedly elevated after LPS challenge. Furthermore, celastrol induced HO-1 and HSP70 expressions increase in nuclear levels of Nrf2 and HSF-1, respectively, and increase cardiac GSH level 8h after LPS challenge.
  
  
  CONCLUSIONS
  Anti-inflammatory and anti-oxidant effects of celastrol contribute to prevent circulatory failure in sepsis. Induction of HO-1 and HSP70 by celastrol participates in these beneficial effects.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Li
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Taipei Medical University, Taipei, Taiwan; Department of Anesthesiology, Catholic Mercy Hospital, Hsinchu, Taiwan.
authors.forename: Kwok-Keung
authors.initials: KK
authors.lastname: Lam
authors.affiliation: Department of Physiology & Biophysics, Taipei, Taiwan.
authors.forename: Pao-Yun
authors.initials: PY
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan. Electronic address: ymlee@mail.ndmctsgh.edu.tw.
authors.forename: Yen-Mei
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D051381:Rats; D011921:Rats, Inbred WKY; D013481:Superoxides; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase; D005978:Glutathione; C050414:celastrol
keywords: Celastrol; Circulatory failure; Heat shock protein 70; Heme oxygenase-1; Sepsis