title: Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation.
abstract: OBJECTIVE
  Beta cell death triggered by pro-inflammatory cytokines plays a central role in the pathogenesis of type 1 diabetes and loss of transplanted islets. The nuclear factor κB (NF-κB) signalling pathway is a key regulator of beta cell stress response, survival and apoptosis. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, has been demonstrated to be a potent, safe, anti-inflammatory molecule that can inhibit NF-κB signalling. Therefore, we evaluated the ability of WA to protect mouse and human islets from the damaging effects of pro-inflammatory cytokines in vitro and following intraportal transplantation.
  
  
  METHODS
  Mouse and human islets were treated with a cytokine cocktail, and NF-κB activation was measured by immunoblots, p65 nuclear translocation and chromatin immunoprecipitation of p65-bound DNA. Intraportal transplantation of a marginal mass of syngeneic mouse islets was performed to evaluate the in vivo protective effect of WA.
  
  
  RESULTS
  Treatment with WA substantially improved islet engraftment of syngeneic islets (83% for infusion with 200 islets + WA; 0% for 200 islets + vehicle) in a mouse model of diabetes, compared with marginal graft controls with superior islet function in WA-treated mice confirmed by glucose tolerance test. Treatment of human and mouse islets with WA prevented cytokine-induced cell death, inhibited inflammatory cytokine secretion and protected islet potency.
  
  
  CONCLUSIONS
  WA was shown to be a strong inhibitor of the inflammatory response in islets, protecting against cytokine-induced cell damage while improving survival of transplanted islets. These results suggest that WA could be incorporated as an adjunctive treatment to improve islet transplant outcome.
authors: Institute of Biomedical Studies, Baylor University, Waco, TX, USA.
authors: J A
authors: JA
authors: SoRelle
authors: T
authors: T
authors: Itoh
authors: H
authors: H
authors: Peng
authors: M A
authors: MA
authors: Kanak
authors: K
authors: K
authors: Sugimoto
authors: S
authors: S
authors: Matsumoto
authors: M F
authors: MF
authors: Levy
authors: M C
authors: MC
authors: Lawrence
authors: B
authors: B
authors: Naziruddin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D017209:Apoptosis; D018929:Cell Culture Techniques; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D054358:Withanolides / Q000627:therapeutic use*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016328:NF-kappa B; D054358:Withanolides; C009684:withaferin A