title: A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis.
abstract: BACKGROUND
  The underlying molecular mechanism that leads to development of chronic pancreatitis remains elusive. The aim of this study is to understand the downstream inflammatory signaling involved in progression of chronic pancreatitis, and to use withaferin A (WA), a small molecule inhibitor of nuclear factor κB (NFκB), to prevent progression of chronic pancreatitis.
  
  
  METHODS
  Two different protocols were used to induce pancreatitis in mice: standard and stringent administration of cerulein. The severity of pancreatitis was assessed by means of pancreatic histology and serum amylase levels. Immunohistochemistry and flow-cytometric analysis was performed to visualize immune cell infiltration into the pancreas. Real-time PCR and Western blot were used to analyze the downstream signaling mechanism involved in the development of chronic pancreatitis.
  
  
  RESULTS
  The severity of cerulein-induced pancreatitis was reduced significantly by WA, used as either preventive or curative treatment. Immune cell infiltration into the pancreas and acinar cell death were efficiently reduced by WA treatment. Expression of proinflammatory and proapoptotic genes regulated by NFκB activation was increased by cerulein treatment, and WA suppressed these genes significantly. Sustained endoplasmic reticulum stress activation by cerulein administration was reduced. NLRP3 inflammasome activation in cerulein-induced pancreatitis was identified, and this was also potently blocked by WA. The human pancreatitis tissue gene signature correlated with the mouse model.
  
  
  CONCLUSIONS
  Our data provide evidence for the role of NFκB in the pathogenesis of chronic pancreatitis, and strongly suggest that WA could be used as a potential therapeutic drug to alleviate some forms of chronic pancreatitis.
authors.affiliation: Institute of Biomedical Studies, Baylor University, Waco, TX, USA. mazhar.kanak@vcuhealth.org.|Department of Surgery, Transplantation Division, Virginia Commonwealth University, Richmond, VA, USA. mazhar.kanak@vcuhealth.org.
authors.forename: Mazhar A
authors.initials: MA
authors.lastname: Kanak
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Rauf
authors.initials: R
authors.lastname: Shahbazov
authors.affiliation: Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA.
authors.forename: Gumpei
authors.initials: G
authors.lastname: Yoshimatsu
authors.affiliation: Department of Surgery, Transplantation Division, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Marlon F
authors.initials: MF
authors.lastname: Levy
authors.affiliation: Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lawrence
authors.affiliation: Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA. BashooN@BaylorHealth.edu.|Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA. BashooN@BaylorHealth.edu.
authors.forename: Bashoo
authors.initials: B
authors.lastname: Naziruddin
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010195:Pancreatitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051996:Transcription Factor RelA / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects; D054358:Withanolides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D051996:Transcription Factor RelA; D054358:Withanolides; C009684:withaferin A
keywords: Inflammation; Nuclear factor κB; Pancreatitis; Withaferin A