withaferin-a and Pancreatitis

The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.

Topics: Animals; Anti-Inflammatory Agents; Gene Expression Regulation; Glyburide; Humans; Indomethacin; Inflammasomes; Inflammation; Interleukin-18; Interleukin-1beta; Myeloid Differentiation Factor 88; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreas; Pancreatitis; Signal Transduction; Toll-Like Receptor 3; Withanolides

Acute pancreatitis is an inflammatory disorder of the pancreas that may precipitate due to various reasons such as chronic alcoholism, gall stone obstruction, and life style. Current treatment options offer limited efficacy, as they provide only symptomatic relief. This study is an attempt to study the effects of Withaferin A (WFA) against Cerulein-induced acute pancreatitis in mice. Animals were pretreated with WFA via intraperitoneal route, for 7 days. Plasma amylase and lipase, tissue malondialdehyde (MDA), and glutathione were evaluated for all groups. Western blot analysis; haematoxylin and eosin staining of the liver, lung, and pancreas; immunohistochemistry for nitrotyrosine; and myeloperoxidase activity were performed. Haematoxylin and eosin stained sections significantly revealed the altered architecture and thereby damage in the pancreas, lungs, and liver that has been low in treatment groups. Increased myeloperoxidase and nitrotyrosine have also been reduced upon treatment with WFA. Increased levels of MDA, NO, and expression of myeloperoxidase and nitrotyrosine in the parameters estimated add evidence to the role of oxidative stress and inflammation in acute pancreatitis. WFA evidently altered these conditions upon pretreatment. Our study shows that this novel steroidal compound has potent anti-inflammatory property. Natural compounds can therefore be good remedies against many diseases if incorporated in routine diet as dietary supplement.

Topics: Acute Disease; Animals; Ceruletide; Inflammation; Male; Mice; Oxidative Stress; Panax; Pancreatitis; Withania; Withanolides

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.. 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.. 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.. 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.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cytokines; Cytoprotection; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Endoplasmic Reticulum Stress; Female; Inflammasomes; Inflammation Mediators; Male; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatitis; Pancreatitis, Chronic; Transcription Factor RelA; Translocation, Genetic; Withanolides