Reduction in O-GlcNAcylation Mitigates the Severity of Inflammatory Response in Cerulein-Induced Acute Pancreatitis in a Mouse Model

Abstract

Acute pancreatitis (AP) involves premature trypsinogen activation, which mediates a cascade of pro-inflammatory signaling that causes early stages of pancreatic injury. Activation of the transcription factor κB (NF-κB) and secretion of pro-inflammatory mediators are major events in AP. O-GlcNAc transferase (OGT), a stress-sensitive enzyme, was recently implicated to regulate NF-κB activation and inflammation in AP in vitro. This study aims to determine whether a pancreas-specific transgenic reduction in OGT in a mouse model affects the severity of AP in vivo. Mice with reduced pancreatic OGT (OGTPanc+/−) at 8 weeks of age were randomized to cerulein, which induces pancreatitis, or saline injections. AP was confirmed by elevated amylase levels and on histological analysis. The histological scoring demonstrated that OGTPanc+/− mice had decreased severity of AP. Additionally, serum lipase, LDH, and TNF-α in OGTPanc+/− did not significantly increase in response to cerulein treatment as compared to controls, suggesting attenuated AP induction in this model. Our study reveals the effect of reducing pancreatic OGT levels on the severity of pancreatitis, warranting further investigation on the role of OGT in the pathology of AP.

A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury

“…The results showed that EF-treatment suppressed the expression of IL-1β, IL-6, TNF-α, iNOS and COX-2 both at mRNA and protein levels, and reduced the concentration of NO in the cell supernatant induced by LPS in a dose-dependent manner ( Figure 2A–L ). Neuclear factor kappa-B (NF-κB), a canonical regulator of inflammation and immunity, is activated by inflammatory stimuli and translocated into the nucleus to trigger the transcription of downstream proinflammatory genes, involving in various cellular functions ( Guo et al, 2022 ; Moore et al, 2022 ). As shown in Figures 2M,N , EF-treatment could reduce the ratio of phosphorylated-NF-κB p65/p65, phosphorylated-IκBα/IκBα and interfere the translocation of NF-κB p65 from cytoplasm to nucleus in LPS-stimulated primary microglia.…”