Phillygenin ameliorates tight junction proteins reduction, fibrosis, and apoptosis in mice with chronic colitis via TGR5-mediated PERK-eIF2α-Ca2+ pathway

• DOI: 10.1016/j.jpha.2024.101042
• Publication Date: 2024-07-14T10:33:11Z
• Authors: Huanhuan Xue; Peijie Li; Jing Guo; Tinggui Chen; Shifei Li; Liwei Zhang
• Keywords: Ulcerative colitis; TGR5; Intestinal fibrosis; PERK-eIF2α-Ca2+ pathway; Original Article; Therapeutics. Pharmacology; RM1-950; Phillygenin

Ulcerative colitis (UC) is an idiopathic, relapsing, and etiologically complicated chronic inflammatory bowel disease. Despite substantial progress in the management of UC, outcomes mucosal barrier repair are unsatisfactory. In this study, phillygenin (PHI) treatment alleviated symptoms mice, including body weight loss, severe disease activity index scores, colon shortening, splenomegaly, oxidative stress, response. particular, PHI ameliorated tight junction proteins (TJs) reduction, fibrosis, apoptosis, intestinal stem cell activity, indicating that exerted beneficial effects on mice with colitis. NCM460 cells damage model, dextran sulfate sodium triggered sequential induction TJs apoptosis. Takeda G protein-coupled receptor-5 (TGR5) dysfunction mediated injury. Moreover, enhanced suppressed fibrosis apoptosis to maintain function, depending TGR5 activation. promoted activation elevated intracellular cyclic adenosine monophosphate levels HEK 293T transfected expression plasmids. Cellular thermal shift assay molecular docking studies confirmed directly binds TGR5, agonist TGR5. The process PERK-eIF2α pathway-mediated endoplasmic reticulum Ca2+ release was involved injury as well, which associated dysfunction. When were pretreated PHI, pathway blocked. conclusion, our study demonstrated a novel mechanism inhibited PERK-eIF2α-Ca2+ through against DSS-induced