Abstract
Abstract Background Inflammatory bowel diseases (IBDs) like Crohn’s disease (CD) and ulcerative colitis (UC) are chronic gastrointestinal disease with complex pathogenesis, leading to a lack of effective treatments. The efficacy of CU104, a new blocker of endothelial dysfunction,1 in other IBD models with a CD-like phenotype2 and its specific mechanism of action in colitis are still unknown. Methods To evaluate the therapeutic potential of CU104, we induced colitis using dextran sodium sulfate (DSS) in IL-10 knockout mice3 and assessed its effectiveness. Additionally, we used Caco-2, HCT-116, and HT-29 cells to investigate its impact on intestinal barrier function, inflammatory signal pathway, actin dynamics,4 and gene expression through FITC-dextran permeability, trans-epithelial electrical resistance (TEER), reporter gene, gene expression profiling, and immune assays. Results CU104 demonstrated therapeutic efficacy in DSS-induced colitis in IL-10 KO mice by potently suppressing innate immune activation, vascular and intestinal barrier dysfunction, and immune cell recruitment. Mechanistically, CU104 inhibited the activation of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) and interferon regulatory factor (IRF),5 as well as the ezrin/radixin/moesin (ERM) signaling pathways6 in vitro and in vivo, which play critical roles in maintaining barrier integrity and regulating immune cell recruitment during inflammation by regulating actin dynamics. Conclusion Our findings suggest that CU104, a pseudo-sugar derivative of cholesterol that regulates actin dynamics and inflammatory signaling, could be a promising new treatment for CD along with UC.
Published Version
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