Sophocarpine Alleviates Inflammationinduced Colonic Epithelial Barrier Dysfunction in Ulcerative Colitis

Abstract

Background: Sophocarpine, a quinoline alkaloid derived from Sophora alopecuroides L., is known for its anti-inflammatory effects. These effects are achieved by modulating both nuclear factor-κB (NF-κB) pathway and node-like receptors pyrin domain containing 3 (NLRP3) inflammasome. However, whether sophocarpine could alleviate colonic inflammation requires further exploration.Objectives: The present work focused on investigating the potential of sophocarpine for treating colonic epithelial barrier dysfunction in ulcerative colitis.Materials and Methods: An inflammatory model was initially developed using human colorectal adenocarcinoma cells (Caco-2) induced by lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α), which was used for investigating how sophocarpine affected inflammation-mediated colonic epithelial barrier function and monitoring levels of inflammatory responses. Besides, the colonic epithelial barrier integrity was evaluated through measuring transepithelial/transendothelial electrical resistance (TEER). Lastly, we conducted Western blotting for assessing zonula occludens-1 (ZO-1), claudin-1, p65, p-p65, IκBα, p-IκBα, MLC, p-MLC, and myosin light chain kinase (MLCK) protein levels. Besides, the beneficial effect of sophocarpine was also evaluated in a mouse mode of ulcerative colitis.Results: Upon LPS stimulation, Caco-2 cells exhibited enhanced TNF-α and interleukin (IL)-1β levels, along with reduced IL-4 and IL-10 levels, decreased TEER values, increased fluorescein isothiocyanate (FITC)-dextran concentrations, and suppressed ZO-1 and claudin-1 protein levels. In contrast, sophocarpine treatment at varying concentrations attenuated the detrimental effects of LPS induction. Notably, sophocarpine could reverse TNF-α-induced colonic epithelial barrier dysfunction through significantly decreasing p65, IκBα, and MLC protein phosphorylation levels within LPS-treated Caco-2 cells. Sophocarpine administration also mitigated inflammatory damages within the ulcerative colitis mouse model.Conclusion: According to these findings, sophocarpine prevents inflammatory damage in the colonic epithelial barrier by targeting the NF-κB/MLCK/MLC signaling pathway, indicating a novel intervention strategy to ameliorate ulcerative colitis.

Keywords: Sophocarpine; colonic inflammation; epithelial barrier dysfunction; NF-κB/MLCK/MLC signaling pathway