Atractylenolide-1 Alleviates Ulcerative Colitis via Restraining RhoA/ROCK/MLC Pathway-Mediated Intestinal Barrier Dysfunction

Abstract

Using Atractylenolide-1 (AT-1) is a confident strategy for the treatment of ulcerative colitis (UC) due to its natural origin and notable pharmacological activity. The study investigated the therapeutic effect of AT-1 in dextran sodium sulfate (DSS)-induced mice and Caco-2 cells while also exploring the underlying molecular mechanisms. In this study, AT-1 treatment could reduce weight loss and colon shortening and significantly reduce disease activity index (DAI), spleen index, and histopathological scores in UC mice. And AT-1 was observed to restore cell necrosis and monolayer damage and restored F-actin-mediated tight junction (TJ) protein redistribution to alleviate mucosal injury in UC mice and Caco-2 cells. Moreover, AT-1 regulated alanine, aspartic acid, and glutamate metabolism; increased the content of related metabolites; and promoted cell proliferation to restore damaged mucous membranes in UC mice. The results of molecular docking and molecular dynamics simulation showed that the binding of AT-1 to RhoA had a stable conformation, and it was speculated that RhoA was the main target of AT-1. Further investigations revealed that the interference of RhoA disrupted the regulatory pathway of AT-1. Thus, AT-1 could inhibit the reduction of TJ proteins, alter DSS-mediated cytoskeletal migration, promote amino acid metabolism, and subsequently reduce the permeability of the colon epithelium, thereby restoring mucosal barrier dysfunction features.