Andrographolide derivative CX-10 alleviates ulcerative colitis by modulating autophagy and cellular stress

Abstract

Ulcerative colitis (UC) is a debilitating inflammatory bowel disease that poses significant challenges in clinical management. Despite existing therapies, many patients fail to achieve adequate symptom relief, underscoring the need to address the underlying mechanisms contributing to the pathogenesis of UC. Andrographis paniculata has been extensively studied in traditional Chinese medicine for its anti-inflammatory properties. This study aimed to evaluate the effects of CX-10, a derivative of andrographolide, on ‍autophagy, oxidative stress, and inflammation in UC. Using dextran sulfate sodium (DSS)-induced mouse model of UC, our ‍findings demonstrated that CX-10 treatment resulted in significant reductions in body weight loss, Disease Activity Index ‍(DAI), and histopathological injury scores, characterized by decreased inflammatory cell infiltration and mucosal damage compared to DSS-treated controls. Quantitative real-time PCR (qRT-PCR) revealed a marked restoration of autophagy-related genes Becn1 and Atg5 in CX-10-treated colonic tissues. Western blot analysis further confirmed enhanced autophagic flux, evidenced by significant increases in the LC3-II/I ratio. CX-10 treatment also led to reduced endoplasmic reticulum (ER) stress, indicated by decreases in the transcript and protein levels of GRP78 and CHOP. Consistent with the in vivo findings, in vitro studies demonstrated that CX-10 effectively enhanced autophagy and reduced oxidative stress in lipopolysaccharides (LPS)-treated HT-29 colonic epithelial cells and RAW 264.7 macrophages. This was accompanied by a marked decrease in reactive oxygen species (ROS) levels, as determined by DCFDA assays. In conclusion, CX-10 exerts protective effects against DSS-induced UC through modulation of autophagy and oxidative stress pathways, suggesting its potential as a novel therapeutic agent for managing UC.