Oroxyloside protects against dextran sulfate sodium-induced colitis by inhibiting ER stress via PPARγ activation

• Published in: Chinese journal of natural medicines Vol. 22; no. 4; pp. 307 - 317
• Main Authors: TAO, Lei, DOU, Renjie, CHEN, Xueming, CAO, Yu, DAI, Zhen, HU, Ziyan, MA, Zhi, GE, Xiaoming, ZHANG, Ling, WANG, Xiaoping
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.04.2024
• Subjects: Animals; Colitis; Colitis - chemically induced; Colitis - drug therapy; Dextran Sulfate; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress - drug effects; ER stress; Humans; Male; Mice; Mice, Inbred C57BL; Oroxyloside; PPAR gamma - genetics; PPAR gamma - metabolism; PPARγ; Protective Agents - pharmacology; Reactive Oxygen Species - metabolism; ER stress; Colitis; PPARγ; Oroxyloside
• ISSN: 1875-5364; 1875-5364
• DOI: 10.1016/S1875-5364(24)60615-1

Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), may result from immune system dysfunction, leading to the sustained overproduction of reactive oxygen species (ROS) and subsequent cellular oxidative stress damage. Recent studies have identified both peroxisome proliferator-activated receptor-γ (PPARγ) and endoplasmic reticulum (ER) stress as critical targets for the treatment of IBD. Oroxyloside (C22H20O11), derived from the root of Scutellariabaicalensis Georgi, has traditionally been used in treating inflammatory diseases. In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the PPARγ antagonist GW9662 (1 mg·kg−1, i.v.) in vivo. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. However, PPARγ siRNA transfection blocked the anti-inflammatory effect of oroxyloside and even abolished ROS generation and ER stress activation inhibited by oroxyloside in vitro. In conclusion, our study demonstrates that oroxyloside ameliorates DSS-induced colitis by inhibiting ER stress via PPARγ activation, suggesting that oroxyloside might be a promising effective agent for IBD.