A novel danshensu derivative ameliorates experimental colitis by modulating NADPH oxidase 4‐dependent NLRP3 inflammasome activation. Issue 22 (17th September 2020)

• Record Type: Journal Article
• Authors: Pan, Li‐Long; Ren, Zhengnan; Liu, Yanyan; Zhao, Yalei; Li, Hongli; Pan, Xiaohua; Fang, Xin; Liang, Wenjie; Wang, Yang; Yang, Jun; Sun, Jia
• Is Part Of: Journal of cellular and molecular medicine. Volume 24:Issue 22(2020)
• Page Start: 12955
• Page End: 12969
• Publication Date: 2020-09-17
• Subjects: DSC -- inflammatory bowel disease -- NADPH oxidase 4 -- NLRP3 inflammasome -- reactive oxygen species; Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.15890
• Languages: English
• ISSNs: 1582-1838

Abstract

Abstract: We have previously reported a novel compound [4‐(2‐acetoxy‐3‐((R)‐3‐(benzylthio)‐1‐methoxy‐1‐oxopropan‐2‐ylamino)‐3‐oxopropyl)‐1, 2‐phenylene diacetate (DSC)], derived from danshensu, exhibits cytoprotective activities in vitro. Here, we investigated the effects and underlying mechanisms of DSC on dextran sodium sulphate (DSS)‐induced experimental colitis. We found that DSC treatment afforded significant protection against the development of colitis, evidencing by suppressed inflammatory responses and enhanced barrier integrity. Intriguingly, DSC specifically down‐regulated DSS‐induced colonic NADPH oxidase 4 (Nox4) expression, accompanied by a balanced redox status, suppressed nuclear factor‐κB (NF‐κB) and NLRP3 inflammasome activation and up‐regulated nuclear factor (erythroid‐derived 2)‐like 2 and haeme oxygenase‐1 expression. In vitro study also demonstrated DSC also markedly decreased Nox4 expression and activity associated with inhibiting reactive oxygen species generation, NF‐κB activation and NLRP3 inflammasome activation in bone marrow‐derived macrophages. Either lentiviral Nox4 shRNA‐mediated Nox4 knockdown or Nox4‐specific small‐interfering RNA mimicked effects of DSC by suppressing NLPR3 inflammasome activation to alleviate experimental colitis or inflammatory macrophage response. Collectively, our results provide the first evidence that DSC ameliorates experimental colitis partly through modulating Nox4‐mediated NLRP3 inflammasome activation.