Gingerenone A Attenuates Ulcerative Colitis via Targeting IL‐17RA to Inhibit Inflammation and Restore Intestinal Barrier Function

• Published in: Advanced science Vol. 11; no. 28; pp. e2400206 - n/a
• Main Authors: Liang, Jian, Dai, Weigang, Liu, Chuanghui, Wen, Yifan, Chen, Chen, Xu, Yifei, Huang, Song, Hou, Shaozhen, Li, Chun, Chen, Yongming, Wang, Wei, Tang, Hailin
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-07-2024; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - metabolism; Colorectal cancer; Cytokines; Diarrhea; Disease Models, Animal; Drug dosages; gingerenone A; il‐17RA signaling; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammatory bowel disease; intestinal barrier; Intestinal Barrier Function; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Investigations; Kinases; Male; Mice; Mice, Inbred C57BL; Pathogenesis; Proteins; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - metabolism; Signal Transduction - drug effects; Tumor necrosis factor-TNF; Tumorigenesis; Tumors; ulcerative colitis; il‐17RA signaling; ulcerative colitis; gingerenone A; inflammation; intestinal barrier
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202400206

Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti‐inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL‐17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL‐17RA protein through pull‐down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus‐mediated IL‐17RA/Act1 knock‐down or GA co‐treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS‐induced inflammation and barrier dysfunction, suggesting a critical role of IL‐17RA signaling for GA‐mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL‐17RA to inhibit inflammatory signaling activation.
This investigation demonstrates that Gingerenone A protected against DSS‐induced ulcerative colitis via inhibiting IL‐17 signaling and downstream inflammatory signaling activation to alleviate inflammation and enhance intestinal barrier function.