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

Author:

Liang Jian123,Dai Weigang4,Liu Chuanghui1,Wen Yifan1,Chen Chen1,Xu Yifei5,Huang Song13,Hou Shaozhen1,Li Chun1,Chen Yongming2,Wang Wei1,Tang Hailin2ORCID

Affiliation:

1. School of Pharmaceutical Sciences State Key Laboratory of Traditional Chinese Medicine Syndrome Guangzhou University of Chinese Medicine Guangzhou 510006 China

2. State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐Sen University Cancer Center Guangzhou 510060 China

3. Dongguan Institute of Guangzhou University of Chinese Medicine Dongguan 523808 China

4. Center of Ganstric Cancer The First Affiliated Hospital Sun Yat‐Sen University Guangzhou 510062 China

5. Shenzhen Traditional Chinese Medicine Hospital The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine Shenzhen 518033 China

Abstract

AbstractUlcerative 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.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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