Natural compound fraxinellone ameliorates intestinal fibrosis in mice via direct intervention of HSP47-collagen interaction in the epithelium  

作　　者：Jie Wang Mei Bai Cui Zhang Ning An Li Wan Xiao-ning Wang Rong-hui Du Yan Shen Zhi-yao Yuan Xu-dong Wu Xue-feng Wu Qiang Xu 

机构地区：[1]State Key Laboratory of Pharmaceutical Biotechnology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,210000,China [2]School of Basic Medical Sciences,Nanjing Medical University,Nanjing,210000,China [3]Department of Periodontology,Nanjing Stomatological Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,210000,China

出　　处：《Acta Pharmacologica Sinica》2023年第12期2469-2478,共10页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(Nos.82073910,82173871,21937005);the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(Grant No.KF-GN-202101);Fundamental Research Funds for the Central University(021414380503).

摘　　要：Intestinal fibrosis is a common complication of inflammatory bowel disease.There is still a lack of effective drugs for the prevention or treatment of intestinal fibrosis.Heat shock protein 47(HSP47)plays a key role in the development of intestinal fibrosis.In this study we investigated the therapeutic potential and underlying mechanisms of fraxinellone,a degraded limonoid isolated from the root bark of Dictamnus dasycarpus,in the treatment of intestinal fibrosis.Intestinal fibrosis was induced in mice by dextran sodium sulfate(DSS)treatment.DDS-treated mice were administered fraxinellone(7.5,15,30 mg·kg^(−1)·d^(−1),i.g.)for 45 days.We showed that fraxinellone administration dose-dependently alleviated DSS-induced intestinal impairments,and reduced the production of intestinal fibrosis biomarkers such asα-smooth muscle actin(SMA),collagen I,hydroxyproline,fibronectin and laminin,and cytokines such as TGF-β,TNF-αand IL-β.We then established in vitro intestinal fibrosis cell models in SW480 and HT-29 cells,and demonstrated that treatment with fraxinellone(3,10,30μM)significantly relieved TGF-β-induced fibrosis responses by inhibiting the TGF-β/Smad2/3 signaling pathway.Molecular docking suggested that the fraxinellone might disrupt the interaction between HSP47 and collagen,which was confirmed by coimmunoprecipitation experiments.SPR analysis showed that fraxinellone had a high affinity for HSP47 with a Kd value of 3.542×10^(−5)M.This study provides a new example of HSP47-collagen intervention by a natural compound and has important implications for the clinical treatment of inflammation-induced issue fibrosis.

关 键 词：intestinal fibrosis inflammatory bowel disease fraxinellone HSP47 COLLAGEN antifibrotic drugs 

分 类 号：R285.5[医药卫生—中药学]