N-n-Butyl haloperidol iodide ameliorates liver fibrosis and hepatic stellate cell activation in mice  

作　　者：Dai-fei Shen He Cheng Bo-zhi Cai Wen-feng Cai Bin Wang Qing Zhu Yue-bin Wu Man Liu Run-ji Chen Fen-fei Gao Yan-mei Zhang Yong-dong Niu Gang-gang Shi 

机构地区：[1]Department of Pharmacology,Shantou University Medical College,Shantou,515041,China [2]Qingyuan Maternal and Child Health Hospital,Qingyuan,511515,China [3]Laboratory of Molecular Cardiology,The First Affiliated Hospital,Shantou University Medical College,Shantou,515041,China

出　　处：《Acta Pharmacologica Sinica》2022年第1期133-145,共13页中国药理学报（英文版）

基　　金：This work was supported by the Research Team Project of the Natural Science Foundation of Guangdong Province of China(No.9351503102000001).The authors thank the Pharmacological Department and Shantou University Medical College for providing the platform for our research.

摘　　要：N-n-Butyl haloperidol iodide(F_(2))is a novel compound that has antiproliferative and antifibrogenic activities.In this study we investigated the therapeutic potential of F_(2) against liver fibrosis in mice and the underlying mechanisms.Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride(CCl4)or thioacetamide(TAA).The mice received F_(2)(0.75,1.5 or 3 mg·kg^(−1)·d^(−1),ip)for 4 weeks of fibrosis induction.We showed that F_(2) administration dose-dependently ameliorated CCl4-or TAA-induced liver fibrosis,evidenced by significant decreases in collagen deposition and c-Jun,TGF-βreceptor II(TGFBR2),α-smooth muscle actin(α-SMA),and collagen I expression in the liver.In transforming growth factor beta 1(TGF-β1)-stimulated LX-2 cells(a human hepatic stellate cell line)and primary mouse hepatic stellate cells,treatment with F_(2)(0.1,1,10μM)concentration-dependently inhibited the expression ofα-SMA,and collagen I.In LX-2 cells,F_(2) inhibited TGF-β/Smad signaling through reducing the levels of TGFBR2;pretreatment with LY2109761(TGF-βsignaling inhibitor)or SP600125(c-Jun signaling inhibitor)markedly inhibited TGF-β1-induced induction ofα-SMA and collagen I.Knockdown of c-Jun decreased TGF-βsignaling genes,including TGFBR2 levels.We revealed that c-Jun was bound to the TGFBR2 promoter,whereas F_(2) suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-βsignaling and inhibitα-SMA and collagen I upregulation.In conclusion,the therapeutic benefit of F_(2) against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-β1.F_(2) may thus be a potentially new effective pharmacotherapy for human liver fibrosis.

关 键 词：liver fibrosis N-n-butyl haloperidol iodide ANTIFIBROTIC C-JUN TGFBR2 TGF-βsignaling human hepatic stellate cell line LX-2 

分 类 号：R96[医药卫生—药理学] R657.3[医药卫生—药学]