A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin αv expression  

作　　者：Na Zhang Shuang-shuang Zhao Yi-xuan Zhang Yu-cheng Wang Rong-guang Shao Ju-xian Wang Hong-wei He 

机构地区：[1]NHC Key Laboratory of Biotechnology of Antibiotics,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences,Beijing 100050,China [2]The Joint Program in Infection and Immunity,Guangzhou Women and Children’s Medical Center,Guangzhou Medical University,Guangzhou 510623,China [3]Institut Pasteur of Shanghai,Chinese Academy of Sciences,Shanghai 200031,China

出　　处：《Acta Pharmacologica Sinica》2020年第5期661-669,共9页中国药理学报（英文版）

基　　金：the Fundamental Research Funds for the Central Universities(3332019083);the National Natural Science Foundation of China(Nos.81673497,81903695);the CAMS Innovation Fund for Medical Sciences(No.2019-I2M-1–001);the National Science&Technology Major Project"Key New Drug Creation and Manufacturing Program",China(No.2019ZX09201001).

摘　　要：Chronic tissue injury with fibrosis results in the disruption of tissue architecture,organ dysfunction,and eventual organ failure.Therefore,the development of effective antifibrotic drugs is urgently required.IMB-S7 is novel biphenyl compound derived from bifendate(biphenyldicarboxylate)that is used for the treatment of chronic hepatitis in China.In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent.In bile duct ligation(BDL)rat model,oral administration of IMB-S7(400 mg·kg^−1·d^−1,for 14 days)significantly ameliorated BDL-induced liver necrosis,bile duct proliferation,and collagen accumulation.We then showed that IMB-S7 treatment markedly suppressed the TGF-β/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs,as well as in liver samples of BDL rats,thus inhibiting the transcription of most fibrogenesis-associated genes,including TGF-β1,COL1A1,and ACTA2.Furthermore,IMB-S7 treatment significantly suppressed the expression of integrinαv at the mRNA and protein levels in TGF-β-treated LX2 cells and liver samples of BDL rats.Using integrinαv overexpression and silencing,we demonstrated that integrinαv activity correlated positively with the activation of TGF-β/Smad pathway.Based on dual luciferase assay and DNA affinity precipitation assay,we revealed that IMB-S7 inactivated integrinαv through competitively inhibiting the binding of Sp1,a transcription factor,to the integrinαv(ITGAV)promoter(−173/−163 bp).These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrinαv signaling,and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.

关 键 词：BIFENDATE IMB-S7 hepaticfibrosis integrinαv SP1 TGF-β/Smad pathway bile duct ligation LX2 cells 

分 类 号：R285.5[医药卫生—中药学]