Chuanxiong Rhizoma extracts prevent cholestatic liver injury by targeting H3K9ac-mediated and cholangiocyte-derived secretory protein PAI-1 and FN  

作　　者：LI Yajing MA Zhi DING Mingning JIA Kexin XU Bing ZHOU Fei LUO Ranyi XUE Xiaoyong WU Ruiyu GAO Feng LI Xiaojiaoyang 

机构地区：[1]School of Life Sciences,Beijing University of Chinese Medicine,Beijing 100029,China [2]School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 100029,China

出　　处：《Chinese Journal of Natural Medicines》2023年第9期694-709,共16页中国天然药物（英文版）

基　　金：the Beijing Municipal Science&Technology Commission(No.7212174);the National High-Level Talents Special Support Program to XL,the National Natural Science Foundation of China(Nos.82274186 and 82004045);National Key Research and Development Program on Modernization of Traditional Chinese Medicine(No.2022YFC-3502100);Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202006).

摘　　要：Chuanxiong Rhizoma(CX,the dried rhizome of Ligusticum wallichii Franch.),a well-known traditional Chinese medicine,is clinically used for treating cardiovascular,cerebrovascular and hepatobiliary diseases.Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies.Currently,little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells(HSCs).The study aimed to evaluate the hepatoprotective activity of different CX extracts including the aqueous,alkaloid,phenolic acid and phthalide extracts of CX(CX_(AE),CX_(AL),CX_(PA)and CX_(PHL))and investigate the intercellular communication-related mechanisms by which the most effective extracts work on cholestatic liver injury.The active compounds of different CX extracts were identified by UPLC-MS/MS.A cholestatic liver injury mouse model induced by bile duct ligation(BDL),and transforming growth factor-β(TGF-β)-treated human intrahepatic biliary epithelial cholangiocytes(HIBECs)and HSC cell line(LX-2 cells)were used for in vivo and in vitro studies.Histological and other biological techniques were also applied.The results indicated that CX_(AE),CX_(AL)and CX_(PHL)significantly reduced ductular reaction(DR)and improved liver fibrosis in the BDL mice.Meanwhile,both CX_(AE)and CX_(PHL)suppressed DR in injured HIBECs and reduced collagen contraction force and the expression of fibrosis biomarkers in LX-2 cells treated with TGF-β.CX_(PHL)suppressed the transcription and transfer of plasminogen activator inhibitor-1(PAI-1)and fibronectin(FN)from the‘DR-like’cholangiocytes to activated HSCs.Mechanistically,the inhibition of PAI-1 and FN by CX_(PHL)was attributed to the untight combination of the acetyltransferase KAT2A and SMAD3,followdd by the suppression of histone 3 lysine 9 acetylation(H3K9ac)-mediated transcription in cholangiocytes.In conclusion,CX_(PHL)exerts stronger anti-cholestatic activity in vivo and in vitro th

关 键 词：Chuanxiong Rhizoma Cholestatic liver injury Ductular reaction CHOLANGIOCYTES Hepatic stellate cell 

分 类 号：R965[医药卫生—药理学] R917[医药卫生—药学]