MgIG Attenuates Oxaliplatin-induced Hepatotoxicity through Suppression of Connexin 43 in Hepatic Stellate Cells  

作　　者：Yuzhu Cao Yawen Xia Yufei Wang Hang Shi Yuanyuan Wu Yin Lu 

机构地区：[1]School of Pharmacy,Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,Jiangsu,China [2]Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor,Nanjing University of Chinese Medicine,Nanjing,Jiangsu,China

出　　处：《Journal of Clinical and Translational Hepatology》2023年第3期584-594,共11页临床与转化肝病杂志（英文版）

基　　金：the Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica(No.JKLPSE201501);the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(No.2020YLXK20);the Science and Technology Development Foundation of Nanjing Medical University(No.NMUB2019186).

摘　　要：Background and Aims:Oxaliplatin is widely used in can-cer chemotherapy with adverse effects such as liver toxicity.Magnesium isoglycyrrhizinate(MgIG)has hepatoprotective effects,but the underlying mechanism remains elusive.The study’s aim was to investigate the mechanism underlying the hepatoprotective effects of MgIG against oxaliplatin-induced liver injury.Methods:A xenografted colorectal cancer mouse model was established with MC38 cells.Mice were given ox-aliplatin(6 mg/kg/week)for 5 weeks to mimic oxaliplatin-induced liver injury in vivo.LX-2 human hepatic stellate cell s(HSCs)were employed for in vitro studies.Serological tests,hematoxylin and eosin staining,oil red O staining and trans-mission electron microscopy were used for histopathological examinations.Real-time PCR,western blotting,immuno-fluorescence and immunohistochemical staining were used to determine Cx43 mRNA or protein levels.Flow cytometry was used to assay reactive oxygen species(ROS)and mito-chondrial membrane.Short hairpin RNA targeting Cx43 was lentivirally transduced in LX-2 cells.Ultra-high performance liquid chromatography-tandem mass spectrometry was used to determine MgIG and metabolite concentration.Results:MgIG(40 mg/kg/day)treatment significantly reduced se-rum aspartate transaminase(AST)and alanine transami-nase(ALT)levels in the mouse model,and alleviated liver pathological changes,including necrosis,sinusoidal expan-sion,mitochondrial damage,and fibrosis.MgIG reduced the abnormal expression of Cx43 in the mitochondria and nuclei of HSCs.MgIG inhibited the activation of HSCs via reducing ROS generation,mitochondrial dysfunction,and N-cadherin transcription.MgIG’s inhibition of HSCs activation was abol-ished after knockdown of Cx43 in LX-2 cells.Conclusions:Cx43 mediated MgIG’s hepatoprotective effects against ox-aliplatin-induced toxicity.

关 键 词：Magnesium isoglycyrrhizinate HEPATOPROTECTIVE 18α-Glycyrrhetinic acid Mitochondrial dysfunction Hepatic stellate cell Connexin 43. 

分 类 号：R575[医药卫生—消化系统]