Molecular Mechanism Of Oroxylin A Induced Apoptosis Of Activated Hepatic Stellate Cells Through Endoplasmic Reticulum Stress Pathway

Liver fibrosis is a compensatory response secondary to tissue repair after various forms of chronic liver injury accompanied by massive production of extracellular matrix(ECM)and deposition in the liver,impairing normal liver over-production ECM and deposited in the liver.During hepatic injury,hepatic stellate cells(HSCs)change from a resting state to an activated state and are the main source of myofibroblast-like cells.Worldwide,chronic liver disease,such as liver fibrosis,is one of the causes of death.There are more than 100 million hepatitis B virus carriers in our country,which a considerable number of people will develop liver fibrosis and cirrhosis.Therefore,effective prevention and treatment of liver fibrosis is a serious medical problem to be solved.The classical pathways of apoptosis are the death receptor pathway and the mitochondrial pathway.In addition,there is an endoplasmic retieulum(ER)pathway,an apoptotic pathway activated by ER stress.In recent years,studies have shown that in the process of hepatic fibrosis,there is a clear imbalance of energy metabolism in HSCs,which inhibits the regulation of the relevant energy regulation signaling pathway,thereby affecting the expression of intracellular calcium homeostasis,protein phosphorylation,signaling pathway and transcription factors,causing endoplasmic reticulum stress(ERS)response.However,at present,the pathogenesis of liver fibrosis has not yet been fully elucidated,the treatment of drugs is not ideal,such as strong liver tablets,compound methionine choline tablets,these drugs need further evaluation of the safety and efficacy.It has led to many researchers to focus on natural medicines such as Oroxylin A(OA).Some studies have found that antitumor effect is one of the most important and the most important OA biological activity.Summary of domestic and foreign scholars on the anti-tumor effect of OA study found that OA mainly by inducing apoptosis of tumor cells,reversing drug resistance of tumor cells,inhibiting tumor cell invasion and metastasis,inducing tumor cell cycle arrest,inhibiting tumor angiogenesis mechanism.However,its therapeutic role in liver fibrosis has not been elucidated yet.Therefore,we propose a scientific hypothesis that OA can improve hepatic fibrosis by activating ERS to promote apoptosis of activated HSCs.This paper first studied the role of OA in improving liver fibrosis.Mouse model of hepatic fibrosis was established by intraperitoneal injection of carbon tetrachloride(CCl4).Four weeks later,the mice were given low,middle and high doses of OA.Serum and pathological results showed that OA could significantly reduce liver injury,reduce collagen content and improve liver fibrosis indicators.Electron microscope observation of liver tissue endoplasmic reticulum morphological changes and found that OA can significantly promote the lumen of the endoplasmic reticulum and translucent vacuole formation,indicating that OA can promote the activation of ERS.Therefore,we infer that OA may regulate the activation of activated HSCs apoptosis by activating the ERS pathway and improving liver fibrosis.In vitro HSCs-T6 cell line experiments further validation,first screened the best effect of OA on the role of HSCs,and then dose-dependent detection of OA on HSCs proliferation and apoptosis.The study found that OA can dose-dependently down-regulate the expression of Fibronectin,College and a-SMA.Description of OA on liver fibrosis have a certain therapeutic effect.On this basis,further explore the mechanism of OA to promote apoptosis of activated HSCs,and we found that OA can upregulate the expression of endoplasmic reticulum stress(ERS)markers such as CHOP,GRP78 and Calnexin,activate the ERS pathway:PERK,IRE1? and ATF6,thereby promoting the activation of HSCs apoptosis.In summary,the study of this paper made it clear that OA has certain protective effect on liver injury,and further proves that OA can activate ERS to promote the apoptosis of activated HSCs and further alleviate the molecular mechanism of hepatic fibrosis.The research in this thesis provides theoretical and experimental basis for the development of natural medicine.