目的 基于網(wǎng)絡(luò)藥理學(xué)預(yù)測逍遙散治療代謝相關(guān)脂肪性肝?。∕AFLD，曾用名非酒精性脂肪性肝炎，NASH）相關(guān)機(jī)制，并觀察逍遙散對MAFLD模型小鼠肝損傷的保護(hù)作用及機(jī)制。方法 通過TCMSP數(shù)據(jù)庫獲取逍遙散各組成味藥的活性成分及潛在靶點(diǎn)，利用Gencards、OMIM數(shù)據(jù)庫獲取MAFLD疾病靶點(diǎn)，構(gòu)建蛋白質(zhì)相互作用（PPI）網(wǎng)絡(luò)，進(jìn)行基因本體論（GO）功能及京都基因與基因組百科全書（KEGG）通路富集分析，構(gòu)建成分-靶點(diǎn)-通路網(wǎng)絡(luò)，并對核心靶點(diǎn)和主要活性成分進(jìn)行分子對接驗(yàn)證。通過喂食蛋氨酸及膽堿缺乏（MCD）飼料構(gòu)建MAFLD小鼠模型，給予多烯磷脂酰膽堿膠囊（178mg·kg^-1·d^-1）或逍遙散低、中、高劑量（1.437、2.874、5.748g·kg^-1·d^-1）進(jìn)行干預(yù)，測定各組小鼠血清天冬氨酸氨基轉(zhuǎn)移酶（AST）、丙氨酸氨基轉(zhuǎn)移酶（ALT）活性及三酰甘油（TG）、總膽固醇（TC）水平；HE染色考察各組小鼠肝組織病理變化；Western blotting法檢測PTGS2、ESR1、NOS2及PPARG的蛋白表達(dá)情況。結(jié)果 經(jīng)篩選得到逍遙散治療MAFLD的作用靶點(diǎn)有133個，核心成分主要有槲皮素、木犀草素、山柰酚、豬苓酸C等，關(guān)鍵靶點(diǎn)為PTGS2、ESR1、NOS2及PPARG等，主要的生物學(xué)通路為與腫瘤相關(guān)信號通路、糖尿病并發(fā)癥中的AGE-RAGE信號通路、IL^-17信號通路及非酒精性脂肪肝相關(guān)信號通路等，分子對接結(jié)果顯示槲皮素、木犀草素及山柰酚與PTGS2、ESR1、NOS2及PPARG等均有較強(qiáng)的結(jié)合。體內(nèi)動物實(shí)驗(yàn)表明，與模型組比較，逍遙散各組小鼠AST、ALT、TG、TC水平均顯著降低（P＜0.05）；肝組織病理損傷均得到改善；與模型組比較，逍遙散中、高劑量組小鼠PTGS2、ESR1及NOS2蛋白表達(dá)顯著降低（P＜0.01），PPARG蛋白表達(dá)顯著升高（P＜0.01）。結(jié)論 逍遙散可能通過調(diào)控PTGS2、ESR1、NOS2及PPARG等靶標(biāo)，IL^-17信號通路及非酒精性脂肪肝相關(guān)信號通路等多種途徑治療MAFLD。

Objective To explore the mechanism of Xiaoyaosan in the treatment of metabolic associated fatty liver disease (MAFLD, used to be known as nonalcoholic steatohepatitis, NASH) based on network pharmacology and in vivo experiments.Methods The active components and potential targets of Xiaoyaosan were obtained from TCMSP database, and the disease targets of MAFLD were obtained from Gencards and OMIM database. A protein-protein interaction (PPI) network based on active components and disease common targets was constructed, Metascape platform was used for gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, the "component-target-pathway" network was constructed, and autodock software was used for molecular docking verification of key compounds and targets. MAFLD mouse model was established by feeding methionine and choline deficient L-amino acid diet (MCD). Polyene Phosphatidylcholine Capsules (178 mg·kg^-1·d^-1) or Xiaoyaosan (1.437, 2.874, 5.748 g·kg^-1·d^-1) were given to intervene. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG) and total cholesterol (TC) in serum of mice in each group were measured, pathological changes of liver tissues of mice in each group were investigated by HE staining. The protein expressions of PTGS2, ESR1, NOS2 and PPARG were detected by Western blotting.Results 160 active components of Xiaoyaosan and 619 corresponding action targets were obtained, including 133 action targets for the treatment of MAFLD. The core components of Xiaoyaosan in the treatment of MAFLD were quercetin, luteolin, kaempferol and polyporenic acid C and so on, and the key targets were PTGS2, ESR1, NOS2 and PPARG etc. The main biological pathways are tumor related signaling pathways, AGE-RAGE signaling pathways in diabetic complications, IL-17 signaling pathways, and nonalcoholic fatty liver related signal pathways. Molecular docking results show that quercetin, luteolin and kaempferol are strongly associated with PTGS2, ESR1, NOS2 and PPARG. In vivo animal experiments showed that compared with the model group, the levels of AST, ALT, TG and TC in Xiaoyaosan group were significantly reduced (P <0.05), and the pathological damage of liver tissue was improved. Compared with the model group, the expressions of PTGS2, ESR1 and NOS2 protein in the middle and high dosage groups of Xiaoyaosan were significantly decreased (P <0.01), while the expression of PPARG protein was significantly increased (P <0.01).Conclusion Xiaoyaosan may treat MAFLD by regulating targets such as PTGS2, ESR1, NOS2 and PPARG, IL-17 signal pathway and nonalcoholic fatty liver related signal pathway.

R285.5

國家重點(diǎn)研發(fā)計(jì)劃項(xiàng)目(2019YFC1708801);廣東省重點(diǎn)領(lǐng)域研發(fā)計(jì)劃(2020B1111120002);黑龍江省“頭雁”團(tuán)隊(duì)支持項(xiàng)目(黑龍江省頭雁行動領(lǐng)導(dǎo)小組文件[2019]5號);國家中醫(yī)藥管理局中醫(yī)藥傳承與創(chuàng)新“百千萬”人才工程-岐黃工程首席科學(xué)家支持項(xiàng)目(國中醫(yī)藥人教函[2021]7號);國家中醫(yī)藥管理局中醫(yī)藥傳承與創(chuàng)新“百千萬”人才工程(岐黃工程)岐黃學(xué)者支持項(xiàng)目(國中醫(yī)藥人教函[2018]284號)