基于网络药理学及实验验证探讨大黄的抗胆汁淤积作用机制  

Action Mechanism of Rhubarb’s Anti-cholestasis Based on Network Pharmacology and Experimental Validation

作　　者：胡智 周凌烨 胡锦芳[1] 刘建明 HU Zhi;ZHOU Ling-ye;HU Jin-fang;LIU Jian-ming(Department of Pharmacy,the First Affiliated Hospital of Nanchang University,Nanchang 330006,China;School of Pharmacy,Nanchang University,Nanchang 330031,China)

机构地区：[1]南昌大学第一附属医院药学部,南昌330006 [2]南昌大学药学院,南昌330031

出　　处：《南昌大学学报（医学版）》2024年第6期8-15,共8页Journal of Nanchang University：Medical Sciences

基　　金：国家自然科学基金地区项目(82360735);江西省自然科学基金面上项目(20232BAB206137);江西省卫健委科技计划项目(202510234);江西省中医药管理局科研项目(2023B1340);南昌大学第一附属医院青年培育项目(YFYPY202275)。

摘　　要：目的利用网络药理学方法筛选大黄抗胆汁淤积的活性成分,对其潜在靶点与机制进行整合分析,并通过大鼠体内实验探讨大黄可能的作用机制。方法从TCMSP数据库中检索、筛选大黄的活性成分及作用靶点,利用GeneCards、OMIM和DisGeNET数据库确定与胆汁淤积相关的疾病靶点,通过Cytoscape 3.7.2软件构建“中药-成分-靶点-疾病”调控网络,并进行GO和KEGG富集分析,预测大黄的抗胆汁淤积作用机制。将30只大鼠随机分为5组:正常对照组(Control组)、ANIT诱导胆汁淤积的模型组(75 mg·kg^(-1)ANIT灌胃,Model组)、低剂量大黄防治组(75 mg·kg^(-1)ANIT+50 mg·kg^(-1)大黄水提物灌胃,Low组)、中剂量大黄防治组(75 mg·kg^(-1)ANIT+100 mg·kg^(-1)大黄水提物灌胃,Medium组)、高剂量大黄防治组(75 mg·kg^(-1)ANIT+150 mg·kg^(-1)大黄水提物灌胃,High组),每组6只,观察大黄水提物对胆汁淤积大鼠血清学、肝脏损伤和蛋白表达的影响。结果共筛选出16个活性成分和56个相关潜在靶点,以及30个(30/2608)疾病靶点与大黄抗胆汁淤积相关。PPI网络分析发现TNF、TP53、CASP3、IL1B(IL-1β)等可能是大黄抗胆汁淤积的核心靶点;GO和KEGG分析显示乙型肝炎通路、脂质代谢与动脉粥样硬化通路、脂质代谢与MAPK信号转导通路、p53信号通路以及人类免疫缺陷病毒1型感染通路与大黄抗胆汁淤积作用密切相关。大鼠实验表明,大黄水提物能改善胆汁淤积大鼠的血清生化异常,可显著降低肝组织TNFα和IL-1β水平(P<0.05),可降低肝组织TP53、CASP3、MYC蛋白表达(P<0.05)。结论大黄通过影响TNF、TP53、CASP3、IL1B(IL-1β)、MYC等靶点基因,以及乙型肝炎通路、脂质代谢与动脉粥样硬化通路、脂质代谢与MAPK信号转导通路、p53信号通路、人类免疫缺陷病毒1型感染通路,来调控TP53、Cleaved-CASP3等信号通路,降低炎症反应,改善细胞凋亡而发挥抗胆汁淤积作用。Objective To screen active ingredients of Rhubarb against cholestasis using network pharmacology,conduct an integrated analysis of its potential targets and mechanisms,and explore the possible action mechanism of Rhubarb through in vivo experiments.Methods The active ingredients and targets of rhubarb were retrieved and screened from TCMSP database,and the disease targets related to cholestasis were identified using GeneCards,OMIM,and DisGeNET databases.The regulatory network of“TCM-ingredient-target-disease”was constructed using Cytoscape 3.7.2 software,and GO and KEGG enrichment analyses were performed to predict the action mechanism of rhubarb against cholestasis.30 rats were randomly divided into 5 groups with 6 rats in each group:a normal control group(Control Group),an ANIT-induced cholestasis model group(75 mg·kg^(-1)ANIT administered by gavage,Model Group),a low-dose rhubarb group(75 mg·kg^(-1)ANIT+50 mg·kg^(-1)rhubarb water extract administered by gavage,Low Group),a medium-dose rhubarb group(75 mg·kg^(-1)ANIT+100 mg·kg^(-1)rhubarb water extract administered by gavage,Medium Group),and a high-dose rhubarb group(75 mg·kg^(-1)ANIT+150 mg·kg^(-1)rhubarb water extract administered by gavage,High Group).The effects of rhubarb water extract on serum biochemistry,liver damage,and protein expression in rats with cholestasis were observed.Results A total of 16 active ingredients and 56 related potential targets were screened,and 30 of the 2608 disease targets were found to be associated with rhubarb’s anti-cholestasis.PPI network analysis identified TNF,TP53,CASP3,and IL1B(IL-1β)as potential core targets of rhubarb’s anti-cholestasis action;GO and KEGG analyses revealed that the hepatitis B pathway,lipid metabolism and atherosclerosis,MAPK signal transduction pathway,p53 signaling pathway,and human immunodeficiency virus type 1 infection pathway were closely related to the anticholestasis effect of rhubarb.Rat experiments demonstrated that rhubarb water extract could improve serum biochemical abno

关 键 词：大黄 胆汁淤积 网络药理学 实验验证 作用机制 动物 实验 大鼠 

分 类 号：R-332[医药卫生] R285.5