基于网络药理学探讨水臌贴靶向铜死亡治疗肝硬化腹水的潜在作用机制  

Network pharmacology‑based study on potential mechanism of Shuigu Paste targeting copper death for treating cirrhotic ascites

作　　者：杨海琳 柴海生 戴瑶瑶 高司成 欧阳豪 祝峻峰 YANG Hailin;CHAI Haisheng;DAI Yaoyao;GAO Sicheng;OUYANG Hao;ZHU Junfeng(Department of Hepatology,Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China)

机构地区：[1]上海中医药大学附属岳阳中西医结合医院肝病科,上海201203

出　　处：《上海中医药杂志》2024年第4期30-36,44,共8页Shanghai Journal of Traditional Chinese Medicine

基　　金：国家自然科学基金项目(82074386);上海市科委“科技创新行动计划”生物医药科技支撑专项(23S21900100);上海市卫健委肝硬化腹水(水臌病)上海市中医专病联盟项目(2021-2023);上海中医药大学附属岳阳中西医结合医院中医/中西医优势专科建设专项[YW(2023-2024)-01-03]。

摘　　要：目的采用网络药理学方法探讨水臌贴治疗肝硬化腹水的潜在靶标及作用机制。方法利用中药系统药理学数据库与分析平台(TCMSP)获取水臌贴中活性成分及其活性成分所对应的药物靶点。通过人类基因综合数据库(GeneCards)、美国国家生物技术信息中心(NCBI)数据库获取肝硬化腹水的疾病靶点。利用韦恩(Venn)在线工具获得水臌贴活性成分和肝硬化腹水的共同作用靶点。运用Cytoscape软件构建水臌贴活性成分与靶点间相互作用网络关系图。应用Webgetal数据库进行基因本体(GO)和京都基因与基因组百科全书(KEGG)数据库信号通路富集分析。通过文献获得调控铜死亡的靶基因并筛选其与水臌贴活性成分、肝硬化腹水3者的共同靶基因,采用CB-Dock2分子对接技术评估水臌贴活性成分与共同靶基因的结合潜力。结果从水臌贴中筛选出具有作用靶点的50个有效活性成分,其中关键成分为槲皮素、山柰酚、异鼠李素等,水臌贴调控铜死亡治疗肝硬化腹水的核心作用靶点基因为铁氧还原蛋白1基因(FDX1)、二氢硫辛酸脱氢酶基因(DLD)、谷氨酰胺合成酶基因(GLS)、环粒蛋白激酶抑制剂2A基因(CDKN2A),KEGG分析涉及的信号通路主要为D-谷氨酰胺和D-谷氨酸代谢、精氨酸生物合成、近端小管碳酸氢盐回收等。结论水臌贴可以靶向铜死亡过程的关键基因构成的网络,发挥治疗肝硬化腹水的系统药理作用。Objective To investigate the potential targets and mechanism of action of Shuigu Paste(SGP)in treating cirrhotic ascites using network pharmacology approaches.Methods Active components of SGP and their corresponding drug targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).Disease targets for cirrhotic ascites were obtained from the Human Gene Database(GeneCards)and the National Center for Biotechnology Information(NCBI).Common targets between SGP active components and cirrhotic ascites were determined using the Online Venn Diagram Tool.An interaction network of SGP active components and targets was constructed with Cytoscape software.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed using the Webgetal database.Target genes regulating copper death were identified through literature review,and the common target genes among those regulating copper death,SGP active components and cirrhotic ascites were selected.The binding potential of SGP active components with common target genes was evaluated using CB-Dock2 molecular docking method.Results Fifty effective active components with target actions were screened from SGP,with key components including quercetin,kaempferol,and isorhamnetin,etc.The core target genes of SGP in regulating copper death for treating cirrhotic ascites were ferredoxin 1(FDX1),dihydrolipoamide dehydrogenase(DLD),glutaminase(GLS),and cyclin-dependent kinase inhibitor 2A(CDKN2A).KEGG analysis highlighted pathways such as D⁃glutamine and D-glutamate metabolism,arginine biosynthesis,and proximal tubule bicarbonate reclamation.Conclusion SGP can target the network of key genes in the copper death process,and exert a systemic pharmacological effect on the treatment of cirrhotic ascites.

关 键 词：肝硬化腹水 水臌贴 铜死亡 槲皮素 网络药理学 中药研究 作用机制 

分 类 号：R285[医药卫生—中药学]