基于网络药理学探讨“白术-茯苓”配伍治疗代谢综合征的作用机制

Discussion on the Mechanism of "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" Compatibility in the Treatment of Metabolic Syndrome Based on Network Pharmacology

目的:基于网络药理学探讨"白术-茯苓"治疗代谢综合征(metabolic syndrome, MS)的作用机制。方法:结合中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform, TCMSP)和文献检索,筛选"白术-茯苓"药对的活性成分。通过PharmMapper数据库预测各成分作用靶点,并使用Universal Protein(UniProt)数据库规范靶点名称。从人类基因数据库(GeneCards)、治疗靶标数据库(therapeutic target database, TTD)、DisGeNET三个数据库中筛选MS相关靶点后,与"白术-茯苓"各成分作用靶点合并取交集得到"白术-茯苓"治疗MS的潜在靶点,导入Cytoscape 3.7.2软件构建"药物-成分-靶点"网络。通过String平台和Cytoscape软件构建蛋白质互相作用网络,并用插件CytoHubba筛选核心靶点。用R软件对"白术-茯苓"治疗MS的潜在靶点进行基因本体(gene ontology, GO)分子功能富集分析和京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)通路富集分析。结果:筛选得到"白术-茯苓"活性成分26种,治疗MS的重要成分为茯苓新酸A、14-乙酰基-12-千里光酰基-8-顺式白术三醇、茯苓新酸B、7,9(11)-去氢茯苓酸、茯苓新酸C等;潜在治疗靶点47个,核心靶点包括血清白蛋白(albumin, ALB)、表皮生长因子受体(epidermal growth factor receptor, EGFR)、丝裂原活化蛋白激酶1 (mitogen-activated protein kinase 1,MAPK1)、雌激素受体1 (estrogen receptor, ESR1)、MAPK8、MAPK14等;分子功能主要涉及调节类固醇激素受体活性、类固醇结合、核受体活性等;信号通路主要涉及雌激素信号通路、晚期糖基化终产物及其受体(advanced glycation end product-receptor, AGE-RAGE)信号通路、叉头转录因子(forkhead box O,FoxO)信号通路、受体酪氨酸激酶(receptor tyrosine-protein kinase, ErbB)信号通路、白细胞介素-17(interleukin17,IL-17)信号通路等。结论:"白术-茯苓"药对可通过多成分、多靶点、多途径发挥对MS的治疗作用,为实验研究提供一定理论参考。

Objective: To explore the mechanism of "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" in the treatment of metabolic syndrome(MS) based on network pharmacology.Methods: Combined with traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP) and literature retrieval, the active components of "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" were screened.The target of each component was predicted by PharmMapper database, and the target name was standardized by Universal Protein(UniProt) database.After screening MS related targets from human GeneCards databases, therapeutic target databases(TTD) and DisGeNET,they were combined with the action targets of various components of "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" to obtain the potential targets of "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" for the treatment of MS and introduced into Cytoscape 3.7.2 software to build the "drug-component-target" network.The protein-protein interaction network was constructed by STRING platform and Cytoscape software, and the core targets were screened by the plug-in cytohubba.The potential targets of "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" in the treatment of MS were analyzed by gene ontology(GO) molecular function enrichment analysis and kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis with R software.Results: 26 active components of "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" were screened.The important components for the treatment of MS were Poria neoacid A,14-acetyl-12-senecio acyl-8-cis Atractylodes macrocephala triol, Poria neoacid B,7,9(11)-dehydrogenated Poria acid, Poria neoacid C,etc.There were 47 potential therapeutic targets, including serum albumin(ALB),epidermal growth factor receptor(EGFR),mitogen-activated protein kinase 1(MAPK1),estrogen receptor 1(ESR1),MAPK8,MAPK14,etc.Molecular functions mainly involve regulating steroid hormone receptor activity, steroid binding, nuclear receptor activity and so on.The signaling pathway mainly involves estrogen signaling pathway, advanced glycation end product-receptor(AGE-RAGE) signaling pathway, forkhead box O(FoxO) signaling pathway, receptor tyrosine-protein kinase(ErbB) signaling pathway and interleukin-17(IL-17) signaling pathway, etc.Conclusion: "Baizhu(Rhizoma Atractylodis Macrocephalae)-Fuling(Poria)" can play a therapeutic role on MS through multi-component, multi-target and multi-channel, which provides a certain theoretical reference for experimental research.