基于网络药理学探究“酸枣仁-柏子仁”药对治疗失眠的作用机制

Study on the Action Mechanism of "Suanzaoren-Baiziren" in Treating Insomnia Based on Network Pharmacology

目的:通过网络药理学方法探讨“酸枣仁-柏子仁”药对治疗失眠(insomnia)的作用机制。方法:基于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)检索酸枣仁、柏子仁的活性成分及相关靶点。在GeneCards数据库和在线人类孟德尔遗传数据库(online mendelian inheritance in man,OMIM)中检索失眠相关靶点。通过在线软件Venn 2.1.0将失眠相关靶点与“酸枣仁-柏子仁”活性成分相关靶点取交集,即为“酸枣仁-柏子仁”治疗失眠的潜在靶点,绘制韦恩图,并利用Cytoscape 3.8.2软件构建“中药-活性成分-疾病靶点”网络。将潜在靶点导入STRING平台,得到潜在靶点蛋白的互作关系,利用Cytoscape 3.8.2软件构建PPI网络图,并使用“Network Analyzer”插件进行拓扑分析筛选核心靶点。将潜在靶点导入David 6.8数据库进行基因本体(gene ontology,GO)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)信号通路富集分析。结果:在TCMSP数据库中检索得到酸枣仁活性成分9个、柏子仁活性成分5个,相关靶点53个。在GeneCards数据库和OMIM数据库获得失眠相关靶点2 930个。通过在线软件Venn 2.1.0将失眠相关靶点与“酸枣仁-柏子仁”活性成分相关靶点取交集,得到23个“酸枣仁-柏子仁”治疗失眠的潜在靶点。“中药-活性成分-疾病靶点”网络拓扑分析得到关键活性成分为(S)-衡州乌药碱[(S)-coclaurine]、花生四烯酸(arachidonic acid)及酸李碱(zizyphusine)。PPI网络拓扑分析得到SLC6A4、SLC6A3、CASP3、SLC6A2、ADRA1B、PPARG、NOS3可能为“酸枣仁-柏子仁”治疗失眠的核心靶点基因。GO功能富集分析得到生物学过程57个,细胞组成8个,分子功能16个。KEGG信号通路富集分析得到15条信号通路。结论:“酸枣仁-柏子仁”药对可通过多成分、多靶点、多层次发挥对失眠的治疗作用。

Objective:To study on the action mechanism of "Suanzaoren(Semen Ziziphi Spinosae)-Baiziren(Semen Platycladi)" in treating insomnia based on network pharmacology.Methods:Based on the traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP),the active components and related targets of Suanzaoren and Baiziren were retrieved.Insomnia-related targets were searched in GeneCards database and online mendelian inheritance in man(OMIM).Through the online software Venn 2.1.0,the intersection of insomnia related targets and the active ingredient related targets of "Suanzaoren-Baiziren" was regarded as the potential target of "Suanzaoren-Baiziren" to treat insomnia;then the Wayne map was drawn,and the network of "Chinese medicinal-active ingredient-disease target" was constructed by using the Cytascape 3.8.2 software.The potential targets were imported into the STRING platform to obtain the potential interaction relationship of the potential target protein.The PPI network diagram was constructed by using Cytoscape 3.8.2 software,and the core target was screened by topological analysis using the "Network Analyzer" plug-in.The potential targets were imported into the David 6.8 database for gene ontology(GO) function enrichment analysis and Kyoto Encyclopedia of genes and genomes(KEGG) signal pathway enrichment analysis.Results:A total of 9 active components of Suanzaoren,5 active components of Baiziren,and 53 related targets were retrieved from TCMSP database.A total of 2 930 insomnia related targets were obtained in GeneCards database and OMIM database.Through the online software Venn2.1.0,the insomnia related targets were intersected with those related to the active ingredient of "Suanzaoren-Baiziren",and 23 potential targets of "Suanzaoren-Baiziren" for insomnia treatment were obtained.The network topology analysis of " Chinese medicinal-active ingredient-disease target" showed that the key active ingredients were(S)-Coclaurine arachidonic acid,and zizyphusine.PPI network topology analysis showed that SLC6A4,SLC6A3,CASP3,SLC6A2,ADRA1B,PPARG,NOS3 could be the core target genes of "Suanzaoren-Baiziren" in the treatment of insomnia.Through GO function enrichment analysis,57 biological processes,8 cell components and 16 molecular functions were obtained.Through the enrichment analysis of KEGG signal pathway,56 signal pathways were obtained.Conclusion:"Suanzaoren-Baiziren" can play a therapeutic role in insomnia through multiple components,multiple targets and multiple levels.