基于网络药理学和生物信息学探索逍遥散和柴胡疏肝散“同病异治”抑郁症的作用机制

Study on Mechanism of Xiaoyao Powder and Chaihu Shugan Powder for Treating Depression in “the Same Disease with Different Treatments” Based on Network Pharmacology and Bioinformatics

摘要: 目的：使用网络药理学和生物信息学对在线数据库相关药材和疾病的数据进行挖掘并应用计算机工具探索逍遥散和柴胡疏肝散两个中药方剂“同病异治”抑郁症的活性成分和作用机制。方法：从TCMID、TCMSP、BATMAN-TCM 3个数据库中获取逍遥散和柴胡疏肝散两个药方组分、活性成分及其对应药物靶点信息。基于PharmGKB、DrugBank、OMIM、TTD、GeneCards五个疾病数据库结合NCBI-GEO生物芯片筛选抑郁症疾病靶点，比较药物靶点与疾病靶点的相关性。利用String在线分析工具和Cytoscape3.8.0对药物活性成分–疾病靶点进行可视化作图，采用拓扑分析、模块分析、GO富集分析和KEGG通路分析探索逍遥散和柴胡疏肝散“同病异治”抑郁症的关键基因与潜在靶点及作用通路。结果：逍遥散的活性成分有75个、对应的基因靶点有1960个，柴胡舒肝散的活性成分、对应的基因靶点有138个、1548个；逍遥散、柴胡疏肝散共有靶点就只有265个，为潜在抗抑郁靶点。经过网络分析以及拓扑和模块分析，得到MAPK14、NOS3、TOP2A、PTGS1、PTGS2、NCOA2、PTPN1、GABRA1、ESR2、AR、HSP90-1、PRSS1这12个基因靶点都可被认为是两个方剂共同抗抑郁的潜在靶点；逍遥散特有抗抑郁靶点有：GLUL、CREB1、GAD1、SLC6A1、GAD2、DAO、ADCY5、PPP1R1B、CRHR1、SLC1A2；柴胡疏肝散特有抗抑郁靶点是ALB。逍遥散和柴胡疏肝散作用抑郁症通路主要集中在癌症相关转录失调通路，钙信号通路，MAPK信号通路，调节干细胞多能性的信号通路；逍遥散特有抗抑郁通路主要集中在丙氨酸、天冬氨酸和谷氨酸代谢，GABA能突触，谷氨酸能突触等通路上。结论：柴胡疏肝散逍遥散和柴胡疏肝散能够通过相同靶点作用于抑郁症，也可以通过各自特有的靶点作用于抑郁症，从而有效治疗抑郁症，通过可视化和数据分析成分–靶点–疾病的相关性来阐释“同病异治”的科学内涵。

Abstract: Objective: Using network pharmacology, bioinformatics and computer tools to mine the data of related medicinal materials and diseases in the online database, and to explore the active components and mechanism of Xiaoyao Powder and Chaihu Shugan Powder in the treatment of depression with the same disease with different treatments. Method: Through the TCMID, TCMSP, BATMAN-TCM to get compositions, active ingredients and the corresponding drug targets information of Xiaoyao Powder and Chaihu Shugan Powder. Five disease databases, PharmGKB, Drug Bank, OMIM, TTD, and Gene Cards, were combined with NCBI-GEO biochip to screen disease targets for depression, the correlation between drug targets and disease targets was compared. This paper used String online analysis tools and Cytoscape 3.8.0 to visualize the active ingredients of drugs-disease targets, used topological analysis, module analysis, GO enrichment analysis and KEGG pathway analysis to explore the key genes and potential targets and pathways of depression in Xiaoyao Powder and Chaihu Shugan Powder in “the same disease with different treatments. Results: There were 75 active ingredients and 1960 gene targets of Xiaoyao Powder, 138 active ingredients and 1548 gene targets of Chaihu Shugan Powder. There were 265 targets of Xiaoyao Powder and Chaihu Shugan Powder, which were potential antidepressant targets. Through network analysis, topology and module analysis, MAPK14, NOS3, TOP2A, PTGS1, PTGS2, NCOA2, PTPN1, GABRA1, ESR2, AR, HSP90-1, and PRSS1 were found to be potential anti-depression targets of the two prescriptions. The specific antidepres-sant targets of Xiaoyao Powder were GLUL, CREB1, GAD1, SLC6A1, GAD2, DAO, ADCY5, PPP1R1B, CRHR1, SLC1A2; the specific antidepressant target of Chaihu Shugan Powder was ALB. Xiaoyao Powder and Chaihu Shugan Powder mainly focused on cancer-related transcription disorders, calcium signaling pathways, MAPK signaling pathways, and signaling pathways regulating pluripotency of stem cells. The specific antidepressant pathways of Xiaoyao Powder mainly focused on the metabolism of alanine, aspartate and glutamate, GABAergic and glutamatergicsynapses. Conclusion: Xiaoyao Powder and Chaihu Shugan Powder can effectively treat depression through the same target action on depression, or through their own specific target actions on depression. The scientific connotation of “treating the same disease differently” is explained through the correlation between visualization and data analysis components-targets-diseases.