基于数据挖掘及网络药理学方法探讨肝郁脾虚型功能性消化不良用药规律及机制研究

Exploring rule of medication and mechanism for treating function dyspepsia with liver depression and spleen deficiency based on data mining and network pharmacology

目的基于数据挖掘及网络药理学联用的方法探索肝郁脾虚型功能性消化不良(function dyspepsia,FD)用药规律并探讨核心中药的功效网络,从组方用药规律和功效网络构建联合角度阐释"理-法-方-药"一致性的科学性。方法检索中国知网、万方数据库、维普数据库中治疗肝郁脾虚型FD的文献,将符合要求的文献进行筛选和数据提取,对方剂中性味归经、药物频次、用药剂量以及关联规则、聚类和复杂网络进行分析。对核心药物进行成分靶点筛选,与肝郁脾虚型FD的靶点映射,利用Cytoscape构建疾病-药物-成分-靶点网络,并对交集靶点利用String数据库进行蛋白-蛋白相互作用(protein-protein interactions,PPI)网络分析和DAVID数据库进行京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路分析。结果共筛选出文献207篇,处方207个,中药119味,药性以温、平、微寒为主,药味以苦、辛、甘为主,归经主要为脾、胃、肺、肝;使用频次在15以上的有30种中药,其中柴胡的使用频次最高;甘草6 g的剂量使用频次最高;关联规则表明柴胡-白芍,白芍-白术、柴胡,白芍-茯苓、白术、柴胡分别为同一个组里支持度最高的组合;聚类分析可将中药分为5类;复杂网络分析显示白术、柴胡、甘草、半夏、麦芽、茯苓和枳壳在肝郁脾虚型FD方剂中占据着核心地位。综合频数、聚类以及关联规则和复杂网络分析结果,柴胡、甘草、白术、茯苓治疗肝郁脾虚型FD的关键成分为槲皮素、山柰酚、甘草次酸等,核心靶点为蛋白激酶Bα(protein kinase Bα,AKT1)、白细胞介素-6(interleukin-6,IL-6)、丝裂原激活的蛋白激酶(mitogen-activatedproteinkinase3,MAPK3)等,主要作用通路为磷脂酰肌醇-3-羟激酶(phosphatidylinositol-3-hydroxykinase,PI3K)-蛋白激酶B(protein kinase B,Akt)信号通路、神经活性配体-受体相互作用等。结论从组方用药规律和功效网络构建联合角度阐释了"理-法-方-药"一致性的科学性,数据挖掘分析揭示了中医药治疗肝郁脾虚型FD的核心药物以及配伍规律,同时得到治疗该病潜在的中药配伍,中药复方治疗肝郁脾虚型FD以疏肝理气、健脾益气为主,组方的核心中药柴胡、甘草、白术、茯苓可能是通过槲皮素、山柰酚、甘草次酸等成分作用于IL-6等靶点,参与PI3K-Akt信号通路、神经活性配体-受体相互作用等通路发挥治疗肝郁脾虚型FD的作用,为中医药治疗肝郁脾虚型FD提供新方法、新思路,并为下一步研究其作用机制提供理论依据。

Objective Based on the method of data mining and network pharmacology to explore the drug rule of functional dyspepsia(FD) with liver depression and spleen deficiency and the efficacy network of core Chinese medicine, interpretation of the scientific nature of "principle-method-prescription-medicine" consistency from the perspective of combining prescriptions and medication rules and efficacy network construction. Methods The literature on the treatment of FD with liver depression and spleen deficiency were searched in CNKI, Wanfang, and VIP database, and data that meet the requirements were screened and extracted. The neutral flavor of the prescription, the frequency of the drug, the dosage and association rules, clustering and complex networks are analyzed. The core drugs obtained from the analysis were screened for component targets, mapped to the target of FD with liver depression and spleen deficiency, used Cytoscape to construct a disease-drug-component-target network, and used String database to perform protein-protein interactions(PPI) network analysis and used DAVID database to perform Kyoto encyclopedia of genes and genomes(KEGG) pathway analysis. Results A total of 207 literatures and 207 prescriptions were screened out. There were 119 traditional Chinese medicines. The medicinal properties were mainly warm, calm and slightly cold. The medicinal tastes were mainly bitter, pungent, and sweet. The main meridians were spleen, stomach, lung and liver;There were 30 kinds of traditional Chinese medicine used more than 15 times, among which the single-drug frequency of Chaihu(Bupleurum chinense) was the highest;The dose(6 g) of Gancao(Glycyrrhiza uralensis) was the most frequent;The association rules indicate that B. chinense-Baishao(Paeonia lactiflora), P. lactiflora-Baizhu(Atractylodes macrocephala), B. chinense, P. lactiflora-Fuling [Poria cocos], A. macrocephala, B. chinense was the most supported combination in the same group;Cluster analysis can divide Chinese medicine into five categories;Complex network analysis shows that A. macrocephala, B. chinense, G. uralensis, Banxia [Pinellia ternate], malt, P. coco, and Zhike(Aurantii Fructus) occupied the core position in FD prescription of liver stagnation and spleen deficiency. Based on the results of frequency, clustering, association rules and complex network analysis, the key components of B. chinense, G. uralensis, A. macrocephala, and P. cocos in the treatment of FD with liver depression and spleen deficiency were quercetin, kaempferol, glycyrrhetinic acid, etc. The core target was protein kinase Bα(AKT1), interleukin-6(IL-6), mitogen-activated protein kinase 3(MAPK3), etc. The main pathways were phosphatidylinositol-3-hydroxykinase(PI3 K)-Akt signaling pathway, neuroactive ligand-receptor interaction. Conclusion This study explained the scientificity of the consistency of "principle-method-prescription-medicine" from the perspective of the combination of prescriptions and medication rules and efficacy network construction. Data mining analysis revealed the core drugs and compatibility rules of traditional Chinese medicine for the treatment of FD with liver depression and spleen deficiency. Potential Chinese medicine compatibility for the treatment of this disease. Chinese herbal compound in treatment of FD with liver depression and spleen deficiency is mainly based on soothing the liver and regulating qi, invigorating the spleen and replenishing qi. The core traditional Chinese medicines of B. chinense, G. uralensis, A. macrocephala, P. cocos may be through quercetin, kaempferol, glycyrrhetinic acid, isorhamnetin, naringenin and other ingredients act on targets such as IL-6. The PI3 K-Akt signaling pathway, neuroactive ligand-receptor interaction and other pathways play the role of treating FD with liver depression and spleen deficiency, providing new methods and ideas for traditional Chinese medicine treatment of FD with liver depression and spleen deficiency, and for the next step to study its mechanism of action provide theoretical basis.