基于网络药理学探讨四君子汤“异病同治”原发性肝癌与胃癌的作用机制

Exploring the Mechanism of Sijunzi Decoction of “Treating Different Diseases with the Same Method” in Treating Primary Liver Cancer and Gastric Cancer Based on Network Pharmacology

摘要: 目的：基于网络药理学研究四君子汤“异病同治”原发性肝癌与胃癌的通路及途径。方法：获得经方四君子汤活性成分，其通过TCMSP知识库，再利用Uniprot蛋白质元数据库转换所需的靶点基因。本文研究仅选用了四大数据库，其中数据库为TTD、GeneCards、DrugBank及OMIM，处理此四个数据库数据相互增补原发性肝癌(Primary liver cancer, PLC)和胃癌(Gastric cancer, GC)疾病关键靶向基因，再引用JVENN网站绘制韦恩图，得到处理后韦恩图具体数据，再通过Cytoscape 3.9.1软件工具构建“药物–活性成分–靶点–疾病”关系网络图。再进一步利用STRING数据库，输入数据中得到的关键靶向点，绘制蛋白质相互关系图(PPI)，再次使用Cytoscape 3.9.1软件中的扩展程序中的相关指标值(度值，degree；介数，Betweenness)，将PPI的核心靶点与靶向预测进行分析。最后就是进行基因本体(GO)富集分析和京都基因与基因组百科全书(KEGG)通路富集分析，同样在DAVID数据库帮助下对上述处理后得到的数据分析。结果：本文研究中的经方经过数据重重筛选，治疗异病PLC与GC的有效成分和目标靶向点分别是114个和106个，而较相关的关键靶点经degree值排名前八有丝氨酸/苏氨酸蛋白激酶(AKT1)、肿瘤抑制基因P53 (TP53)、血管内皮生长因子A (VEGFA)、胱天蛋白酶3 (CASP3)、肿瘤坏死因子(TNF)、核蛋白类癌基因(MYC)、前列腺素内过氧化物合酶2 (PTGS2)、白细胞介素-1β (IL1B)。在基因本体中生物功能的富集分析重点显示了基因表达正向调控方面上显著为高通路，同时也反映在药物反应及转录DNA模板正向调控的重要性信号通路。结论：本文基于中医理论与网络药理学的研究表明，经方四君子汤异病同治PLC、GC是多通路、多途径、多靶点的极为复杂过程，主要通过参与细胞的基因正向表达、转录DNA表达、药物反应、多种相关酶的调控等发挥治疗疾病的作用。

Abstract: Objective: To study the Mechanism of Action of Sijunzi Decoction on “Same Treatment for Different Diseases” in Primary Liver Cancer and Gastric Cancer Based on Network Pharmacology. Method: We get the active ingredients of Sijunzi Decoction, use the TCMSP knowledge base and then use the Uniprot Protein Element database to convert the necessary target genes. This study selected only four major databases, including TTD, GeneCards, DrugBank and OMIM, which were processed to supplement the major target genomes of primary liver cancer (PLC) and stomach cancer (GC), and then used the JVENN website to draw Wayne maps. After processing specific data from the Wayne map, the software tool Cytoscape 3.9.1 was used to create a network diagram of “drug-active-target- disease. Next, we use the STRING database to enter the most important target points obtained from the data, create a Protein Interaction Chart (PPI) and analyze the most important PPI target points with target predictions again with the corresponding indicator values (degree, precipitation, median, Bedouin) in the Cytoscape 3.9.1 software extension. Finally, it includes gene concentration analysis (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), as well as data obtained through analysis and processing by the David database. Result: In this study, the menstrual diet was carefully validated against data. The active ingredients and targets for the treatment of heterogeneous PLC and GC were 114 and 106 respectively. The more relevant key targets were evaluated using the first eight degrees of serine/sulfate kinase (AKT1), namely the tumor suppressor gene P53 (TP53), Endothelial growth factor A (VEGFA), vesicular protease 3 (CASP3), tumour necrosis factor TNF, nucleic acid oncogen (MYC) and interleukin-1β (IL1B). Analysis of the concentration of biological functions in the genome shows that gene expression in positive regulation is significantly higher, which is also reflected in important signaling pathways that positively regulate drug response and DNA transcription patterns. Conclusion: Based on the theory of traditional Chinese medicine and research of network pharmacology, this article points out that PLC and GC are extremely complex processes with multiple pathways, channels and applications that are mainly involved in positive expression of cellular genes, transcription of DNA expression, and drug reactions. It regulates and controls various related enzymes to exert therapeutic effects on disease.