十神汤治疗新型冠状病毒肺炎机制的网络药理学探讨

Mechanism of Shishentang on Treating COVID-19 Based on Network Pharmacology

目的:基于网络药理学探寻十神汤治疗新型冠状病毒肺炎(COVID-19)的活性成分、关键靶点和作用机制,为该方的临床应用提供参考。方法:采用TCMSP数据库检索十神汤中葛根、升麻、陈皮、甘草、川芎、紫苏叶、白芷、麻黄、赤芍、香附的化学成分和作用靶点,并通过UniProt数据库查询靶点对应的基因;采用STRING数据库进行蛋白质-蛋白质相互作用分析,通过度值(Degree)筛选关键靶点、通过DisGeNET数据库对关键靶点所属的类型进行归属;运用Cytoscape 3.7.2软件构建、分析网络;使用DAVID数据库对十神汤治疗COVID-19关键靶点进行基因本体(GO)富集分析和KEGG通路富集分析,以探究其作用机制。结果:十神汤中的中药大多归肺、脾经,共有活性化合物213个,其265个靶点中有73个靶点是与新型冠状病毒(SARS-CoV-2)的受体血管紧张素转化酶2 (ACE2)在结肠中呈现共表达;关键靶点涉及CASP3、MAPK3、EGF、CTNNB1、CASP8、BCL2L1等;GO分析得到GO条目136个(P<0.05),其中生物过程(BP)条目91个,细胞成分(CC)条目21个,分子功能(MF)条目24个;KEGG通路富集筛选得到61条信号通路(P<0.05),主要涉及细胞凋亡、MAPK、Ras信号通路等。结论:十神汤可能以多成分、多靶点形式调控与ACE2共表达的蛋白以及细胞凋亡、MAPK、Ras信号通路,发挥抑制COVID-19患者炎症反应、缓解肺损伤的作用,从而达到治疗COVID-19的目的。

Objective: To explore the active compounds, key targets and possible mechanism of Shishentang in the treatment of COVID-19 based on network pharmacology, which provides reference for clinical application. Methods: TCMSP database was used to search the chemical constituents and action targets of Puerariae lobatae radix, Cimicifugae rhizome, Citri reticulatae pericarpium, Glycyrrhizae radix et rhizome, Chuanxiong rhizoma, Perillae folium, Angelicae dahuricae radix, Ephedrae herba, Paeoniae radix rubra, Cyperi rhizoma and in Shishentang compound, and the corresponding genes of the targets were searched by UniProt database. STRING database was used for protein-protein interaction analysis. Degree value was used to screen key targets, and DisGeNET database was used to attribute the types of key targets. Cytoscape 3.7.2 software was used to construct and analyze the network. DAVID database was used to conduct gene ontology(GO) enrichment analysis and KEGG pathway enrichment analysis on key targets of Shishentang in the treatment of novel coronavirus pneumonia(COVID-19) to explore its mechanism of action. Results: Most of the traditional Chinese medicines in Shishentang were distributed to the lung and spleen channels. There were 213 active compounds and 265 potential targets, 73 of the potential targets were co-expressed in the colon with the receptor angiotensin-converting enzyme 2(ACE2) of the novel coronavirus(SARS-CoV-2). The key targets involved CASP3, MAPK3, EGF, CTNNB1, CASP8 and BCL2 L1, etc. GO analysis resulted in 136 GO entries(P<0.05), including 91 entries for biological process(BP), 21 entries for cell composition(CC), and 24 entries for molecular function(MF). 61 signaling pathways(P<0.05) were obtained through enrichment and screening of KEGG pathway, which were mainly involved in cell apoptosis, MAPK, RAS signaling pathway, etc. Conclusion: Shishentang can inhibit inflammatory response and alleviate lung injury in patients with covid-19, so as to achieve the purpose of treating covid-19 through multi-component and multi-target regulation on proteins co-expressed with ACE2 as well as cell apoptosis, MAPK and Ras signaling pathways.