中药复方分期治疗新冠肺炎的网络药理学分析

A Network Pharmacological Analysis of Traditional Chinese Medicine Formulas in Staging Treatment of New Coronavirus Pneumonia

目的用网络药理学方法探讨《新型冠状病毒感染的肺炎诊疗方案》第四、五版推荐的分期治疗所用四个中药治疗新冠肺炎(COVID-19)的多成分、多靶标的机理及与疾病过程证候的关联。方法通过ETCM、TCMID、PubChem数据库以及文献报道,搜索四个复方中每味中药的性味归经、成分和靶标,用Cytoscape软件构建和分析网络,用STRING对靶标进行功能富集分析。结果四个复方都重点作用于脾经和肺经,此外,初期、恢复期复方侧重脾经,中期侧重胃、大肠经,重症期侧重心、肝经。初期和恢复期用药都是温性或平性,中期、重症期有寒性用药。中期、重症期复方的苦味药比例最大,恢复期复方的苦味药比例最小。四个复方的共性是:都作用在包括免疫系统、病毒翻译与复制、内分泌系统、信号转导等生物过程的21个信号通路上;靶标包含7个两两相互作用的核糖体蛋白;靶标包含一系列相互作用的类固醇激素受体。不同之处是:只有初、中期复方的靶标网络包含构成NF-kappa B复合物的蛋白;只有重症期复方的靶标网络包含6个构成线粒体呼吸链复合物I的蛋白;恢复期复方的靶标还富集在神经节律与功能恢复相关的4个通路上。结论从中医认知角度看,四个复方的组建完全符合中医治病求因、辨证论治的原则。从网络药理学角度看,四个复方通过多成分、多靶标对机体起到多个方面的调控,针对性地治疗不同分期的COVID-19。它们共同作用的重点器官是肺和脾,并各有侧重。它们都具有调节免疫、抑制病毒复制、消除炎症、改善机体代谢等功能。此外,初期、中期复方更侧重调节免疫、避免细胞因子风暴;重症期复方还有为细胞提供能量、保护心肌细胞的作用;恢复期复方还有神经保护与功能恢复的作用。

Objective To explore the mechanisms of the four traditional Chinese medicine formulas recommended in the fourth and fifth edition of the"Handbook of Traditional Chinese Medicine Diagnosis and Treatment of COVID-19"for staging treatment of COVID-19 by network pharmacology.Methods The properties,flavors,meridian tropisms,compounds and targets of each herb in the four formulas were collected from ETCM,TCMID,PubChem database and literature search.Cytoscape software was used to construct and analysis networks.STRING was applied for functional enrichment analysis of targets.Results The major meridian tropisms of the four formulas are the spleen and lung meridian.In addition,the formulas for initial and convalescent stage focus on the spleen meridian,the mid-term stage formula focuses on the stomach and large intestine meridian,and the severe stage formula puts particular emphasis on the heart and liver meridian.Herbs in formulas for initial and convalescent stage are warm or even,while those for mid-term and severe stage include cold herbs.The proportion of bitter herbs in formulas for mid-term and severe stage is the largest,while it is the smallest in formula for convalescent stage.All of the four formulas act on 21 pathways which belong to immune system,viral mRNA translation and replication,endocrine system and signal transduction;and their targets contain 7 densely interacting ribosomal proteins and a series of interacting steroid hormone receptors.On the other hand,only target networks of the formulas for initial and mid-term stage contain the proteins that make up the NF-kappa B complex;only the target network of the formula for the severe stage contains six proteins that make up the mitochondrial respiratory chain complex I;and the target network of the formula for the convalescent stage is enriched in the four pathways related to the function of the nervous system.Conclusion From the perspective of TCM cognition,the formation of the four formulas fully conforms to the principle of TCM theory.From the perspective of network pharmacology,the four formulas can regulate the body in many ways by multi-components and multi-targets,and specifically treat the COVID-19 at different stages.The major common targeting organs of the four formulas are the lung and the spleen,while each formula has its own special targeting organs.They all have the function of regulating immunity,inhibiting virus replication,eliminating inflammation and improving metabolism.In addition,the initial and mid-term stage formulas are more focused on regulating immunity and avoiding cytokine storms;the severe stage formula also provides energy for cells and protects cardiomyocytes;and the convalescent stage formula has a neural protection function.