基于系统生物学比较温病“辛凉三剂”方证的病理机制差异

Pathological Mechanism of Xinliang Three Syndromes(Febrile Disease)based on System Biology

目的:应用系统生物学方法,构建“辛凉三剂”方证表征-基因-通路网络,探讨温病“辛凉三剂”方证的病理机制差异。方法:①基于第七版《方剂学》获取“辛凉三剂的”方证表征;②在Symmap、HPO数据库及PolySearch2文献挖掘服务器中检索“辛凉三剂”方证表征的靶点;③利用String数据库及Cytoscape 3.7.2构建“表征-基因”可视化网络,并利用其MCODE拓展功能筛选核心网络;④利用Metascape平台进行基因功能和通路富集分析。结果:桑菊饮证、银翘散证、白虎汤证表征基因分别有244个、410个、172个,三者交集基因8个(ALPL、AQP2、AVP、AVPR2、CD36、ED4、HMOX1、TARDBP),以加压素V2受体、血小板糖蛋白受体为代表性作用靶点。桑菊饮证、银翘散证、白虎汤证表征的基因互作关系分别有28个、42个、19个,生物进程分别有168个、288个、71个,KEGG通路分别有86个、108个、50个。除共同涉及的基因和信号通路外,桑菊饮证涉及基因有TNF、CCL2、CCR1和CXCL8等,通路中以T细胞受体信号通路为主;银翘散证涉及基因有ERCC、XPA和DDB2等,通路中以Jak-STAT信号通路为主;白虎汤证涉及基因有HSPA2、HSF1、HSP90AA1和ITPR2等,通路中以MAPK信号通路、钙信号通路为主。结论:“辛凉三剂”方证的共有信号通路NOD样受体信号通路引发炎症而发热。风热犯肺证(桑菊饮证)和风热袭卫证(银翘散证)的Toll样受体信号通路、NF-kB信号通路、B细胞受体信号通路、T细胞受体信号通路与Jak-STAT信号通路均为免疫与炎症相关信号通路,可以通过免疫炎症反应引起机体发热。经文献资料查询,风热犯肺证(桑菊饮证)的咳嗽表征是由其独有的RIG-I样受体信号通路介导NF-kB激活所致。风热袭卫证(银翘散证)的MAPK信号通路在共同通路的基础上加重机体发热程度。肺胃热盛证(白虎汤证)的热盛汗出与钙离子通路的异常表达有关。

Objective:To construct the characterization-gene-pathway network of“Xinliang Sanji”prescription and syndrome by using systems biology method,and to explore the differences in the pathological mechanism of“Xinliang Sanji”prescription and syndrome of febrile diseases.Methods:①Acquired the prescription and syndrome characterization of“Xinliang Sanji”based on the seventh edition of“Prescriptions”;②Searched Symmap,HPO database and PolySearch2 literature mining server for the targets of“Xinliang Sanji”prescription characterization;③Use String database and Cytoscape 3.7.2 to build a“representation-gene”visualization network,and use its MCODE extension function to screen the core network;④Use Metascape platform to analyze gene function and pathway enrichment.Results:There were 244,410,and 172 characteristic genes in Sangju drink syndrome,Yinqiao powder syndrome and Baihu decoction syndrome,respectively,and 8 intersection genes(ALPL,AQP2,AVP,AVPR2,CD36,ED4,HMOX1,TARDBP)),with vasopressin V2 receptor and platelet glycoprotein receptor as representative targets.There are 28,42,and 19 gene interaction relationships,168,288,and 71 in biological processes,and 86,42,and 71 in KEGG pathway,respectively.108,50.In addition to the commonly involved genes and signaling pathways,the genes involved in Sangju drink syndrome include TNF,CCL2,CCR1,and CXCL8,etc.,and the T cell receptor signaling pathway is the main pathway;the genes involved in Yinqiao San syndrome include ERCC,XPA,and DDB2 et al.,the Jak-STAT signaling pathway is the main pathway;the genes involved in Baihu decoction syndrome include HSPA2,HSF1,HSP90AA1 and ITPR2,etc.,and the MAPK signaling pathway and the calcium signaling pathway are the main pathways.Conclusion:The common signaling pathway NOD-like receptor signaling pathway of“Xinliang Sanji”formula causes inflammation and fever.Toll-like receptor signaling pathway,NF-κB signaling pathway,B cell receptor signaling pathway,and T cell receptor signaling pathway are related to wind-heat attacking the lung syndrome(Sangju drink syndrome)and wind-heat attacking Wei syndrome(Yinqiao powder syndrome).JAK-STAT signaling pathways are both immune and inflammation-related signaling pathways,which can cause body fever through immune-inflammatory responses.According to the literature search,the cough symptoms of wind-heat invading the lung syndrome(Sangju drink syndrome)are caused by the activation of NF-κB mediated by its unique RIG-I-like receptor signaling pathway.The MAPK signaling pathway of wind-heat attacking Wei syndrome(Yinqiao San syndrome)aggravates the degree of body fever on the basis of the common pathway.Heat-saturated sweating in lung-stomach heat syndrome(Baihu decoction syndrome)is related to the abnormal expression of calcium ion pathway.