世界中医药

基金项目:国家自然科学基金面上项目(81874463）；湖南省科技厅科技创新平台与人才计划(2017SK4005）；湖南省中医药管理局资助项目（201824，202046）；湖南中医药大学研究生创新课题项目（2018CX07）；湖南中医药大学中西结合一流学科开放基金项目（2018ZXYJH10，2018ZXYJH13）；湖南省教育厅一般项目（18C0404，19C1405）；湖南中医药大学科研基金项目（2019XJJJ044）

作者	单位
陈瑶1，周德生1，颜思阳2，杨仁义2，刘峻呈2，谭惠中2，宋洋1	1 湖南中医药大学第一附属医院，长沙，410007； 2 湖南中医药大学，长沙，410208

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中文摘要:

目的：采用生物信息学方法，分析脑梗死气虚血瘀证、阴虚血瘀证证型相关特异性基因及共性基因，并对三七通舒胶囊联合丁苯酞治疗脑梗死血瘀证的通用分子机制进行探讨，为中西医结合防治脑梗死提供理论依据。方法：分析GEO芯片数据，筛选获得脑梗死气虚血瘀证、阴虚血瘀证差异基因，将2种血瘀证差异基因取交集得证型相关特异性基因与血瘀证共性基因3个子集。从蛋白质-蛋白质相互作用（PPI）共表达网络、基因本体（GO）及京都基因与基因组百科全书（KEGG）富集分析角度，探讨2种血瘀证特异基因的作用异同。筛选三七通舒胶囊联合丁苯酞活性成分靶点与血瘀证共性基因整合，获得“药物-疾病-证型”共同靶点，拓扑分析聚焦核心靶点并行分子对接，并构建共同靶点PPI网络并行富集分析，探讨三七通舒胶囊联合丁苯酞治疗脑梗死血瘀证的作用机制。结果：获取脑梗死气虚血瘀证差异基因2 092个、阴虚血瘀证差异基因2 160个，其中气虚血瘀证特异基因422个、阴虚血瘀证特异基因490个及血瘀证共性基因1 670个。其中气虚血瘀证、阴虚血瘀证差异基因均通过多组分、多功能、多途径发挥作用，但气虚血瘀证中MMP-9、EIF4A3等靶点相互作用最强，主要通过T细胞受体信号通路等发挥作用；阴虚血瘀证中EGFR、STAT3等靶点相互作用最强，并通过ErbB信号通路发挥作用。筛选获得274个药物靶点，整合血瘀证共性基因后得32个共同靶点，拓扑分析后聚焦核心靶点SRC，分子对接发现氢键连接、混合Pi键连接和疏水作用可能是主要作用形式。三七通舒胶囊联合丁苯酞以多组分、多功能、多途径的形式介导趋化因子信号通路，cAMP信号通路等在脑梗死血瘀证中发挥作用。结论：2种血瘀证证型相关特异基因分析揭示了证型富集特点，为证型相关研究提供依据。“药物-疾病-证型”共同靶点的分析结果揭示了三七通舒胶囊联合丁苯酞治疗脑梗死血瘀证可能的通用分子机制。为中西医结合治疗脑梗死提供依据。

English Summary:

To analyze the specific and common genes related to qi deficiency and blood stasis syndrome and yin deficiency and blood stasis syndrome of cerebral infarction by bioinformatics method，and to explore the mechanism of Sanqi Tongshu Capsule combined with butylphthalide in the treatment of blood stasis syndrome of cerebral infarction in order to provide theoretical basis for the prevention and treatment of cerebral infarction with combination of traditional Chinese and Western medicine.Methods:GEO chip data was analyzed，differential genes of qi deficiency and blood stasis syndrome was obtained and screened.From the perspective of PPI co-expression network，GO and KEGG enrichment analysis，the similarities and differences of the 2 blood stasis syndrome-specific genes were discussed.Sanqi Tongshu Capsules combined with butylphthalide active ingredient targets and blood stasis syndrome common gene integration was screened，and a common target of “drug-disease-syndrome” was obtained.Topological analysis focusing on core targets and parallel molecular docking，and common targets PPI network parallel enrichment analysis was constructed to explore the mechanism of Sanqitongshu Capsule combined with butylphthalide in the treatment of cerebral infarction with blood stasis syndrome.Results:A total of 2 092 differential genes of qi deficiency and blood stasis syndrome and 2 160 differential genes of yin deficiency and blood stasis syndrome of cerebral infarction were obtained，including 422 specific genes of qi deficiency and blood stasis syndrome，490 specific genes of yin deficiency and blood stasis syndrome and 1 670 common genes of blood stasis syndrome.Among them，there were 422 specific genes for qi deficiency and blood stasis syndrome，490 specific genes for Yin deficiency and blood stasis syndrome，and 1 670 common genes for blood stasis syndrome.Among them，the differential genes of qi deficiency and blood stasis syndrome and yin deficiency and blood stasis syndrome play a role through multi-component，multi-function，and multiple pathways.However，targets such as MMP-9 and EIF4A3 in qi deficiency and blood stasis syndrome have the strongest interaction，mainly through T cell receptors.In yin deficiency and blood stasis syndrome，EGFR，STAT3 and other targets have the strongest interaction，and they play a role through the ErbB signaling pathway.A total of 274 drug targets were screened and 32 common targets were obtained after integration of the common genes of blood stasis syndrome.After topological analysis，the core target SRC was focused.Hydrogen bond connection，mixed Pi bond connection and hydrophobic interaction were found to be the main action forms in molecular docking.The enrichment results of GO and KEGG showed that Sanqi Tongshu Capsule combined with butylphthalide mediated chemokine signaling pathway and cAMP signaling pathway in the form of multi-component，multi-function and multi-pathway in the blood stasis syndrome of cerebral infarction.Conclusion:The analysis of specific genes related to the 2 types of blood stasis syndrome reveals the enrichment characteristics of syndrome types and provides a basis for the related research of syndrome types.The analysis of the common target of “drug-disease-syndrome” reveals the possible general mechanism of Sanqi Tongshu Capsule combined with butylphthalide in the treatment of blood stasis syndrome of cerebral infarction，which provides basis for the treatment of cerebral infarction with the combination of traditional Chinese medicine and Western medicine.

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