基于“异病同治”理论探讨银丹心脑通软胶囊通过HIF1α-MMP9介导的HIF1α信号通路治疗脑卒中和冠心病的共同机制  

Exploring the common mechanism of Yindan Xinnaotong soft capsule in the treatment of stroke and coronary heart disease through HIF1α-MMP9-mediated HIF1αsignaling pathway

作　　者：高洁 董一凤[2] 王思梦 何如尚 江廷参 伍明江 吴红华[2] 李星[4] 樊官伟 朱彦[2] 吕明[2] GAO Jie;DONG Yi-feng;WANG Si-meng;HE Ru-shang;JIANG Ting-can;WU Ming-jiang;WU Hong-hua;LI Xing;FAN Guan-wei;ZHU Yan;LV Ming(College of Traditional Chinese Medicine,Hebei University,Baoding 071002,China;State Key Laboratory of Component-based Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China;Zunyi Medical and Pharmaceutical College,Zunyi 563000,China;Guizhou Bailing Group Pharmaceutical Co.Ltd.,Guiyang 550000,China;First Teaching Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300193,China)

机构地区：[1]河北大学中医学院,河北保定071002 [2]天津中医药大学,组分中药国家重点实验室,天津301617 [3]遵义医药高等专科学校,贵州遵义563000 [4]贵州百灵企业集团制药股份有限公司,贵州贵阳550000 [5]天津中医药大学第一附属医院,天津300193

出　　处：《药学学报》2023年第6期1401-1411,共11页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82104431);天津市教委科研计划项目(2022KJ148);2023年度贵州省科技支撑计划(202321565067621298)。

摘　　要：冠心病和脑卒中是最常见的心脑血管疾病,具有诸多共同的病理基础。银丹心脑通软胶囊(YDXNT)是治疗脑卒中和冠心病的常用药,但其治疗二者的共同机制尚不十分清楚。运用网络药理、实验验证、分子对接等手段探究YDXNT基于“异病同治”理论治疗脑卒中和冠心病的共同机制。通过文献挖掘并利用IPA、ETCM、HERB、Swiss Target Prediction、OMIM和GeneCards等网络数据库筛选并预测YDXNT治疗冠心病和脑卒中的潜在共同靶点。通过IPA软件进行PPI、GO和KEGG分析,得到YDXNT治疗脑卒中和冠心病共同的核心靶点、通路和功能。通过免疫荧光验证YDXNT对核心靶点的作用。应用UPLC-QTOF/MS和分子对接筛选和预测YDXNT主要活性成分及其和核心靶点的相互作用。网络分析共得到YDXNT治疗脑卒中和冠心病的151个共同靶点,缺氧诱导因子1α(hypoxia-inducible factor-1α,HIF1α)-基质金属蛋白酶9(matrix metalloproteinase-9,MMP9)介导的HIF1α信号通路为其共同机制之一。YDXNT可呈剂量依赖性地降低氧糖剥夺/复氧诱导的心肌细胞(HL^(-1))和星形胶质细胞(HA)中线粒体质量的增加及HIF1α和MMP9蛋白的表达。野黄芩苷可能为YDXNT治疗缺血性脑卒中和冠心病的主要活性物质。综上,HIF1α-MMP9介导的HIF1α信号通路为YDXNT治疗缺血性心脑疾病的共同机制之一,为中医药“异病同治”理论科学内涵的深入研究提供支撑和依据。Coronary heart disease(CHD)and stroke are the most well-known cardiovascular diseases,which share many common pathological basis.Yindan Xinnaotong soft capsule(YDXNT)is a commonly used Chinese patent medicine in the treatment of stroke and CHD.However,its action of mechanism of co-treatment for stroke and CHD is still unclear.The aim of this study was to explore the common mechanism of YDXNT in co-treatment of CHD and stroke using network pharmacology,experimental verification and molecular docking.An integrated literature mining and databases of IPA,ETCM,HERB,Swiss Target Prediction,OMIM and GeneCards were used to screen and predict active ingredients and potential targets of YDXNT in co-treatment of CHD and stroke.The protein-protein interaction network,GO analysis and pathway analysis were analyzed by IPA software.The effect of YDXNT on core targets was verified by immunofluorescence.UPLC-QTOF/MS and molecular docking were used to screen and predict the main active constituents of YDXNT and their interactions with core targets.A total of 151 potential targets are predicted for YDXNT in co-treatment of CHD and stroke.Hypoxia-inducible factor-1α(HIF1α)-matrix metalloproteinase-9(MMP9)-mediated HIF1αsignaling pathway serves as one of the common mechanisms.YDXNT could reduce the increase of mitochondrial fluorescence intensity and the protein expression of HIF1αand MMP9 in HL^(-1) and HA induced by oxygen and glucose deprivation/reperfusion(OGD/R)in a dose-dependent manner.Baicalin may be the material basis for treating stroke and CHD with YDXNT.In conclusion,the HIF1αsignaling pathway is one of the common key mechanisms of YDXNT in the co-treatment of stroke and CHD.The study provides support and basis for the in-depth scientific connotation of the traditional Chinese medicine theory of"same treatment to different diseases".

关 键 词：银丹心脑通软胶囊 冠心病 脑卒中 HIF1α信号通路 异病同治 

分 类 号：R966[医药卫生—药理学]