基于药物-靶点-疾病关联网络的丹参-降香药对治疗缺血性脑卒中的作用机制探究及候选中药识别

Investigation of the mechanism of action and identification of candidate traditional Chinese medicines for the treatment of ischemic stroke in the Danshen-Jiangxiang pair based on drug-target-disease association network

丹参-降香药对治疗缺血性脑卒中(IS)疗效比较显著,研究丹参-降香药对治疗IS的作用机制是发现对IS有疗效候选中药(TCM)的有效途径。传统药理学方法难以从系统角度全面分析丹参-降香治疗IS的效应物质并解释其作用机制。本研究基于药物-靶点-症候-疾病关联网络,利用复杂网络理论进行系统的研究。在利用丹参、降香及IS的关联信息构建蛋白质-蛋白质相互作用网络和“药对-药效成分-靶点-IS”网络的基础上,分析不同网络拓扑特征并基于多个中心性指标识别出降香中的福诺尼汀以及丹参中的隐丹参酮和丹参酮IIA为药效成分;前列腺素G/H合酶2、视黄酸受体RXR-α、钠通道蛋白5型亚基α、前列腺素G/H合酶1和β-2肾上腺素能受体为核心靶蛋白。进一步,提出一种基于TCM症候筛选IS候选药物的方法,利用“药对-TCM症候-症候群-中风”网络发现关键TCM症候和症候群。结果表明,蒲黄、三棱和泽兰3味中药可能是对IS具有潜在治疗作用的候选中药,为治疗IS的药物开发提供了理论参考。

The therapeutic efficacy of Danshen and Jiangxiang in the treatment of ischemic stroke(IS)is relatively significant.Studying the mechanism of action of Danshen and Jiangxiang in the treatment of IS can effectively identify candidate traditional Chinese medicines(TCM)with efficacy.However,it is challenging to analyze the effector substances and explain the mechanism of action of Danshen-Jiangxiang from a systematic perspective using traditional pharmacological approaches.In this study,a systematic study was conducted based on the drug-target-symptom-disease association network using complex network theory.On the basis of the association information about Danshen,Jiangxiang and IS,the protein-protein interaction(PPI)network and the“drug pair-pharmacodynamic ingredient-targetIS”network were constructed.The different topological features of the networks were analyzed to identify the core pharmacodynamic ingredients including formononetin in Jiangxiang,cryptotanshinone and tanshinone IIA in Danshen as well as core target proteins such as prostaglandin G/H synthase 2,retinoic acid receptor RXR-alpha,sodium channel protein type 5 subunit alpha,prostaglandin G/H synthase 1 and beta-2 adrenergic receptor.Further,a method for screening IS candidates based on TCM symptoms was proposed to identify key TCM symptoms and syndromes using the“drug pair-TCM symptom-syndrome-IS”network.The results showed that three TCMs,namely Puhuang,Sanleng and Zelan,might be potential therapeutic candidates for IS,which provided a theoretical reference for the development of drugs for the treatment of IS.