结合机器学习和分子通路分析,揭示了中药复方文心颗粒的抗心律失常靶点网络

IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology
Taiyi Wang, Ming Lu, Qunqun Du, Xi Yao, Peng Zhang, Xiaonan Chen, Weiwei Xie, Zheng Li, Yuling Ma and Yan Zhu
{"title":"结合机器学习和分子通路分析,揭示了中药复方文心颗粒的抗心律失常靶点网络","authors":"Taiyi Wang, Ming Lu, Qunqun Du, Xi Yao, Peng Zhang, Xiaonan Chen, Weiwei Xie, Zheng Li, Yuling Ma and Yan Zhu","doi":"10.1039/C7MB00003K","DOIUrl":null,"url":null,"abstract":"<p >Wenxin Keli (WK), a Chinese patent medicine, is known to be effective against cardiac arrhythmias and heart failure. Although a number of electrophysiological findings regarding its therapeutic effect have been reported, the active components and system-level characterizations of the component–target interactions of WK have yet to be elucidated. In the current study, we present the first report of a new protective effect of WK on suppressing anti-arrhythmic-agent-induced arrhythmias. In a model of isolated guinea pig hearts, rapid perfusion of quinidine altered the heart rate and prolonged the Q–T interval. Pretreatment with WK significantly prevented quinidine-induced arrhythmias. To explain the therapeutic and protective effects of WK, we constructed an integrated multi-target pharmacological mechanism prediction workflow in combination with machine learning and molecular pathway analysis. This workflow had the ability to predict and rank the probability of each compound interacting with 1715 target proteins simultaneously. The ROC value statistics showed that 97.786% of the values for target prediction were larger than 0.8. We applied this model to carry out target prediction and network analysis for the identified components of 5 herbs in WK. Using the 124 potential anti-arrhythmic components and the 30 corresponding protein targets obtained, an integrative anti-arrhythmic molecular mechanism of WK was proposed. Emerging drug/target networks suggested ion channel and intracellular calcium and autonomic nervous and hormonal regulation had critical roles in WK-mediated anti-arrhythmic activity. A validation of the proposed mechanisms was achieved by demonstrating that calaxin, one of the WK components from Gansong, dose-dependently blocked its predicted target Ca<small><sub>V</sub></small>1.2 channel in an electrophysiological assay.</p>","PeriodicalId":90,"journal":{"name":"Molecular BioSystems","volume":" 5","pages":" 1018-1030"},"PeriodicalIF":3.7430,"publicationDate":"2017-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1039/C7MB00003K","citationCount":"14","resultStr":"{\"title\":\"An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis†\",\"authors\":\"Taiyi Wang, Ming Lu, Qunqun Du, Xi Yao, Peng Zhang, Xiaonan Chen, Weiwei Xie, Zheng Li, Yuling Ma and Yan Zhu\",\"doi\":\"10.1039/C7MB00003K\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Wenxin Keli (WK), a Chinese patent medicine, is known to be effective against cardiac arrhythmias and heart failure. Although a number of electrophysiological findings regarding its therapeutic effect have been reported, the active components and system-level characterizations of the component–target interactions of WK have yet to be elucidated. In the current study, we present the first report of a new protective effect of WK on suppressing anti-arrhythmic-agent-induced arrhythmias. In a model of isolated guinea pig hearts, rapid perfusion of quinidine altered the heart rate and prolonged the Q–T interval. Pretreatment with WK significantly prevented quinidine-induced arrhythmias. To explain the therapeutic and protective effects of WK, we constructed an integrated multi-target pharmacological mechanism prediction workflow in combination with machine learning and molecular pathway analysis. This workflow had the ability to predict and rank the probability of each compound interacting with 1715 target proteins simultaneously. The ROC value statistics showed that 97.786% of the values for target prediction were larger than 0.8. We applied this model to carry out target prediction and network analysis for the identified components of 5 herbs in WK. Using the 124 potential anti-arrhythmic components and the 30 corresponding protein targets obtained, an integrative anti-arrhythmic molecular mechanism of WK was proposed. Emerging drug/target networks suggested ion channel and intracellular calcium and autonomic nervous and hormonal regulation had critical roles in WK-mediated anti-arrhythmic activity. A validation of the proposed mechanisms was achieved by demonstrating that calaxin, one of the WK components from Gansong, dose-dependently blocked its predicted target Ca<small><sub>V</sub></small>1.2 channel in an electrophysiological assay.</p>\",\"PeriodicalId\":90,\"journal\":{\"name\":\"Molecular BioSystems\",\"volume\":\" 5\",\"pages\":\" 1018-1030\"},\"PeriodicalIF\":3.7430,\"publicationDate\":\"2017-03-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1039/C7MB00003K\",\"citationCount\":\"14\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular BioSystems\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2017/mb/c7mb00003k\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular BioSystems","FirstCategoryId":"1085","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2017/mb/c7mb00003k","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
引用次数: 14

摘要

温心颗粒(WK)是一种中成药,对心律失常和心力衰竭都有疗效。尽管已经报道了一些关于其治疗效果的电生理学发现,但WK的有效成分和组分-靶点相互作用的系统水平特征尚未阐明。在目前的研究中,我们首次报道了WK对抑制抗心律失常药物引起的心律失常的新保护作用。在离体豚鼠心脏模型中,快速灌注奎尼丁可改变心率并延长Q-T间期。预处理WK可显著预防奎尼丁诱发的心律失常。为了解释WK的治疗和保护作用,我们结合机器学习和分子通路分析构建了一个集成的多靶点药理学机制预测工作流。该工作流程能够预测每种化合物同时与1715个目标蛋白相互作用的概率并对其进行排序。ROC值统计显示,97.786%的目标预测值大于0.8。我们应用该模型对WK中5种中草药的鉴定成分进行了目标预测和网络分析。利用获得的124个潜在抗心律失常成分和30个相应的蛋白靶点,提出了WK抗心律失常的综合分子机制。新出现的药物/靶标网络表明,离子通道、细胞内钙、自主神经和激素调节在wk介导的抗心律失常活动中起着关键作用。通过在电生理试验中证明甘松的一种WK成分calaxin以剂量依赖性阻断其预测靶点CaV1.2通道,从而验证了所提出的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis†

An integrated anti-arrhythmic target network of a Chinese medicine compound, Wenxin Keli, revealed by combined machine learning and molecular pathway analysis†

Wenxin Keli (WK), a Chinese patent medicine, is known to be effective against cardiac arrhythmias and heart failure. Although a number of electrophysiological findings regarding its therapeutic effect have been reported, the active components and system-level characterizations of the component–target interactions of WK have yet to be elucidated. In the current study, we present the first report of a new protective effect of WK on suppressing anti-arrhythmic-agent-induced arrhythmias. In a model of isolated guinea pig hearts, rapid perfusion of quinidine altered the heart rate and prolonged the Q–T interval. Pretreatment with WK significantly prevented quinidine-induced arrhythmias. To explain the therapeutic and protective effects of WK, we constructed an integrated multi-target pharmacological mechanism prediction workflow in combination with machine learning and molecular pathway analysis. This workflow had the ability to predict and rank the probability of each compound interacting with 1715 target proteins simultaneously. The ROC value statistics showed that 97.786% of the values for target prediction were larger than 0.8. We applied this model to carry out target prediction and network analysis for the identified components of 5 herbs in WK. Using the 124 potential anti-arrhythmic components and the 30 corresponding protein targets obtained, an integrative anti-arrhythmic molecular mechanism of WK was proposed. Emerging drug/target networks suggested ion channel and intracellular calcium and autonomic nervous and hormonal regulation had critical roles in WK-mediated anti-arrhythmic activity. A validation of the proposed mechanisms was achieved by demonstrating that calaxin, one of the WK components from Gansong, dose-dependently blocked its predicted target CaV1.2 channel in an electrophysiological assay.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Molecular BioSystems
Molecular BioSystems 生物-生化与分子生物学
CiteScore
2.94
自引率
0.00%
发文量
0
审稿时长
2.6 months
期刊介绍: Molecular Omics publishes molecular level experimental and bioinformatics research in the -omics sciences, including genomics, proteomics, transcriptomics and metabolomics. We will also welcome multidisciplinary papers presenting studies combining different types of omics, or the interface of omics and other fields such as systems biology or chemical biology.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信