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双参宁心胶囊通过调节线粒体自噬减轻小型猪心肌缺血再灌注损伤：网络药理学及体内实验

Shuangshen Ningxin capsule alleviates myocardial ischemia-reperfusion injury in miniature pigs by modulating mitophagy: network pharmacology and experiments in vivo.

作者信息

Jia Feifan, Chen Yuanyuan, Xin Gaojie, Li Lingmei, Liu Zixin, Xu Sujuan, Gao Jiaming, Meng Hongxu, Shi Yue, Ma Yanlei, Li Lei, Fu Jianhua

机构信息

National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China.

出版信息

Chin Med. 2023 Sep 20;18(1):120. doi: 10.1186/s13020-023-00810-z.

DOI:10.1186/s13020-023-00810-z
PMID:37730607
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10510173/
Abstract

BACKGROUND: Myocardial ischemia/reperfusion injury (MI/RI) is involved in a variety of pathological states for which there is no effective treatment exists. Shuangshen Ningxin (SSNX) capsule which is developed by Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine has been demonstrated to alleviate MI/RI, but its mechanism remains to be further elucidated. METHODS: The MI/RI miniature pigs model was constructed to assess the pharmacodynamics of SSNX by blocking the proximal blood flow of the left anterior descending branch of the cardiac coronary artery through an interventional balloon. The principal chemical compounds and potential targets of SSNX were screened by HPLC-MS and SwissTargetPrediction. The targets of MI/RI were identified based on Online Mendelian Inheritance in Man (OMIM) and GeneCards. Cytoscape 3.9.0 was applied to construct a protein-protein interaction (PPI) network, and Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using metascape. To further validate the mechanism of SSNX, Molecular docking, Transmission electron microscopy, and Western blot analysis were used to test the effectiveness of targets in related pathways. RESULTS: Our results indicated that SSNX significantly improved cardiac function, attenuated myocardial I/R injury. Through network analysis, a total of 15 active components and 201 targets were obtained from SSNX, 75 of which are potential targets for the treatment of MI/RI. KEGG and MCODE analysis showed that SSNX is involved in the mitophagy signaling pathway, and ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb2 are key components associated with the mitophagy. Further experimental results proved that SSNX protected mitochondrial structure and function, and significantly reduced the expression of mitophagy-related proteins PTEN-induced putative kinase 1 (PINK1), Parkin, FUN14 domain containing 1 (FUNDC1) and Bcl-2/E1B-19 kDa interacting protein 3 (BNIP3) in MI/RI miniature pigs. CONCLUSION: In our study, the integration of network pharmacology and experiments in vivo demonstrated that SSNX interfered with MI/RI by inhibiting mitophagy.

摘要

背景：心肌缺血/再灌注损伤（MI/RI）涉及多种病理状态，目前尚无有效的治疗方法。中国中医科学院西苑医院研制的双参宁心（SSNX）胶囊已被证明可减轻MI/RI，但其作用机制仍有待进一步阐明。 方法：通过介入球囊阻断心脏冠状动脉左前降支近端血流，构建MI/RI小型猪模型，以评估SSNX的药效学。采用高效液相色谱-质谱联用（HPLC-MS）和瑞士靶点预测软件筛选SSNX的主要化学成分和潜在靶点。基于人类孟德尔遗传在线数据库（OMIM）和基因卡片数据库（GeneCards）鉴定MI/RI的靶点。应用Cytoscape 3.9.0构建蛋白质-蛋白质相互作用（PPI）网络，并使用metascape进行基因本体论（GO）功能注释和京都基因与基因组百科全书（KEGG）通路富集分析。为进一步验证SSNX的作用机制，采用分子对接、透射电子显微镜和蛋白质免疫印迹分析来检测相关通路中靶点的有效性。 结果：我们的结果表明，SSNX显著改善心脏功能，减轻心肌I/R损伤。通过网络分析，从SSNX中总共获得了15种活性成分和201个靶点，其中75个是治疗MI/RI的潜在靶点。KEGG和MCODE分析表明，SSNX参与了线粒体自噬信号通路，人参皂苷Rg1、人参皂苷Rb1和人参皂苷Rb2是与线粒体自噬相关的关键成分。进一步的实验结果证明，SSNX保护线粒体结构和功能，并显著降低MI/RI小型猪中线粒体自噬相关蛋白PTEN诱导的假定激酶1（PINK1）、帕金蛋白（Parkin）、含FUN14结构域蛋白1（FUNDC1）和Bcl-2/E1B-19 kDa相互作用蛋白3（BNIP3）的表达。 结论：在我们的研究中，网络药理学与体内实验相结合表明，SSNX通过抑制线粒体自噬来干预MI/RI。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbb8/10510173/5a30b3dddb23/13020_2023_810_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbb8/10510173/5a30b3dddb23/13020_2023_810_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbb8/10510173/4afcb3a39d9d/13020_2023_810_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbb8/10510173/c86c52dd2179/13020_2023_810_Fig5_HTML.jpg
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Decoding interaction between mitochondria and endoplasmic reticulum in ischemic myocardial injury: targeting natural medicines.

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[2]
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[3]
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本文引用的文献

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Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation.

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