The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Cardiothoracic Surgery Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China.
J Ethnopharmacol. 2022 Jan 10;282:114611. doi: 10.1016/j.jep.2021.114611. Epub 2021 Sep 17.
Ilex pubescens (I. pubescens), has been widely used to treat cardiovascular disease (CVD) in South China. Several studies have revealed aspect of its phytochemistry and pharmacological activities in cardiovascular diseases, but its active compounds and mechanisms of action are still unclear. The aim of this study was to search for the active compounds and the pharmacological mechanisms of I. pubescens for myocardial ischemia-reperfusion injury (MI/RI) by an integrative pharmacology-based investigation.
The main targets of compounds in I. pubescens were predicted using the TargetNet webserver (http://targetnet.scbdd.com). The network between compounds and predicted targets related to MI/RI and compounds was constructed. Functional enrichment analysis was performed to investigate the specific functions and pathways involved in the candidate I. pubescens targets acting on MI/RI, which were further validated by in vitro and in vivo experiments.
A total of 191 targets were predicted for 64 chemical compounds in I. pubescens. Following Venn's analysis, we found that 38 candidate targets of I. pubescens were associated with protective effects against MI/RI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that these targets were related to estrogen signaling pathway. Importantly, the cardioprotective effects of I. pubescens and its active compounds were evaluated and the regulatory effects on key targets of heat shock protein 90 alpha family class A member 1 (HSP90AA1) and Estrogen receptor 1 (ESRα) in estrogen signaling pathway were validated in vitro and in vivo.
Our discoveries revealed that I. pubescens ameliorated MI/RI by regulating HSP90AA1 and ESRα in estrogen signaling pathway.
冬青（Ilex pubescens）在中国南方被广泛用于治疗心血管疾病（CVD）。多项研究揭示了其在心血管疾病方面的部分植物化学和药理学活性，但其中的活性化合物和作用机制仍不清楚。本研究旨在通过综合药理学研究，寻找冬青治疗心肌缺血再灌注损伤（MI/RI）的活性化合物和作用机制。
使用 TargetNet 网络服务器（http://targetnet.scbdd.com）预测冬青中化合物的主要靶标。构建化合物与预测的与 MI/RI 相关的靶标之间的网络。进行功能富集分析，以研究候选冬青靶标作用于 MI/RI 的特定功能和途径，这些靶标通过体外和体内实验进一步验证。
共预测了冬青中 64 种化学化合物的 191 个靶标。通过 Venn 分析，我们发现 38 个候选冬青靶标与 MI/RI 的保护作用有关。基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析表明，这些靶标与雌激素信号通路有关。重要的是，评估了冬青及其活性化合物的心脏保护作用，并在体外和体内验证了其对热休克蛋白 90α家族 A 成员 1（HSP90AA1）和雌激素受体 1（ESRα）等关键靶标在雌激素信号通路中的调节作用。
我们的发现表明，冬青通过调节雌激素信号通路中的 HSP90AA1 和 ESRα 改善了 MI/RI。
