益心复脉颗粒通过PI3K/AKT/FOXO途径调节自噬,从而改善衰老小鼠的病窦综合征。

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Lianzi Jin, Ping Hou
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引用次数: 0

摘要

目的:通过运用网络药理学和分子对接技术,我们可以深入研究益心复美颗粒(YXFMs)的复杂工作原理及其对皱纹小鼠病窦综合征(SSS)的影响。具体来说,我们旨在了解 YXFMs 如何通过 PI3K/AKT/FOXO 途径增强自噬作用:方法:我们使用 BATMAN-TCM 数据库汇编了人参、藁本、麦冬、五味子、丹参和黄芪的有效成分和药用价值。我们还使用 Genecards、OMIM 和 Disgenet 文件来确定疾病目标。我们使用 Cytoscape 程序生成了 "疾病-药物-关键目标 "的层次图。此外,我们还利用 STRING 数据库建立了靶蛋白相互作用(PPI)网络。然后,使用 Cluster Profiler R 软件包对靶标进行 GO 功能富集评价和 KEGG 通路富集分析。在 PPI 系统的基础上,我们通过分子对接选择了交流最频繁的靶点和物质。为了进一步验证这些选择,我们进行了体内研究。通过诱导小鼠模型来研究因年龄变化导致心率降低的小鼠中受损的中房节点(SAN)。通过心电图和马森染色评估得出结果。透射电子显微镜用于评估 SAN 细胞的自噬水平。采用 Western 印迹法分析了 YXFMs 对衰老小鼠 SSS 治疗过程中 PI3K/AKT/FOXO 信号转导过程中蛋白质表达的影响:结果:获得了142种有效成分、1858个靶点、1226个疾病靶点和266个交叉靶点。PPI网络的关键靶点包括TP53、AKT1、CTNNB1、INS和TNF等。根据GO功能分析,YXFMs在SSS治疗中的作用机制可能主要与控制跨膜离子转运、心脏收缩、调节血液循环和其他生物过程有关。根据 KEGG 通路富集分析结果,确定它们主要富集于多种信号转导通路,如 PI3K-Akt 信号转导途径、MAPK 信号转导过程、AGE-RAGE 信号转导途径、FOXO 信号转导途径、HIF-1 信号转导过程和其他一些途径。分子对接表明,五种化合物与关键候选靶蛋白 AKT1 和 INS 有很好的结合。通过体内研究,我们注意到了 YXFMs 的显著效果。这些效果包括抑制衰老诱导的SSS、降低R-R间期、提高心率、减少纤维化、提高自噬过程水平以及PI3K/AKT/FOXO信号通路中关键蛋白分子的表达水平:本研究初步预测了 YXFMs 治疗 SSS 的潜力。结论:这项研究初步预测了 YXFMs 在治疗 SSS 方面的潜力,表明 YXFMs 可能有能力靶向与该疾病相关的关键蛋白和关键路径。我们还进行了进一步的测试,以发现新的发现和证据,为解决由衰老引发的 SSS 问题提供思路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Yixin-Fumai granules modulate autophagy through the PI3K/AKT/FOXO pathway and lead to amelioration of aging mice with sick sinus syndrome.

Objective: By employing network pharmacology alongside molecular docking techniques, we can delve into the intricate workings of Yixin-Fumai granules (YXFMs) and their impact on sick sinus syndrome (SSS) within wrinkles mice. Specifically, we aim to understand how YXFMs enhance autophagy through the PI3K/AKT/FOXO path.

Methods: The active ingredients and medicinal uses of Ginseng, ligusticum wallichii, Ophiopogon, Schisandra, salvia, and astragalus were compiled using the BATMAN-TCM database. We also used Genecards, OMIM, and Disgenet files to identify the disease goals. A hierarchical diagram of "disease-drug-key targets" was generated using the Cytoscape programs. In addition, we established a target protein interaction (PPI) network using the STRING database. Then, the Cluster Profiler R package was used to conduct GO functional enrichment evaluation and KEGG pathway enrichment analyses of the targets. Based on the PPI system, we chose the top communicating targets and substances over molecular docking. In vivo studies were performed to validate these selections further. The mouse model was induced to study the damaged sinoatrial node (SAN) in mice with lower heart rates due to age-related changes. Electrocardiogram and Masson staining assessments were performed to obtain the results. The transmission electron microscope was used to assess the autophagy level of SAN cells. Western blot was employed to analyze the impact of YXFMs on protein expression in the PI3K/AKT/FOXO signaling process throughout SSS therapy in aging mice.

Results: One hundred forty-two active ingredients, 1858 targets, 1226 disease targets, and 266 intersection targets were obtained. The key targets of the PPI network encompassed TP53, AKT1, CTNNB1, INS, and TNF, among others. According to GO functional analysis, the mechanism underlying YXFMs in SSS treatment may primarily be associated with the control of ion transport across membranes, cardiac contraction, regulation of blood circulation, and other biological processes. Based on the results of KEGG pathway enrichment analysis, it was determined that they were mainly enriched in multiple pathways of signaling such as the PI3K-Akt signaling route, MAPK signaling process, AGE-RAGE signaling path, FOXO signaling path, HIF-1 signaling process, and several other paths. Molecular docking demonstrated that five compounds had excellent binding to the key candidate target proteins AKT1 and INS. Through the in vivo studies, we noticed notable effects when administering YXFMs. These effects included the suppression of aging-induced SSS, a decrease in the R-R interval, a rise in heart rate, a reduction in fibrosis, a boost in the autophagy process level, and a spike in the levels of expression of key protein molecules in the PI3K/AKT/FOXO signaling path.

Conclusion: This research has made preliminary predictions about the potential of YXFMs in treating SSS. It suggests that YXFMs may have the ability to target key proteins and critical paths associated with the condition. Further testing has been conducted to discover new findings and evidence of ideas for tackling SSS triggered by aging.

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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
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