Sepsis causes multiple organ injuries, among which the heart is one most severely damaged organ. Melatonin (MEL) alleviates septic myocardial injury, although a systematic and comprehensive approach is still lacking to understand the precise protective machinery of MEL. This study aimed to examine the underlying mechanisms of MEL on improvement of septic myocardial injury at a systematic level. This study integrated three analytic modalities including database investigations, RNA-seq analysis, and weighted gene co-expression network analysis (WCGNA), in order to acquire a set of genes associated with the pathogenesis of sepsis. The Drugbank database was employed to predict genes that may serve as pharmacological targets for MEL-elicited benefits, if any. A pharmacological protein–protein interaction network was subsequently constructed, and 66 hub genes were captured which were enriched in a variety of immune response pathways. Notably, PIK3CG, one of the hub genes, displayed high topological characteristic values, strongly suggesting its promise as a novel target for MEL-evoked treatment of septic myocardial injury. Importantly, molecular docking simulation experiments as well as in vitro and in vivo studies supported an essential role for PIK3CG in MEL-elicited effect on septic myocardial injury. This study systematically clarified the mechanisms of MEL intervention in septic myocardial injury involved multiple targets and multiple pathways. Moreover, PIK3CG-governed signaling cascade plays an important role in the etiology of sepsis and septic myocardial injury. Findings from our study provide valuable information on novel intervention targets for the management of septic myocardial injury. More importantly, this study has indicated the utility of combining a series of techniques for disease target discovery and exploration of possible drug targets, which should shed some light on elucidation of experimental and clinical drug action mechanisms systematically.

中文翻译：

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使用网络药理学和加权基因共表达网络分析鉴定 PIK3CG 作为脓毒症心肌损伤的枢纽


脓毒症会导致多种器官损伤，其中心脏是受损最严重的器官之一。褪黑素 (MEL) 可减轻脓毒性心肌损伤，但仍缺乏系统且全面的方法来了解 MEL 的精确保护机制。本研究旨在系统地探讨 MEL 改善脓毒性心肌损伤的潜在机制。本研究整合了数据库调查、RNA-seq分析和加权基因共表达网络分析（WCGNA）三种分析模式，以获得一组与脓毒症发病机制相关的基因。 Drugbank 数据库用于预测可能作为 MEL 带来的益处的药理学靶标的基因（如果有的话）。随后构建了药理学蛋白质-蛋白质相互作用网络，并捕获了 66 个枢纽基因，这些基因富含多种免疫反应途径。值得注意的是，中心基因之一 PIK3CG 显示出较高的拓扑特征值，强烈表明其有望成为 MEL 诱发的脓毒性心肌损伤治疗的新靶点。重要的是，分子对接模拟实验以及体外和体内研究支持 PIK3CG 在 MEL 引发的脓毒性心肌损伤中发挥重要作用。本研究系统阐明了MEL干预脓毒症心肌损伤涉及多靶点、多途径的机制。此外，PIK3CG 控制的信号级联在脓毒症和脓毒性心肌损伤的病因学中发挥着重要作用。我们的研究结果为脓毒性心肌损伤管理的新干预目标提供了有价值的信息。 更重要的是，这项研究表明了结合一系列技术来发现疾病靶点和探索可能的药物靶点的实用性，这将为系统地阐明实验和临床药物作用机制提供一些启示。