Jiang Feng, Zeng Zhicong, Zhou Xu, Tan Meiling, Zhang Weiwei, Li Mingyue, Zhang Xiaoduo, Song Yinzhi, Wei Shanyin, Lin Fengxia
Department of Cardiology, Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518000, China.
Wenhua Community Health Service Center, Shenzhen Luohu Hospital Group, Shenzhen 518000, China.
Evid Based Complement Alternat Med. 2022 May 25;2022:4918343. doi: 10.1155/2022/4918343. eCollection 2022.
Inflammation and immune response play a key role in myocardial injury and repair after myocardial infarction (MI), while the relevant regulatory mechanisms of immune infiltration in MI have been fully explored. Ferroptosis is an iron-dependent form of regulated cell death characterized by an excessive accumulation of iron and lipid peroxides and involves in the pathogenesis of myocardial infarction. In the present study, by integrating intelligent data acquisition, data mining, network pharmacology, and computer-assisted target fishing, we developed a highly efficient system for screening immunity- and ferroptosis-related biomarkers and immunomodulatory ability of herbal ingredients.
Immune infiltration analysis of GSE97320 showed significant neutrophil infiltration in the myocardial infarction group compared to the healthy group, and 807 differentially expressed genes (DEGs) were obtained (526 up-regulated and 281 downregulated). Among these DEGs, 73 immune-related and 8 ferroptosis-related DEGs were obtained. Further protein-protein interaction network analysis revealed 30 hub genes. The DEGs were enriched in a total of 107 biological processes, of which neutrophil-related biological processes were the most significant, enriched in 31 cellular components such as bead-binding hemoglobin complex, hemoglobin complex, and enriched in 36 functions such as bead-binding hemoglobin complex and hemoglobin complex. The DEGs were also enriched in 21 KEGG pathways such as lipid-atherosclerosis and formation of neutrophil extracellular traps. Further analysis identified Toll-like receptor-4 (TLR4) as the key gene, and based on TLR4, 17 herbal ingredients and 6 herbal medicines were predicted by using HERB and Coremine databases. Further molecular docking analysis showed that TLR4 could bind to salvianolic acid b and stigmasterol. The molecular dynamics analysis revealed that TLR4 could bind to salvianolic acid b, stigmasterol, and resveratrol in the stable phase with the binding between TLR4 and salvianolic acid b being the most stable.
TLR4 is a key gene that is related to ferroptosis and immune cell infiltration. Further analysis revealed that 17 herbal ingredients and 6 herbal medicines were predicted to have potential interactions with TLR4. These predicted herbal ingredients/medicines may act synergistically to protect against myocardial injury after MI through suppressing neutrophil extracellular traps. The protective effects may be associated with immune cell infiltration and ferroptosis.
炎症和免疫反应在心肌梗死后的心肌损伤和修复中起关键作用，而心肌梗死中免疫浸润的相关调控机制已得到充分研究。铁死亡是一种铁依赖性的程序性细胞死亡形式，其特征是铁和脂质过氧化物过度积累，并参与心肌梗死的发病机制。在本研究中，通过整合智能数据采集、数据挖掘、网络药理学和计算机辅助靶点筛选，我们开发了一种高效系统，用于筛选免疫和铁死亡相关生物标志物以及草药成分的免疫调节能力。
对GSE97320进行免疫浸润分析显示，与健康组相比，心肌梗死组中性粒细胞浸润显著，共获得807个差异表达基因（DEGs）（526个上调和281个下调）。在这些DEGs中，获得了73个免疫相关和8个铁死亡相关的DEGs。进一步的蛋白质-蛋白质相互作用网络分析揭示了30个核心基因。这些DEGs共富集于107个生物学过程，其中中性粒细胞相关生物学过程最为显著，富集于31个细胞成分，如珠结合血红蛋白复合物、血红蛋白复合物，并富集于36个功能，如珠结合血红蛋白复合物和血红蛋白复合物。这些DEGs还富集于21条KEGG通路，如脂质动脉粥样硬化和中性粒细胞胞外陷阱的形成。进一步分析确定Toll样受体4（TLR4）为关键基因，并基于TLR4，利用HERB和Coremine数据库预测了17种草药成分和6种草药。进一步的分子对接分析表明，TLR4可与丹酚酸B和豆甾醇结合。分子动力学分析表明，TLR4可在稳定期与丹酚酸B、豆甾醇和白藜芦醇结合，其中TLR4与丹酚酸B的结合最为稳定。
TLR4是与铁死亡和免疫细胞浸润相关的关键基因。进一步分析表明，预测有17种草药成分和6种草药与TLR4存在潜在相互作用。这些预测的草药成分/药物可能通过抑制中性粒细胞胞外陷阱协同作用，保护心肌梗死后的心肌损伤。其保护作用可能与免疫细胞浸润和铁死亡有关。
