网络毒理学和分子对接研究有机磷农药致心脏毒性损伤的非乙酰胆碱酯酶机制和靶标。

Network toxicology and molecular docking to investigative the non-acetylcholinesterase mechanisms and targets of cardiotoxicity injury induced by organophosphorus pesticides.

机构信息

Jiangxi Medical College, Shangrao, Jiangxi, China.

Department of Cardiovascular, ShangRao People's Hospital, Shangrao, Jiangxi, China.

出版信息

Medicine (Baltimore). 2024 Oct 11;103(41):e39963. doi: 10.1097/MD.0000000000039963.

DOI:10.1097/MD.0000000000039963

PMID:39465796

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11479526/

Abstract

BACKGROUND

Organophosphorus pesticides (OPPs) are widely used in the world, however, OPP poisoning often occurs because of improper use and lack of protective measures. Cardiotoxicity injury induced by OPPs is insidious, and it does not receive attention until the end stage of OPP poisoning. Heart failure or arrhythmia gradually becomes the main lethal cause of OPP poisoning patients.

METHODS

In this study, network toxicology and molecular docking were employed to investigate the non-acetylcholinesterase targets and mechanisms of cardiotoxicity injury induced by OPPs.

RESULTS

One hundred twenty-three targets of dichlorvos, 205 targets of methidathion, and 337 targets of malathion were searched from SwissTargetPreict, STITCH and PharmMapper database. Additionally, 1379 targets related to cardiotoxicity injury were acquired from GeneCards and OMIM database. Ninety-six mutual targets between OPPs and cardiotoxicity injury were considered as the potential cardiotoxicity injury targets induced by OPPs. The protein-protein interaction (PPI) network was constructed using STING database, and 21 core targets were identified by Cytoscape software, such as AKT1, ESR1, HSP90AA1, MAPK1, MMP9, and MAPK8. Gene ontology and KEGG enrichment analysis revealed that cell migration, apoptotic process, protein phosphorylation and signal transduction were the major biological functions associated with OPPs-induced cardiotoxicity injury, and OPPs-induced cardiotoxicity injury might be regulated by MAPK, PI3K-Akt, VEGF signaling pathway. Docking results manifested that the best binding target for dichlorvos, methidathion and malathion were MAPK9 (-7.1 kcal/mol), MAPK1 (-8.1 kcal/mol) and HSP90AA1 (-8.6 kcal/mol) with the lowest affinity, respectively.

CONCLUSION

The core targets and non-AchE mechanisms were explored by network toxicology and molecular docking, providing a theoretical basis for the treatment of OPP-induced cardiotoxicity injury.

摘要

背景

有机磷农药（OPPs）在世界范围内广泛使用，然而，由于使用不当和缺乏保护措施，OPPs 中毒经常发生。OPPs 引起的心脏毒性损伤是隐匿的，直到 OPP 中毒的终末期才受到关注。心力衰竭或心律失常逐渐成为 OPP 中毒患者的主要致死原因。

方法

本研究采用网络毒理学和分子对接技术研究 OPPs 引起的心脏毒性损伤的非乙酰胆碱酯酶靶标和机制。

结果

从 SwissTargetPreict、STITCH 和 PharmMapper 数据库中搜索到敌敌畏的 123 个靶标、甲拌磷的 205 个靶标和马拉硫磷的 337 个靶标。此外，从 GeneCards 和 OMIM 数据库中获得了 1379 个与心脏毒性损伤相关的靶标。将 OPPs 和心脏毒性损伤之间的 96 个共同靶标视为 OPPs 引起的潜在心脏毒性损伤靶标。使用 STING 数据库构建蛋白质-蛋白质相互作用（PPI）网络，并用 Cytoscape 软件鉴定出 21 个核心靶标，如 AKT1、ESR1、HSP90AA1、MAPK1、MMP9 和 MAPK8。基因本体和 KEGG 富集分析表明，细胞迁移、凋亡过程、蛋白磷酸化和信号转导是与 OPPs 诱导的心脏毒性损伤相关的主要生物学功能，而 OPPs 诱导的心脏毒性损伤可能受 MAPK、PI3K-Akt、VEGF 信号通路调节。对接结果表明，敌敌畏、甲拌磷和马拉硫磷的最佳结合靶标分别为 MAPK9（-7.1 kcal/mol）、MAPK1（-8.1 kcal/mol）和 HSP90AA1（-8.6 kcal/mol），结合亲和力最低。