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网络毒理学和分子对接研究农业化学品噻菌灵毒性的作用机制。

Network toxicological and molecular docking to investigate the mechanisms of toxicity of agricultural chemical Thiabendazole.

机构信息

Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products/Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, Guangxi Minzu University, Nanning, 530006, China; Department of Pharmacology, Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Guangxi Institute of Chinese Medicine and Pharmaceutical Science, Naning, 530022, China.

School of Material Science and Engineering, Hubei University of Automotive Technology, Shiyan, 442000, China.

出版信息

Chemosphere. 2024 Sep;363:142711. doi: 10.1016/j.chemosphere.2024.142711. Epub 2024 Jul 2.

Abstract

Food safety is closely linked to human health. Thiabendazole is widely used as a fungicide and deodorant on agricultural products like vegetables and fruits to prevent fungal infections during transport and storage. This study aims to investigate the toxicity and potential mechanisms of Thiabendazole using novel network toxicology and molecular docking techniques. First, the ADMETlab2.0 and ADMETsar databases, along with literature, predicted Thiabendazole's potential to induce cancer and liver damage. Disease target libraries were constructed using GeneCards and TCMIP databases, while Thiabendazole target libraries were constructed using Swiss Target Prediction and TCMIP databases. The Venn database identified potential targets associated with Thiabendazole-induced cancer and liver injury. Protein-protein interaction (PPI) networks were derived from the STRING database, and gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathways were obtained from the DAVID database. Molecular docking assessed the binding affinity between Thiabendazole and core targets. The study revealed 29 potential targets for Thiabendazole-induced cancer and 30 potential targets for liver injury. PPI identified 5 core targets for Thiabendazole-induced cancers and 4 core targets for induced liver injury. KEGG analysis indicated that Thiabendazole might induce gastric and prostate cancer via cyclin-dependent kinase 2 (CDK2) and epidermal growth factor receptor (EGFR) targets, and liver injury through the same targets, with the p53 signaling pathway being central. GO analysis indicated that Thiabendazole-induced cancers and liver injuries were related to mitotic cell cycle G2/M transition and DNA replication. Molecular docking showed stable binding of Thiabendazole with core targets including CDK1, CDK2, EGFR, and checkpoint kinase 1 (CHEK1). These findings suggest Thiabendazole may affect the G2/M transition of the mitotic cell cycle through the p53 signaling pathway, potentially inducing cancer and liver injury. This study provides a theoretical basis for understanding the potential molecular mechanisms underlying Thiabendazole toxicity, aiding in the prevention and treatment of related diseases. Additionally, the network toxicology approach accelerates the elucidation of toxic pathways for uncharacterized agricultural chemicals.

摘要

食品安全与人类健康密切相关。噻菌灵作为一种杀菌剂和除味剂,广泛应用于蔬菜和水果等农产品上,以防止在运输和储存过程中发生真菌感染。本研究旨在采用新型网络毒理学和分子对接技术研究噻菌灵的毒性及其潜在机制。首先,使用 ADMETlab2.0 和 ADMETsar 数据库以及文献资料,预测噻菌灵诱导癌症和肝损伤的潜力。使用 GeneCards 和 TCMIP 数据库构建疾病靶标库,使用 SwissTargetPrediction 和 TCMIP 数据库构建噻菌灵靶标库。Venn 数据库鉴定出与噻菌灵诱导的癌症和肝损伤相关的潜在靶标。从 STRING 数据库中提取蛋白质-蛋白质相互作用(PPI)网络,从 DAVID 数据库中获得基因本体论(GO)和京都基因与基因组百科全书(KEGG)通路。采用分子对接评估噻菌灵与核心靶标的结合亲和力。研究发现 29 个潜在的噻菌灵诱导癌症靶标和 30 个潜在的噻菌灵诱导肝损伤靶标。PPI 鉴定出 5 个噻菌灵诱导癌症的核心靶标和 4 个噻菌灵诱导肝损伤的核心靶标。KEGG 分析表明,噻菌灵可能通过细胞周期蛋白依赖性激酶 2(CDK2)和表皮生长因子受体(EGFR)靶标诱导胃癌和前列腺癌,并通过相同靶标诱导肝损伤,p53 信号通路是关键。GO 分析表明,噻菌灵诱导的癌症和肝损伤与有丝分裂细胞周期 G2/M 期过渡和 DNA 复制有关。分子对接表明,噻菌灵与核心靶标(包括 CDK1、CDK2、EGFR 和检查点激酶 1(CHEK1))具有稳定的结合。这些发现表明,噻菌灵可能通过 p53 信号通路影响有丝分裂细胞周期的 G2/M 期过渡,从而潜在地诱导癌症和肝损伤。本研究为了解噻菌灵毒性的潜在分子机制提供了理论依据,有助于预防和治疗相关疾病。此外,网络毒理学方法加速了对未明确的农用化学品毒性途径的阐明。

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