利用网络毒理学和分子对接策略有效分析柠檬酸乙酰三丁酯对衰老的毒性和机理。

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology Pub Date : 2024-11-22 DOI:10.1016/j.tox.2024.154009

Qiu Zheng , Qingping Peng , Jianlin Shen , Huan Liu

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引用次数: 0

摘要

本研究旨在应用网络毒理学策略研究柠檬酸乙酰三丁酯（ATBC）的潜在毒性及其诱发衰老的分子机制。利用 ChEMBL、SwissTargetPrediction 和 CellAge 数据库，我们确定了 32 个与 ATBC 暴露和衰老相关的潜在靶点。随后通过 STRING 和 Cytoscape 软件进行了优化，突出了 11 个核心靶点，包括表皮生长因子受体、STAT3 和 BCL-2。对基因本体（GO）和《京都基因与基因组百科全书》（KEGG）通路的综合分析表明，ATBC诱导衰老的核心靶点主要富集在与细胞增殖、端粒缩短、癌症和细胞衰老的正向调控相关的通路中。在这些通路中，我们选择了细胞衰老通路的四个核心基因（MAPK14、CDK2、MDM2 和 PIK3CA）与 Autodock 进行分子对接，结果证实 ATBC 与核心靶点之间具有很高的结合亲和力。总之，这些研究结果表明，ATBC可能通过调节细胞增殖、端粒缩短通路、癌症相关通路和细胞衰老通路的正向调控来促进人体衰老。这项研究为探索 ATBC 诱发人类衰老的分子机制奠定了理论基础，同时也为研究人员评估各种化学产品的潜在毒性提供了一个系统而有效的框架。

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Efficient analysis of toxicity and mechanisms of Acetyl tributyl citrate on aging with network toxicology and molecular docking strategy

The aim of this study was to apply a network toxicology strategy to investigate the potential toxicity and the molecular mechanisms underlying the aging-induced toxicity of acetyl tributyl citrate (ATBC). Utilizing the ChEMBL, SwissTargetPrediction, and CellAge databases, we identified 32 potential targets associated with ATBC exposure and aging. Subsequent optimization by STRING and Cytoscape software highlighted 11 core targets, including EGFR, STAT3, and BCL-2. A comprehensive analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that core targets of ATBC-induced senescence were predominantly enriched in pathways related to the positive regulation of cell proliferation, telomere shortening, cancer, and cellular senescence. Among these pathways, we selected four core genes of the cellular senescence pathway (MAPK14, CDK2, MDM2, and PIK3CA) for molecular docking with Autodock, which confirmed the high binding affinity between ATBC and the core targets. In conclusion, these findings indicate that ATBC may contribute to human aging by modulating the positive regulation of cell proliferation, the telomere shortening pathway, the cancer-related pathway, and the cellular senescence pathway. This study establishes a theoretical basis for exploring the molecular mechanisms of human aging induced by ATBC, alongside a systematic and effective framework for researchers to assess the potential toxicity of various chemical products.

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来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.