Identification of autophagy-related signatures in doxorubicin-induced cardiotoxicity

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY Toxicology and applied pharmacology Pub Date : 2024-08-30 DOI:10.1016/j.taap.2024.117082

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Abstract

Purpose

Doxorubicin is an antibiotic drug used clinically to treat infectious diseases and tumors. Unfortunately, it is cardiotoxic. Autophagy is a cellular self-decomposition process that is essential for maintaining homeostasis in the internal environment. Accordingly, the present study was proposed to characterize the autophagy-related signatures of doxorubicin-induced cardiotoxicity.

Methods

Datasets related to doxorubicin-induced cardiotoxicity were retrieved by searching the GEO database and differentially expressed genes (DEGs) were identified. DEGs were taken to intersect with autophagy-related genes to obtain autophagy-related signatures, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network were performed on them. Further, construction of miRNA-hub gene networks and identification of target drugs to reveal potential molecular mechanisms and therapeutic strategies. Animal models of doxorubicin-induced cardiotoxicity were constructed to validate differences in gene expression for autophagy-related signatures.

Results

PBMC and heart samples from the GSE37260 dataset were selected for analysis. There were 995 and 2357 DEGs in PBMC and heart samples, respectively, and they had 23 intersecting genes with autophagy-related genes. RT-qPCR confirmed the differential expression of 23 intersecting genes in doxorubicin-induced cardiotoxicity animal models in general agreement with the bioinformatics results. An autophagy-related signatures consisting of 23 intersecting genes is involved in mediating processes and pathways such as autophagy, oxidative stress, apoptosis, protein ubiquitination and phosphorylation. Moreover, Akt1, Hif1a and Mapk3 are hub genes in autophagy-associated signatures and their upstream miRNAs are mainly rno-miR-1188-5p, rno-miR-150-3p and rno-miR-326-3p, and their drugs are mainly CHEMBL55802, Carboxyamidotriazole and 3-methyladenine.

Conclusion

This study identifies for the first-time autophagy-related signatures in doxorubicin's cardiotoxicity, which could provide potential molecular mechanisms and therapeutic strategies for doxorubicin-induced cardiotoxicity.

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鉴定多柔比星诱发心脏毒性的自噬相关特征

目的：多柔比星是一种抗生素药物，临床上用于治疗传染病和肿瘤。不幸的是，它具有心脏毒性。自噬是一种细胞自我分解过程，对维持细胞内环境的平衡至关重要。因此，本研究旨在描述多柔比星诱发心脏毒性的自噬相关特征：方法：通过搜索 GEO 数据库检索与多柔比星诱导的心脏毒性相关的数据集，并确定差异表达基因（DEGs）。将 DEGs 与自噬相关基因进行交叉以获得自噬相关特征，并对其进行基因本体（GO）/京都基因和基因组百科全书（KEGG）富集分析和蛋白-蛋白相互作用（PPI）网络分析。此外，还构建了 miRNA 中枢基因网络并鉴定了靶向药物，以揭示潜在的分子机制和治疗策略。构建了多柔比星诱导的心脏毒性动物模型，以验证自噬相关特征基因表达的差异：从 GSE37260 数据集中选取了白细胞介素和心脏样本进行分析。PBMC和心脏样本中分别有995个和2357个DEGs，它们与自噬相关基因有23个交叉基因。RT-qPCR证实了23个交叉基因在多柔比星诱导的心脏毒性动物模型中的差异表达，与生物信息学结果基本一致。由 23 个交叉基因组成的自噬相关特征参与了自噬、氧化应激、细胞凋亡、蛋白质泛素化和磷酸化等过程和途径。此外，Akt1、Hif1a和Mapk3是自噬相关特征的枢纽基因，其上游miRNA主要是rno-miR-1188-5p、rno-miR-150-3p和rno-miR-326-3p，其药物主要是CHEMBL55802、羧酰胺三唑和3-甲基腺嘌呤：本研究首次发现了多柔比星心脏毒性中与自噬相关的特征，为多柔比星诱导的心脏毒性提供了潜在的分子机制和治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.