Os Efeitos da Doxorrubicina na Biossíntese e no Metabolismo do Heme em Cardiomiócitos

Wang, Zuoyan; Gao, Jinyang; Teng, Honghong; Peng, Jianjun

doi:10.36660/abc.20190437

Cited by 4 publications

(2 citation statements)

References 33 publications

(38 reference statements)

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“…These two datasets were based on a doxorubicin-induced acute heart injury mouse model performed through intraperitoneal administration of doxorubicin in a dose of 15 mg/kg for 4 or 5 days [ 25 , 26 ]. After combining and reanalyzing the datasets, we screened out a total of 120 DEGs between the normal myocardial tissue and the toxic myocardial tissue, of which parts were confirmed by previous reports in terms of the expression trend, such as Ctgf [ 27 ], Aox1 [ 28 ], Alas2 [ 29 ], and Ly86 [ 30 ]. However, Btg2 was upregulated after doxorubicin treatment in our study, while a previous study found it to be downregulated [ 31 ].…”

Section: Discussionmentioning

confidence: 73%

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity

Zhang

Hao

et al. 2023

Mediators of Inflammation

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Doxorubicin is one of the most common antitumor drugs. However, cardiotoxicity’s side effect limits its clinical applicability. In the present study, Gene Expression Omnibus (GEO) datasets were applied to reanalyze differentially expressed genes (DEGs) and construct weighted correlation network analysis (WGCNA) modules of doxorubicin-induced cardiotoxicity in wild-type mice. Several other bioinformatics analyses were performed to pick out the hub gene, and then the correlation between the hub gene and immune infiltration was evaluated. In total, 120 DEGs were discovered in a mouse model of doxorubicin-induced cardiotoxicity, and PF-04217903, propranolol, azithromycin, etc. were found to be potential drugs against this pathological condition. Among all the DEGs, 14 were further screened out by WGCNA modules, of which Limd1 was upregulated and finally regarded as the hub gene after being validated in other GEO datasets. Limd1 was upregulated in the peripheral blood mononuclear cell (PBMC) of the rat model, and the area under curve (AUC) of the receiver operating characteristic curve (ROC) in diagnosing cardiotoxicity was 0.847. The GSEA and PPI networks revealed a potential immunocyte regulatory role of Limd1 in cardiotoxicity. The proportion of “dendritic cells activated” in the heart was significantly elevated, while “macrophage M1” and “monocytes” declined after in vivo doxorubicin application. Finally, Limd1 expression was significantly positively correlated with “dendritic cells activation’ and negatively correlated with “monocytes” and “macrophages M1’. In summary, our results suggested that limd1 is a valuable biomarker and a potential inflammation regulator in doxorubicin-induced cardiotoxicity.

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Section: Discussionmentioning

confidence: 73%

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity

Zhang

Hao

et al. 2023

Mediators of Inflammation

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“…A high number of mitochondria and low antioxidant defense of cardiomyocytes make these cells vulnerable to oxidative damage by ROS [ 62 , 63 , 64 , 65 ]. Dox-induced production of ROS leads to dysregulated calcium and iron transport [ 61 , 64 , 65 ] and reduced oxidative phosphorylation (respiration) and ATP production [ 64 , 65 , 66 ]. Dox was also shown to block the antioxidant system in cardiac muscles, represented by the sirtuins family proteins SIRT1 and SIRT3 [ 67 , 68 ].…”

Section: Genetic Polymorphisms and Cardiotoxicity In Dox-treated Pati...mentioning

confidence: 99%

Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy

Bagdasaryan

Chubarev

Smolyarchuk

et al. 2022

Cancers

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Breast cancer (BC) is the prevailing malignancy and major cause of cancer-related death in females. Doxorubicin is a part of BC neoadjuvant and adjuvant chemotherapy regimens. The administration of anthracycline derivates, such as doxorubicin, may cause several side effects, including hematological disfunction, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Cardiotoxicity is a major adverse reaction to anthracyclines, and it may vary depending on individual differences in doxorubicin pharmacokinetics. Determination of specific polymorphisms of genes that can alter doxorubicin metabolism was shown to reduce the risk of adverse reactions and improve the safety and efficacy of doxorubicin. Genes which encode cytochrome P450 enzymes (CYP3A4 and CYP2D6), p-glycoproteins (ATP-binding cassette (ABC) family members such as Multi-Drug Resistance 1 (MDR1) protein), and other detoxifying enzymes were shown to control the metabolism and pharmacokinetics of doxorubicin. The effectiveness of doxorubicin is defined by the polymorphism of cytochrome p450 and p-glycoprotein-encoding genes. This study critically discusses the latest data about the role of gene polymorphisms in the regulation of doxorubicin’s anti-BC effects. The correlation of genetic differences with the efficacy and safety of doxorubicin may provide insights for the development of personalized medical treatment for BC patients.

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Identification of novel biomarkers involved in doxorubicin-induced acute and chronic cardiotoxicity, respectively, by integrated bioinformatics

Qian

Liu

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThe mechanisms of doxorubicin (DOX) cardiotoxicity were complex and controversial, with various contradictions between experimental and clinical data. Understanding the differences in the molecular mechanism between DOX-induced acute and chronic cardiotoxicity may be an ideal entry point to solve this dilemma.MethodsMice were injected intraperitoneally with DOX [(20 mg/kg, once) or (5 mg/kg/week, three times)] to construct acute and chronic cardiotoxicity models, respectively. Survival record and ultrasound monitored the cardiac function. The corresponding left ventricular (LV) myocardium tissues were analyzed by RNA-seq to identify differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) found the key biological processes and signaling pathways. DOX cardiotoxicity datasets from the Gene expression omnibus (GEO) database were combined with RNA-seq to identify the common genes. Cytoscape analyzed the hub genes, which were validated by quantitative real-time PCR. ImmuCo and ImmGen databases analyzed the correlations between hub genes and immunity-relative markers in immune cells. Cibersort analyzed the immune infiltration and correlations between the hub genes and the immune cells. Logistic regression, receiver operator characteristic curve, and artificial neural network analysis evaluated the diagnosis ability of hub genes for clinical data in the GEO dataset.ResultsThe survival curves and ultrasound monitoring demonstrated that cardiotoxicity models were constructed successfully. In the acute model, 788 DEGs were enriched in the activated metabolism and the suppressed immunity-associated signaling pathways. Three hub genes (Alas1, Atp5g1, and Ptgds) were upregulated and were negatively correlated with a colony of immune-activating cells. However, in the chronic model, 281 DEGs showed that G protein-coupled receptor (GPCR)-related signaling pathways were the critical events. Three hub genes (Hsph1, Abcb1a, and Vegfa) were increased in the chronic model. Furthermore, Hsph1 combined with Vegfa was positively correlated with dilated cardiomyopathy (DCM)-induced heart failure (HF) and had high accuracy in the diagnosis of DCM-induced HF (AUC = 0.898, P = 0.000).ConclusionAlas1, Atp5g1, and Ptgds were ideal biomarkers in DOX acute cardiotoxicity. However, Hsph1 and Vegfa were potential biomarkers in the myocardium in the chronic model. Our research, first, provided bioinformatics and clinical evidence for the discovery of the differences in mechanism and potential biomarkers of DOX-induced acute and chronic cardiotoxicity to find a therapeutic strategy precisely.

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Os Efeitos da Doxorrubicina na Biossíntese e no Metabolismo do Heme em Cardiomiócitos

Cited by 4 publications

References 33 publications

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity

Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy

Identification of novel biomarkers involved in doxorubicin-induced acute and chronic cardiotoxicity, respectively, by integrated bioinformatics

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