Ontology highlight
ABSTRACT:
PROVIDER: PRJNA765675 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16027640.fastq.gz | Fastqsanger.gz |
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Project description:Phosphodiesterase 10A (PDE10A), by degrading cAMP/cGMP, play critical roles in cardiovascular biology/disease. Cardiotoxicity is a clinical complication of chemotherapy. We aim to determine the role of PDE10A in cancer growth and cardiotoxicity induced by doxorubicin (DOX), a chemotherapy drug. We found that PDE10A deficiency/inhibition alleviated DOX-induced cardiotoxicity in C57Bl/6J mice, including myocardial atrophy, apoptosis, and dysfunction. RNAseq study revealed several PDE10A-regulated signaling associated with DOX-induced cardiotoxicity. In cancer cells, PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX in various cancer-cell lines. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protected against DOX-induced cardiotoxicity. In isolated cardiomyocytes (CMs), PDE10A contributed to DOX-induced CM death via promoting mitochondrial dysfunction, and to CM atrophy via potentiating foxo3 signaling. Collectively, our study elucidates a novel role for PDE10A in cardiotoxicity and cancer growth in vitro and in vivo, and suggest that PDE10A inhibition may represent a novel strategy in cancer therapy.
2023-06-22 | GSE224157 | GEO
Project description:The urgent need to understand the molecular modulation associated with chronic cardiotoxicity of doxorubicin (DOX) has prompted us to investigate the ubiquitome profile of aged cardiac muscle. Using old CD-1 male mice administered with a DOX dosage established to induce cardiotoxicity, we performed a comprehensive analysis of the proteomic profile of the enriched pool of poly-ubiquitinated proteins obtained from cardiac muscle using tandem ubiquitin-binding entities (TUBEs). GeLC-MS/MS and subsequent bioinformatic analysis revealed several proteins with the poly-ubiquitination modification involved in DOX-induced cardiotoxicity. Increased poly-ubiquitination levels were found for sarcomeric proteins including alpha-actinin-2 and desmin as well as mitochondrial proteins such as ATP synthase subunit beta and cytochrome b-c1 complex subunit 1. Thus, impaired protein ubiquitination emerges as an enduring consequence of DOX-induced cardiotoxicity. The present exploratory analysis could be considered an important starting point for further studies targeting molecular pathways under the side effects of the widely used anticancer drug DOX.
2025-06-30 | PXD048078 | Pride
Project description:This study aimed to determine whether methylation signature of peripheral blood mononuclear cells (PBMCs) prior to the start of the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients as well as determine if DOX treatment changed methlation profiles. The Illumina Infinium 450 Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 450k CpGs PBMCs samples before and after treatment. Samples included 10 samples from patients with normal ejection fraction after DOX treatment, 9 samples from patients with abnormal ejection fraction (indicative of cardiotoxicity) after DOX treatment.
2021-12-29 | GSE178887 | GEO
Project description:Background: Acute doxorubicin (DOX)-induced cardiotoxicity leads to electrophysiological changes, including QT prolongation, reduced QRS voltages, and T wave abnormalities. We previously demonstrated in mice that the effects of DOX on cardiac electrophysiology are sex-dependent. Objectives: Determine sex- and age-specific cardiotoxic effects of DOX on human cardiac electrophysiology and whether targeting p38 MAPKs could be cardioprotective in human hearts. Methods: Human cardiac slices were cultured for 24 hours with DOX (0-50 M). Slices were optically mapped to measure action potential duration (APD80) and transverse conduction velocity (CVT). Tissues were preserved for RNA sequencing. In separate slices, p38 MAPK inhibitors SB203580 or Compound 62, were applied alongside DOX. Results: DOX induced dose-dependent APD80 prolongation in young female and old hearts of both sexes. Phase 3 APD80 prolongation was associated with increased Cacna1c expression in young females. DOX also slowed CVT in young males and females, as well as in old males, despite increased Scn5a gene expression in young hearts of both sexes and increased Gja1 in young females. Furthermore, inhibiting p38 MAPKs with SB203580 did not prevent DOX-induced APD80 prolongation and CVT slowing, while pan-p38 MAPK inhibitor Compound 62 attenuated these effects in male and female hearts, suggesting a role for p38 and/or p38 MAPKs in mediating DOX cardiotoxicity in human hearts. Conclusions: Acute DOX-induced electrophysiological cardiotoxicity is sex- and age-dependent. This study introduces novel patient-specific diagnostic markers for detecting acute DOX-induced cardiotoxicity. Additionally, targeting p38γ and p38δ MAPKs in human hearts could offer a new cardioprotective therapy during DOX chemotherapy.
2026-03-13 | GSE307214 | GEO
Project description:Cardiotoxicity is serious adverse reaction of cancer chemotherapy and may lead to critical heart damage. Imatinib mesylate (IMB), a selective tyrosine kinase inhibitor, is sometimes accompanied by severe cardiovascular complications. To minimize the risk, early biomarkers of such complications are of utmost importance. MicroRNAs (miRNAs) are, nowadays intensively studied as potential biomarkers of many pathological processes. Many miRNAs appear to be specific in some tissues, including heart. Here, we have explored the potential of specific miRNAs to be early markers of IMB-induced cardiotoxicity. Doxorubicin (DOX), an anthracycline with well-known cardiotoxicity, was used for comparison. NMRI mice were treated with IMB or DOX for nine days in doses corresponding to the highest recommended doses in oncological patients. Then, plasmatic levels of miRNAs were analyzed by miRNA microarrays and selected cardio-specific miRNAs were quantified using qPCR. The plasmatic level of miR-1a, miR-133a, miR-133b, miR-339, miR-7058, miR-6236 and miR-6240 were the most different between IMB-treated and control mice. Interestingly, most of the miRNAs affected by DOX were also affected by IMB with the same trends. Concerning selected microRNAs in hearts of individual mice, only miR-34a was significantly increased after DOX treatment and only miR-205 was significantly decreased after IMB and DOX treatment. However, changes in any miRNA expression did not correlate with level of troponin T, classical marker of heart injury.
2020-01-01 | GSE121275 | GEO
Project description:Doxorubicin (DOX) and other anthracyclines are effective chemotherapeutic agents, however, their use is influenced by the risk of cardiotoxicity. We still have an incomplete understanding of the cardiomyocyte protective pathways activated after anthracycline-induced cardiotoxicity (AIC).Danshen injection (DSI), astaxanthin (AXT) and diosmetin (DMT) are effective in the treatment of cardiovascular diseases, but the mechanism of protection against adriamycin-induced cardiotoxicity is unclear. Here, we performed RNA-seq screening in H9c2 cardiomyocytes to determine the potential protective mechanisms of Danshen injection, astaxanthin and diosmetin against AIC.
2024-10-30 | GSE246548 | GEO
Project description:Doxorubicin (DOX) is one of the most effective chemotherapeutic agents for various types of cancers. However, DOX often causes cardiotoxicity referred to as DOX-induced cardiomyopathy (DIC). In this experiment, transcriptome changes induced by doxorubicin were examined in human PSC-derived cardiomyocytes.
2026-02-08 | GSE255505 | GEO
Project description:Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for explore the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a practical approach for using donor-specific iPSC-CMs to predict personalized doxorubicin (DOX)-induced cardiotoxicity (DIC) prior to chemotherapy. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice, and largely replicated the reported mechanisms of DIC. By categorizing iPSC-CMs into DOX-resistant and DOX-sensitive cell lines based on their phenotypic reactions to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we assessed the limitations of the model for identification of potential genetic/molecular biomarker and pinpointed a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. We also discussed the selection of DOX dose and exposure duration for inter-individual variability of DIC assessment. Our results support the utility of donor-specific iPSC-CMs in assessing inter-individual difference and enabling personalized cardiotoxicity prediction. Further studies will encompass a large panel of donor-specific iPSC-CMs to investigate the role of the DND1 and known DIC genetic variants, and to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.
2024-09-07 | GSE242692 | GEO
Project description:Doxorubicin (DOX) is the cornerstone of chemotherapy regimens for many malignancies, but its clinical usage is limited by severe cardiotoxicity. Accumulating evidence suggest that nicotinamide adenine dinucleotide (NAD+) depletion contributes to DOX-induced cardiotoxicity, making NAD+ boosting an appealing strategy. Nicotinamide mononucleotide (NMN) is an NAD+ precursor that shows promising therapeutic effects in various diseases. To understand the impact of NMN on gene expression in myocardial tissue of DOX-exposed mice, a RNA-seq assay was carried out.
2023-06-03 | GSE233644 | GEO