The effects of Baz2b-knockout on doxorubicin-induced cardiotoxicity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236165 | GEO | 2025/06/24
REPOSITORIES: GEO
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Project description:Wild-type (WT) and Otub1-heterozygously knock-out mice were applied in the study. Doxorubicin (DOX)-induced subacute cardiotoxicity mouse model was established by 6 intraperitoneal injections during a 2-week period. The differentially expressed genes were analyzed by RNA-sequencing and clustering analyses.
2024-08-16 | GSE240959 | GEO
Project description:The effects of Baz2b-knockout on doxorubicin-induced cardiotoxicity
| PRJNA989160 | ENA
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: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:Doxorubicin (DOX) cardiotoxicity is an important factor of heart failure. The only clinically approved drug is dexrazoxane, while its side effect of secondary malignancies severely limited its application. It is urgent to find other alternative efficacious molecular for these chemotherapy patients. Colchicine is a safe and well tolerated anti-inflammation drug which also functions in attenuating the reactive oxygen species (ROS) generation. High dose of colchicine was reported block the autophagosome-lysosome fusion in cancer cells due to its destabilization effect to the microtubule system, while how colchicine affects the autophagic flux in cardiomyocytes is largely unknown. Recent years low dose of colchicine administration was reported helpful to the patients with pericarditis, postprocedural atrial fibrillation and coronary artery disease, most of the research attributed it to its anti-inflammation effect. Whether the autophagic flux regulated by colchicine also benefits to DOX induced heart failure remains unclear. Doxorubicin (DOX) administration was used to establish heart failure models in vivo and in vitro. Results showed that DOX blocked the autophagic vacuoles degradation, leading to damaged mitochondria and ROS accumulation. Heart failure characteristics were obviously improved after low dose of colchicine administration. Mechanistically, low dose of colchicine promoted the autolysosome degradation, cleared the damaged mitochondria, and ROS accumulation induced by the DOX and as a result attenuated DOX cardiotoxicity.
2024-06-20 | GSE247345 | GEO
Project description:Doxorubicin (Dox) poses a considerable threat to patients owing to its cardiotoxicity, thus limiting its clinical utility. Optimal cardioprotective intervention strategies are needed to suppress tumor growth but also minimize cardiac side effects. Here, we showed that tVNS improved the imbalanced autonomic tone, ameliorated impaired cardiac function and fibrosis, attenuated myocyte apoptosis, and mitochondrial dysfunction compared to those in the Dox group. The beneficial effects were attenuated by methyllycaconitine citrate (MLA). The transcript profile revealed that there were 248 differentially expressed genes and the protection of tVNS and retardation of MLA were related to inflammatory response and NADPH oxidase activity. In addition, tVNS synergizing with Dox inhibited tumor growth and lung metastasis and promoted apoptosis of tumor cells in an anti-tumor immunity manner. These results indicated that non-invasive neuromodulation can play a dual role in preventing Dox-induced cardiotoxicity and suppressing tumor growth through inflammation and oxidative stress.
2024-01-28 | GSE253959 | GEO
Project description:The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m6A) plays an essential role in numerous biological processes. However, the roles of m6A and m6A demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using Alkbh5-knockout (KO), Alkbh5-knockin (KI), and Alkbh5-myocardial-specific knockout (ALKBH5flox/flox, αMyHC-Cre) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both Alkbh5 whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an m6A-dependent manner through posttranscriptional mRNA regulation and reduced Rasal3 mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.
2023-03-08 | GSE224215 | 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 an effective chemotherapeutic agent against a broad range of tumors. However, a threshold dose of doxorubicin causes an unacceptably high incidence of heart failure and limits its clinical utility. We have established two models of doxorubicin cardiotoxicity in mice: 1) in an acute model, mice are treated with 15mg/kg of doxorubicin once; 2) in a chronic model, they receive 3mg/kg weekly for the first 12 of a total of 18 weeks. Using echocardiography, we have monitored left ventricular function of the mouse hearts during treatment in chronic model and seen the expected development of dilated cardiomyopathy (DCM). Treated mice showed histological abnormalities similar to those seen in patients with doxorubicin cardiomyopathy. To investigate transcriptional regulation in these models, we used a microarray we generated with over 5000 independent cDNA clones from murine heart and skeletal muscle. We have identified genes that respond to doxorubicin exposure in both model systems, and confirmed these results using real-time PCR. In the acute model, a set of genes is regulated early and rapidly returns to baseline levels, consistent with the half-life of doxorubicin. In the chronic model, which mimics the clinical situation much more closely, we identified dysregulated genes that implicate specific mechanisms of cardiac toxicity and may serve as biomarkers of doxorubicin induced dilated cardiomyopathy. Keywords: time course
2005-07-22 | GSE2965 | GEO
Project description:The anthracycline, doxorubicin (Dox), is widely used in oncology, but it may it may cause a cardiomyopathy which has dismal prognosis and cannot be effectively prevented. The secretome of multipotent human amniotic fluid-derived stem cells (hAFS) has previously been demonstrated to reduce ischemic cardiac damage. Here, it is shown that the hAFS conditioned medium (hAFS-CM) antagonizes senescence and apoptosis of cardiomyocytes and cardiac progenitor cells, two major features of Dox cardiotoxicity. Mechanistic studies with primary mouse neonatal cardiomyocytes reveal that hAFS-CM inhibition of Dox-elicited senescence and apoptosis is paralleled by decreased DNA damage and is associated with nuclear translocation of NF-kB and upregulation of a set of genes controlled by NF-kB, namely Il6 and Cxcl1, which promote cardiomyocyte survival, and Cyp1b1 and Abcb1, which encode for proteins involved in Dox metabolism and efflux, respectively. The PI3K/Akt signaling cascade, upstream of NF-kB, is potently activated by the hAFS-CM and pre-treatment with a PI3K inhibitor abrogates NF-kB accumulation into the nucleus, modulation of its target genes, and prevention of Dox-initiated senescence and apoptosis in response to the hAFS-CM. This work may lay the ground for the development of a stem cell-based paracrine therapy of chemotherapy-related cardiotoxicity.
2016-10-30 | GSE74513 | GEO