دورية أكاديمية
Mitigation of doxorubicin-induced cardiotoxicity by dichloroacetate: potential roles of restoration of PGC-1α/SIRT3 signaling and suppression of oxidative stress and apoptosis.
| العنوان: | Mitigation of doxorubicin-induced cardiotoxicity by dichloroacetate: potential roles of restoration of PGC-1α/SIRT3 signaling and suppression of oxidative stress and apoptosis. |
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| المؤلفون: | Saleh MF; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Egypt. Ahmedelsayedgoda@pharm.tanta.edu.eg., Elsayad ME, Goda AE |
| المصدر: | European review for medical and pharmacological sciences [Eur Rev Med Pharmacol Sci] 2021 Nov; Vol. 25 (21), pp. 6573-6584. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Verduci Country of Publication: Italy NLM ID: 9717360 Publication Model: Print Cited Medium: Internet ISSN: 2284-0729 (Electronic) Linking ISSN: 11283602 NLM ISO Abbreviation: Eur Rev Med Pharmacol Sci Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Rome : Verduci, [1997- |
| مواضيع طبية MeSH: | Antibiotics, Antineoplastic/*adverse effects , Cardiotoxicity/*prevention & control , Dichloroacetic Acid/*therapeutic use , Doxorubicin/*adverse effects, Animals ; Apoptosis/drug effects ; Cardiotoxicity/genetics ; Cardiotoxicity/pathology ; Dichloroacetic Acid/pharmacology ; Female ; Heart Ventricles/drug effects ; Heart Ventricles/pathology ; Mice ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/pathology ; Oxidative Stress/drug effects ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics ; Signal Transduction/drug effects ; Sirtuin 3/genetics |
| مستخلص: | Objective: Doxorubicin (DOX) is an effective chemotherapeutic agent used in the treatment of various neoplasms. Nevertheless, its therapeutic efficacy is hampered by life-threatening heart failure. Therefore, the current study was undertaken to investigate whether dichloroacetate (DCA), a metabolic and mitochondrial modulator, when administered at a therapeutically feasible dose could potentially reverse acute DOX cardiotoxicity. Furthermore, the possible underlying mechanisms of cardioprotection were also assessed. Materials and Methods: Different techniques were performed to assess cardiac injury like echocardiography, histopathology, transmission electron microscope, biomarkers of cardiac injury, and oxidative stress markers. Further, the expression levels of mRNA and protein were quantified by PCR and immunohistochemistry, respectively. Results: Echocardiography showed that mice that received DOX/DCA combination were protected against heart failure. Additionally, histopathology and transmission electron microscopy revealed structural damage alleviation by DOX/DCA combination, which was confirmed biochemically via significant suppression of elevated CK-MB and AST levels. Mechanistically, DOX dysregulated the expression of PGC-1α and SIRT-3 genes which are key to normal mitochondrial functioning. Of note, co-treatment with DCA effectively restored PGC-1α/SIRT-3 signaling and normalized the mitochondrial DNA index. Moreover, events downstream of DOX-triggered mitochondrial dysfunction such as oxidative stress and p53-dependent apoptosis were all abrogated by combination with DCA. Conclusions: The present study is the first to provide in vivo evidence that DCA is effective in protecting against acute DOX cardiotoxicity. Additionally, the study highlights the potential of administering metabolic modulators to safeguard against DOX cardiotoxicity. |
| المشرفين على المادة: | 0 (Antibiotics, Antineoplastic) 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) 0 (Sirt3 protein, mouse) 80168379AG (Doxorubicin) 9LSH52S3LQ (Dichloroacetic Acid) EC 3.5.1.- (Sirtuin 3) |
| تواريخ الأحداث: | Date Created: 20211117 Date Completed: 20220325 Latest Revision: 20220325 |
| رمز التحديث: | 20231215 |
| DOI: | 10.26355/eurrev_202111_27100 |
| PMID: | 34787860 |
| قاعدة البيانات: | MEDLINE |
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