{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:54Z","timestamp":1785428154527,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T00:00:00Z","timestamp":1693872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Cardiomyopathy (particularly dilated cardiomyopathy (DCM)) significantly contributes to development and progression of heart failure (HF), and inflammatory factors further deteriorate the symptoms. Morphological and functional defects of the heart in doxorubicin (DOX)-induced cardiomyopathy (cardiotoxicity) are similar to those of DCM. We used anagonist of PGC-1\u03b1 (PPAR (peroxisome proliferator-activated receptor-gamma)-\u03b3 coactivator-1\u03b1) that is considered as the \u2018master regulator\u2019 of mitochondrial biogenesis with an aim to rescue the DOX-induced deleterious effects on the heart. Forty male C57BL\/6J mice (8 weeks old) were divided in four groups, Control, DOX, ZLN005, and ZLN005 + DOX (n = 10 each group). The DOX-induced (10 mg\/kg, single dose) cardiomyopathy mimics a DCM-like phenotype with marked morphologic alteration in cardiac tissue and functional derangements. Significant increased staining was observed for Masson Trichrome\/Picrosirius red and \u03b1-Smooth Muscle Actinin (\u03b1-SMA) that indicated enhanced fibrosis in the DOX group compared to the control that was attenuated by (peroxisome proliferator-activated receptor-gamma (PPAR-\u03b3) coactivator) (PGC)-1\u03b1 (alpha) agonist (four doses of 2.5 mg\/kg\/dose; cumulative dose = 10 mg\/kg). Similarly, elevated expression of necroptosis markers along with enhanced oxidative stress in the DOX group were alleviated by PGC-1\u03b1 agonist. These data collectively suggested the potent therapeutic efficacy of PGC-1\u03b1 agonist in mitigating the deleterious effects of DOX-induced cardiomyopathy, and it may be targeted in developing the future therapeutics for the management of DCM\/HF.<\/jats:p>","DOI":"10.3390\/antiox12091720","type":"journal-article","created":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T09:46:20Z","timestamp":1693907180000},"page":"1720","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["PGC-1\u03b1 Agonist Rescues Doxorubicin-Induced Cardiomyopathy by Mitigating the Oxidative Stress and Necroptosis"],"prefix":"10.3390","volume":"12","author":[{"family":"Shipra","sequence":"first","affiliation":[{"name":"Department of Cardiac Biochemistry, AIIMS, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8010-2223","authenticated-orcid":false,"given":"Manoj Kumar","family":"Tembhre","sequence":"additional","affiliation":[{"name":"Department of Cardiac Biochemistry, AIIMS, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milind Padmakar","family":"Hote","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic & Vascular Surgery, AIIMS, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neetu","family":"Bhari","sequence":"additional","affiliation":[{"name":"Dermatology & Venereology, AIIMS, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramakrishnan","family":"Lakshmy","sequence":"additional","affiliation":[{"name":"Department of Cardiac Biochemistry, AIIMS, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Senthil","family":"Kumaran","sequence":"additional","affiliation":[{"name":"Department of N. M. R. (MRI Facility), AIIMS, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1159\/000415646","article-title":"Cardiac transplantation for the treatment of end stage ischemic cardiomyopathy","volume":"36","author":"Primo","year":"1988","journal-title":"Adv. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1161\/01.CIR.93.5.841","article-title":"Report of the 1995 World Health Organization\/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies","volume":"93","author":"Richardson","year":"1996","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1001\/jama.2013.6296","article-title":"Clinical ascertainment of health outcomes among adults treated for childhood cancer","volume":"309","author":"Hudson","year":"2013","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"214","DOI":"10.2174\/157340311799960645","article-title":"Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment","volume":"7","author":"Volkova","year":"2011","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1002\/cncr.11407","article-title":"Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials","volume":"97","author":"Swain","year":"2003","journal-title":"Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2","article-title":"A clinicopathologic analysis of adriamycin cardiotoxicity","volume":"32","author":"Lefrak","year":"1973","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1007\/s00059-011-3470-3","article-title":"Mechanisms and management of doxorubicin cardiotoxicity","volume":"36","author":"Shi","year":"2011","journal-title":"Herz"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1038\/nm.2919","article-title":"Identification of the molecular basis of doxorubicin-induced cardiotoxicity","volume":"18","author":"Zhang","year":"2012","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/s41422-019-0164-5","article-title":"The molecular machinery of regulated cell death","volume":"29","author":"Tang","year":"2019","journal-title":"Cell Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41419-021-03614-x","article-title":"Regulated cell death pathways in doxorubicin-induced cardiotoxicity","volume":"12","author":"Christidi","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.bbrc.2019.12.027","article-title":"Dexrazoxane ameliorates doxorubicin-induced cardiotoxicity by inhibiting both apoptosis and necroptosis in cardiomyocytes","volume":"523","author":"Yu","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9603271211066066","DOI":"10.1177\/09603271211066066","article-title":"Protective effects ofnecrostatin-1 on doxorubicin-induced cardiotoxicity in rat heart","volume":"41","author":"ErdogmusOzgen","year":"2022","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.immuni.2013.02.003","article-title":"Necroptosis: The release of damage-associated molecular patterns and its physiological relevance","volume":"38","author":"Kaczmarek","year":"2013","journal-title":"Immunity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1172\/JCI62423","article-title":"Alarmins: Awaiting a clinical response","volume":"122","author":"Chan","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9248640","DOI":"10.1155\/2018\/9248640","article-title":"Pharmaceutical Induction of PGC-1\u03b1 Promotes Retinal Pigment Epithelial Cell Metabolism and Protects against Oxidative Damage","volume":"2018","author":"Satish","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13395-016-0110-x","article-title":"PGC-1\u03b1 modulates necrosis, inflammatory response, and fibrotic tissue formation in injured skeletal muscle","volume":"6","author":"Dinulovic","year":"2016","journal-title":"Skelet. Muscle"},{"key":"ref_18","first-page":"1452696","article-title":"PGC-1\u03b1, Inflammation, and Oxidative Stress: An Integrative View in Metabolism","volume":"2020","author":"Ortega","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.biochi.2019.12.001","article-title":"SIRT1\/PGC-1 pathway activation triggers autophagy\/mitophagy and attenuates oxidative damage in intestinal epithelial cells","volume":"170","author":"Liang","year":"2020","journal-title":"Biochimie"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"118346","DOI":"10.1016\/j.lfs.2020.118346","article-title":"Short-term doxorubicin cardiotoxic effects: Involvement of cardiac Thyrotropin Releasing Hormone system","volume":"261","author":"PeresDiaz","year":"2020","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9577874","DOI":"10.1155\/2021\/9577874","article-title":"Nrf2 Activation Attenuates Chronic Constriction Injury-Induced Neuropathic Pain via Induction of PGC-1\u03b1-Mediated Mitochondrial Biogenesis in the Spinal Cord","volume":"2021","author":"Sun","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s10571-017-0567-0","article-title":"The PGC-1\u03b1 Activator ZLN005 Ameliorates Ischemia-Induced Neuronal Injury In Vitro and In Vivo","volume":"38","author":"Xu","year":"2018","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1161\/CIRCRESAHA.119.314681","article-title":"Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy","volume":"126","author":"Wallace","year":"2020","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6534","DOI":"10.1111\/jcmm.15305","article-title":"Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions","volume":"24","author":"Osataphan","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7411","DOI":"10.18632\/aging.103088","article-title":"PGC-1\u03b1activatorZLN005promotes maturation of cardiomyocytes derived from human embryonic stem cells","volume":"12","author":"Liu","year":"2020","journal-title":"Aging"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.gendis.2020.12.006","article-title":"PGC-1\u03b1 promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes","volume":"8","author":"Zhou","year":"2021","journal-title":"Genes Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"166080","DOI":"10.1016\/j.bbadis.2021.166080","article-title":"Cardiac hypertrophy drives PGC-1\u03b1 suppression associated with enhanced O-glycosylation","volume":"1867","author":"Brainard","year":"2021","journal-title":"Biochim. Et Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhu, P., Ma, H., Cui, S., Zhou, X., Xu, W., Yu, J., and Li, J. (2022). ZLN005 Alleviates In Vivo and In Vitro Renal Fibrosis viaPGC-1\u03b1-Mediated Mitochondrial Homeostasis. Pharmaceuticals, 15.","DOI":"10.3390\/ph15040434"},{"key":"ref_29","first-page":"101070","article-title":"PGC-1\u03b1 attenuates the oxidative stress-induced impaired osteogenesis and angiogenesis regulation effects of mesenchymal stem cells in the presence of diabetic serum","volume":"27","author":"Shi","year":"2021","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cardiores.2005.01.026","article-title":"PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells","volume":"66","author":"Valle","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1089\/ars.2015.6508","article-title":"8-Hydroxy-2-Deoxyguanosine Levels and Cardiovascular Disease: A Systematic Review and Meta-Analysis of the Literature","volume":"24","author":"DiMinno","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e008226","DOI":"10.1161\/JAHA.117.008226","article-title":"Relationship Between Plasma 8-OH-Deoxyguanosine and Cardiovascular Disease and Survival in Type 2 Diabetes Mellitus: Results From the ADVANCE Trial","volume":"7","author":"Thomas","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1161\/CIRCHEARTFAILURE.109.864785","article-title":"Cardiac-specific overexpression of catalase identifies hydrogen peroxide-dependent and-independent phases of myocardial remodeling and prevents the progression to overt heart failure in G(alpha)q-over expressing transgenic mice","volume":"3","author":"Qin","year":"2010","journal-title":"Circ. Heart Fail."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e016862","DOI":"10.1161\/JAHA.120.016862","article-title":"Extracellular Superoxide Dismutase Is Associated With Left Ventricular Geometry and Heart Failure in Patients With Cardiovascular Disease","volume":"9","author":"Li","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.freeradbiomed.2007.12.007","article-title":"Extracellular superoxide dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction","volume":"44","author":"vanDeel","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4870","DOI":"10.1128\/MCB.23.14.4870-4881.2003","article-title":"S100B inhibits myogenic differentiation and myotube formationin a RAGE-independent manner","volume":"23","author":"Sorci","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/jcp.22035","article-title":"S100B protein in myoblasts modulates myogenic differentiation via NF-kappa B-dependent inhibition of MyoD expression","volume":"223","author":"Tubaro","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.bbamcr.2010.11.015","article-title":"S100B in myoblasts regulates the transition from activation to quiescence and from quiescence to activation and reduces apoptosis","volume":"1813","author":"Tubaro","year":"2011","journal-title":"Biochim. Et Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1161\/CIRCULATIONAHA.108.769331","article-title":"High-Mobility Group Box-1 in Ischemia-Reperfusion Injury of the Heart","volume":"117","author":"Andrassy","year":"2008","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00395-012-0267-3","article-title":"Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway","volume":"107","author":"Yao","year":"2012","journal-title":"Basic Res. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8087","DOI":"10.1038\/s41598-022-11994-z","article-title":"Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor","volume":"12","author":"Bosire","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4848","DOI":"10.3892\/mmr.2020.11583","article-title":"Cathepsin B aggravated doxorubicin-induced myocardial injury via NF-\u03baB signalling","volume":"22","author":"Liu","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"H1143","DOI":"10.1152\/ajpheart.00601.2014","article-title":"Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-\u03b1\/ASK1\/JNK pathway","volume":"308","author":"Wu","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.omtn.2022.09.019","article-title":"Cathepsin B deteriorates diabetic cardiomyopathy induced by streptozotocin via promoting NLRP3-mediatedpyroptosis","volume":"30","author":"Liu","year":"2022","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1161\/CIRCULATIONAHA.118.034609","article-title":"Inhibiting Fibronectin Attenuates Fibrosis and Improves Cardiac Function in a Model of Heart Failure","volume":"138","author":"Potter","year":"2018","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1161\/01.CIR.0000140973.60992.9A","article-title":"Increased Collagen Type I Synthesis in Patients With Heart Failure of Hypertensive Origin","volume":"110","author":"Querejeta","year":"2004","journal-title":"Circulation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S1071-9164(99)90034-9","article-title":"Left and right ventricular collagen type I\/III ratios and remodeling post-myocardial infarction","volume":"5","author":"Wei","year":"1999","journal-title":"J. Card. Fail."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/9\/1720\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:46:39Z","timestamp":1760129199000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/12\/9\/1720"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,5]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["antiox12091720"],"URL":"https:\/\/doi.org\/10.3390\/antiox12091720","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,5]]}}}