{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:19:01Z","timestamp":1772497141328,"version":"3.50.1"},"reference-count":76,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/DTP-FTO\/1489\/2014 \u2013 POCI01-0145-FEDER-016537, UID\/MULTI\/04378\/2019, UIDB\/04423\/2020, UID\/DTP\/00617\/2020, UIDB\/04423\/2020, UIDP\/04423\/2020"],"award-info":[{"award-number":["PTDC\/DTP-FTO\/1489\/2014 \u2013 POCI01-0145-FEDER-016537, UID\/MULTI\/04378\/2019, UIDB\/04423\/2020, UID\/DTP\/00617\/2020, UIDB\/04423\/2020, UIDP\/04423\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/129359\/2017 and SFRH\/BPD\/110001\/2015"],"award-info":[{"award-number":["SFRH\/BD\/129359\/2017 and SFRH\/BPD\/110001\/2015"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Mitoxantrone (MTX) is a pharmaceutical drug used in the treatment of several cancers and refractory multiple sclerosis (MS). Despite its therapeutic value, adverse effects may be severe, namely the frequently reported cardiotoxicity, whose mechanisms need further research. This work aimed to assess if inflammation or oxidative stress-related pathways participate in the cardiotoxicity of MTX, using the mouse as an animal model, at two different age periods (infant or adult mice) using two therapeutic relevant cumulative doses. Histopathology findings showed that MTX caused higher cardiac toxicity in adults. In MTX-treated adults, at the highest dose, noradrenaline cardiac levels decreased, whereas at the lowest cumulative dose, protein carbonylation increased and the expression of nuclear factor kappa B (NF-\u03baB) p65 subunit and of M1 macrophage marker increased. Moreover, MTX-treated adult mice had enhanced expression of NF-\u03baB p52 and tumour necrosis factor (TNF-\u03b1), while decreasing interleukin-6 (IL-6). Moreover, while catalase expression significantly increased in both adult and infant mice treated with the lowest MTX cumulative dose, the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glutathione peroxidase only significantly increased in infant animals. Nevertheless, the ratio of GAPDH to ATP synthase subunit beta decreased in adult animals. In conclusion, clinically relevant doses of MTX caused dissimilar responses in adult and infant mice, being that inflammation may be an important trigger to MTX-induced cardiotoxicity.<\/jats:p>","DOI":"10.3390\/ph14060510","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T21:56:44Z","timestamp":1622066204000},"page":"510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Inflammation as a Possible Trigger for Mitoxantrone-Induced Cardiotoxicity: An In Vivo Study in Adult and Infant Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-3147","authenticated-orcid":false,"given":"Ana","family":"Reis-Mendes","sequence":"first","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7355-8502","authenticated-orcid":false,"given":"Jos\u00e9 Lu\u00eds","family":"Dores-Sousa","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2359-6321","authenticated-orcid":false,"given":"Ana Isabel","family":"Padr\u00e3o","sequence":"additional","affiliation":[{"name":"Research Center in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sport, University of Porto, 4200-450 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4727-727X","authenticated-orcid":false,"given":"Margarida","family":"Duarte-Ara\u00fajo","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, University of Porto, 4050-313 Porto, Portugal"},{"name":"Department of Immune-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4756-5917","authenticated-orcid":false,"given":"Jos\u00e9 Alberto","family":"Duarte","sequence":"additional","affiliation":[{"name":"Research Center in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sport, University of Porto, 4200-450 Porto, Portugal"},{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Paredes, Portugal"}]},{"given":"V\u00edtor","family":"Seabra","sequence":"additional","affiliation":[{"name":"IINFACTS\u2014Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Paredes, Portugal"}]},{"given":"Salom\u00e9","family":"Gon\u00e7alves-Monteiro","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"MOREHealth, Outcomes Research Lab, Portuguese Institute of Oncology at Porto Francisco Gentil (IPO Porto), 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-3494","authenticated-orcid":false,"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry, Chemistry Department, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"CIIMAR\u2014Interdisciplinary Centre of Marine and Environmental Research, 4450-208 Porto, Portugal"}]},{"given":"Maria Lourdes","family":"Bastos","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0471-2756","authenticated-orcid":false,"given":"Vera Marisa","family":"Costa","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2174\/1389200216666151103114926","article-title":"The Role of the Metabolism of Anticancer Drugs in Their Induced-Cardiotoxicity","volume":"17","author":"Sousa","year":"2015","journal-title":"Curr. Drug Metab."},{"key":"ref_2","unstructured":"Chabner, B.A., and Long, D.L. (2011). Topoisomerase II inhibitors. Cancer Chemotherapy and Biotherapy: Principles and Practice, Lippincot Williams and Wilkins."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1212\/WNL.63.12_suppl_6.S15","article-title":"Mechanism of action of mitoxantrone","volume":"63","author":"Fox","year":"2004","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2165\/00023210-200418060-00010","article-title":"Mitoxantrone: A review of its use in multiple sclerosis","volume":"18","author":"Scott","year":"2004","journal-title":"CNS Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1021\/tx400130v","article-title":"The heart as a target for xenobiotic toxicity: The cardiac susceptibility to oxidative stress","volume":"26","author":"Costa","year":"2013","journal-title":"Chem. Res. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1517\/14740338.4.2.219","article-title":"Toxicity of the topoisomerase II inhibitors","volume":"4","author":"Seiter","year":"2005","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3988\/jcn.2014.10.4.289","article-title":"Cardiotoxicity of mitoxantrone treatment in a german cohort of 639 multiple sclerosis patients","volume":"10","author":"Fleischer","year":"2014","journal-title":"J. Clin. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Rivera, V.M., Jeffery, D.R., Weinstock-Guttman, B., Bock, D., and Dangond, F. (2013). Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis) study. BMC Neurol., 13.","DOI":"10.1186\/1471-2377-13-80"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1161\/CIRCULATIONAHA.114.008788","article-title":"Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling","volume":"131","author":"Frieler","year":"2015","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1161\/CIRCRESAHA.116.302317","article-title":"Innate immunity and the failing heart: The cytokine hypothesis revisited","volume":"116","author":"Mann","year":"2015","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1161\/CIRCRESAHA.116.303577","article-title":"The Biological Basis for Cardiac Repair after Myocardial Infarction: From Inflammation to Fibrosis","volume":"119","author":"Prabhu","year":"2016","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhou, B., Rao, L., Peng, Y., Wang, Y., Li, Y., Gao, L., Chen, Y., Xue, H., Song, Y., and Liao, M. (2009). Functional polymorphism of the NFKB1 gene promoter is related to the risk of dilated cardiomyopathy. BMC Med. Genet., 10.","DOI":"10.1186\/1471-2350-10-47"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Santos, D.G., Resende, M.F., Mill, J.G., Mansur, A.J., Krieger, J.E., and Pereira, A.C. (2010). Nuclear Factor (NF) kappaB polymorphism is associated with heart function in patients with heart failure. BMC Med. Genet., 11.","DOI":"10.1186\/1471-2350-11-89"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"H2181","DOI":"10.1152\/ajpheart.00554.2011","article-title":"Oxidative stress and heart failure","volume":"301","author":"Tsutsui","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3389\/fphys.2013.00042","article-title":"Cytokine-induced oxidative stress in cardiac inflammation and heart failure-how the ubiquitin proteasome system targets this vicious cycle","volume":"4","author":"Voigt","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","article-title":"Mechanisms of physiological and pathological cardiac hypertrophy","volume":"15","author":"Nakamura","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1161\/CIRCRESAHA.115.306565","article-title":"Cardiac Fibrosis: The Fibroblast Awakens","volume":"118","author":"Travers","year":"2016","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5456","DOI":"10.1073\/pnas.070036297","article-title":"Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction","volume":"97","author":"Kurrelmeyer","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1161\/01.CIR.97.14.1392","article-title":"Tumor necrosis factor-alpha confers resistance to hypoxic injury in the adult mammalian cardiac myocyte","volume":"97","author":"Nakano","year":"1998","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1172\/JCI119114","article-title":"Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death","volume":"98","author":"Krown","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1161\/01.RES.81.4.627","article-title":"Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha","volume":"81","author":"Kubota","year":"1997","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23814","DOI":"10.1074\/jbc.M909695199","article-title":"C p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system","volume":"275","author":"Craig","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/01.shk.0000226341.32786.b9","article-title":"Jak\/STAT\/SOCS signaling circuits and associated cytokine-mediated inflammation and hypertrophy in the heart","volume":"26","author":"Terrell","year":"2006","journal-title":"Shock"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/cncr.11032","article-title":"Treatment of large cell lymphoma in elderly patients with a mitoxantrone, cyclophosphamide, etoposide, and prednisone regimen: Long-term follow-up results","volume":"97","author":"Rigacci","year":"2003","journal-title":"Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/pbc.20834","article-title":"Improved outcome in childhood acute myeloid leukemia in Singapore with the MRC AML 10 protocol","volume":"48","author":"Tan","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/BF00172015","article-title":"Novantrone for childhood malignant solid tumors. A pediatric oncology group phase II study","volume":"4","author":"Pratt","year":"1986","journal-title":"Investig. New Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1200\/JCO.2000.18.9.1867","article-title":"Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia","volume":"18","author":"Dahl","year":"2000","journal-title":"J. Clin. Oncol."},{"key":"ref_28","first-page":"1247","article-title":"Cardiac function in 5-year survivors of childhood cancer: A long-term follow-up study","volume":"170","author":"Hauptmann","year":"2010","journal-title":"Arch. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1200\/JCO.2013.49.3205","article-title":"Modifiable risk factors and major cardiac events among adult survivors of childhood cancer","volume":"31","author":"Armstrong","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"93","DOI":"10.7326\/M15-0424","article-title":"Cardiac Outcomes in Adult Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy: A Cross-sectional Study","volume":"164","author":"Mulrooney","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"h7026","DOI":"10.1136\/bmj.h7026","article-title":"Adult survivors of childhood cancer are at high risk of cardiac abnormalities, study finds","volume":"352","author":"Wise","year":"2016","journal-title":"BMJ"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Minotti, G. (2010). Cardiovasclular toxicity of antitumor drugs: Dimension of the problem in children. Cardiotoxicity of Non-Cardiovascular Drugs, John Wiley & Sons, Ltd.","DOI":"10.1002\/9780470660379"},{"key":"ref_33","unstructured":"Howlader, N.N.A., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., Lewis, D.R., and Chen, H.S. (2020, April 09). SEER Cancer Statistics Review 1975\u20132017, Available online: https:\/\/seer.cancer.gov\/csr\/1975_2017\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.tox.2015.01.006","article-title":"The age factor for mitoxantrone\u2019s cardiotoxicity: Multiple doses render the adult mouse heart more susceptible to injury","volume":"329","author":"Duarte","year":"2015","journal-title":"Toxicology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/ijc.2910590418","article-title":"Circadian changes in mitoxantrone toxicity in mice: Relationship with plasma pharmacokinetics","volume":"59","author":"Levi","year":"1994","journal-title":"Int. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.peptides.2017.07.007","article-title":"Pituitary adenylate cyclase-activating polypeptide (PACAP) protects against mitoxantrone-induced cardiac injury in mice","volume":"95","author":"Subramaniam","year":"2017","journal-title":"Peptides"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s12012-013-9230-2","article-title":"Mitochondrial cumulative damage induced by mitoxantrone: Late onset cardiac energetic impairment","volume":"14","author":"Rossato","year":"2014","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/S0272-2712(18)30598-5","article-title":"Aminotransferases in disease","volume":"9","author":"Rej","year":"1989","journal-title":"Clin. Lab. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/bcpt.12143","article-title":"Cumulative mitoxantrone-induced haematological and hepatic adverse effects in a subchronic in vivo study","volume":"114","author":"Rossato","year":"2014","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_40","first-page":"1465","article-title":"Chrysin attenuates cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity","volume":"30","author":"Anghel","year":"2015","journal-title":"Histol. Histopathol."},{"key":"ref_41","first-page":"194","article-title":"Comparative study of doxorubicin, mitoxantrone, and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model","volume":"52","author":"Alderton","year":"1992","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s10637-007-9037-8","article-title":"Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: Comparative studies against doxorubicin and mitoxantrone","volume":"25","author":"Cavalletti","year":"2007","journal-title":"Investig. New Drugs"},{"key":"ref_43","first-page":"343","article-title":"Cardiac evaluation of mitoxantrone","volume":"67","author":"Unverferth","year":"1983","journal-title":"Cancer Treat. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.maturitas.2016.03.022","article-title":"Adrenergic signaling in heart failure and cardiovascular aging","volume":"93","author":"Santulli","year":"2016","journal-title":"Maturitas"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s12325-011-0091-4","article-title":"Creatine phosphate: Pharmacological and clinical perspectives","volume":"29","author":"Strumia","year":"2012","journal-title":"Adv. Ther."},{"key":"ref_46","first-page":"45","article-title":"Creatine and phosphocreatine: A review of their use in exercise and sport","volume":"32","author":"Clark","year":"1997","journal-title":"J. Athl. Train."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41569-018-0044-6","article-title":"Metabolic remodelling in heart failure","volume":"15","author":"Bertero","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.tox.2010.01.019","article-title":"Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy","volume":"270","author":"Carvalho","year":"2010","journal-title":"Toxicology"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Brand\u00e3o, S., Reis-Mendes, A., Domingues, P., Alberto Duarte, J., Lourdes Bastos, M., Carvalho, F., Ferreira, R., and Costa, V.M. (2021). Exploring the effects of the anticancer drugs doxorubicin and mitoxantrone on cardiac mitochondrial proteome using a murine model. Toxicology, Submitted.","DOI":"10.1016\/j.tox.2021.152852"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0300-483X(93)90135-F","article-title":"Oxidative stress in mouse heart by antitumoral drugs: A comparative study of doxorubicin and mitoxantrone","volume":"77","author":"Llesuy","year":"1993","journal-title":"Toxicology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1016\/j.bbadis.2013.04.029","article-title":"Hydrogen peroxide production regulates the mitochondrial function in insulin resistant muscle cells: Effect of catalase overexpression","volume":"1832","author":"Barbosa","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_52","first-page":"815","article-title":"The effect of doxorubicin and its analogue mitoxantrone on cardiac muscle and on serum lipids: An experimental study","volume":"22","author":"Koutinos","year":"2002","journal-title":"Anticancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4067","DOI":"10.1007\/s00204-020-02874-4","article-title":"Mitoxantrone impairs proteasome activity and prompts early energetic and proteomic changes in HL-1 cardiomyocytes at clinically relevant concentrations","volume":"94","author":"Costa","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1002\/med.20073","article-title":"Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls","volume":"27","author":"Aldini","year":"2007","journal-title":"Med. Res. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e98278","DOI":"10.1172\/jci.insight.98278","article-title":"TNF receptor-activated factor 2 mediates cardiac protection through noncanonical NF-\u03baB signaling","volume":"3","author":"Evans","year":"2018","journal-title":"JCI Insight"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"173090","DOI":"10.1016\/j.ejphar.2020.173090","article-title":"Macrophage M1\/M2 polarization","volume":"877","author":"Yunna","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nri3520","article-title":"Macrophages in atherosclerosis: A dynamic balance","volume":"13","author":"Moore","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e002860","DOI":"10.1161\/JAHA.115.002860","article-title":"Systematic Evaluation of the Cellular Innate Immune Response during the Process of Human Atherosclerosis","volume":"5","author":"Rijs","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1089\/ars.2010.3228","article-title":"Aging and immune function: Molecular mechanisms to interventions","volume":"14","author":"Ponnappan","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1089\/ars.2009.2930","article-title":"Targeting the vicious inflammation-oxidative stress cycle for the management of heart failure","volume":"13","author":"Khaper","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1023\/A:1011401825680","article-title":"The role of interleukin-6 in the failing heart","volume":"6","author":"Wollert","year":"2001","journal-title":"Heart Fail. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"H926","DOI":"10.1152\/ajpheart.00436.2001","article-title":"Differential expression of TNF-alpha, IL-6, and IGF-1 by graded mechanical stress in normal rat myocardium","volume":"282","author":"Palmieri","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.etap.2019.03.006","article-title":"Low doses of Bisphenol A have pro-inflammatory and pro-oxidant effects, stimulate lipid peroxidation and increase the cardiotoxicity of Doxorubicin in cardiomyoblasts","volume":"69","author":"Quagliariello","year":"2019","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Quagliariello, V., Vecchione, R., Coppola, C., Di Cicco, C., De Capua, A., Piscopo, G., Paciello, R., Narciso, V., Formisano, C., and Taglialatela-Scafati, O. (2018). Cardioprotective Effects of Nanoemulsions Loaded with Anti-Inflammatory Nutraceuticals against Doxorubicin-Induced Cardiotoxicity. Nutrients, 10.","DOI":"10.3390\/nu10091304"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Quagliariello, V., Passariello, M., Rea, D., Barbieri, A., Iovine, M., Bonelli, A., Caronna, A., Botti, G., De Lorenzo, C., and Maurea, N. (2020). Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models. J. Pers. Med., 10.","DOI":"10.3390\/jpm10040179"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1159\/000095762","article-title":"In vivo effects of mitoxantrone on the production of pro- and anti-inflammatory cytokines by peripheral blood mononuclear cells of secondary progressive multiple sclerosis patients","volume":"13","author":"Angelucci","year":"2006","journal-title":"Neuroimmunomodulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.lfs.2015.10.025","article-title":"Men and mice: Relating their ages","volume":"152","author":"Dutta","year":"2016","journal-title":"Life Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"117242","DOI":"10.1016\/j.lfs.2019.117242","article-title":"Correlation between mouse age and human age in anti-tumor research: Significance and method establishment","volume":"242","author":"Wang","year":"2020","journal-title":"Life Sci."},{"key":"ref_69","unstructured":"Edwards, L.D., Fox, A.W., and Stonier, P.D. (2010). Phase I: The first opportunity for extrapolation from animal data to human exposure. Principles and Practice of Pharmaceutical Medicine, Wiley-Blackwell."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_71","first-page":"12","article-title":"Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies?","volume":"37","author":"Archie","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0021-9258(19)52451-6","article-title":"Protein measurement with the Folin phenol reagent","volume":"193","author":"Lowry","year":"1951","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1021\/bi00702a015","article-title":"Kinetics of the firefly luciferase catalyzed reactions","volume":"13","author":"DeLuca","year":"1974","journal-title":"Biochemistry"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s00204-003-0510-7","article-title":"Hepatotoxicity of 3,4-methylenedioxyamphetamine and alpha-methyldopamine in isolated rat hepatocytes: Formation of glutathione conjugates","volume":"78","author":"Carvalho","year":"2004","journal-title":"Arch. Toxicol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/j.biocel.2013.04.014","article-title":"Bladder cancer-induced skeletal muscle wasting: Disclosing the role of mitochondria plasticity","volume":"45","author":"Oliveira","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1007\/s00204-015-1582-x","article-title":"A breakthrough on Amanita phalloides poisoning: An effective antidotal effect by polymyxin B","volume":"89","author":"Garcia","year":"2015","journal-title":"Arch. Toxicol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/6\/510\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:08:22Z","timestamp":1760162902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/14\/6\/510"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,26]]},"references-count":76,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ph14060510"],"URL":"https:\/\/doi.org\/10.3390\/ph14060510","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,26]]}}}