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However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18\u201320\u00a0months) CD-1 male mice received biweekly DOX administrations, for 3\u00a0weeks, to reach a cumulative dose of 9.0\u00a0mg\/kg. One week (1W) or two months (2\u00a0M) after the last DOX administration, the heart was collected to determine both drug\u2019s short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-\u03baB) p65 immunopositive cells increased and a trend toward increased NF-\u03baB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1\u03b2, p62, and microtubule-associated protein 1A\/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2\u00a0M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-\u03baB p65, myeloperoxidase, LC3-I, and LC3-II expression\u00a0decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment\u00a0cardiac monitoring.<\/jats:p>","DOI":"10.1007\/s00204-023-03586-1","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T08:02:27Z","timestamp":1694073747000},"page":"3163-3177","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The role of inflammation and antioxidant defenses in the cardiotoxicity of doxorubicin in elderly CD-1 male mice"],"prefix":"10.1007","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-3147","authenticated-orcid":false,"given":"Ana","family":"Reis-Mendes","sequence":"first","affiliation":[]},{"given":"Mariana","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 Alberto","family":"Duarte","sequence":"additional","affiliation":[]},{"given":"Margarida","family":"Duarte-Ara\u00fajo","sequence":"additional","affiliation":[]},{"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[]},{"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Maria Lourdes","family":"Bastos","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0471-2756","authenticated-orcid":false,"given":"Vera Marisa","family":"Costa","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,9,7]]},"reference":[{"key":"3586_CR1","doi-asserted-by":"publisher","first-page":"154","DOI":"10.3389\/fcell.2019.00154","volume":"7","author":"BC Albensi","year":"2019","unstructured":"Albensi BC (2019) What is nuclear factor kappa B (NF-\u03baB) doing in and to the mitochondrion? 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