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from FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P., in the scope of the project UIDP\/04378\/2020 and UIDB\/04378\/2020 of the Research Unit on Applied Molecular Biosciences-UCIBIO and the project LA\/P\/0140\/2020 of the Associate Laboratory Institute for Health and Bioeconomy-i4HB."]}]},{"name":"FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P","award":["This work was funded by national funds from FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P., in the scope of the project UIDP\/04378\/2020 and UIDB\/04378\/2020 of the Research Unit on Applied Molecular Biosciences-UCIBIO and the project LA\/P\/0140\/2020 of the Associate Laboratory Institute for Health and Bioeconomy-i4HB."],"award-info":[{"award-number":["This work was funded by national funds from FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P., in the scope of the project UIDP\/04378\/2020 and UIDB\/04378\/2020 of the Research Unit on Applied Molecular 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Tecnologia, I.P","award":["This work was funded by national funds from FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P., in the scope of the project UIDP\/04378\/2020 and UIDB\/04378\/2020 of the Research Unit on Applied Molecular Biosciences-UCIBIO and the project LA\/P\/0140\/2020 of the Associate Laboratory Institute for Health and Bioeconomy-i4HB."],"award-info":[{"award-number":["This work was funded by national funds from FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P., in the scope of the project UIDP\/04378\/2020 and UIDB\/04378\/2020 of the Research Unit on Applied Molecular Biosciences-UCIBIO and the project LA\/P\/0140\/2020 of the Associate Laboratory Institute for Health and Bioeconomy-i4HB."]}]},{"name":"FCT-Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P","award":["Ana Reis-Mendes and Vera Marisa Costa acknowledge FCT for their Grants: SFRH\/ BD\/129359\/2017 and SFRH\/BPD\/110001\/2015, respectively, being the latter funded by national funds through FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P., under the Norma Transit\u00f3ria\u2014DL57\/2016\/ CP1334\/CT0006."],"award-info":[{"award-number":["Ana Reis-Mendes and Vera Marisa Costa acknowledge FCT for their Grants: SFRH\/ BD\/129359\/2017 and SFRH\/BPD\/110001\/2015, respectively, being the latter funded by national funds through FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia, I.P., under the Norma Transit\u00f3ria\u2014DL57\/2016\/ CP1334\/CT0006."]}]},{"DOI":"10.13039\/501100006752","name":"Universidade do Porto","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006752","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflammation"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Doxorubicin (DOX) is a topoisomerase II inhibitor used in cancer therapy. Despite its efficacy, DOX causes serious adverse effects, such as short- and long-term cardiotoxicity. This work aimed to assess the short- and long-term cardiotoxicity of DOX and the role of inflammation and antioxidant defenses on that cardiotoxicity in a mice model. Adult CD-1 male mice received a cumulative dose of 9.0\u00a0mg\/kg of DOX (2 biweekly intraperitoneal injections (ip), for 3\u00a0weeks). One week (1W) or 5\u00a0months (5M) after the last DOX administration, the heart was collected. One week\u00a0after DOX, a significant increase in p62, tumor necrosis factor receptor (TNFR) 2, glutathione peroxidase 1, catalase, inducible nitric oxide synthase (iNOS) cardiac expression, and a trend towards an increase in interleukin (IL)-6, TNFR1, and B-cell lymphoma 2 associated X (Bax) expression was observed. Moreover, DOX induced a decrease on\u00a0nuclear factor erythroid-2 related factor 2 (Nrf2) cardiac expression. In both 1W and 5M, DOX led to a high density of infiltrating M1 macrophages, but only the 1W-DOX group had a significantly higher number of nuclear factor \u03baB (NF-\u03baB) p65 immunopositive cells. As late effects (5M), an increase in Nrf2, myeloperoxidase, IL-33, tumor necrosis factor-\u03b1 (TNF-\u03b1), superoxide dismutase 2 (SOD2) expression, and a trend towards increased catalase expression were observed. Moreover, B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), and carbonylated proteins expression decreased, and a trend towards decreased p38 mitogen-activated protein kinase (MAPK) expression were seen. Our study demonstrated that DOX induces adverse outcome pathways related to inflammation and oxidative stress, although activating different time-dependent response mechanisms.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s10753-023-01908-0","type":"journal-article","created":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T03:25:13Z","timestamp":1697253913000},"page":"264-284","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Role of Nrf2 and Inflammation on the Dissimilar Cardiotoxicity of Doxorubicin in Two-Time Points: a Cardio-Oncology In Vivo Study Through Time"],"prefix":"10.1007","volume":"47","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":"Ana Isabel","family":"Padr\u00e3o","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":[[2023,10,14]]},"reference":[{"key":"1908_CR1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200216666151103114926","author":"A Reis-Mendes","year":"2015","unstructured":"Reis-Mendes, A., E. 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