Browsing by Author "Costa, Vera Marisa"
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- Biomarkers of NRF2 signalling: Current status and future challengesPublication . Morgenstern, Christina; Lastres-Becker, Isabel; Demirdöğen, Birsen Can; Costa, Vera Marisa; Daiber, Andreas; Foresti, Roberta; Motterlini, Roberto; Kalyoncu, Sibel; Arioz, Burak I.; Genc, Sermin; Jakubowska, Monika; Trougakos, Ioannis P.; Piechota-Polanczyk, Aleksandra; Mickael, Michel; Santos, Marlene; Kensler, Thomas W.; Cuadrado, Antonio; Copple, Ian M.The cytoprotective transcription factor NRF2 regulates the expression of several hundred genes in mammalian cells and is a promising therapeutic target in a number of diseases associated with oxidative stress and inflammation. Hence, an ability to monitor basal and inducible NRF2 signalling is vital for mechanistic understanding in translational studies. Due to some caveats related to the direct measurement of NRF2 levels, the modulation of NRF2 activity is typically determined by measuring changes in the expression of one or more of its target genes and/or the associated protein products. However, there is a lack of consensus regarding the most relevant set of these genes/proteins that best represents NRF2 activity across cell types and species. We present the findings of a comprehensive literature search that according to stringent criteria identifies GCLC, GCLM, HMOX1, NQO1, SRXN1 and TXNRD1 as a robust panel of markers that are directly regulated by NRF2 in multiple cell and tissue types. We assess the relevance of these markers in clinically accessible biofluids and highlight future challenges in the development and use of NRF2 biomarkers in humans.
- Cardiac molecular remodeling by anticancer drugs: Doxorubicin affects more metabolism while mitoxantrone impacts more autophagy in adult CD-1 male micePublication . Brandão, Sofia Reis; Reis-Mendes, Ana; Duarte-Araújo, Margarida; Neuparth, Maria João; Rocha, Hugo; Carvalho, Félix; Ferreira, Rita; Costa, Vera MarisaDoxorubicin (DOX) and mitoxantrone (MTX) are classical chemotherapeutic agents used in cancer that induce similar clinical cardiotoxic effects, although it is not clear if they share similar underlying molecular mechanisms. We aimed to assess the effects of DOX and MTX on the cardiac remodeling, focusing mainly on metabolism and autophagy. Adult male CD-1 mice received pharmacologically relevant cumulative doses of DOX (18 mg/kg) and MTX (6 mg/kg). Both DOX and MTX disturbed cardiac metabolism, decreasing glycolysis, and increasing the dependency on fatty acids (FA) oxidation, namely, through decreased AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) content and decreased free carnitine (C0) and increased acetylcarnitine (C2) concentration. Additionally, DOX heavily influenced glycolysis, oxidative metabolism, and amino acids turnover by exclusively decreasing phosphofructokinase (PFKM) and electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH) content, and the concentration of several amino acids. Conversely, both drugs downregulated autophagy given by the decreased content of autophagy protein 5 (ATG5) and microtubule-associated protein light chain 3 (LC3B), with MTX having also an impact on Beclin1. These results emphasize that DOX and MTX modulate cardiac remodeling differently, despite their clinical similarities, which is of paramount importance for future treatments.