Percorrer por autor "Amado, Francisco"
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- Estrogen receptors in urogenital schistosomiasis and bladder cancer: Estrogen receptor alpha-mediated cell proliferationPublication . Bernardo, Carina; Santos, Júlio; Costa, Céu; Tavares, Ana; Amaro, Teresina; Marques, Igor; Gouveia, Maria João; Félix, Vítor; Afreixo, Vera; Brindley, Paul J.; Costa, José Manuel; Amado, Francisco; Helguero, Luisa; Santos, Lúcio L.Estrogen-like metabolites have been identified in S. haematobium, the helminth parasite that causes urogenital schistosomiasis (UGS) and in patients´ blood and urine during UGS. Estrogen receptor (ER) activation is enriched in the luminal molecular subtype bladder cancer (BlaCa). To date, the significance of ER to these diseases remains elusive. We evaluated ERα and ERβ expression in UGS-related BlaCa (n = 27), UGS-related non-malignant lesions (n = 35), and noninfected BlaCa (n = 80). We investigated the potential of ERα to recognize S. haematobium-derived metabolites by docking and molecular dynamics simulations and studied ERα modulation in vitro using 3 BlaCa cell lines, T24, 5637 and HT1376. ERα was expressed in tumor and stromal cells in approximately 20% noninfected cases and in 30% of UGS-related BlaCa, predominantly in the epithelial cells. Overall, ERα expression was associated with features of tumor aggressiveness such as high proliferation and p53 positive expression. ERα expression correlated with presence of schistosome eggs. ERβ was widely expressed in both cohorts but weaker in UGS-related cases. molecular dynamics simulations of the 4 most abundant S. haematobium-derived metabolites revealed that smaller metabolites have comparable affinity for the ERα active state than 17β-estradiol, while the larger metabolites present higher affinity. Our in vitro findings suggested that ERα activation promotes proliferation in ERα expressing BlaCa cells and that this can be reverted with anti-estrogenic therapy. In summary, we report differential ER expression between UGS-related BlaCa and noninfected BlaCa and provide evidence supporting a role of active ERα during UGS and UGS-induced carcinogenesis.
- Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomicsPublication . Bernardo, Carina; Cunha, Maria Cláudia; Santos, Júlio Henrique; da Costa, José M Correia; Brindley, Paul J; Lopes, Carlos; Amado, Francisco; Ferreira, Rita; Vitorino, Rui; Santos, Lúcio LaraInfection due to Schistosoma haematobium is carcinogenic. However, the cellular and molecular mechanisms underlying urogenital schistosomiasis (UGS)-induced carcinogenesis have not been well defined. Conceptually, early molecular detection of this phenomenon, through non-invasive procedures, seems feasible and is desirable. Previous analysis of urine collected during UGS suggests that estrogen metabolites, including depurinating adducts, may be useful for this purpose. Here, a new direction was pursued: the identification of molecular pathways and potential biomarkers in S. haematobium-induced bladder cancer by analyzing the proteome profiling of urine samples from UGS patients. GeLC-MS/MS followed by protein-protein interaction analysis indicated oxidative stress and immune defense systems responsible for microbicide activity are the most representative clusters in UGS patients. Proteins involved in immunity, negative regulation of endopeptidase activity, and inflammation were more prevalent in UGS patients with bladder cancer, whereas proteins with roles in renal system process, sensory perception, and gas and oxygen transport were more abundant in subjects with urothelial carcinoma not associated with UGS. These findings highlighted a Th2-type immune response induced by S. haematobium, which seems to be further modulated by tumorigenesis, resulting in high-grade bladder cancer characterized by an inflammatory response and complement activation alternative pathway. These findings established a starting point for the development of multimarker strategies for the early detection of UGS-induced bladder cancer.
- Proteomics advances in the last decade: What is next?Publication . Penque, Deborah; Simoes, Tania; Amado, FranciscoDuring the first decade of this millennium, we have witnessed of the most remarkable advances in the field of proteomics since the word proteome was introduced by Marc Wilkins in 1995. High degree of technical innovations has been successfully achieved to meet the ongoing challenges mostly associated with the need to know and map all proteins, their variants and functional networks in a given cell/tissue/organism at a particular time/condition. The best example of this ambition is the Human Proteome Project (HPP), launched by the Human Proteome Organization (HUPO), designed to map the entire human proteome. Completion of this project will certainly enhance our understanding of human cell/molecular biology and provide new tools for better health and disease control
- Quantitative Proteomic Analysis of Skeletal Muscle Detergent-Resistant Membranes in a Smith-Lemli-Opitz Syndrome MousePublication . Cardoso, Maria Luís; Vitorino, Rui; Reguengo, Henrique; Casal, Susana; Fernandes, Rui; Duarte, Isabel; Lamas, Sofia; Alves, Renato; Amado, Francisco; Marques, FranklimSmith-Lemli-Opitz syndrome (SLOS) is an inborn error of metabolism affecting the last step of cholesterol biosynthesis. It is characterized by a deficiency of the enzyme 7- dehydrocholesterol reductase and accumulation of 7-dehydrocholesterol (7DHC) in cells and body fluids. Given the similarities between 7DHC and cholesterol, 7DHC can be incorporated into cell membranes in lieu of cholesterol. Nevertheless, due to their structural differences and distinct affinity to other membrane components, this substitution alters membrane properties and one can expect to find abnormalities in membrane protein composition. In order to identify differences in membrane proteins that could facilitate our understanding of SLOS physiopathology, we isolated detergent-resistant membranes (DRMs) from the skeletal muscle of Dhcr7T93M/T93M mice and C57/BL6 controls and performed comparative proteomic analysis using iTRAQ for peptide quantification. A total of 133 proteins were identified in the DRM fraction: 17 (13%) proteins demonstrated increased expression in SLOS mice, whereas, 21 (16%) showed decreased expression. Characterization of functional point of view and bioenergetics pathway and transmembrane transport responded to the major differences between the two groups of animals.
- Role of mitochondrial antioxidant defense systems in fatty acid β-oxidation defectsPublication . Rocha, Hugo; Ferreira, Rita; Vitorino, Rui; Almeida, Vanessa; Santa, Cátia; Lopes, Lurdes; Vilarinho, Laura; Amado, FranciscoMitochondrial fatty acid oxidation (FAO) plays a pivotal role in energy homeostasis, namely during periods of fasting or metabolic stress. FAO defects are a group of inherited metabolic disorders that encompass at least twelve distinct enzyme or transporter deficiencies, and can present with a wide range of clinical symptoms with various degrees of severity. Besides recent advances, many doubts still remain on the degree and characteristics of mitochondrial dysfunction on FAOD and its contribution to the clinical phenotype.