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- Sweet Cherries as Anti-Cancer Agents: From Bioactive Compounds to FunctionPublication . Fonseca, Lara R. S.; Silva, Gonçalo R.; Luís, Ângelo; Cardoso, Henrique J.; Correia, Sara; Vaz, CV; Duarte, Ana Paula; Socorro, SílviaSweet cherries (Prunus avium L.) are among the most appreciated fruits worldwide because of their organoleptic properties and nutritional value. The accurate phytochemical composition and nutritional value of sweet cherries depends on the climatic region, cultivar, and bioaccessibility and bioavailability of specific compounds. Nevertheless, sweet cherry extracts are highly enriched in several phenolic compounds with relevant bioactivity. Over the years, technological advances in chemical analysis and fields as varied as proteomics, genomics and bioinformatics, have allowed the detailed characterization of the sweet cherry bioactive phytonutrients and their biological function. In this context, the effect of sweet cherries on suppressing important events in the carcinogenic process, such as oxidative stress and inflammation, was widely documented. Interestingly, results from our research group and others have widened the action of sweet cherries to many hallmarks of cancer, namely metabolic reprogramming. The present review discusses the anticarcinogenic potential of sweet cherries by addressing their phytochemical composition, the bioaccessibility and bioavailability of specific bioactive compounds, and the existing knowledge concerning the effects against oxidative stress, chronic inflammation, deregulated cell proliferation and apoptosis, invasion and metastization, and metabolic alterations. Globally, this review highlights the prospective use of sweet cherries as a dietary supplement or in cancer treatment.
- Suppressed glycolytic metabolism in the prostate of transgenic rats overexpressing calcium-binding protein regucalcin underpins reduced cell proliferationPublication . Vaz, CV; Marques, Ricardo; Cardoso, HJ; Baptista, Cláudio; Socorro, SílviaRegucalcin (RGN) is a calcium-binding protein underexpressed in human prostate cancer cases, and it has been associated with the suppression of cell proliferation and the regulation of several metabolic pathways. On the other hand, it is known that the metabolic reprogramming with augmented glycolytic metabolism and enhanced proliferative capability is a characteristic of prostate cancer cells. The present study investigated the influence of RGN on the glycolytic metabolism of rat prostate by comparing transgenic adult animals overexpressing RGN (Tg-RGN) with their wild-type counterparts. Glucose consumption was significantly decreased in the prostate of Tg-RGN animals relatively to wild-type, and accompanied by the diminished expression of glucose transporter 3 and glycolytic enzyme phosphofructokinase. Also, prostates of Tg-RGN animals displayed lower lactate levels, which resulted from the diminished expression/activity of lactate dehydrogenase. The expression of the monocarboxylate transporter 4 responsible for the export of lactate to the extracellular space was also diminished with RGN overexpression. These results showed the effect of RGN in inhibiting the glycolytic metabolism in rat prostate, which was underpinned by a reduced cell proliferation index. The present findings also suggest that the loss of RGN may predispose to a hyper glycolytic profile and fostered proliferation of prostate cells.
- Glucose and glutamine handling in the Sertoli cells of transgenic rats overexpressing regucalcin: plasticity towards lactate productionPublication . Mateus, Inês; Feijó, Mariana; Espínola, Luís M; Vaz, CV; Correia, Sara; Socorro, SílviaSertoli cells (SCs) possess the unparalleled ability to provide the germ line with growth factors and nutrients. Although SCs can oxidize amino acids, e.g., glutamine, they mostly metabolize glucose, producing high amounts of lactate, the germ cells preferential substrate. Regucalcin (RGN) is a calcium-binding protein that has been indicated as a regulator of cell metabolism. In this study, we investigated glucose and glutamine handling in the SCs of transgenic rats overexpressing RGN (Tg-RGN) comparatively with wild-type (Wt) littermates. Primary SCs isolated from adult Tg-RGN animals and maintained in culture for 24 hours, produced and exported more lactate, despite consuming less glucose. These observations were underpinned by increased expression of alanine transaminase, and augmented glutamine consumption, suggesting that alternative routes are contributing to the enhanced lactate production in the SCs of Tg-RGN rats. Moreover, lactate seems to be used by germ cells, with diminished apoptosis being detected in the seminiferous tubules of Tg-RGN animals cultured ex vivo. The obtained results showed a distinct metabolism in the SCs of Wt and Tg-RGN rats widening the roles assigned to RGN in spermatogenesis. These findings also highlighted the plasticity of SCs metabolism, a feature that would be exploited in the context of male infertility.
- The Pros and Cons of Estrogens in Prostate Cancer: An Update with a Focus on PhytoestrogensPublication . Figueira, Marília I; Carvalho, Tiago; Monteiro, Joana; Cardoso, Henrique J.; Correia, Sara; Vaz, CV; Duarte, Ana Paula; Socorro, SílviaThe role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment.
- Sweet Cherry Extract Targets the Hallmarks of Cancer in Prostate Cells: Diminished Viability, Increased Apoptosis and Suppressed Glycolytic MetabolismPublication . Silva, Gonçalo; Vaz, CV; Catalão, Beatriz; Ferreira, Susana; Cardoso, HJ; Duarte, A. P.; Socorro, SílviaThe present work evaluated the anticancer properties of sweet cherry (Prunus avium) extract on human prostate cells. Several sweet cherry cultivars from Fundão (Portugal) were methanol-extracted and their phytochemical composition characterized. The Saco "late harvest" extract was highly-enriched in anthocyanins and selected for use in biological assays. Non-neoplastic (PNT1A) and neoplastic (LNCaP and PC3) human prostate cells were treated with 0-2,000 μg/ml of extract for 48-96 h. Cell viability was evaluated by the MTT assay. Apoptosis, oxidative stress, and glycolytic metabolism were assessed by Western blotting and enzymatic assays. Glucose consumption and lactate production were measured spectrophotometrically. Saco cherry extract diminished the viability of neoplastic and non-neoplastic cells, whereas enhancing apoptosis in LNCaP. Cherry extract-treatment also diminished oxidative damage and suppressed glycolytic metabolism in LNCaP cells. These findings widened the knowledge on the mechanisms by which cherry extract modulate cell physiology, demonstrating their broad action over the hallmarks of cancer.
- The diverse roles of calcium-binding protein regucalcin in cell biology: from tissue expression and signalling to diseasePublication . Marques, Ricardo; Baptista, Cláudio; Vaz, CV; Correia, Sara; Socorro, SílviaRegucalcin (RGN) is a calcium (Ca(2+))-binding protein widely expressed in vertebrate and invertebrate species, which is also known as senescence marker protein 30, due to its molecular weight (33 kDa) and a characteristically diminished expression with the aging process. RGN regulates intracellular Ca(2+) homeostasis and the activity of several proteins involved in intracellular signalling pathways, namely, kinases, phosphatases, phosphodiesterase, nitric oxide synthase and proteases, which highlights its importance in cell biology. In addition, RGN has cytoprotective effects reducing intracellular levels of oxidative stress, also playing a role in the control of cell survival and apoptosis. Multiple factors have been identified regulating the cell levels of RGN transcripts and protein, and an altered expression pattern of this interesting protein has been found in cases of reproductive disorders, neurodegenerative diseases and cancer. Moreover, RGN is a serum-secreted protein, and its levels have been correlated with the stage of disease, which strongly suggests the usefulness of this protein as a potential biomarker for monitoring disease onset and progression. The present review aims to discuss the available information concerning RGN expression and function in distinct cell types and tissues, integrating cellular and molecular mechanisms in the context of normal and pathological conditions. Insight into the cellular actions of RGN will be a key step towards deepening the knowledge of the biology of several human diseases.
- Chemical signature and antimicrobial activity of Central Portuguese Natural Mineral Waters against selected skin pathogensPublication . Oliveira, AS; Vaz, CV; Silva, Ana; Ferreira, Sandra S.; Correia, Sara; Ferreira, Raquel; Granadeiro, Luiza Breitenfeld ; Oliveira, J. Martinez de; Oliveira, Rita Palmeira de; Pereira, C; Cruz, MT; Oliveira, Ana Palmeira deThe common therapeutic indications of Portuguese Natural Mineral Waters (NMWs) are primarily for respiratory, rheumatic and muscu- loskeletal systems. However, these NMWs have been increasingly sought for dermatologic purposes. Opposing to what is observed in the major European Thermal Centres, there are few scientific evidences supporting the use of Portuguese NMWs for clinical applications. The aim of this study was to characterize the antimicrobial profile of individual NMWs from the central region of Portugal and correlate the results with their physicochemical characterization. An extensive multivariate analysis (principal component analysis) was also performed to further investigate this possible correlation. Six collection strains representing skin microbiota, namely Staphylococcus aureus, Escher- ichia coli, Corynebacterium amycolatum, Candida albicans, Staphylococcus epidermidis and Cutibac- terium acnes, were analysed, and their antimicrobial profile was determined using Clinical and Laboratory Standards Institute M07-A10, M45-A2, M11-A6 and M27-A3 microdilution methods. Different NMWs presented different antimicrobial profiles against the strains used; the physicochemical composition of NMWs seemed to be correlated with the different susceptibility profiles. Cutibacterium acnes showed a particularly high susceptibility to all NMWs belong- ing sulphurous/bicarbonated/sodic ionic profile, exhibiting microbial reductions up to 65%. However, due to the complex physicochemical composition of each water an overall conclusion regarding the effect of a specific ion on the growth of different microor- ganisms is yet to be known.
- Paradoxical and contradictory effects of imatinib in two cell line models of hormone-refractory prostate cancerPublication . Cardoso, HJ; Vaz, CV; Correia, Sara; Figueira, Marília I; Marques, Ricardo; Baptista, Cláudio; Socorro, SílviaImatinib mesylate is a chemotherapeutic drug that inhibits the tyrosine kinase activity of c-KIT and has been successfully used to treat leukemias and some solid tumors. However, its application for treatment of hormone-refractory prostate cancer (HRPC) has shown modest effectiveness and did not follow the outcomes in cultured cells or animal models. Moreover, the molecular pathways by which imatinib induces cytotoxicity in prostate cancer cells are poorly characterized.