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- Modulation of the uptake of critical nutrients by breast cancer cells by lactate: Impact on cell survival, proliferation and migrationPublication . Guedes, Marta; Araújo, João R.; Correia-Branco, Ana; Gregório, Inês; Martel, Fátima; Keating, ElisaThis work aimed to characterize the uptake of folate and glucose by breast cancer cells and to study the effect of lactate upon the transport of these nutrients and upon cell viability, proliferation and migration capacity. Data obtained showed that: a) MCF7 cells uptake (3)H-folic acid ((3)H-FA) at physiological but not at acidic pH; b) T47D cells accumulate (3)H-FA and (14)C-5-methyltetrahydrofolate ((14)C-5-MTHF) more efficiently at acidic than at physiological pH; c) (3)H-deoxyglucose ((3)H-DG) uptake by T47D cells is sodium-independent, inhibited by cytochalasin B (CYT B) and stimulated by insulin. Regarding the effect of lactate, in T47D cells, acute (26 min) and chronic (24 h) exposure to lactic acid (LA) stimulated (3)H-FA uptake. Acute exposure to LA also stimulated (3)H-DG uptake and chronic exposure to LA significantly stimulated T47D cell migratory capacity. In conclusion, the transport of folates is strikingly different in two phenotypically similar breast cancer cell lines: MCF7 and T47D cells. Additionally, lactate seems to act as a signaling molecule which increases the uptake of nutrients and promotes the migration capacity of T47D cells.
- Impact of gestational diabetes mellitus in the maternal-to-fetal transport of nutrientsPublication . Araújo, João Ricardo; Keating, Elisa; Martel, FátimaGestational diabetes mellitus (GDM) is a metabolic disorder prevalent among pregnant women. This disease increases the risk of adverse perinatal outcomes and diseases in the offspring later in life. The human placenta, the main interface between the maternal and fetal blood circulations, is responsible for the maternal-to-fetal transfer of nutrients essential for fetal growth and development. In this context, the aim of this article is to review the latest advances in the placental transport of macro and micronutrients and how they are affected by GDM and its associated conditions, such as elevated levels of glucose, insulin, leptin, inflammation, and oxidative stress. Data analyzed in this article suggest that GDM and its associated conditions, particularly high levels of glucose, leptin, and oxidative stress, disturb placental nutrient transport and, consequently, fetal nutrient supply. As a consequence, this disturbance may contribute to the fetal and postnatal adverse health outcomes associated with GDM.
- Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal lifePublication . Keating, Elisa; Correia-Branco, Ana; Araújo, João R,; Meireles, Manuela; Fernandes, Rita; Guardão, Luísa; Guimarães, João T.; Martel, Fátima; Calhau, ConceiçãoThe aim of this study was to understand whether high folic acid (HFA) exposure during the perigestational period induces metabolic dysfunction in the offspring, later in life. To do this, female Sprague-Dawley rats (G0) were administered a dose of folic acid (FA) recommended for pregnancy (control, C, 2 mg FA/kg of diet, n=5) or a high dose of FA (HFA, 40 mg FA/kg of diet, n=5). Supplementation began at mating and lasted throughout pregnancy and lactation. Body weight and food and fluid intake were monitored in G0 and their offspring (G1) till G1 were 13 months of age. Metabolic blood profiles were assessed in G1 at 3 and 13 months of age (3M and 13M respectively). Both G0 and G1 HFA females had increased body weight gain when compared with controls, particularly 22 (G0) and 10 (G1) weeks after FA supplementation had been stopped. G1 female offspring of HFA mothers had increased glycemia at 3M, and both female and male G1 offspring of HFA mothers had decreased glucose tolerance at 13M, when compared with matched controls. At 13M, G1 female offspring of HFA mothers had increased insulin and decreased adiponectin levels, and G1 male offspring of HFA mothers had increased levels of leptin, when compared with matched controls. In addition, feeding of fructose to adult offspring revealed that perigestational exposure to HFA renders female progeny more susceptible to developing metabolic unbalance upon such a challenge. The results of this work indicate that perigestational HFA exposure the affects long-term metabolic phenotype of the offspring, predisposing them to an insulin-resistant state.
- The chemopreventive effect of the dietary compound kaempferol on the MCF-7 human breast cancer cell line is dependent on inhibition of glucose cellular uptakePublication . Azevedo, Cláudia; Correia-Branco, Ana; Araújo, João R.; Guimarães, João T.; Keating, Elisa; Martel, FátimaOur aim was to investigate the effect of several dietary polyphenols on glucose uptake by breast cancer cells. Uptake of H-3-deoxy-D-glucose (H-3-DG) by MCF-7 cells was time-dependent, saturable, and inhibited by cytochalasin B plus phloridzin. In the short-term (26min), myricetin, chrysin, genistein, resveratrol, kaempferol, and xanthohumol (10-100 mu M) inhibited H-3-DG uptake. Kaempferol was found to be the most potent inhibitor of H-3-DG uptake [IC50 of 4 mu M (1.6-9.8)], behaving as a mixed-type inhibitor. In the long-term (24h), kaempferol (30 mu M) was also able to inhibit H-3-DG uptake, associated with a 40% decrease in GLUT1 mRNA levels. Interestingly enough, kaempferol (100 mu M) revealed antiproliferative (sulforhodamine B and H-3-thymidine incorporation assays) and cytotoxic (extracellular lactate dehydrogenase activity determination) properties, which were mimicked by low extracellular (1mM) glucose conditions and reversed by high extracellular (20mM) glucose conditions. Finally, exposure of cells to kaempferol (30 mu M) induced an increase in extracellular lactate levels over time (to 731 +/- 32% of control after a 24 h exposure), due to inhibition of MCT1-mediated lactate cellular uptake. In conclusion, kaempferol potently inhibits glucose uptake by MCF-7 cells, apparently by decreasing GLUT1-mediated glucose uptake. The antiproliferative and cytotoxic effect of kaempferol in these cells appears to be dependent on this effect.
- Transient receptor potential vanilloid 1 is expressed in human cytotrophoblasts: Induction of cell apoptosis and impairment of syncytializationPublication . Costa, M. A.; Fonseca, B. M.; Keating, E.; Teixeira, N. A.; Correia-da-Silva, G.The normal development of placenta relies essentially on a balanced proliferation, differentiation andapoptosis of cytotrophoblasts. These processes are tightly regulated by several hormones, cytokines,lipids and other molecules and anomalies in these events are associated with gestational complications.The cation channel transient receptor potential vanilloid 1 (TRPV1) is expressed in several organs andtissues and it participates in cellular events like nociception, inflammation and cell death. However, theexpression and importance of this receptor in human placenta still remains unknown. In this work, wefound that TRPV1 is expressed in human cytotrophoblasts and syncytiotrophoblasts. Furthermore, theTRPV1 agonists capsaicin and anandamide decreased cytotrophoblast viability and induced morpho-logical alterations, such as chromatin condensation and fragmentation, which suggest the occurrenceof apoptosis. Also, both TRPV1 agonists induced a loss of mitochondrial membrane potential and anincrease of caspase 3/7 activity and production of reactive species of oxygen and nitrogen. Furthermore,capsaicin (10 M) impaired the spontaneous in vitro differentiation of cytotrophoblasts into syncytiotro-phoblasts by triggering TRPV1, as observed by the decrease in placental alkaline phosphatase activity andin human chorionic gonadotropin secretion. On the other hand, anandamide decreased placental alkalinephosphatase activity via a TRPV1-independent mechanism but did not influence the secretion of humanchorionic gonadotropin. In conclusion, we showed that TRPV1 is expressed in human cytotrophoblastsand syncytiotrophoblasts and also reported the involvement of this receptor in cytotrophoblast apoptosisand differentiation.
- 2-Arachidonoylglycerol impairs human cytotrophoblast cells syncytialization: influence of endocannabinoid signalling in placental developmentPublication . Costa, M. A.; Keating, E.; Fonseca, B. M.; Teixeira, N. A.; Correia-da-Silva, G.A balanced cytotrophoblast cell turnover is crucial for placental development and anomalies in this process associated with gestational diseases. The endocannabinoid system (ECS) has emerged as a new player in several biological processes. However, its influence during placental development is still unknown. We report here the expression of the endocannabinoid 2-arachidonoylglycerol (2-AG) main metabolic enzymes in human cytotrophoblasts and syncytiotrophoblast. We also showed that 2-AG induced a decrease in placental alkaline phosphatase activity, human chorionic gonadotropin secretion and Leptin mRNA levels. Moreover, 2-AG reduced glial cell missing 1 and syncytin-2 transcription and the number of nuclei in syncytium. These effects were mediated by cannabinoid receptors and may result from 2-AG inhibition of the cAMP/PKA signalling pathway. Our data suggest that 2-AG may interfere with the biochemical and morphological differentiation of human cytotrophoblasts, through a CB receptor-dependent mechanism, shedding light on a role for the ECS in placental development.
- Exposure to non-nutritive sweeteners during pregnancy and lactation: Impact in programming of metabolic diseases in the progeny later in lifePublication . Araújo, João Ricardo; Martel, Fátima; Keating, ElisaThe nutritional environment during embryonic, fetal and neonatal development plays a crucial role in the offspring’s risk of developing diseases later in life. Although non-nutritive sweeteners (NNS) provide sweet taste without contributing to energy intake, animal studies showed that long-term consumption of NSS, particularly aspartame, starting during the perigestational period may predispose the offspring to develop obesity and metabolic syndrome later in life. In this paper, we review the impact of NNS exposure during the perigestational period on the long-term disease risk of the offspring, with a particular focus on metabolic diseases. Some mechanisms underlying NNS adverse metabolic effects have been proposed, such as an increase in intestinal glucose absorption, alterations in intestinal microbiota, induction of oxidative stress and a dysregulation of appetite and reward responses. The data reviewed herein suggest that NNS consumption by pregnant and lactating women should be looked with particular caution and requires further research.