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- Energy restriction, exercise and atorvastatin treatment improve endothelial dysfunction and inhibit miRNA-155 in the erectile tissue of the aged ratPublication . Rocha, B.; Rodrigues, A. R.; Tomada, I.; Martins, M. J.; Guimarães, J. T.; Gouveia, A. M.; Almeida, H.; Neves, D.Background: Endothelial dysfunction underlies cardiovascular disease that frequently affects aged individuals. Characterized by local decrease in nitric oxide, it results from down-regulation of endothelial nitric oxide synthase (eNOS) expression/activity. Aiming to elucidate the molecular mechanisms involved in age-related endothelial dysfunction and to unveil potential therapeutic targets, we tested how diet pattern, exercise and atorvastatin modulate the expression of eNOS, inducible NOS (iNOS), endothelin-1, sirtuins (SIRT) and microRNA-155 in the erectile tissue of high-fat fed aged rats. Methods: Sprague-Dawley male rats fed with high-fat diet until they completed 12 months were grouped and subjected to energy restriction (ER), ER and atorvastatin, or, ER, atorvastatin and physical exercise. Controls were fed with standard rodent chow. The blood pressure was measured using the tail-cuff method before sacrifice at 18 months. Glucose, total cholesterol, HDL, triglyceride and CRP were assessed in blood and eNOS, endothelin-1, iNOS and sirtuins were detected by immunofluorescence in the penis sections; eNOS, endothelin-1, iNOS, SIRT2–4 and SIRT6–7 were semi-quantified by western blotting in tissue homogenates. MicroRNA-155 was quantified using RT-PCR in formalin-fixed paraffin embedded sections. To compare the studied variables, two-tail student t test was used. Results: Atorvastatin promotes eNOS expression and is more efficient than ER or exercise in the control of hyperlipidemia and inflammation. Among the studied sirtuins, detected for the first time in the erectile tissue of the aged rat, SIRT2 aligns with eNOS expression. Both proteins exhibit over-expression in animals with combined exercise, atorvastatin and ER. Analysis of microRNA-155 expression also suggests its intervention in the regulation of eNOS expression. ER, particularly when combined with atorvastatin, was able to reverse the increase of iNOS and endothelin-1 in high-fat fed rats. Conclusions: The present results indicate that the association of ER, atorvastatin and exercise is more efficient than isolated interventions in the prevention of endothelial dysfunction.
- Effects of extracts of selected medicinal plants upon hepatic oxidative stressPublication . Gião, M.S.; Pestana, D.; Faria, A.; Guimarães, J.T.; Pintado, M.E.; Calhau, C.; Azevedo, I.; Malcata, F.X.Aqueous extracts of a few medicinal plants traditionally used in Portugal have been assayed for their effects upon hepatic oxidative stress in mice. Previous in vitro studies had allowed characterization of agrimony, sage, savory, and raspberry in terms of overall antioxidant capacity and phenolic content. In the present study, the antioxidant effect and safety of these four plants were evaluated in vivo. For this purpose, mice ingested extracts in aqueous form (or water, used as the control) for 4 weeks; damage to lipids, proteins, and DNA was evaluated by oxidative cell biomarkers by the end of that period. Levels of hepatic glutathione and activities of enzymes involved in metabolism thereof were also determined. Finally, catalase and superoxide dismutase (SOD) activities were quantified, as these enzymes play a crucial role in antioxidant defense. When compared with the control, both raspberry and savory produced significant lipid protection; however, protein damage was significantly lower only in raspberry-treated animals. On the other hand, DNA damage was prevented only by savory. All plants led to a decrease in catalase activity, whereas all but sage also produced a decrease in SOD activity. With regard to glutathione levels and activities of enzymes involved in its metabolism, the aforementioned extracts exhibited different effects. In general, raspberry appeared to be the most promising extract, followed by savory, sage, and agrimony, sorted by decreasing performance in protection; the latter was even slightly toxic. Hence, the plants tested possess compounds with interesting biological activities that may support eventual inclusion in food or feed as functional additives.
- 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.