Our aim was to investigate the effect of several dietary polyphenols on glucose uptake by breast cancer cells. Uptake of (3)H-deoxy-D-glucose ((3)H-DG) by MCF-7 cells was time-dependent, saturable, and inhibited by cytochalasin B plus phloridzin. In the short-term (26 min), myricetin, chrysin, genistein, resveratrol, kaempferol, and xanthohumol (10-100 µM) inhibited (3)H-DG uptake. Kaempferol was found to be the most potent inhibitor of (3)H-DG uptake [IC50 of 4 µM (1.6-9.8)], behaving as a mixed-type inhibitor. In the long-term (24 h), kaempferol (30 µM) was also able to inhibit (3)H-DG uptake, associated with a 40% decrease in GLUT1 mRNA levels. Interestingly enough, kaempferol (100 µM) revealed antiproliferative (sulforhodamine B and (3)H-thymidine incorporation assays) and cytotoxic (extracellular lactate dehydrogenase activity determination) properties, which were mimicked by low extracellular (1 mM) glucose conditions and reversed by high extracellular (20 mM) glucose conditions. Finally, exposure of cells to kaempferol (30 µM) 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.

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The 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, nZ5) or a high dose of FA (HFA, 40 mg FA/kg of diet, nZ5). 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.

An adequate maternal nutrition during pregnancy is crucial for the health outcome of offspring in adulthood. Maternal undernutrition during critical periods of fetal development can program the fetus for metabolic syndrome (MetS) later in life, especially when postnatally challenged with a hypernutritive diet. Adipogenesis, which begins in utero and accelerates in neonatal life, is a major candidate for developmental programming. During fetal development, the hypothalamic-pituitary-adrenal (HPA) axis is extremely susceptible to programming, and the HPA tone is increased throughout life in undernourished conditions. As a consequence, an alteration in the expression and function of glucocorticoid (GC) receptors and of the major GC regulatory enzymes (11β-hydroxysteroid dehydrogenase 1 and -2) occurs. In this review, we will give insights into the role of maternoplacental adverse interactions under the specific context of maternal undernutrition, for later-in-life MetS development, with a special emphasis on the role of GCs.

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Folic acid (FA) is a vitamin essential for normal cellular functions, growth, and development. Because humans cannot synthesize this micronutrient, it must be obtained from dietary sources through intestinal absorption. The intestinal tract is a major target for oxidative stress. Our aim was to investigate the effect of oxidative stress upon the uptake of FA by Caco-2 cells. Oxidative stress was induced by exposure of the cells to tert-butyl hydroperoxide (TBH) for 1 h. TBH (3,000 μM) induced an increase in biomarkers of oxidative stress, while maintaining cell viability and proliferation. In relation to the apical uptake of (3)H-FA, TBH (3,000 μM) reduced the cellular accumulation of (3)H-FA (10 nM), although the characteristics (kinetics, pH dependence, and inhibitory profile) of (3)H-FA uptake were not changed. This effect was associated with a decrease in the mRNA steady-state levels of proton-coupled folate transporter and folate receptor alpha and of the efflux transporter multidrug resistance protein 2. Moreover, TBH (3,000 μM) did not affect the noncarrier-mediated apical uptake of (3)H-FA. Finally, the effect of TBH upon (3)H-FA apical uptake was not dependent on protein kinase A, protein kinase C, mitogen-activated protein kinases, phosphoinositide 3-kinase, nuclear factor kappa B, and protein tyrosine kinases, but was completely prevented by dietary polyphenols (resveratrol, quercetin, and EGCG). These results suggest that oxidative stress at the intestinal level may result in a reduction in the intestinal absorption of dietary FA and that polyphenolic dietary components may offer protection against oxidative stress-induced inhibition of intestinal FA absorption.