Myoinositol Reduces Inflammation and Oxidative Stress in Human Endothelial Cells Exposed In Vivo to Chronic Hyperglycemia.

Myo-inositol (Myo) improves insulin resistance, glucose metabolism, and helps gestational diabetes (GDM) management. GDM is associated with a pro-inflammatory state and increased oxidative stress, which are both involved in vascular damage in diabetes. Our aim was to study Myo anti-inflammatory/antioxidant potential effects on an in vitro model of human umbilical vein endothelial cells (HUVECs). To this end, monocyte cell adhesion to HUVECs, adhesion molecule membrane exposure, and oxidative stress levels were determined in cells from control (C-) and GDM women treated during pregnancy either with diet only (GD-) or with diet plus Myo (GD+Myo). To deeply study the vascular effects of Myo, the same evaluations were performed in C- and GD-HUVECs following 48 h in vitro stimulation with Myo. Notably, we first observed that GD-HUVECs obtained from women assuming Myo supplementation exhibited a significantly decreased number of monocytes that adhered to endothelial cells, less adhesion molecule exposure, and lower intracellular reactive oxygen species (ROS) levels in the basal state as compared to GD-HUVECs obtained from women treated by diet only. This Myo anti-inflammatory/antioxidant effect was confirmed by 48 h in vitro stimulation of GD-HUVECs as compared to controls. Altogether, these results strongly suggest that Myo may exert protective actions against chronic inflammation induced by endothelial dysfunction in diabetes.

Role of Polyphenols and Carotenoids in Endothelial Dysfunction: An Overview from Classic to Innovative Biomarkers.

Nowadays, the dramatically increased prevalence of metabolic diseases, such as obesity and diabetes mellitus and their related complications, including endothelial dysfunction and cardiovascular disease, represents one of the leading causes of death worldwide. Dietary nutrients together with healthy lifestyles have a crucial role in the endothelium health-promoting effects. From a growing body of evidence, active natural compounds from food, including polyphenols and carotenoids, have attracted particular attention as a complementary therapy on atherosclerosis and cardiovascular disease, as well as preventive approaches through the attenuation of inflammation and oxidative stress. They mainly act as radical scavengers by promoting a variety of biological mechanisms, such as improvements in endothelial function, blood pressure, platelet activity, and insulin sensitivity, and by modulating various known biomarkers. The present review highlights the role of polyphenols and carotenoids in early endothelial dysfunction with attention to their beneficial effect in modulating both classical and recent technologically generated emerging biomarkers. These, alone or in combination, can play an important role in the prediction, diagnosis, and evolution of cardiovascular disease. However, a main challenge is to speed up early and prompt new interventions in order to prevent or slow down disease progression, even with an adequate intake of bioactive compounds. Hence, there is an urgent need of new more validated, appropriate, and reliable diagnostic and therapeutic biomarkers useful to diagnose endothelial dysfunction at an earlier stage.

Inositol and antioxidant supplementation: Safety and efficacy in pregnancy.

Pregnancies complicated by diabetes have largely increased in number over the last 50 years. Pregnancy is characterized by a physiologic increase in insulin resistance, which, associated with increased oxidative stress and inflammations, could induce alterations of glucose metabolism and diabetes. If not optimally controlled, these conditions have a negative impact on maternal and foetal outcomes. To date, one can resort only to diet and lifestyle to treat obesity and insulin resistance during pregnancy, and insulin remains the only therapeutic option to manage diabetes during pregnancy. However, in the last years, in a variety of experimental models, inositol and antioxidants supplementation have shown insulin-sensitizing, anti-inflammatory, and antioxidant properties, which could be mediated by some possible complementary mechanism of action. Different isomers and multiple combinations of these compounds are presently available: Aim of the present review article is to examine the existing evidence in order to clarify and/or define the effects of different inositol- and antioxidant-based supplements during pregnancy complicated by insulin resistance and/or by diabetes. This could help the clinician's evaluation and choice of the appropriate supplementation regimen.

Epigallocatechin gallate, a green tea polyphenol, mediates NO-dependent vasodilation using signaling pathways in vascular endothelium requiring reactive oxygen species and Fyn.

Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, mimics metabolic actions of insulin to inhibit gluconeogenesis in hepatocytes. Because signaling pathways regulating metabolic and vasodilator actions of insulin are shared in common, we hypothesized that EGCG may also have vasodilator actions to stimulate production of nitric oxide (NO) from endothelial cells. Acute intra-arterial administration of EGCG to mesenteric vascular beds isolated ex vivo from WKY rats caused dose-dependent vasorelaxation. This was inhibitable by L-NAME (NO synthase inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), or PP2 (Src family kinase inhibitor). Treatment of bovine aortic endothelial cells (BAEC) with EGCG (50 microm) acutely stimulated production of NO (assessed with NO-specific fluorescent dye DAF-2) that was inhibitable by l-NAME, wortmannin, or PP2. Stimulation of BAEC with EGCG also resulted in dose- and time-dependent phosphorylation of eNOS that was inhibitable by wortmannin or PP2 (but not by MEK inhibitor PD98059). Specific knockdown of Fyn (but not Src) with small interfering RNA inhibited both EGCG-stimulated phosphorylation of Akt and eNOS as well as production of NO in BAEC. Treatment of BAEC with EGCG generated intracellular H(2)O(2) (assessed with H(2)O(2)-specific fluorescent dye CM-H(2)DCF-DA), whereas treatment with N-acetylcysteine inhibited EGCG-stimulated phosphorylation of Fyn, Akt, and eNOS. We conclude that EGCG has endothelial-dependent vasodilator actions mediated by intracellular signaling pathways requiring reactive oxygen species and Fyn that lead to activation of phosphatidylinositol 3-kinase, Akt, and eNOS. This mechanism may explain, in part, beneficial vascular and metabolic health effects of green tea consumption.

Dehydroepiandrosterone mimics acute actions of insulin to stimulate production of both nitric oxide and endothelin 1 via distinct phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-dependent pathways in vascular endothelium.

Dehydroepiandrosterone (DHEA) is an adrenal steroid and nutritional supplement that may improve insulin sensitivity. Although steroid hormones classically act by regulating transcription, they may also signal through cell surface receptors to mediate nongenomic actions. Because DHEA may augment insulin sensitivity, we hypothesized that DHEA mimics vascular actions of insulin to acutely activate signaling pathways in endothelium-mediating production of nitric oxide (NO) and endothelin 1 (ET-1). Treatment of bovine aortic endothelial cells with either insulin or DHEA (100 nm, 5 min) stimulated significant increases in NO production (assessed with NO-selective fluorescent dye diaminofluorescein 2). These responses were abolished by pretreatment of cells with L-NAME (nitro-L-arginine methyl ester; NO synthase inhibitor) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. Under similar conditions, insulin- or DHEA-stimulated phosphorylation of Akt (Ser473) and endothelial nitric oxide synthase (Ser1179) was inhibited by pretreatment of cells with wortmannin (but not MAPK kinase inhibitor PD98059). Acute DHEA treatment also caused phosphorylation of MAPK (Thr202/Tyr204) that was inhibitable by PD98059 (but not wortmannin). DHEA treatment of bovine aortic endothelial cells (100 nM, 5 min) stimulated a 2-fold increase in ET-1 secretion that was abolished by pretreatment of cells with PD98059 (but not wortmannin). We conclude that DHEA has acute, nongenomic actions in endothelium to stimulate production of the vasodilator NO via PI 3-kinase-dependent pathways and secretion of the vasoconstrictor ET-1 via MAPK-dependent pathways. Altering the balance between PI 3-kinase- and MAPK-dependent signaling in vascular endothelium may determine whether DHEA has beneficial or harmful effects relevant to the pathophysiology of diabetes.