Loss of PC prevented diet-induced hyperglycemia and insulin resistance but depleted NADPH and glutathione, which exacerbated oxidative stress and correlated with elevated liver inflammation.
The dysfunction can be reversed by improving the acute hyperglycemia and it can be prevented entirely by the administration of NADPH oxidase inhibitors.
Sorbitol level was markedly elevated secondary to hyperglycemia and reflecting activation of the polyol metabolism pathway causing a decrease in the availability of reducing molecules (glutathione, NADPH, NAD<sup>+</sup>).
Overproduction of reactive oxygen species (ROS) by NADPH oxidase (NOX) activation has been considered the essential mechanism induced by hyperglycemia in various tissues.
Silencing of PKC-ßI gene through use of specific siRNAs abolished the effects of both hyperglycaemia and PMA on endothelial cell NADPH oxidase activity, O2 (•-) production and apoptosis and consequently improved the integrity and function of an in vitro model of human cerebral barrier comprising HBMEC, astrocytes and pericytes.
AR activity as photometrically determined by NADPH consumption was effectively inhibited by the AR inhibitor epalrestat. oxLDL-dependent AR upregulation was further increased under hyperglycemic conditions (30 mmol/L D-glucose) as compared to osmotic control, suggesting a synergistic effect of hyperlipidemia and hyperglycemia.
These include vitamin E, which blunts the rise in mesangial diacylglycerol levels induced by hyperglycemia; statins and (possibly) policosanol, which down-regulate NADPH oxidase activity by diminishing isoprenylation of Rac1; lipoic acid, whose potent antioxidant activity antagonizes the impact of oxidant stress on TGF-beta expression; pyridoxamine, which inhibits production of advanced glycation endproducts; arginine, high-dose folate, vitamin C, and salt restriction, which may support glomerular production of nitric oxide; and estrogen and soy isoflavones, which may induce nitric oxide synthase in glomerular capillaries while also interfering with TGF-beta signaling.