Signaling of Reactive Oxygen and Nitrogen Species in Diabetes Mellitus

Abstract

Disorder of physiological signaling functions of reactive oxygen species(ROS) superoxide and hydrogen peroxide and reactive nitrogen species (RNS) nitric oxide and peroxynitrite is an important feature of diabetes mellitus type 1 and type 2. It is now known that hyperglycemic conditions of cells are associated with the enhanced levels of ROS mainly generated by mitochondria and NADPH oxidase. It has been established that ROS stimulate many enzymatic cascades under normal physiological conditions, but hyperglycemia causes ROS overproduction and the deregulation of ROS signaling pathways initiating the development of diabetes mellitus. On the other hand the deregulation of RNS signaling leads basically to a decrease in NO formation with subsequent damaging disorders. In the present work we will consider the pathological changes of ROS and RNS signaling in enzyme/gene regulated processes catalyzed by protein kinases C and B (Akt/B), phosphatidylinositol 3′-kinase (PI3-kinase), extracellular signal-regulated kinase 1/2 (ERK1/2) and some others. Furthermore we will discuss a particularly important role of several ROS-regulated genes and adapter proteins such as the p66shc, FOXO3a and Sirt2. The effects of low and high ROS levels in diabetes will be also considered. Thus the regulation of damaging ROS levels in diabetes by antioxidants and free radical scavengers must be one of promising treatment of this disease, however, because of the inability of traditionalantioxidative vitamin E and C to interact with superoxide and hydrogen peroxide,new free radical scavengers such as flavonoids, quinones and synthetic mimetics of superoxide dismutase (SOD) should be intensively studied.

Activation of FoxO1/ PGC-1α prevents mitochondrial dysfunction and ameliorates mesangial cell injury in diabetic rats

“…Multiple lines of evidence indicate that increased oxidant stress is a main pathophysiological factor leading to the development of DN [1][2][3] . It is now thought that the mitochondrial electron-transport system is a major source of reactive oxygen species (ROS) overproduction in diabetes and diabetes-associated complications [4][5][6] and that high glucose (HG) may induce excessive ROS production and mitochondrial dysfunction [7] . Thus, the regulation of aberrant ROS levels may be a promising approach for treating DN.…”

Schiff base SH11 with tuberculostatic and radical scavenging activities against INH-induced oxidative hepatic damage

“…The simple analysis of compound SH11 with empirical formula C 15 6.85 (t, J = 7.9 Hz, 1H), 4.07 (d, J = 7.0 Hz, 2H), 1.36 (t, J = 6.9 Hz, 3H), Figure 3.…”

“…Some studies provide information about possible mechanisms by which low antioxidant defense can increase the risk of different associated diseases and promote the progression of the diseases [15,16]. Treatment with antioxidants offers protection against hepatotoxicity induced by isoniazid by reducing lipid peroxidation and restoring the antioxidant defense system [3,6].…”

Role of advanced glycation end products in the onset of diabetic kidney disease complications

“…The four pathways described are the result of persistent hyperglycemia and converge in the formation of AGEs, with formation of ROS, mainly superoxide anion, contributing to altering intracellular redox status, leading to oxidative stress 29,30,33 . Therefore, the increased ROS in DM, together with the reduction of antioxidant defenses are related to the onset of diabetic complication 31,33,34 . ROS increase leads to DNA breaking, which activates poly ADP-ribose polymerase (PARP), reducing the Role of AGEs in diabetic kidney disease activity of glyceraldehyde-3-phosphate (GAPDH), a key enzyme in the glycolytic pathway, which, in turn, activates the polyol pathway, increases the formation of AGEs, PKC activation, and increases the flow of hexosamines 35 .…”

“…Thus, there seems to be a cyclic activation of AGEs through increased ROS, suggesting the induction of a ROS-AGE-RAGE pathway. In this context, the increased O 2 -production by the electron transport chain appears to be the link between oxidative stress, AGE, and diabetes complications 30,33,34 . However, the mechanism by which the increased O 2 -production resulting from hyperglycemia is related to tissue damage that results in diabetic complications still needs to be elucidated.…”