Toshiyo Sonta

Protein Kinase C–Dependent Increase in Reactive Oxygen Species (ROS) Production in Vascular Tissues of Diabetes: Role of Vascular NAD(P)H Oxidase

Hyperglycemia seems to be an important causative factor in the development of micro- and macrovascular complications in patients with diabetes. Several hypotheses have been proposed to explain the adverse effects of hyperglycemia on vascular cells. Both protein kinase C (PKC) activation and oxidative stress theories have increasingly received attention in recent years. This article shows a PKC-dependent increase in oxidative stress in diabetic vascular tissues. High glucose level stimulated reactive oxygen species (ROS) production via a PKC-dependent activation of NAD(P)H oxidase in cultured aortic endothelial cells, smooth muscle cells, and renal mesangial cells. In addition, expression of NAD(P)H oxidase components were shown to be upregulated in vascular tissues and kidney from animal models of diabetes. Furthermore, several agents that were expected to block the mechanism of a PKC-dependent activation of NAD(P)H oxidase clearly inhibited the increased oxidative stress in diabetic animals, as assessed by in vivo electron spin resonance method. Taken together, these findings strongly suggest that the PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism responsible for increased oxidative stress in diabetes.

High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase.

Abstract: Background: Nonalcoholic steatohepatitis is a clinicopathologic condition that may progress to liver fibrosis. Hyperglycemia is supposed to be one of the factors inducing hepatic fibrogenesis, but the mechanism has not been fully clarified. Oxidative stress is increasingly found in patients with diabetes/hyperglycemia in which conditions reactive oxygen species (ROS) are produced.

A possible target of antioxidative therapy for diabetic vascular complications-vascular NAD(P)H oxidase

A growing body of evidence has shown that oxidative stress may be involved in the development of vascular complications associated with diabetes. However, the molecular mechanism for increased reactive oxygen species (ROS) production in diabetes remains uncertain. Among various possible mechanisms, attention have increasingly been paid to NAD(P)H oxidase as the most important source of ROS production in vascular cells. High glucose level stimulates ROS production through protein kinase C (PKC)-dependent activation of vascular NAD(P)H oxidase. Furthermore, the expression of NAD(P)H oxidase components is increased in micro- and macrovascular tissues of diabetic animals in association with various functional disorders and histochemical abnormalities. These results suggest that vascular NAD(P)H oxidase-driven ROS production may contribute to the onset or development of diabetic micro- or macrovascular complications. In this point of view, the possible new strategy of antioxidative therapy for diabetic vascular complications is discussed in this review.

The beneficial effect of mesalazine on esophageal ulcers in intestinal Behcet's disease

Intestinal Behcets disease in a 19-year-old girl was diagnosed because of the history of recurrent oral aphthous ulcers and typical endoscopic findings of esophageal and ileal ulcers. Her symptoms (e.g., dysphagia and retrosternal pain) were gradually relieved by treatment with prednisolone and total parenteral nutrition. However, about one month later, oral and esophageal ulcers appeared again. Mesalazine was added. Oral and esophageal ulcers healed promptly, and have not relapsed for about one year. Although mesalazine appears to act locally in the small intestine and colon, the therapeutic effect of mesalazine in this case may be explained by the systemic antiinflammatory effect. This case suggests that mesalazine is an effective drug and is a good candidate in the treatment of intestinal Behcets disease, especially accompanied with esophageal involvement.