NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes?

The incidence of obesity and non-esterified ('free') fatty acid-associated metabolic disorders such as the metabolic syndrome and diabetes is increasing dramatically in most countries. Although the pathogenesis of these metabolic disorders is complex, there is emerging evidence that ROS (reactive oxygen species) are critically involved in the aberrant signalling and tissue damage observed in this context. Indeed, it is now widely accepted that ROS not only play an important role in physiology, but also contribute to cell and tissue dysfunction.

NOX1 NADPH oxidase regulation by the NOXA1 SH3 domain.

We investigated the role of the single SH3 domain of NOXA1 in NOX1 NADPH oxidase function using wild-type and mutated NOXA1 and the products of two variant NOXA1 transcripts isolated from CaCo2 cells by reverse transcription polymerase chain reaction. The first variant, NOXA1(trunc), contained a number of point mutations, including A51T, T261A, and a nonsense mutation at position 274. On transfection into K562 cells stably expressing NOX1 and NOXO1, both NOXA1(trunc) and an equivalent truncated wild-type NOXA1(1-273) were expressed as approximately 29-kDa truncated NOXA1 proteins lacking both PB1 and SH3 domains, yet both were as active as wild-type NOXA1 in phorbol-stimulated superoxide generation.

Mechanisms of activation of NADPH oxidases.

The members of the NOX family of enzymes are expressed in a variety of tissues and serve a number of functions. There is a high level of conservation of primary protein sequence, as well as functional features, although specialized responses are beginning to emerge. In this context, our data demonstrate that the NOX1 cytoplasmic domains interact efficiently with the cytoplasmic subunits of the phagocyte NADPH oxidase and identify the second cytoplasmic loop of NOX electron transporters as a crucial domain for enzyme function.

A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia?

Because of population ageing, dementias are likely to become a major scourge of the 21st century. Causes of dementia include Alzheimer's disease, cerebrovascular disease, and lesser known entities such as frontotemporal dementia or dementia with Lewy bodies. Neuroinflammation is likely to play an important role in the pathogenesis of dementia by the killing of neurons through inflammatory mechanisms.