Availability of cysteine, in its reduced form, in the cell is a limiting step in intracellular glutathione synthesis. Several agents have been tested for their efficacy in this respect. Among the ones that hold clinical promise are N-acetylcysteine and a-lipoate.⁵ Both agents have proved to be safe for human use. a-Lipoate has been recently introduced in the United States as a dietary supplement. It has been used in Germany for a long time for the treatment of diabetic polyneuropathies. Recently the laboratory of Klip has reported that a-lipoate also stimulates glucose uptake by cultured skeletal muscle cells.

Thiols As Critical Determinants of Cell Function and Response to Stress
To develop a better understanding of the exact mechanisms that underlie reactive oxygen species-dependent disorders in biological systems, recent studies have focused on the regulation of gene expression by oxidants, antioxidants, and other determinants of the intracellular reduction-oxidation (redox) state.^7-9 At least two well-defined transcription factors, nuclear factor (NF)-kB and activator protein (AP)-I are regulated by the intracellular redox state. One major clinical significance of NF-KB activation is that it enhances HIV gene expression. The long terminal repeat of HIV-I has been shown to contain two NF-kB binding sites that may be crucial in regulating AIDS latency. AP-1 is an important mediator of tumor promotion, and is thus a focal point in cancer research.

Certain intracellular protein and nonprotein thiols are known to act as "redox sensors" that signal for much of the activity of the aforementioned transcription factors.⁷ Under conditions of oxidative stress, certain thiols such as glutathione and thioredoxin are transformed from a reduced sulflhydryl (-SH) state to an oxidized disulfide (-S-S-) state. This change serves as a signal for redox-sensitive transactivation to start. In the nucleus, these transcription factors are known to require a reducing atmosphere to be able to bind with the consensus DNA sites and initiate transactivation. Again, certain protein thiols in the nucleus regulate this DNA binding. In brief, subtle changes in intracellular thiol-disulfide status have an important bearing on the molecular events associated with cellular response to the stress. For example, it is suggested that elevated GSSG/GSH in the cytosol may be implicated in NF-kB activation.^7,10 A number of studies have shown that physical exercise may increase the tissue GSSG/GSH ratio, but does this lead to NF-kB activation? We are currently conducting a pilot human study to address this issue. If indeed physical exercise induces NF-kB activation, does this mean that the rate of progression of AIDS may be accelerated in strenuously exercising HIV-positive individuals? This is one of many exercise-induced oxidative stress-related issues that deserve careful attention. Activation of NF-KB may also upregulate the expression of adhesion and other molecules that are known to be implicated in the etiology of atherosclerotic and diabetic complications.

So, is exercising bad? Certainly not. A physically active lifestyle coupled with well-balanced nutrition is of great help. However, antioxidant defenses of active tissues can be overwhelmed by excess reactive oxygen generated during exercise. A vivid understanding of the possible mechanisms that may contribute to exercise-induced oxygen toxicity, associated physiological response, and the design of appropriate measures to circumvent or minimize such toxicity is fundamental to (1) enhancing the effectiveness of physical exercise as a preventive and therapeutic tool in clinical practice and (2) controlling exercise-induced oxygen toxicity-dependent tissue damage and augmentation of other possible health risks.