Blood transfusion in clinical medicine

The chemistry and biological activities of N-acetylcysteine

Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.

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Targeting oxidative stress in disease: promise and limitations of antioxidant therapy.

Ionizing radiation (IR) induces DNA strand breaks leading to cell death or deleterious genome rearrangements. In the present study, we examined the role of N-acetyl-L-cysteine (NAC), a clinically proven safe agent, for it’s ability to protect against -ray-induced DNA strand breaks and/or DNA deletions in yeast andmammals. In the yeast Saccharomyces cerevisiae, DNA deletions were scored by reversion to histidine prototrophy. Human lymphoblastoid cells were examined for the frequency of -H2AX foci formation, indicative of DNA double strand break formation. DNA strand breaks were also measured in mouse peripheral blood by the alkaline comet assay. In yeast, NAC reduced the frequency of IR-induced DNA deletions. However, NAC did not protect against cell death. NAC also reduced -H2AX foci formation in human lymphoblastoid cells but had no protective effect in the colony survival assay. NAC administration via drinking water fully protected against DNA strand breaks in mice whole-body irradiated with 1Gy but not with 4Gy. NAC treatment in the absence of irradiation was not genotoxic. These data suggest that, given the safety and efficacy of NAC in humans, NAC may be useful in radiation therapy to prevent radiation-mediated genotoxicity, but does not interfere with efficient cancer cell killing. © 2009 Published by Elsevier B.V.

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Mutation research/fundamental and molecular mechanisms of mutagenesis: special issue: DNA repair and genetic instability.

Type 2 diabetes is a worldwide increasing disease resulting from the interaction between a subject’s genetic makeup and lifestyle. In genetically predisposed subjects, the combination of excess caloric intake and reduced physical activity induces a state of insulin resistance. When beta cells are no longer able to compensate for insulin resistance by adequately increasing insulin production, impaired glucose tolerance appears, characterized by excessive postprandial hyperglycemia. Impaired glucose tolerance may evolve into overt diabetes. These 3 conditions, ie, insulin resistance, impaired glucose tolerance, and overt diabetes, are associated with an increased risk of cardiovascular disease. Because all these conditions are also accompanied by the presence of an oxidative stress, this article proposes oxidative stress as the pathogenic mechanism linking insulin resistance with dysfunction of both beta cells and endothelium, eventually leading to overt diabetes and cardiovascular disease. This hypothesis,...

Is Oxidative Stress the Pathogenic Mechanism Underlying Insulin Resistance, Diabetes, and Cardiovascular Disease? The Common Soil Hypothesis Revisited

Generation of normal human red cell volume, hemoglobin content, and membrane area distributions by "birth" or regulation?

1. A study has been made of the formation and regression of synapses formed by spinal nerves 16 and 17 in axolotl hind-limb flexor muscles following the severing of nerve 16, using histological, ultrastructural and electrophysiological techniques. 2. Axolotl hind-limb flexor myofibres possessed 'en plaque' end-plates from either spinal nerve 16 or 17 or both at intervals of about 1000 micronm along their length; the myofibre's length constant was about 700 micronm allowing electrophysiological observations of at least two of these synapses during a single impalement; transmitter release at these synapses could be described by binomial statistics and in a given set of ionic conditions the binomial statistic parameter n was directly proportional to the size of the nerve terminals whilst the binomial statistic parameter p was invariant to changes in nerve terminal size. 3. The distribution of synapses formed by spinal nerves 16 and 17 in different sectors of the axolotl hind-limb flexor muscles was determined from a study of evoked end-plate potentials; the middle and proximal sectors of the flexor muscles contained myofibres which received an innervation from nerve 16 only, whereas the sectors surrounding these contained myofibres innervated either by nerve 16 or nerve 17 or by both nerves. 4. Six days following the severing of spinal nerve 16, evoked transmitter release from the synapses formed by this nerve had failed; transmission was subsequently recorded at a few synapses formed by nerve 17 in the middle and proximal sectors of the flexor muscles which are not normally innervated by this nerve and these synapses had a low n; during the succeeding four weeks the value of n at the synapses increased to a size about 70% that of the terminals normally formed by nerve 16 at these sites. 5. Four weeks after severing nerve 16, myofibres which possessed synapses formed by nerve 17 also possessed synapses from re-innervating nerve 16 and these were sometimes formed at the same synaptic sites as those occupied by nerve 17. 6. In the subsequent sixteen weeks, the n value of synapses formed by nerve 17 declined whilst the n values of synapses formed by re-innervating nerve 16 on the same myofibres matured to their control size. 7. It is suggested that on severing nerve 16 collateral sprouting of nearby intact nerve 17 occurs and these collateral sprouts innervate the denervated synaptic sites, although the sprouts arenot as well matched to the denervated synaptic sites as are the original nerve terminals; thus if nerve 16 returns it preferentially forms synapses at its original synaptic sites, and the collateral synapses formed by nerve 17 regress.

The formation and regression of synapses during the re-innervation of axolotl striated muscles.

Glutathione Synthesis and Turnover in the Human Erythrocyte ALIGNMENT OF A MODEL BASED ON DETAILED ENZYME KINETICS WITH EXPERIMENTAL DATA

Glutathione is an intracellular antioxidant that often becomes depleted in pathologies with high oxidative loads. We investigated the provision of cysteine for glutathione synthesis to the human erythrocyte (red blood cell; RBC). Almost all plasma cysteine exists as cystine, its oxidized form. In vitro, extracellular cystine at 1.0 mM sustained glutathione synthesis in glutathione-depleted RBCs, at a rate of 0.206 +/- 0.036 micromol (L RBC)(-1)min(-1) only 20% of the maximum rate obtained with cysteine or N-acetylcysteine. In plasma-free solutions, N-acetylcysteine provides cysteine by intracellular deacetylation but to achieve maximum rates of glutathione synthesis by this process in vivo, plasma N-acetylcysteine concentrations would have to exceed 1.0 mM, which is therapeutically unattainable. (1)H-NMR experiments demonstrated that redox exchange reactions between NAC and cystine produce NAC-cysteine, NAC-NAC and cysteine. Calculations using a mathematical model based on these results showed that plasma concentrations of N-acetylcysteine as low as 100 microM, that are attainable therapeutically, could potentially react with plasma cystine to produce approximately 50 microM cysteine, that is sufficient to produce maximal rates of glutathione synthesis. We conclude that the mechanism of action of therapeutically administered N-acetylcysteine is to reduce plasma cystine to cysteine that then enters the RBC and sustains glutathione synthesis.

Julia E. Raftos

Papers

Generation of normal human red cell volume, hemoglobin content, and membrane area distributions by "birth" or regulation?

The formation and regression of synapses during the re-innervation of axolotl striated muscles.

Glutathione Synthesis and Turnover in the Human Erythrocyte ALIGNMENT OF A MODEL BASED ON DETAILED ENZYME KINETICS WITH EXPERIMENTAL DATA

Role of N-acetylcysteine and cystine in glutathione synthesis in human erythrocytes.

Kinetics of uptake and deacetylation of N-acetylcysteine by human erythrocytes