Long Acting Beta Agonist List

For example, in one study erythrocyte GSH content in ALS patients was significantly lower than for agematched controls; similarly, GR activity was also decreased. Another study reported that mRNA levels for GST pi were significantly down regulated in the spinal cord, motor cortex, and the sensory cortex of ALS patients. Furthermore a cohort of patients with a unique haplotype signature in the glutathione synthase gene was found to correlate with ALS patients who had exposures to metals and chemical solvents. The cystine authors speculated that because the haplotype covers the entire gene, changes anywhere. These deleterious effects could manifest as mutations leading to decreased synthesis of GSH; however, GSH levels were not determined in this study.Mechanistic studies over the past decade also speak to the role of GSH in progression of ALS.Time dependent loss of GSH may explain part of the reason for latency of ALS onset.As discussed above, mitochondrial GSH likely plays an Hesperidin important role in neurodegenerative diseases.This depletion of mitochondrial GSH likely contributed to increased apoptosis compared to controls when ethacrynic acid was added. Puzzled by these findings, the authors hypothesized that the difference might be related either to a differences in activity of the SOD mutants or to different subcellular localizations of the different SOD mutants.Thus, the antioxidant superoxidescavenging activity of SOD paradoxically appears to be necessary for the prooxidant effect of GSH depletion, inducing cell death.As for the differential subcellular localization of SOD, it is predominately localized in the cytoplasm, but can be found in the nucleus, ER, and mitochondria.Clearly, not all mutations of SOD confer the same ALS phenotype, and differential localization may be an important determinant that requires further study.Protein aggregation has also been suggested to play a key role in ALS. SOD typically exists as a dimer; and this dimer formation is thought to protect the enzyme from damage and misfolding.However, SOD can selfassociate into higherlevel oligomers, ultimately forming cytotoxic aggregates. Recently, this sitespecific glutathionylation was shown to destabilize and alter the structure of the SOD dimer, increasing its dissociation constant over fold. The resultant increase in monomeric SOD increases the likelihood of protein damage and aggregate formation.These studies suggest that glutathionylation of SOD may contribute directly to progression of ALS.Thus, expansion of the frataxin gene causes iron accumulation within the mitochondria, likely creating a milieu that enhances oxidative stress. Erythrocytes from FA patients were found to have a decreased concentration of reduced GSH but comparable levels of total GSH, compared to nonFA patients, consistent with an increase in proteinbound GSH. A later study then documented that FA patients have increased spinal cord proteinSSG levels compared to healthy controls. This increase in glutathionylated proteins reflects an increased oxidative environment and likely explains the diminished amount of free GSH in the FA patients.The diminished NADPH content indicates that its supply could not keep up with the demand for reducing equivalents.Consequently, the ability of GR to recycle GSSG to GSH would be limited by the supply of NADPH.Thus, in different contexts knockout and overexpression of frataxin gave comparable results.

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