918 publications from this institution
It is proposed that a primary mechanism leading to neuronal cell death in common neurodegenerative diseases is interference with proteasome function. This can involve genetic defects, direct inactivation of the proteasome (e.g., by reactive oxygen species), or overloading with proteins. The latter can be caused by excessive production of normal proteins or by the formation of poorly degradable proteins as a result of genetic mutations, faulty posttranslational modification, or protein modification by reactive oxygen or nitrogen species. Blockage of the proteasome leads to increased oxidative and nitrative stress, the latter apparently due to upregulation of nitric oxide synthase. Thus, agents that increase proteasome function may be generally neuroprotective, as may be NOS inhibitors. Proteasome inhibitors should be used with caution as therapeutic agents.
Elevated levels of reactive nitrogen species (RNS) such as peroxynitrite have been implicated in over 50 diverse human diseases as measured by the formation of the RNS biomarker 3-nitrotyrosine. Recently, an additional RNS was postulated to contribute to 3-nitrotyrosine formation in vivo; nitryl chloride formed from the reaction of nitrite and neutrophil myeloperoxidase-derived hypochlorous acid (HOCl). Whether nitryl chloride nitrates intracellular protein is unknown. Therefore, we exposed intact human HepG2 and SW1353 cells or cell lysates to HOCl and nitrite and examined each for 3-nitrotyrosine formation by: 1) Western blotting, 2) using a commercial 3-nitrotyrosine enzyme-linked immunosorbent assay kit, 3) flow cytometric analysis, and 4) confocal microscopic analysis. With each approach, no significant 3-nitrotyrosine formation was observed in either whole cells or cell lysates. However, substantial 3-nitrotyrosine was observed when peroxynitrite (100 microm) was added to cells or cell lysates. These data suggest that nitryl chloride formed from the reaction of nitrite with HOCl does not contribute to the elevated levels of 3-nitrotyrosine observed in human diseases.
No abstract is provided for this article.
Non D-loop direct repeats (DRs) in mitochondrial DNA (mtDNA) have been commonly implicated in the mutagenesis of mtDNA deletions associated with neuromuscular disease and ageing. Further, these DRs have been hypothesized to put a constraint on the lifespan of mammals and are under a negative selection pressure. Using a compendium of 294 mammalian mtDNA, we re-examined the relationship between species lifespan and the mutagenicity of such DRs. Contradicting the prevailing hypotheses, we found no significant evidence that long-lived mammals possess fewer mutagenic DRs than short-lived mammals. By comparing DR counts in human mtDNA with those in selectively randomized sequences, we also showed that the number of DRs in human mtDNA is primarily determined by global mtDNA properties, such as the bias in synonymous codon usage (SCU) and nucleotide composition. We found that SCU bias in mtDNA positively correlates with DR counts, where repeated usage of a subset of codons leads to more frequent DR occurrences. While bias in SCU and nucleotide composition has been attributed to nucleotide mutational bias, mammalian mtDNA still exhibit higher SCU bias and DR counts than expected from such mutational bias, suggesting a lack of negative selection against non D-loop DRs.
No abstract is provided for this article.
An antioxidant is a substance that, when present at low concentrations compared to those of an oxidizable substrate, significantly delays or prevents oxidation of that substrate. Many substances have been suggested to act as antioxidants in vivo, but few have been proved to do so. The present review addresses the criteria necessary to evaluate a proposed antioxidant activity. Simple methods for assessing the possibility of physiologically-feasible scavenging of important biological oxidants (superoxide, hydrogen peroxide, hydroxyl radical, hypochlorous acid, haem-associated ferryl species, radicals derived from activated phagocytes, and peroxyl radicals, both lipid-soluble and water-soluble) are presented, and the appropriate control experiments are described. Methods that may be used to gain evidence that a compound actually does function as an antioxidant in vivo are discussed. A review of the pro-oxidant and anti-oxidant properties of ascorbic acid that have been reported in the literature leads to the conclusion that this compound acts as an antioxidant in vivo under most circumstances.Key Words: Antioxidantfree radicallipid peroxidationascorbic acidoxygen radicalsDNA damageperoxyl radicalsneutrophilshypochlorous acid.
Sulphite is toxic to the lung and can cause allergic reactions, the most common of which is bronchoconstriction in asthmatics. We show that sulphite can considerably potentiate the inactivation of α 1 ‐antiproteinase caused by peroxynitrite. Addition of peroxynitrite to sulphite generated inactivating species that persisted at pH 7.4 and 37°C for at least 30 min. We propose that formation of protein‐modifying sulphite radicals from SO 2− 3 exposed to ONOO − is a mechanism by which SO 2 could cause lung injury, both by enhancing proteolysis and by creating new antigens that could provoke an immune response.
