918 publications from this institution
The field of antioxidants and free radicals is often perceived as focusing around the use of antioxidant supplements to prevent human disease. In fact, antioxidants/free radicals permeate the whole of life, creating the field of redox biology. Free radicals are not all bad, nor antioxidants all good
Abstract Mutations in parkin are involved in some cases of autosomal recessive juvenile parkinsonism (AR‐JP), but it is not known how they result in nigral cell death. We examined the effect of parkin overexpression on the response of cells to various insults. Wild‐type and AR‐JP‐associated mutant parkins (Del3‐5, T240R, and Q311X) were overexpressed in NT‐2 and SK‐N‐MC cells. Overexpressed wild‐type parkin delayed cell death induced by serum withdrawal, H 2 O 2 , 1‐methyl‐4‐phenylpyridinium (MPP + ), or 4‐hydroxy‐2‐ trans ‐nonenal (HNE) but did not delay cell death caused by the proteasome inhibitor lactacystin. Increases in damage to proteins (protein carbonyls and 3‐nitrotyrosine) were attenuated by wild‐type parkin after serum withdrawal or exposure to H 2 O 2 , MPP + , or HNE but not after exposure to lactacystin. The mutant parkins (of all types) markedly accelerated cell death in response to all the insults, accompanied by increased levels of 8‐hydroxyguanine, protein carbonyls, lipid peroxidation, and 3‐nitrotyrosine and decreased levels of GSH. The viability loss induced by all the insults showed apoptotic features. The presence of parkin mutations in substantia nigra in Parkinson's disease may increase neuronal vulnerability to a range of toxic insults. © 2005 Wiley‐Liss, Inc.
The use of neuroprotective nutraceuticals as a strategy against neurodegenerative diseases such as Parkinson’s disease (PD) has gained considerable traction in recent years. In this review, we highlight ergothioneine (ET)—a naturally occurring thiol/thione derivative abundant in mushrooms—as a promising candidate, given its long half-life, blood–brain barrier penetration, and high bioavailability. Numerous population studies have linked low blood ET levels with increased risk and progression of neurological and other age-related disorders in humans, suggesting that dietary ET may confer neuroprotective benefits. Supporting this, several studies have demonstrated the efficacy of ET treatment in reducing PD-associated molecular damage across various pre-clinical models such as C. elegans, Drosophila, rodent models and human neuronal cultures, leading to marked improvements in disease phenotypes. Here, we summarize some of the proposed mechanisms by which ET may exert neuroprotection in PD, including the reduction of protein aggregation, enhancement of mitochondrial function, mitigation of oxidative stress, and attenuation of apoptosis and neuroinflammation. We also highlight recent clinical trials demonstrating the safety and potential efficacy of ET and propose future research to facilitate the translation of ET into the clinic.
Modification of DNA bases in mammalian chromatin upon treatment with hydrogen peroxide in the presence of ferric and cupric ions was studied. Ten DNA base products in mammalian chromatin were identified and quantitated by the use of gas chromatography-mass spectrometry with selected-ion monitoring after hydrolysis of chromatin and trimethylsilylation of hydrolysates. This technique permitted the analysis of modified DNA bases in chromatin without the necessity of isolation of DNA from chromatin first. Modified bases identified were typical hydroxyl radical-induced products of DNA, indicating the involvement of hydroxyl radical in their formation. This was also confirmed by inhibition of product formation by typical scavengers of hydroxyl radical. The inhibition of product formation was much more prominent in the presence of chelated ions than unchelated ions, indicating a possible site-specific formation of hydroxyl radical when metal ions are bound to chromatin. Hydrogen peroxide in the presence of cupric ions caused more DNA damage than in the presence of ferric ions. Chelation of cupric ions caused a marked inhibition in product formation. By contrast, DNA was damaged more extensively in the presence of chelated ferric ions than in the presence of unchelated ferric ions. The presence of ascorbic acid generally increased the yields of the products, indicating increased production of hydroxyl radical by reduction of metal ions by ascorbic acid. Superoxide dismutase afforded partial inhibition of product formation only in the case of chelated iron ions. The yields of the modified bases in chromatin were lower than those observed with calf thymus DNA under the same conditions.
1. Dihydroxyfumarate slowly autoxidizes at pH6. This reaction is inhibited by superoxide dismutase but not by EDTA. Mn2+ catalyses dihydroxyfumarate oxidation by reacting with O2 leads to to form Mn3+, which seems to oxidize dihydrofumarate rapidly. Cu2+ also catalyses dihydroxyfumarate oxidation, but by a mechanism that does not involve O2 leads to. 2. Peroxidase catalyses oxidation of dihydroxyfumarate at pH6; addition of H2O2 does not increase the rate. Experiments with superoxide dismutase and catalase suggest that there are two types of oxidation taking place: an enzymic, H2O2-dependent oxidation of dihydroxyfumarate by peroxidase, and a non-enzymic reaction involving oxidation of dihydroxyfumarate by O2 leads to. The latter accounts for most of the observed oxidation of dihydroxyfumarate. 3. During dihydroxyfumarate oxidation, most peroxidase is present as compound III, and the enzymic oxidation may be limited by the low rate of breakdown of this compound. 4. Addition of p-coumaric acid to the peroxidase/dihydroxyfumarate system increases the rate of dihydroxyfumarate oxidation, which is now stimulated by addition of H2O2, and is more sensitive to inhibition by catalase but less sensitive to superoxide dismutase. Compound III is decomposed in the presence of p-coumaric acid. p-Hydroxybenzoate has similar, but much smaller, effects on dihydroxyfumarate oxidation. However, salicylate affects neither the rate nor the mechanism of dihydroxyfumarate oxidation. 5. p-Hydroxybenzoate, salicylate and p-coumarate are hydroxylated by the peroxidase/dihydroxyfumarate system. Experiments using scavengers of hydroxyl radicals shown that OH is required. Ability to increase dihydroxyfumarate oxidation is not necessary for hydroxylation to occur.
No abstract is provided for this article.
In this mini-reflection, I explain how during my doctoral work in a Botany Department I first became interested in H2O2 and later in my career in other reactive oxygen species, especially the role of “catalytic” iron and haem compounds (including leghaemoglobin) in promoting oxidative damage. The important roles that H2O2, other ROS and dietary plants play in respect to humans are discussed. I also review the roles of diet-derived antioxidants in relation to human disease, presenting reasons why clinical trials using high doses of natural antioxidants have generally given disappointing results. Iron chelators and ergothioneine are reviewed as potential cytoprotective agents with antioxidant properties that may be useful therapeutically. The discovery of ferroptosis may also lead to novel agents that can be used to treat certain diseases.
There is currently great interest in the possible role of reactive nitrogen species and reactive oxygen species in causing DNA damage that leads to cancer. It appears likely that certain reactive oxygen species can act as complete carcinogens. However, the development of human cancer will depend on other factors such as the extent of DNA damage, antioxidant levels and DNA repair systems. The true picture will only be seen if we have reliable and sensitive techniques for the measurement of DNA damage. In this article we outline various methods for measuring DNA damage base, with special emphasis on HPLC and GC-MS based systems.
Exposure of Neuro-2a and PC12 cells to micromolar concentrations of sulfite caused an increase in reactive oxygen species and a decrease in ATP. Likewise, the biosynthesis of ATP in intact rat brain mitochondria from the oxidation of glutamate was inhibited by micromolar sulfite. Glutamate-driven respiration increased the mitochondrial membrane potential (MMP), and this was abolished by sulfite but the MMP generated by oxidation of malate and succinate was not affected. The increased rate of production of NADH from exogenous NAD+ and glutamate added to rat brain mitochondrial extracts was inhibited by sulfite, and mitochondria preincubated with sulfite failed to reduce NAD+. Glutamate dehydrogenase (GDH) in rat brain mitochondrial extract was inhibited dose-dependently by sulfite as was the activity of a purified enzyme. An increase in the Km (glutamate) and a decrease in Vmax resulting in an attenuation in Vmax/Km (glutamate) at 100 microm sulfite suggest a mixed type of inhibition. However, uncompetitive inhibition was noted with decreases in both Km (NAD+) and Vmax, whereas Vmax/Km (NAD+) remained relatively constant. We propose that GDH is one target of action of sulfite, leading to a decrease in alpha-ketoglutarate and a diminished flux through the tricarboxylic acid cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a decreased MMP, and a decrease in ATP synthesis. Because glutamate is a major metabolite in the brain, inhibition of GDH by sulfite could contribute to the severe phenotype of sulfite oxidase deficiency in human infants.
