Biomedical subjects

Dong-Hoon Hyun

Publications and source records attributed to Dong-Hoon Hyun.

8 recordsLinked to original sources

PubMed2006

Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging.

The plasma membrane (PM) contains redox enzymes that provide electrons for energy metabolism and recycling of antioxidants such as coenzyme Q and alpha-tocopherol. Brain aging and neurodegenerative disorders involve impaired energy metabolism and oxidative damage, but the involvement of the PM redox system (PMRS) in these processes is unknown. Caloric restriction (CR), a manipulation that protects the brain against aging and disease, increased activities of PMRS enzymes (NADH-ascorbate free radical reductase, NADH-quinone oxidoreductase 1, NADH-ferrocyanide reductase, NADH-coenzyme Q10 reductase, and NADH-cytochrome c reductase) and antioxidant levels (alpha-tocopherol and coenzyme Q10) in brain PM during aging. Age-related increases in PM lipid peroxidation, protein carbonyls, and nitrotyrosine were attenuated by CR, levels of PMRS enzyme activities were higher, and markers of oxidative stress were lower in cultured neuronal cells treated with CR serum compared with those treated with ad libitum serum. These findings suggest important roles for the PMRS in protecting brain cells against age-related increases in oxidative and metabolic stress.

Aging↗

PubMed2006

The plasma membrane redox system in aging.

Oxidative stress over time leads to the accumulation of damaged macromolecules and to profound physiological changes that are associated with several age-related diseases. The plasma membrane redox system (PMRS) appears to attenuate oxidative stress acting as a compensatory mechanism during the aging process. The PMRS appears to play a protective role during mitochondrial dysfunction to provide cells with a survival mechanism by lowering oxidative stress. The PMRS accomplishes this by producing more NAD(+) for glycolytic ATP production via transfer of electrons from intracellular reducing equivalents to extracelluar acceptors. Ubiquinone and alpha-tocopherol are key antioxidant molecules in the plasma membrane that are affected by aging and can be up-regulated by dietary interventions such as calorie restriction (CR). Up-regulation of PMRS activity leads to cell survival and membrane homeostasis under stress conditions and during calorie restriction. Further studies of the PMRS may provide not only additional information on the mechanisms involved in aging and CR, but may provide therapeutic targets for the prevention and treatment of age-related diseases.

Aging↗

PubMed2006

Bioenergetics of aging and calorie restriction.

Aging is a physiological process that involves a multi-factorial set of deleterious changes. These alterations are caused by an exponential increase in damage to macromolecules. This process is likely due to the cumulative effects of oxidative stress over time. One area of ongoing research in gerontology has focused on determining why there is an age-dependent decrease in cellular bioenergetics. The aim of this review is to summarize the recent findings on the effects of aging and calorie restriction on energy metabolism. The effect of calorie restriction on age-associated changes in bioenergetic parameters will be examined.

Aging↗

PubMed2005

Effect of overexpression of wild-type or mutant parkin on the cellular response induced by toxic insults.

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.

1-Methyl-4-phenylpyridinium↗

PubMed2004

Interference with ubiquitination causes oxidative damage and increased protein nitration: implications for neurodegenerative diseases.

Inhibition of the proteasomal pathway for degrading abnormal proteins leads to protein aggregation, increased oxidative damage and increased protein nitration. We now show that interference with polyubiquitination has similar consequences. Expression of a dominant-negative mutant form of ubiquitin (K48R) in NT-2 and SK-N-MC cells caused decreased cell growth rates and increased oxidative damage (protein carbonyls and lipid peroxidation), nitric oxide production and elevated protein nitration. It also rendered cells highly sensitive to 4-hydroxy-2,3-trans-nonenal, a neurotoxic end-product of lipid peroxidation, hydrogen peroxide and deprivation of growth factors. Overexpression of wild-type ubiquitin did not produce these effects. Our data show that interference with the ubiquitin-proteasome pathway at a different point and by a different mechanism can produce many of the common features of human neurodegenerative diseases, such as increased lipid peroxidation, protein oxidation and protein nitration. We suggest that defects in this pathway at multiple points could produce the common features of neurodegenerative diseases, and that more such defects remain to be discovered.

Aldehydes↗

PubMed2003

Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins.

Mutations in Cu,Zn-superoxide dismutase (SOD-1) are associated with some familial cases of amyotrophic lateral sclerosis (ALS), but it is not known how they result in cell death. We examined effects of overexpression of wild-type SOD-1 or the G37R or G85R mutations on the accumulation of ubiquitinated and nitrated proteins, and on loss of cell viability induced by the proteasome inhibitor, lactacystin. Wild-type SOD-1 had no effect on proteasomal activity, but the mutants decreased it somewhat. Treatment with lactacystin (1 micro m) caused only limited cell viability loss, even though it induced a marked inhibition of proteasomal activities. However, viability loss due to apoptosis was substantial in response to lactacystin when cells were overexpressing a mutant SOD-1. The frequency of cells showing immunoreactivity against ubiquitinated- or nitrated-proteins was enhanced when wild-type and mutant SOD-1 s were overexpressed. Ubiquitinated or nitrated alpha-tubulin, SOD-1, alpha-synuclein and 68K neurofilaments were observed in the aggregates. Similar aggregates were observed in cells overexpressing mutant parkin (Del3-5, T240R and Q311'X). The nitric oxide synthase inhibitor, l-NAME, decreased viability loss and aggregation, suggesting that nitration of proteins may play an important role in aggregation and in the cell death accompanying it.

Acetylcysteine↗

PubMed2002

Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome.

Mutations in Parkin (a ubiquitin protein ligase) are involved in autosomal recessive juvenile parkinsonism, but it is not known how they cause nigral cell death. We examined the effect of Parkin overexpression on cellular levels of oxidative damage, antioxidant defenses, nitric oxide production, and proteasomal enzyme activity. Increasing expression of Parkin by gene transfection in NT-2 and SK-N-MC cells led to increased proteasomal activity, decreased levels of protein carbonyls, 3-nitrotyrosine-containing proteins, and a trend to a reduction in ubiquitinated protein levels. Transfection of these cells with DNA encoding three mutant Parkins associated with autosomal recessive juvenile parkinsonism (Del 3-5, T240R, and Q311X) gave smaller increases in proteasomal activity and led to elevated levels of protein carbonyls and lipid peroxidation. Turnover of the mutant proteins was slower than that of the wild-type protein, and both could be blocked by the proteasome inhibitor, lactacystin. A rise in levels of nitrated proteins and increased levels of NO2-/NO3- was also observed in cells transfected with mutant Parkins, apparently because of increased levels of neuronal nitric-oxide synthase. The presence of mutant Parkin in substantia nigra in juvenile parkinsonism may increase oxidative stress and nitric oxide production, sensitizing cells to death induced by other insults.

Acetylcysteine↗

PubMed2002

Proteasomal dysfunction induced by 4-hydroxy-2,3-trans-nonenal, an end-product of lipid peroxidation: a mechanism contributing to neurodegeneration?

4-Hydroxy-2,3-trans-nonenal (HNE) is a neurotoxic unsaturated aldehyde end-product of lipid peroxidation. The addition of HNE to NT-2 and SK-N-MC cell lines induces apoptosis and we now investigated the time-course of events occurring prior to apoptosis. Treatment of both NT-2 and SK-N-MC cell lines with HNE led to HNE association with the proteasome, increased levels of protein carbonyls and ubiquitinated proteins, and decreased proteasomal function. There was also decreased metabolic activity, cytochrome c release and activation of caspase 3, followed by apoptotic changes including chromatin condensation, cell shrinkage and DNA fragmentation and laddering. Overexpression of mutant superoxide dismutase 1 proteins associated with amyotrophic lateral sclerosis decreased proteasomal activities in the absence of HNE and accelerated the apoptosis induced by HNE. By contrast, overexpression of wild-type superoxide dismutase 1 did not affect basal levels of proteasomal activity. The data suggest that accumulation of ubiquitinated proteins and impairment of proteasomal function are important events in HNE toxicity. We propose that the proteasomal system is a significant target of HNE neurotoxicity in a wide range of neurodegenerative diseases, especially if abnormal proteins are being expressed.

Aldehydes↗