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Biomedical subjects

J Viña

Publications and source records attributed to J Viña.

At least 37 records · Page 2Linked to original sources
PubMed1999

Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease.

In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with (n = 8) or without (n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (approximately 75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4. 6 +/- 0.9% at rest vs. 9.3 +/- 1.7% after exercise). In nontreated patients, MDA increased from 0.68 +/- 0.08 nmol/ml at rest up to 1. 32 +/- 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 +/- 1.2% preexercise vs. 4.6 +/- 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 +/- 0.15 nmol/ml preexercise vs. 0.64 +/- 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.

Adenosine Triphosphate↗
PubMed1998

AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins.

AIDS patients who receive zidovudine (AZT) frequently suffer from myopathy. This has been attributed to mitochondrial (mt) damage, and specifically to the loss of mtDNA. This study examines whether AZT causes oxidative damage to DNA in patients and to skeletal muscle mitochondria in mice, and whether this damage may be prevented by supranutritional doses of antioxidant vitamins. Asymptomatic HIV-infected patients treated with AZT have a higher urinary excretion (355+/-100 pmol/kg/d) of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxo-dG) (a marker of oxidative damage to DNA) than untreated controls (asymptomatic HIV-infected patients) (182+/-29 pmol/kg/d). This was prevented (110+/-79 pmol/kg/d) by simultaneous oral treatment with AZT plus antioxidant vitamins (C and E). Mice treated with AZT also had a significantly higher urinary excretion of 8-oxo-dG than controls. Skeletal muscle mtDNA of mice treated with AZT had more 8-oxo-dG than controls. mt lipoperoxidation was also increased and skeletal muscle glutathione was oxidized. These effects may be due to an increased peroxide production by muscle mitochondria of AZT-treated animals. Dietary supplements with vitamins C and E at supranutritional doses protect against oxidative damage to skeletal muscle mitochondria caused by AZT.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress.

The effect of aging on indices of oxidative damage in rat mitochondria and the protective effect of the Ginkgo biloba extract EGb 761 was investigated. Mitochondrial DNA from brain and liver of old rats exhibited oxidative damage that is significantly higher than that from young rats. Mitochondrial glutathione is also more oxidized in old than in young rats. Peroxide formation in mitochondria from old animals was higher than in those from young ones. According to morphological parameters (size and complexity), there are two populations of mitochondria. One is composed of large, highly complex mitochondria, and the other population is smaller and less complex. Brain and liver from old animals had a higher proportion of the large, highly complex mitochondria than seen in organs from young animals. Treatment with the Ginkgo biloba extract EGb 761 partially prevented these morphological changes as well as the indices of oxidative damage observed in brain and liver mitochondria from old animals.

Aging↗
PubMed1998

Late onset administration of oral antioxidants prevents age-related loss of motor co-ordination and brain mitochondrial DNA damage.

We have studied the effect of aging on brain glutathione redox ratio, on brain mitochondrial DNA damage and on motor co-ordination in mice and the possible protective role of late onset administration of sulphur-containing antioxidants. Glutathione redox ratios change to a more oxidized state in whole brain with aging but the changes are much more pronounced when this ratio is measured in brain mitochondria. The levels of 8-oxo-7,8-dihydro-2 '-deoxyguanosine in mitochondrial DNA are much higher in the brain of old animals than in those of young ones. Late onset oral administration of sulphur-containing antioxidants partially prevents oxidation of mitochondrial glutathione and DNA. There is an inverse relationship between age-associated oxidative damage to mitochondrial DNA and motor co-ordination in old mice.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Blood glutathione as an index of radiation-induced oxidative stress in mice and humans.

The effect of x-rays on GSH and GSSG levels in blood was studied in mice and humans. An HPLC method that we recently developed was applied to accurately determine GSSG levels in blood. The glutathione redox status (GSH/GSSG) decreases after irradiation. This effect is mainly due to an increase in GSSG levels. Mice received single fraction radiotherapy, at total doses of 1.0 to 7.0 Gy. Changes in GSSG in mouse blood can be detected 10 min after irradiation and last for 6 h within a range of 2.0-7.0 Gy. The highest levels of GSSG (20.1 +/- 2.9 microM), a 4.7-fold increase as compared with controls) in mouse blood are found 2 h after radiation exposure (5 Gy). Breast and lung cancer patients received fractionated radiotherapy at total doses of 50.0 or 60.0 Gy, respectively. GSH/GSSG also decreases in humans in a dose-response fashion. Two reasons may explain the radiation-induced increase in blood GSSG: (a) the reaction of GSH with radiation-induced free radicals resulting in the formation of thyl radicals that react to produce GSSG; and (b) an increase of GSSG release from different organs (e.g., the liver) into the blood. Our results indicate that the glutathione redox ratio in blood can be used as an index of radiation-induced oxidative stress.

Animals↗
PubMed1996

Aging of the liver: age-associated mitochondrial damage in intact hepatocytes.

Mitochondrial damage may be a major cause of cellular aging. So far, this hypothesis had only been tested using isolated mitochondria. The aim of this study was to investigate the involvement of mitochondria in aging using whole liver cells and not isolated mitochondria only. Using flow cytometry, we found that age is associated with a decrease in mitochondrial membrane potential (30%), an increase in mitochondrial size, and an increase in mitochondrial peroxide generation (23%). Intracellular peroxide levels were also increased. The number of mitochondria per cell and inner mitochondrial membrane mass did not change. Gluconeogenesis from glycerol or fructose (mitochondrial-independent) did not change with age, whereas it did from lactate (mitochondrial-dependent). The change in the rate of gluconeogenesis was not accompanied by changes in any of the following parameters: phosphoenolpyruvate carboxykinase or pyruvate carboxylase activities or mitochondrial ATP/ADP or cytosolic NADH/NAD+ ratios. This was caused by a decreased rate of malate export (to 20% of the controls) from mitochondria. The impairment of the mitochondrial malate transporter is posttranscriptional because its expression in Xenopus oocytes using polyadenylated RNA from livers of young or old animals did not change. Ketogenesis from oleate also fell in hepatocytes from old rats. Our results show, for the first time in intact cells, a correlation between age-associated impairment of cell metabolism and specific changes in mitochondrial function and morphology, supporting the hypothesis that mitochondrial damage plays a key role in aging.

Aging↗
PubMed1996

Mitochondrial glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA.

Mitochondria may be primary targets of free radical damage associated with aging. We have found that mitochondrial glutathione is markedly oxidized with aging in rats and mice. The oxidized to reduced glutathione ratio rises with aging in the liver, kidney, and brain. The magnitude of these changes is much higher than that previously found in whole cells of any species previously studied. In the liver, this ratio (expressing GSSG as a percent of GSH) changed from 0.77 +/- 0.19% (n=5) in young rats to 2.47 +/- 1.25% (n=5) in old ones, i.e., 320% of the controls. In the brain and kidney, values for old rats were, respectively, 600 and 540% higher than those of young rats. A marked oxidation of mitochondrial glutathione also occurred in mice. Aging also caused an increase in 8-oxo-7,8-dihydro-2'-deoxyguanosine levels in mtDNA in rats and mice. Oral antioxidant administration protected against both glutathione oxidation and mtDNA damage in rats and mice. Finally, we have found a direct relationship between mtDNA damage and mitochondrial glutathione oxidation. This occurs both in rats (r=0.95) and in mice (r=0.98). This relationship, which has been observed for the first time in these studies, underscores the role of glutathione in the protection against free radical damage that occurs upon aging.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Exercise causes blood glutathione oxidation in chronic obstructive pulmonary disease: prevention by O2 therapy.

The aim of the present study was to determine whether glutathione oxidation occurs in chronic obstructive pulmonary disease (COPD) patients who perform exercise and whether this could be prevented. Blood glutathione red-ox ratio [oxidized-to-reduced glutathione (GSSG/ GSH)] was significantly increased when patients performed exercise for a short period of time until exhaustion. Their resting blood GSSG/GSH was 0.039 +/- 0.008 (SD) (n = 5), whereas after exercise it increased to 0.085 +/- 0.019, P < 0.01. Glutathione oxidation associated with exercise was partially prevented by oxygen therapy (resting value: 0.037 +/- 0.014, n = 5; after exercise: 0.047 +/- 0.016, n = 5, P < 0.01). We conclude that light exercise causes an oxidation of glutathione in COPD patients, which can be partially prevented by oxygen therapy.

Carbon Dioxide↗
PubMed1995

A role for gamma-glutamyl transpeptidase and the amino acid transport system xc- in cystine transport by a human pancreatic duct cell line.

1. The roles of the gamma-glutamyl cycle and the anionic amino acid transport system xc- in mediating L-cystine uptake were investigated in cultured human pancreatic duct PaTu 8902 cells. This cell line exhibits morphological features of normal pancreatic duct cells and expresses gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2), an enzyme involved in the metabolism and regulation of intracellular glutathione (GSH). 2. Uptake of L-cystine (10 microM) was linear for up to 10 min, temperature dependent, Na+ independent, saturable (Michaelis-Menten constant (Km), 86 +/- 25 microM; maximal velocity (Vmax), 109 +/- 33 nmol (mg protein)-1 h-1) and reduced by 80-90% by a 50-fold excess concentration of L-glutamate and L-homocysteic acid, but not L-aspartate. These transport properties resemble those described for system xc-, which exchanges cystine for intracellular glutamate. 3. Acivicin, a known inhibitor of gamma-GT, decreased gamma-GT activity from 2.58 +/- 0.96 to 0.97 +/- 0.11 mU (mg protein)-1 and decreased the initial rates of L-cystine and L-glutamine uptake by 41-55%. Anthglutin (1-gamma-L-glutamyl-2-(2-carboxyphenylhyl)hydrazine), a structurally different inhibitor of gamma-GT, also caused a concentration-dependent (0.01-1 mM) decrease in gamma-GT activity and L-cystine uptake. 4. Neither acivicin nor anthglutin inhibited the uptake of L-glutamate, a poor substrate for gamma-GT. 5. In the presence of a 500-fold excess concentration of glutamate, which should abolish entry of cystine via system xc-, the remaining fraction of cystine transport was inhibited by 50% by acivicin, suggesting that transport is, in part, dependent on the activity of gamma-GT. 6. Cystine transport was also 60-80% inhibited by a series of gamma-glutamyl amino acids (5 mM) including gamma-glutamyl-glutamate, gamma-glutamyl-glutamine and gamma-glutamyl-glycine. alpha-Dipeptides inhibited cystine transport by only 6-22%. 7. These findings demonstrate that in human pancreatic duct PaTu 8902 cells, cystine uptake is mediated by system xc- (50-60%) and the gamma-glutamyl cycle. Our results provide the first evidence linking gamma-GT with cystine transport in human epithelial cells and are of relevance in view of the importance of cystine as a sulphur amino acid source for GSH synthesis in cells exposed to oxidative stress.

Adenosine Triphosphate↗
PubMed1995

L-cysteine and glutathione metabolism are impaired in premature infants due to cystathionase deficiency.

There are conflicting reports in the literature as to whether L-cysteine is an essential amino acid in premature infants as the result of the absence of hepatic cystathionase activity. To analyze the physiological importance of the cystathionase deficiency, we studied sulfur amino acid metabolism in human neonates of different gestational ages. Plasma cystathionine concentrations are higher in premature infants < or = 32 wk gestation (group 1) than in premature infants of 33-36 wk gestational age (group 2) or in full-term infants (group 3), whereas plasma cysteine concentrations are much lower in group 1 and 2 premature infants than in mature infants. Furthermore, erythrocytes from group 1 premature infants synthetize glutathione from L-methionine (a process dependent on the cystathionase pathway) at a much lower rate than do erythrocytes from group 2 premature or full-term infants. Thus, the metabolic flow through the transsulfuration pathway may be insufficient to meet the glutathione and cysteine requirements of very premature infants.

Amino Acids, Sulfur↗
PubMed1994

A high-performance liquid chromatography method for measurement of oxidized glutathione in biological samples.

A high-performance liquid chromatography method to determine oxidized glutathione (GSSG) in biological samples with ultraviolet-visible detection using N-ethylmaleimide to prevent reduced glutathione (GSH) oxidation is described. Previous methods based on high-performance liquid chromatography to quantitative GSH and GSSG are unsuitable for determining GSSG in biological samples. This is due to GSH oxidation during sample processing. N-Ethylmaleimide, but not iodacetic acid, prevents this oxidation. Blood GSH oxidation measured by the widely used method of Reed et al. (Anal. Biochem. 106, 55-62, 1980) can be as high as 24 +/- 6% (n = 6). When blood samples were assayed by our procedure, GSH oxidation was only 0.13 +/- 0.28% (n = 5). GSH can be determined enzymatically, i.e., with glutathione-S-transferase, but perchloric acid should not be used to deproteinize samples. Trichloroacetic acid (15% final concentration) may be used. This method allows an accurate calculation of the GSH/GSSG ratio, which is important for determining oxidative stress in tissues in various pathophysiological situations.

Animals↗
PubMed1994

Antioxidant administration to the mother prevents oxidative stress associated with birth in the neonatal rat.

In the fetal-to-neonatal transition, important circulatory and respiratory changes ensue which lead to oxidative stress evidenced by changes in glutathione status. Administration of N-Acetyl-Cysteine (NAC), a glutathione precursor, to the mother might be a rational approach to protect the fetus against oxidative stress. We have found that NAC administration to pregnant rats partially prevents the change in hepatic GSSG that occurs in the fetal-neonatal transition: GSSG increased 11-fold (from 1 to 12 nmol/g) in controls and less than two-fold (from 5 to 9 nmol/g) in animals exposed to NAC in utero. The GSH/GSSG ratio in liver of NAC-treated newborns was 411 +/- 216 and in liver of controls it was 283 +/- 176. Thus, the oxidative stress that occurs in the fetal-to-neonatal transition is partially prevented by oral NAC administration.

Acetylcysteine↗
PubMed1993

Depletion of tumour glutathione in vivo by buthionine sulphoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth.

We have investigated in Ehrlich-ascites-tumour-bearing mice the effect of buthionine sulphoximine (BSO), a selective inhibitor of GSH synthesis, on the rate of GSH depletion of tumour versus normal tissues and its relation to tumour cell proliferation. In normal tissues, GSH and GSSG remain unchanged or close to normal values during tumour growth, even at the last stage of growth when the animal is close to death. After administration of a single dose of BSO (4 mmol/kg), the rates of GSH depletion and recovery in the tumour and in several normal tissues are very different. BSO depletes GSH in cancer cells to a level of 0.3-0.4 mumol/g. The fall in GSH levels is faster when tumour cells do not proliferate actively. Four treatments of 4 mmol of BSO/kg at 48 h intervals induce a significant decrease (about 44%) in tumour growth. Our data show that the rate of BSO-induced GSH depletion in cancer cells depends on the stage of tumour growth, and that BSO administration also inhibits cancer-cell proliferation. A mechanism involving changes in protein kinase C activity and intracellular pH is proposed to explain the inhibition of cancer growth elicited by BSO.

Animals↗
PubMed1993

Effect of glutathione on canine myocardial ischaemia without reperfusion.

The present study was to evaluate the effect of exogenous glutathione on myocardial damage resulting from permanent (no reperfusion) coronary ligation (3 or 6 h) in anaesthetized dogs. Haemodynamics, infarct size and myocardial glutathione content were determined. Erythrocyte superoxide dismutase (SOD) activity was also determined in coronary venous blood samples. Glutathione was administered by the intraperitoneal route, 100 mg kg-1 as initial dose given 5 min before coronary ligation, and successive doses of 25 mg kg-1 every 40 min throughout the study period. Saline-treated dogs showed myocardial infarction, a decrease in myocardial glutathione content, and a transient increase in SOD activity. Three hours occlusion in glutathione-treated dogs resulted in a small reduction of infarct size, and no changes in myocardial glutathione content and SOD activity. By contrast, administration of glutathione failed to reduce infarct size and failed to prevent myocardial glutathione decrease in dogs subjected to 6 h occlusion. These results indicate that exogenous glutathione is of minor beneficial effect for myocardial damage resulting from permanent coronary occlusion and suggest that endogenous glutathione has a limited role in protecting against myocardial ischaemia without reperfusion.

Animals↗
PubMed1992

Regulation of glutathione metabolism in Ehrlich ascites tumour cells.

Glutathione metabolism was studied in cancer cells during the growth of an Ehrlich ascites tumour. GSH, but not GSSG, content decreases when cell proliferation and the rate of protein synthesis in the tumour decrease. This change correlates with a decrease in the rate of GSH synthesis and an increase in glutathione peroxidase and glutathione S-transferase activities. Glutathione efflux from tumour cells seems to co-ordinate with the rate of GSH synthesis. Cysteine, and not methionine, promotes GSH synthesis in tumour cells. However, changes in the rate of GSH synthesis are not due to limitations in the supply of blood cysteine or to changes in the intracellular amino acid pool of the cancer cells. Our data suggest that changes in protein metabolism accompanying tumour growth in vivo can modulate glutathione content in cancer cells.

Acetylcysteine↗