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Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress.
Coles, LD, Tuite, PJ, Öz, G, Mishra, UR, Kartha, RV, Sullivan, KM, Cloyd, JC, Terpstra, M
Journal of clinical pharmacology. 2018;(2):158-167
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Abstract
Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using 1 H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.
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Glutathione exposes sequential IgE-epitopes in ovomucoid relevant in persistent egg allergy.
Roth-Walter, F, Starkl, P, Zuberbier, T, Hummel, K, Nöbauer, K, Razzazi-Fazeli, E, Brunner, R, Pali-Schöll, I, Kinkel, J, Felix, F, et al
Molecular nutrition & food research. 2013;(3):536-44
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Abstract
SCOPE Patients with persistent egg allergy have more immunoglobulin E (IgE) against sequential than conformational epitopes of ovomucoid (OVO). Here, we aimed to identify compounds capable to render sequential epitopes in egg. METHODS AND RESULTS Glutathione was used for in vitro reduction of OVO and circular dichroism analyses were performed. Glutathione reduced OVO in a concentration-dependent manner. Egg white was analyzed for reduced proteins with a thiol probe and by MALDI-TOF/TOF. In unprocessed total egg white, several reduced proteins were detected by the thiol probe, among them reduced ovalbumin could be confirmed with MS analyses. Egg-allergics or sensitized controls were tested serologically (n = 19) for IgE against native and reduced OVO and in skin prick tests (n = 9). More patients had IgE against reduced than native OVO in Western blots. In skin prick test, five out of seven persistent egg-allergics and none of the controls reacted with reduced OVO. CONCLUSION Reduced egg proteins are present in natural egg white. Glutathione, which is present in egg and furthermore is used as texture-improving additive in processed food, is capable of reducing OVO. Patients with persistent egg allergy reacted rather to reduce the native OVO. Hence, our data indicate that reduction is a novel natural and processing-associated principle, which contributes to the allergenicity of food.
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Blood glutathione as independent marker of lipid peroxidation in heart failure.
Campolo, J, De Maria, R, Caruso, R, Accinni, R, Turazza, F, Parolini, M, Roubina, E, De Chiara, B, Cighetti, G, Frigerio, M, et al
International journal of cardiology. 2007;(1):45-50
Abstract
BACKGROUND Aminothiols have a critical function as intracellular redox buffers and constitute furthermore an important extracellular redox system. Lipid peroxidation is increased in chronic heart failure (CHF), but the contribution of each thiol to oxidative stress in this syndrome has not been evaluated. AIM: To assess the correlation between blood and plasma concentrations of aminothiols and lipid peroxidation as marker of oxidative stress in CHF patients. METHODS Blood reduced glutathione (GSH), plasma total and reduced cysteine, cysteinylglycine, homocysteine, GSH, alpha-tocopherol, ascorbic acid, and free malondialdehyde (MDA) were assessed in samples obtained from 26 CHF heart transplant candidates and 26 age- and gender-matched controls with atherosclerotic risk factors and no history of cardiovascular disease. Results are expressed as median and interquartile range (I-III). RESULTS MDA levels were significantly higher in CHF patients than in controls [1.03 (0.56-1.60) microM vs. 0.70 (0.40-0.83) microM, p=0.006]. Blood reduced GSH concentrations were significantly higher [662 (327-867) microM vs. 416 (248-571) microM, p=0.016], while alpha-tocopherol levels were significantly lower [15 (13-19) microM vs. 21 (17-32) microM, p=0.001] in CHF patients than in controls. By multivariate logistic regression analysis, the only independent predictors of lipid peroxidation, as expressed by MDA levels > or = 1.00 microM, were increased blood GSH concentrations (OR 1.003 per unit, 95% CI 1.001 to 1.006, p=0.008), ischemic (OR 20, 95% CI 2.6 to 155, p=0.004) and non ischemic CHF etiology (OR 11, 95% CI 1.3 to 99, p=0.026). CONCLUSIONS Abnormalities in intracellular GSH cycling are associated to increased lipid peroxidation in CHF.
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An anthocyanin/polyphenolic-rich fruit juice reduces oxidative DNA damage and increases glutathione level in healthy probands.
Weisel, T, Baum, M, Eisenbrand, G, Dietrich, H, Will, F, Stockis, JP, Kulling, S, Rüfer, C, Johannes, C, Janzowski, C
Biotechnology journal. 2006;(4):388-97
Abstract
Oxidative cell damage is involved in the pathogenesis of atherosclerosis, cancer, diabetes and other diseases. Uptake of fruit juice with especially high content of antioxidant flavonoids/polyphenols, might reduce oxidative cell damage. Therefore, an intervention study was performed with a red mixed berry juice [trolox equivalent antioxidative capacity (TEAC): 19.1 mmol/L trolox] and a corresponding polyphenol-depleted juice (polyphenols largely removed, TEAC 2.4 mmol/L trolox), serving as control. After a 3-week run-in period, 18 male probands daily consumed 700 mL juice, and 9 consumed control juice, in a 4-week intervention, followed by a 3-week wash-out. Samples were collected weekly to analyze DNA damage (comet assay), lipid peroxidation (plasma malondialdehyde: HPLC/fluorescence; urinary isoprostanes: GC-MS), blood glutathione (photometrically), DNA-binding activity of nuclear factor-kappaB (ELISA) and plasma carotenoid/alpha-tocopherol levels (HPLC-DAD). During intervention with the fruit juice, a decrease of oxidative DNA damage (p<5x10(-4)) and an increase of reduced glutathione (p<5x10(-4)) and of glutathione status (p<0.05) were observed, which returned to the run-in levels in the subsequent wash-out phase. The other biomarkers were not significantly modulated by the juice supplement. Intervention with the control juice did not result in reduction of oxidative damage. In conclusion, the fruit juice clearly reduces oxidative cell damage in healthy probands.
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Validation of glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T: application to schizophrenia.
Terpstra, M, Vaughan, TJ, Ugurbil, K, Lim, KO, Schulz, SC, Gruetter, R
Magma (New York, N.Y.). 2005;(5):276-82
Abstract
OBJECTIVE Quantitation of glutathione (GSH) in the human brain in vivo using short echo time 1H NMR spectroscopy is challenging because GSH resonances are not easily resolved. The main objective of this study was to validate such quantitation in a clinically relevant population using the resolved GSH resonances provided by edited spectroscopy. A secondary objective was to compare several of the neurochemical concentrations quantified along with GSH using LCModel analysis of short echo time spectra in schizophrenia versus control. MATERIALS AND METHODS GSH was quantified at 4T from short echo STEAM spectra and MEGA-PRESS edited spectra from identical volumes of interest (anterior cingulate) in ten volunteers. Neurochemical profiles were quantified in nine controls and 13 medicated schizophrenic patients. RESULTS GSH concentrations as quantified using STEAM, 1.6 +/- 0.4 micromol/g (mean +/- SD, n = 10), were within error of those quantified using edited spectra, 1.4 +/- 0.4 micromol/g, and were not different (p = 0.4). None of the neurochemical measurements reached sufficient statistical power to detect differences smaller than 10% in schizophrenia versus control. As such, no differences were observed. CONCLUSIONS Human brain GSH concentrations can be quantified in a clinical setting using short-echo time STEAM spectra at 4T.
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Vitamin C augments lymphocyte glutathione in subjects with ascorbate deficiency.
Lenton, KJ, Sané, AT, Therriault, H, Cantin, AM, Payette, H, Wagner, JR
The American journal of clinical nutrition. 2003;(1):189-95
Abstract
BACKGROUND Ascorbate and glutathione play central roles in the defense against free radicals and oxidants that are implicated in chronic diseases. OBJECTIVE The objective was to determine the ability of vitamin C supplements to modulate the concentration of glutathione in human lymphocytes. DESIGN The effect of vitamin C supplements was determined in a sequential study with time points before supplementation, after 13 wk of vitamin C supplements (500 or 1000 mg/d), and after 13 wk of matching placebo. The supplementation group was selected on the basis of low plasma ascorbate (<33 mmol/L) and consisted of 48 healthy men and women, smokers and nonsmokers, aged 25-64 y. Ascorbate and glutathione were measured in purified lymphocytes. RESULTS At baseline, the mean (+/-SD) concentration of plasma ascorbate was 19.5 +/- 7.2 micro mol/L, 22.5 micro mol/L below the median of normal distribution. The ascorbate concentration in plasma was linearly associated with that in lymphocytes (r = 0.53, P < 0.001). On supplementation with vitamin C, lymphocyte ascorbate increased by 51% (from 16.7 +/- 4.9 to 25.3 +/- 6.9 nmol/mg protein; P < 0.001) and was accompanied by an increase of lymphocyte glutathione by 18% (from 22.5 +/- 4.5 to 26.6 +/- 6.5 nmol/mg protein; P < 0.001). After placebo, the ascorbate and glutathione concentrations fell to near baseline concentrations (17.1 +/- 5.4 and 23.5 +/- 6.4 nmol/mg protein, respectively). No significant interaction was observed for sex and smoking status. Finally, the changes in lymphocyte ascorbate after supplementation were strongly associated with changes in lymphocyte glutathione (r = 0.71, P < 0.001). The association suggests that every 1-mol change in ascorbate is accompanied by a change of approximately 0.5 mol in glutathione. CONCLUSION Vitamin C supplements increase glutathione in human lymphocytes.
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Low blood glutathione levels in acute myocardial infarction.
Kharb, S
Indian journal of medical sciences. 2003;(8):335-7
Abstract
BACKGROUND Although experimental studies have demonstrated that reduced glutathione (GSH) is involved in cellular protection from deleterious effects of oxygen free radicals in ischaemia and reperfusion, there are controversial data on the correlation between levels of GSH and the ischaemic process. AIM: The present study was planned to evaluate erythrocyte GSH levels in patients with acute myocardial infarction (AMI). SETTING & DESIGN Erythrocyte GSH levels were determined in 22 patients with AMI and 15 age matched healthy volunteers served as control. MATERIAL & METHODS Erythrocyte GSH levels were measured by using Bentler in AMI and control patients. Also lipid profile was analyzed enzymatically in these subject. STATISTICS The values were expressed as means +/- standard deviation (SD) and data from patients and controls was compared using student's 't'-test. RESULTS AND CONCLUSION GSH levels were significantly decreased in AMI as compared to control (p<0.001). Also, total cholesterol and triglycerides were higher is AMI subjects (p<0.05). These finding suggest that depressed GSH levels may be associated with enhanced protective mechanism to oxidative stress in AMI.
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Effects of a vitamin E-bonded membrane and of glutathione on anemia and erythropoietin requirements in hemodialysis patients.
Usberti, M, Gerardi, G, Micheli, A, Tira, P, Bufano, G, Gaggia, P, Movilli, E, Cancarini, GC, De Marinis, S, D'Avolio, G, et al
Journal of nephrology. 2002;(5):558-64
Abstract
BACKGROUND The oxidative damage of RBC membranes in hemodialysis (HD) patients increases red blood cell (RBC) susceptibility to hemolysis and impairs cell survival. Reduction of the oxidative stress might lead to better control of anemia and reduction of the erythropoietin (rhEPO) dose. METHODS We studied 38 stable HD patients, given a mean dose of rhEPO of 104+/-65 U/kg BW/week, at baseline and during antioxidant treatment with either a full or a 50% dose of EPO. Antioxidant treatment involved the combined use of glutathione, GSH (1200 mg i.v. at the end of each dialysis session) and a vitamin E-bonded HD membrane, CL-E. RBC and reticulocyte counts were done monthly. RBC survival (51Cr T/2) was assayed in 18 patients before and after the end of the study. Oxidative status was determined in 10 patients by measuring plasma concentrations of malondyhaldeide-4-hydroxynonenal (MDA-4HNE), reactive oxygen molecular species (ROMs), and oxydized-LDL (oxLDL) as indices of oxidative stress, alpha-tocopherol and total thiols as single antioxidants, and TAS as a marker of total antioxidant plasma activity. RESULTS Antioxidant treatment significantly reduced the high basal plasma concentrations of MDA4HNE and oxLDL, and significantly increased those of alpha-tocopherol, whereas TAS and thiols were unmodified. These changes lasted after the reduction of EPO. Anemia significantly improved with treatment, due to a significant increase in RBC survival. A close direct linear relationship was detected between plasma levels of vitamin E and hemoglobin. CONCLUSIONS Adequate control of oxidative stress achieves better control of anemia in HD patients. Since several antioxidant systems are impaired in uremia, the combined use of the CL-E membrane and GSH seems to be the best antioxidant therapy so far, with significant saving of the rhEPO dose.
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Selenium and glutathione levels, and glutathione peroxidase activities in blood components of uremic patients on hemodialysis supplemented with selenium and treated with erythropoietin.
Zachara, BA, Adamowicz, A, Trafikowska, U, Trafikowska, A, Manitius, J, Nartowicz, E
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2001;(4):201-8
Abstract
Patients with chronic renal failure (CRF) often have reduced concentrations of selenium (Se) and lowered activities of glutathione peroxidase (GSH-Px) in blood components. The kidney is a major source of plasma GSH-Px. We measured Se and glutathione levels in blood components and red cell and plasma GSH-Px activities in 58 uremic patients on regular (3 times a week) hemodialysis (HD). The dialyzed patients were divided in 4 subgroups and were supplemented for 3 months with: 1) placebo (bakers yeast), 2) erythropoietin (EPO; 3 times a week with 2,000 U after each HD session), 3) Se-rich yeast (300 microg 3 times a week after each HD), and 4) Se-rich yeast plus EPO in doses as above. The results were compared with those for 25 healthy subjects. The Se concentrations and GSH-Px activities in the blood components of dialyzed uremic patients were significantly lower compared with the control group. Treatment of the HD patients with placebo and EPO only did not change the parameters studied. The treatment with Se as well as with Se and EPO caused an increase in Se levels and red cell GSH-Px activity. Plasma GSH-Px activity, however, increased only slowly or did not change after treatment with Se and with Se plus EPO. In the group treated with Se plus EPO the element concentration in blood components was higher compared with the group supplemented with Se alone. The weak or absence of response in plasma GSH-Px activity to Se supply indicates that the impaired kidney of uremic HD patients has reduced possibilities to synthesize this enzyme.
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Glutathione supplementation during cold ischemia does not confer early functional advantage in renal transplantation.
Polyak, MM, Arrington, BO, Kapur, S, Stubenbord, WT, Kinkhabwala, M
Transplantation. 2000;(1):202-5
Abstract
BACKGROUND Reduced glutathione (GSH), a component of University of Wisconsin (UW) solution, is reported to oxidize during storage. Consequently the commercial manufacturer of UW recommends the supplemental addition of GSH to UW before utilization. We investigated the influence of supplemental GSH during cold ischemia on early renal allograft function. METHODS One hundred kidneys were locally procured from heart-beating donors, preserved in our laboratory, and transplanted during an 18-month period. Selected donor, preservation, and outcome characteristics were collected and compared by presence of supplemental GSH and method of preservation. All kidneys were randomized to receive 3.0 mM supplemental GSH to perfusate or no supplementation (control) and were preserved by either cold storage (CS) in UW or machine perfused (MP) in UW-machine perfusate solution (MPS). During MP, perfusion characteristics (flow, resistance, perfusate electrolytes, and pH) were serially measured. RESULTS There were no significant differences among the groups when the donor characteristics of age, serum creatinine, and intra-operative urine output were compared. Preservation characteristics were similar among the groups with the exception of cold ischemia time, which was longer in the MP group compared to CS (26.1 h vs. 21.9 h, P=0.03). When compared with CS, kidneys preserved by MP exhibited a 33.4% increase in immediate function (93% vs. 62%, P=0.01), a corresponding 29.4% decrease in the incidence of delayed graft function (10% vs. 34%, P=0.02), and a 10% improvement in short-term (6-month) graft survival (98% vs. 88%, P=0.02). The addition of GSH supplementation to perfusate resulted in no significant differences in graft outcomes. CONCLUSIONS Despite recommendations by the manufacturer that UW solution be routinely supplemented with GSH, supplemental GSH does not influence early renal allograft function. Our data suggest that a far greater beneficial impact on early graft function is achieved by machine perfusion. We conclude that GSH supplementation of commercially available UW is not necessary.