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Effect of High-Dose Cysteine Supplementation on Erythrocyte Glutathione: A Double-Blinded, Randomized Placebo-Controlled Pilot Study in Critically Ill Neonates.
Calkins, KL, Sanchez, LA, Tseng, CH, Faull, KF, Yoon, AJ, Ryan, CM, Le, T, Shew, SB
JPEN. Journal of parenteral and enteral nutrition. 2016;(2):226-34
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BACKGROUND This study's objective was to determine if parenteral cysteine when compared with isonitrogenous noncysteine supplementation increases erythrocyte reduced glutathione (GSH) in neonates at high risk for inflammatory injury. MATERIAL AND METHODS Neonates with a score for neonatal acute physiology >10 requiring mechanical ventilation and parenteral nutrition (PN) were randomized in a double-blinded, placebo-controlled study to receive parenteral cysteine-HCl (CYS group) or additional PN amino acids (ISO group) at 121 mg/kg/d for ≥7 days. A 6-hour [(13)C2] glycine IV infusion was administered at study week 1 to determine the fractional synthetic rate of GSH (FSR-GSH). RESULTS Baseline characteristics were similar between the CYS (n = 17) and ISO groups (n = 21). Erythrocyte GSH and total glutathione concentrations, GSH:oxidized GSH (GSSG), and FSR-GSH after treatment were not different between groups. However, the CYS group had a larger individual positive change in GSH and total glutathione (infusion day - baseline) compared with the ISO group (P = .02 for each). After adjusting for treatment, a lower enrollment weight and rate of red blood cell transfusion were associated with a decreased change in total glutathione and GSH (P < .05 for each). CONCLUSION When compared with isonitrogenous noncysteine supplementation, high-dose cysteine supplementation for at least 1 week in critically ill neonates resulted in a larger and more positive individual change in GSH. Smaller infants and those who received transfused blood demonstrated less effective change in GSH with cysteine supplementation. The benefit of cysteine remains promising and deserves further investigation.
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Effect of cysteine-rich whey protein (immunocal®) supplementation in combination with resistance training on muscle strength and lean body mass in non-frail elderly subjects: a randomized, double-blind controlled study.
Karelis, AD, Messier, V, Suppère, C, Briand, P, Rabasa-Lhoret, R
The journal of nutrition, health & aging. 2015;(5):531-6
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OBJECTIVES The purpose of the present study was to examine the effect of a cysteine-rich whey protein (Immunocal®) supplementation in combination with resistance training on muscle strength and lean body mass (LBM) in elderly individuals. We hypothesized that the cysteine-rich whey protein (Immunocal®) group would experience a greater increase in muscle strength and lean body mass versus the control group (casein). DESIGN Randomized double-blind controlled intervention study. SETTING Institut de Recherches Cliniques de Montréal in Montreal, Canada. PARTICIPANTS Ninety-nine non-frail elderly subjects were recruited. INTERVENTION Participants were randomly assigned into two groups. The experimental group received a cysteine-rich whey protein isolate (Immunocal®) (20 g/day) and the control group received casein (20 g/day) during a 135-day period. In addition, both groups performed the same resistance training program (3 times per week). MEASUREMENTS Body composition (DXA) and muscle strength (leg press) were measured. RESULTS Of the 99 recruited participants, 84 completed the 135-day study period. Of these, 67 subjects (33 in the casein group and 34 in the Immunocal® group) complied and used at least 80 % of the study product and completed at least 80 % of their training sessions. Results in this selected group show an increase in all three muscle strength variables (absolute, normalized by BW and by LBM) by 31.0 %, 30.9 % and 30.0 %, respectively in the casein group as well as 39.3 %, 39.9 % and 43.3 %, respectively in the Immunocal® group after the intervention (p < 0.05). The increases in muscle strength favored Immunocal® versus casein by approximately 10 % when expressed in kg per kg BW and in kg per kg LBM (p < 0.05). No significant changes were found between pre-and-post intervention in both groups for total LBM. CONCLUSIONS Our findings showed increases in muscle strength in both groups after resistance training, however, significant additional increases were observed in muscle strength with the addition of a cysteine-rich whey protein (Immunocal®) versus casein.
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Acute pantothenic acid and cysteine supplementation does not affect muscle coenzyme A content, fuel selection, or exercise performance in healthy humans.
Wall, BT, Stephens, FB, Marimuthu, K, Constantin-Teodosiu, D, Macdonald, IA, Greenhaff, PL
Journal of applied physiology (Bethesda, Md. : 1985). 2012;(2):272-8
Abstract
Reduced skeletal muscle free coenzyme A (CoASH) availability may decrease the contribution of fat oxidation to ATP production during high-intensity, submaximal exercise or, alternatively, limit pyruvate dehydrogenase complex (PDC) flux and thereby carbohydrate oxidation. Here we attempted to increase the muscle CoASH pool in humans, via pantothenic acid and cysteine feeding, in order to elucidate the role of CoASH availability on muscle fuel metabolism during exercise. On three occasions, eight healthy male volunteers (age 22.9 ± 1.4 yr, body mass index 24.2 ± 1.5 kg/m(2)) cycled at 75% maximal oxygen uptake (Vo(2max)) to exhaustion, followed by a 15-min work output performance test. Muscle biopsies were obtained at rest, and after 60 min and 91.3 ± 3.1 min of exercise (time to exhaustion on baseline visit) on each occasion. Two weeks following the first visit (baseline), 1 wk of oral supplementation with either 3 g/day of a placebo control (glucose polymer; CON) or 1.5 g/day each of d-pantothenic acid and l-cysteine (CP) was carried out prior to the second and third visits in a randomized, counterbalanced, double-blind manner, leaving a 3-wk gap in total between each visit. Resting muscle CoASH content was not altered by supplementation in any visit. Following 60 min of exercise, muscle CoASH content was reduced by 13% from rest in all three visits (P < 0.05), and similar changes in the respiratory exchange ratio, glycogenolysis (∼235 mmol/kg dry muscle), PCr degradation (∼57 mmol/kg dry muscle), and lactate (∼25 mmol/kg dry muscle) and acetylcarnitine (∼12 mmol(.)kg/dry muscle) accumulation was observed during exercise when comparing visits. Furthermore, no difference in work output was observed when comparing CON and CP. Acute feeding with pantothenic acid and cysteine does not alter muscle CoASH content and consequently does not impact on muscle fuel metabolism or performance during exercise in humans.
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Cysteinyl leukotriene antagonism inhibits bronchoconstriction in response to hypertonic saline inhalation in asthma.
Kazani, S, Sadeh, J, Bunga, S, Wechsler, ME, Israel, E
Respiratory medicine. 2011;(5):667-73
Abstract
BACKGROUND In asthma, cysteinyl leukotrienes (CysLTs) play varying roles in the bronchomotor response to multiple provocative stimuli. The contribution of CysLTs on the airway's response to hypertonic saline (HS) inhalation in asthma is unknown. Whether polymorphisms in the leukotriene biosynthetic pathway affect the contribution of CysLTs to this response is also unknown. METHODS In a prospective, randomized, double-blind, placebo-controlled cross-over study, mild and moderate asymptomatic asthmatics underwent inhaled 3% HS challenge by doubling the duration of nebulization (0.5, 1, 2, 4, and 8 min) 2 h after one dose of montelukast (a CysLT receptor 1 [CysLTR1] antagonist) or placebo, and after three-week courses. We examined the effect of the leukotriene C(4) synthase (LTC(4)S) polymorphism (A-444C) on the efficacy of montelukast against HS inhalation in an exploratory manner. RESULTS In 37 subjects, 2 h after administration of montelukast, the mean provocative dose of HS required to cause a 20% drop in FEV(1) (HS-PD(20)) increased by 59% (9.17 ml after placebo vs. 14.55 ml after montelukast, p=0.0154). Three weeks of cysLTR1 antagonism increased the HS-PD(20) by 84% (10.97 vs. 20.21 ml, p=0.0002). Three weeks of CysLTR1 antagonism appeared to produce greater effects on blocking bronchial hyper-responsiveness (2 h vs. three-week HS-PD(20) values 14.55 vs. 20.21 ml respectively, p=0.0898). We did not observe an effect of the LTC(4)S polymorphism on the response to CysLTR1 antagonism in this cohort. CONCLUSIONS A significant proportion of HS-induced bronchoconstriction is mediated by release of leukotrienes as evidenced by substantial acute inhibition with a CysLTR1 antagonist. There was a trend toward greater inhibition of bronchial responsiveness with three weeks of therapy as opposed to acute CysLTR1 antagonism. Clinicaltrials.gov registration number NCT00116324.
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Effect of bariatric surgery on sulphur amino acids and glutamate.
Aasheim, ET, Elshorbagy, AK, Diep, LM, Søvik, TT, Mala, T, Valdivia-Garcia, M, Olbers, T, Bøhmer, T, Birkeland, KI, Refsum, H
The British journal of nutrition. 2011;(3):432-40
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Plasma total cysteine (tCys) concentrations are associated with BMI. To study the relationship between tCys and BMI, we monitored the changes in serum concentrations of tCys and metabolically related compounds in sixty obese patients (BMI 50-60 kg/m(2)) from before to 1 year after either gastric bypass surgery (mean 30 % weight loss) or duodenal switch surgery (mean 41 % weight loss). A total of fifty-eight healthy persons (BMI 17-31 kg/m(2)) served as controls. Before surgery, obese patients had modestly (approximately 17 %) higher mean serum tCys, and markedly (>2-fold) higher glutamate concentrations, than controls (P ≤ 0·001 for both). Serial examinations after surgery revealed that gastric bypass patients had no change in tCys concentrations (P = 0·22), while duodenal switch patients showed a modest (approximately 12 %) but significant decrease in tCys (P < 0·001). Total homocysteine concentrations increased in duodenal switch patients but not in gastric bypass patients. Independent of surgery type, serum concentrations of methionine and cystathionine decreased (P < 0·05 for both), while serum glutathione and taurine remained stable. Glutamate concentrations declined, as did γ-glutamyltransferase activity (P < 0·001 for both). These results show that despite 30 % weight loss, and decreases in methionine, cystathionine and glutamate, there was no significant change in serum tCys in patients after gastric bypass surgery. The decrease in tCys in patients undergoing duodenal switch could be related to malabsorption. The present findings do not suggest that BMI is a causal determinant of plasma tCys.
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Oxidation of plasma cysteine/cystine and GSH/GSSG redox potentials by acetaminophen and sulfur amino acid insufficiency in humans.
Mannery, YO, Ziegler, TR, Park, Y, Jones, DP
The Journal of pharmacology and experimental therapeutics. 2010;(3):939-47
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Variations in plasma sulfur amino acid (SAA) pools are associated with disease risks, but little information is available about the factors affecting plasma SAA pools. Drug metabolism by glutathione (GSH) and sulfate conjugation can, in principle, represent a quantitatively important burden on SAA supply. The present study was designed to determine whether therapeutic doses of acetaminophen (APAP) alter SAA metabolism in healthy human adults. A double-blind, crossover design incorporating four treatment periods with diets providing 100% of the recommended dietary allowance (RDA) for SAA without or with APAP (15 mg/kg) and 0% RDA for SAA without or with APAP, in randomized order. After a 3-day equilibration period, chemically defined diets with 100 or 0% RDA for SAA were given for 2 complete days. On day 3, APAP or placebo was given in two successive doses (6-h interval), and timed plasma samples were collected. With SAA intake at 100% RDA, APAP administration oxidized the plasma cysteine/cystine redox potential (E(h)CySS) but not the plasma GSH/GSSG redox potential (E(h)GSSG). The extent of oxidation caused by APAP was similar to that seen with 0% SAA and no APAP. However, APAP administration with 0% SAA did not cause further oxidation beyond APAP or 0% SAA alone. In contrast, an oxidation of the plasma E(h)GSSG was apparent for SAA insufficiency only with APAP. The results suggest a need to evaluate possible effects of APAP in association with SAA insufficiency as a contributing factor in disease risk.
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Effects of long-term zinc supplementation on plasma thiol metabolites and redox status in patients with age-related macular degeneration.
Moriarty-Craige, SE, Ha, KN, Sternberg, P, Lynn, M, Bressler, S, Gensler, G, Jones, DP
American journal of ophthalmology. 2007;(2):206-211
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PURPOSE To determine the effects of zinc supplementation on plasma thiol metabolites and their redox status in a cohort of patients with age-related macular degeneration (AMD). DESIGN Randomized clinical trial that evaluated the effects of high doses of zinc and antioxidants on plasma biomarkers of oxidative stress. METHODS This was an ancillary study of the Age-Related Eye Disease Study (AREDS). Subjects with AMD were randomized to one of four treatment groups: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg), (2) zinc (80 mg zinc oxide, 2 mg cupric oxide), (3) antioxidants plus zinc, or (4) placebo. At 20 and 80 months after randomization, blood specimens were collected and analyzed for glutathione (GSH), oxidized glutathione (GSSG), cysteine (Cys), and cystine (CySS). RESULTS Although zinc supplementation had no apparent effect on plasma thiol/disulfide redox status at the first blood draw, the group of patients receiving zinc supplementation at the second blood draw had significantly less CySS compared with those not receiving zinc (54.9 vs 64.1 microM; P = .01). There was a time-dependent oxidation of the plasma GHS pool and was not affected by zinc supplementation. CONCLUSIONS Because increased CySS level is associated with aging, oxidative stress, and age-related diseases, the apparent prevention of increased CySS by zinc supplementation warrants additional investigation.
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Minimum methionine requirement and cysteine sparing of methionine in healthy school-age children.
Humayun, MA, Turner, JM, Elango, R, Rafii, M, Langos, V, Ball, RO, Pencharz, PB
The American journal of clinical nutrition. 2006;(5):1080-5
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BACKGROUND Cysteine can provide a portion of the sulfur amino acid requirement in adults. Whether this is true in children-and, if so, to what extent-is not known. OBJECTIVES The objectives were to determine minimum methionine requirements in healthy, school-age children when excess cysteine is provided and to subsequently determine the cysteine-sparing effect by comparing these methionine requirements with those determined previously in the same children when no cysteine was provided. DESIGN Six healthy, school-age children randomly received graded intakes of methionine (0, 2.5, 5, 7.5, 10, and 15 mg . kg(-1) . d(-1)) along with 21 mg cysteine . kg(-1) . d(-1) in the diet. The mean methionine requirement was determined by using a biphasic linear regression crossover analysis of measurements of the rate of appearance of (13)CO(2) in the breath (F(13)CO(2)), which identified a breakpoint at the minimal F(13)CO(2) in response to graded levels of methionine intake. RESULTS The mean and population-safe minimum methionine requirements, in the presence of excess dietary cysteine, were found to be 5.8 and 7.3 mg . kg(-1) . d(-1), respectively. The mean and population-safe (upper 95% CI) methionine requirements, in the absence of dietary cysteine, were previously determined to be 12.9 and 17.2 mg . kg(-1) . d(-1), respectively. These values represent a cysteine-sparing effect of 55% and 58% in comparison with mean and population-safe methionine requirements, respectively. CONCLUSION Excess intake of dietary cysteine results in the reduction in the requirements for methionine to a minimum obligatory requirement level.
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N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals.
Medved, I, Brown, MJ, Bjorksten, AR, Murphy, KT, Petersen, AC, Sostaric, S, Gong, X, McKenna, MJ
Journal of applied physiology (Bethesda, Md. : 1985). 2004;(4):1477-85
Abstract
The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated the effects of the antioxidant compound N-acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to fatigue during prolonged, submaximal exercise in endurance athletes. Eight men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling for 45 min at 71% peak oxygen consumption (VO2 peak) and then to fatigue at 92% VO2 peak. NAC was intravenously infused at 125 mg.kg(-1).h(-1) for 15 min and then at 25 mg.kg(-1).h(-1) for 20 min before and throughout exercise. Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH), reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% VO2 peak was reproducible in preliminary trials (coefficient of variation 5.6 +/- 0.6%) and with NAC was enhanced by 26.3 +/- 9.1% (NAC 6.4 +/- 0.6 min vs. Con 5.3 +/- 0.7 min; P <0.05). NAC increased muscle total and reduced NAC at both 45 min and fatigue (P <0.005). Muscle cysteine and cystine were unchanged during Con, but were elevated above preinfusion levels with NAC (P <0.001). Muscle TGSH (P <0.05) declined and muscle GSH tended to decline (P=0.06) during exercise. Both were greater with NAC (P <0.05). Neither exercise nor NAC affected whole blood TGSH. Whereas blood GSH was decreased and calculated oxidized glutathione increased with exercise (P <0.05), both were unaffected by NAC. In conclusion, NAC improved performance in well-trained individuals, with enhanced muscle cysteine and GSH availability a likely mechanism.