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Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls.
Burini, RC, Borges-Santos, MD, Moreto, F, Yu, YM
Amino acids. 2018;(5):569-576
Abstract
In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-L-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov , NCT00910442).
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Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study.
Honda, Y, Kessoku, T, Sumida, Y, Kobayashi, T, Kato, T, Ogawa, Y, Tomeno, W, Imajo, K, Fujita, K, Yoneda, M, et al
BMC gastroenterology. 2017;(1):96
Abstract
BACKGROUND Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD). METHODS The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. RESULTS Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. CONCLUSIONS This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy. TRIAL REGISTRATION UMIN000011118 (date of registration: July 4, 2013).
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Decreased glutathione and elevated hair mercury levels are associated with nutritional deficiency-based autism in Oman.
Hodgson, NW, Waly, MI, Al-Farsi, YM, Al-Sharbati, MM, Al-Farsi, O, Ali, A, Ouhtit, A, Zang, T, Zhou, ZS, Deth, RC
Experimental biology and medicine (Maywood, N.J.). 2014;(6):697-706
Abstract
Genetic, nutrition, and environmental factors have each been implicated as sources of risk for autism. Oxidative stress, including low plasma levels of the antioxidant glutathione, has been reported by numerous autism studies, which can disrupt methylation-dependent epigenetic regulation of gene expression with neurodevelopmental consequences. We investigated the status of redox and methylation metabolites, as well as the level of protein homocysteinylation and hair mercury levels, in autistic and neurotypical control Omani children, who were previously shown to exhibit significant nutritional deficiencies in serum folate and vitamin B₁₂. The serum level of glutathione in autistic subjects was significantly below control levels, while levels of homocysteine and S-adenosylhomocysteine were elevated, indicative of oxidative stress and decreased methionine synthase activity. Autistic males had lower glutathione and higher homocysteine levels than females, while homocysteinylation of serum proteins was increased in autistic males but not females. Mercury levels were markedly elevated in the hair of autistic subjects vs. control subjects, consistent with the importance of glutathione for its elimination. Thus, autism in Oman is associated with decreased antioxidant resources and decreased methylation capacity, in conjunction with elevated hair levels of mercury.
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Restoration of blood total glutathione status and lymphocyte function following alpha-lipoic acid supplementation in patients with HIV infection.
Jariwalla, RJ, Lalezari, J, Cenko, D, Mansour, SE, Kumar, A, Gangapurkar, B, Nakamura, D
Journal of alternative and complementary medicine (New York, N.Y.). 2008;(2):139-46
Abstract
OBJECTIVES To determine whether supplementation with alpha-lipoic acid (ALA), a glutathione-replenishing disulfide, modulates whole blood total glutathione (GSH + GSSG) levels and improves lymphocyte function in human immunodeficiency virus (HIV)-infected subjects with history of unresponsiveness to highly active antiretroviral treatment (HAART). DESIGN AND SETTING Randomized, double-blinded, placebo-controlled trial conducted at two study sites: an eye clinic at a county hospital in San Jose and a research clinic in San Francisco, California. SUBJECTS A total of 33 HIV-infected men and women with viral load >10,000 copies/cm(3), despite HAART, aged 44-47 years, approximately 36% nonwhite, were enrolled. INTERVENTION Patients were randomly assigned to receive either ALA (300 mg three times a day) or matching placebo for 6 months. MAIN OUTCOME MEASURES The change over 6 months in blood total glutathione status, lymphocyte proliferation response to T-cell mitogens, CD4 cell count, and viral load in patients receiving ALA compared to placebo. RESULTS The mean blood total glutathione level in ALA-supplemented subjects was significantly elevated after 6 months (1.34+/-0.79 vs. 0.81+/-0.18 mmol/L) compared to insignificant change (0.76+/-0.34 vs. 0.76+/-0.22 mmol/L) in the placebo group (ALA vs. placebo: p=0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after 6 months of ALA supplementation compared to progressive decline in the placebo group (ALA vs. placebo: p<0.001 with phytohemagglutinin; p=0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R(2)=0.889). There was no significant change in either HIV RNA level or CD4 count over 6 months in the ALA-supplemented compared to the control group. CONCLUSION Supplementation with alpha-lipoic acid may positively impact patients with HIV and acquired immune deficiency syndrome by restoring blood total glutathione level and improving functional reactivity of lymphocytes to T-cell mitogens.
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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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Abstract
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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Glutamine attenuates post-traumatic glutathione depletion in human muscle.
Fläring, UB, Rooyackers, OE, Wernerman, J, Hammarqvist, F
Clinical science (London, England : 1979). 2003;(3):275-82
Abstract
Glutathione is quantitatively the most important endogenous scavenger system. Glutathione depletion in skeletal muscle is pronounced following major trauma and sepsis in intensive care unit patients. Also, following elective surgery, glutathione depletion occurs in parallel with a progressive decline in muscle glutamine concentration. The present study was designed to test the hypothesis that glutamine supplementation may counteract glutathione depletion in a human trauma model. A homogeneous group of patients (n = 17) undergoing a standardized surgical procedure were prospectively randomly allocated to receive glutamine (0.56 g x day(-1) x kg(-1)) or placebo as part of isonitrogenous and isocaloric nutrition. Percutaneous muscle biopsies and blood samples were taken pre-operatively and at 24 and 72 h after surgery. The concentrations of muscle glutathione and related amino acids were determined in muscle tissue and plasma. In the control (unsupplemented) subjects, total muscle glutathione had decreased by 47+/-8% and 37+/-11% and reduced glutathione had decreased by 53+/-10% and 45+/-16% respectively at 24 and 72 h after surgery (P < 0.05). In contrast, in the glutamine-supplemented group, no significant post-operative decreases in total or reduced glutathione were seen following surgery. Muscle free glutamine had decreased at 72 h after surgery in both groups, by 41.4+/-14.8% (P < 0.05) in the glutamine-supplemented group and by 46.0+/-14.3% (P < 0.05) in the control group. In conclusion, the present study demonstrates that intravenous glutamine supplementation attenuates glutathione depletion in skeletal muscle in humans following standardized surgical trauma.
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Kidney preservation with university of Wisconsin and Celsior solution: a prospective multicenter randomized study.
Faenza, A, Catena, F, Nardo, B, Montalti, R, Capocasale, E, Busi, N, Boggi, U, Vistoli, F, Di Naro, A, Albertazzi, A, et al
Transplantation. 2001;(7):1274-7
Abstract
BACKGROUND Although the University of Wisconsin (U.W.) solution continues to be the most commonly used for intra-abdominal organs, a new solution, Celsior, already used for heart and lungs, has been proposed for kidney and liver preservation. The aim of this research was to assess the effect of Celsior as compared with U.W. on immediate graft function and a 2-year follow-up of kidney transplants. METHODS A prospective multicenter randomized study was designed to evaluate the efficacy of the Celsior solution in the clinical preservation of the kidney. In this report, we present the data collected as of September 2000. One hundred donors were included in the trial resulting in 187 renal transplants. Ninety-nine kidneys were stored in Celsior solution and 88 in U.W. solution. The groups were comparable with regard to donor and recipient characteristics. RESULTS Delayed graft function occurred in 31.3% of the Celsior group and in 33.9% of the U.W. group (P=n.s.). Mean serum creatinine levels and mean daily urinary output were also comparable. Two year graft survival in kidneys preserved with Celsior was 84% as compared with 75% for U.W.-preserved kidneys without any significant statistical difference. CONCLUSIONS Our data show that the preservation of kidneys in Celsior solution in a clinical setting is equivalent to that of U.W. solution. When using Celsior during multiple-organ donor harvesting it would be possible to perform an in situ flush of all intra-abdominal and intrathoracic organs with a single cold storage solution.