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1.
Vitamin D deficiency is associated with an oxidized plasma cysteine redox potential in critically Ill children.
Alvarez, JA, Grunwell, JR, Gillespie, SE, Tangpricha, V, Hebbar, KB
The Journal of steroid biochemistry and molecular biology. 2018;:164-169
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Abstract
Critically ill populations incur high levels of oxidative stress and commonly present with vitamin D deficiency. This study aimed to investigate the relationship between vitamin D status and plasma markers of glutathione (GSH) and cysteine (Cys) redox and immunity in critically ill children. This was a cross-sectional study of n=50 PICU patients. Subjects were categorized according to their plasma 25-hydroxyvitamin D [25(OH)D] concentrations: (<20, 20-30, and ≥30ng/dL). Plasma GSH, glutathione disulfide (GSSG), Cys, and cystine (CySS) were measured with high-performance liquid chromatography, and their associated redox potentials determined (EhGSSG and EhCySS, respectively). Plasma LL-37, an indicator of innate immune function, was assayed with ELISA. Data were analyzed using general linear regression before and after adjustment for age, sex, and race. Results showed that EhCySS was more reduced in subjects with plasma 25(OH)D concentrations ≥30ng/mL compared to those with 25(OH)D concentrations <20ng/mL (P=0.009). Plasma GSH, GSSG, and total GSH decreased with increasing 25(OH)D category (P=0.06, 0.03, and 0.01, respectively), and plasma glutamine levels were lowest in subjects with plasma 25(OH)D concentrations ≥30ng/mL (P=0.004). Plasma LL-37 concentrations did not significantly differ by vitamin D status (P=0.08). In conclusion, vitamin D sufficiency was associated with more reduced plasma EhCySS, indicative of lower oxidative stress in critically ill children. Plasma GSH, GSSG, and glutamine, however, were lower in the vitamin D sufficient group. The role of vitamin D in maintaining redox status during pediatric critical illness requires further study.
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Whey Protein Supplementation Improves Nutritional Status, Glutathione Levels, and Immune Function in Cancer Patients: A Randomized, Double-Blind Controlled Trial.
Bumrungpert, A, Pavadhgul, P, Nunthanawanich, P, Sirikanchanarod, A, Adulbhan, A
Journal of medicinal food. 2018;(6):612-616
Abstract
Clinical side effects from medical therapy play an important role in causing malnutrition among cancer patients. Whey protein isolates (WPIs) have the potential to improve the nutritional status of cancer patients. The present study determined the effects of whey protein supplementation on nutritional status, glutathione (GSH) levels, immunity, and inflammatory markers in cancer patients in Thailand. A total of 42 cancer patients (41-63 years old) who received intravenous chemotherapy were randomized in a double-blind controlled trial at the National Cancer Institute in Thailand. Patients received 40 g of WPI plus zinc and selenium (intervention group, n = 23) or a maltodextrin oral snack (control group, n = 19) every day during the daytime for 12 weeks. Nutritional status, GSH levels, immunity, and inflammatory markers were assessed at baseline, 6, and 12 weeks. Whey protein supplementation significantly increased albumin (2.9%) and immunoglobulin G (4.8%) levels compared to the control group at week 12. Controls showed a significantly lower percent change in GSH levels (6.0%), whereas there was a significant time-dependent increase in the intervention group (11.7%). Whey protein supplementation improved nutrition status scores in the intervention group compared to the control. These data indicate that whey protein supplementation can increase GSH levels and improve nutritional status and immunity in cancer patients undergoing chemotherapy. These results will facilitate implementation of malnutrition risk prevention strategies and improve protein status, including immune function, during chemotherapy.
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Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis.
Chen, Y, Han, M, Matsumoto, A, Wang, Y, Thompson, DC, Vasiliou, V
Advances in experimental medicine and biology. 2018;:37-53
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Abstract
Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.
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Suppression of External NADPH Dehydrogenase-NDB1 in Arabidopsis thaliana Confers Improved Tolerance to Ammonium Toxicity via Efficient Glutathione/Redox Metabolism.
Podgórska, A, Ostaszewska-Bugajska, M, Borysiuk, K, Tarnowska, A, Jakubiak, M, Burian, M, Rasmusson, AG, Szal, B
International journal of molecular sciences. 2018;(5)
Abstract
Environmental stresses, including ammonium (NH₄⁺) nourishment, can damage key mitochondrial components through the production of surplus reactive oxygen species (ROS) in the mitochondrial electron transport chain. However, alternative electron pathways are significant for efficient reductant dissipation in mitochondria during ammonium nutrition. The aim of this study was to define the role of external NADPH-dehydrogenase (NDB1) during oxidative metabolism of NH₄⁺-fed plants. Most plant species grown with NH₄⁺ as the sole nitrogen source experience a condition known as “ammonium toxicity syndrome”. Surprisingly, transgenic Arabidopsis thaliana plants suppressing NDB1 were more resistant to NH₄⁺ treatment. The NDB1 knock-down line was characterized by milder oxidative stress symptoms in plant tissues when supplied with NH₄⁺. Mitochondrial ROS accumulation, in particular, was attenuated in the NDB1 knock-down plants during NH₄⁺ treatment. Enhanced antioxidant defense, primarily concerning the glutathione pool, may prevent ROS accumulation in NH₄⁺-grown NDB1-suppressing plants. We found that induction of glutathione peroxidase-like enzymes and peroxiredoxins in the NDB1-surpressing line contributed to lower ammonium-toxicity stress. The major conclusion of this study was that NDB1 suppression in plants confers tolerance to changes in redox homeostasis that occur in response to prolonged ammonium nutrition, causing cross tolerance among plants.
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Capillary Blood GSH Level Monitoring, Using an Electrochemical Method Adapted for Micro Volumes.
Buchtova, Z, Lackova, Z, Kudr, J, Zitka, Z, Skoda, J, Zitka, O
Molecules (Basel, Switzerland). 2018;(10)
Abstract
Glutathione (γ-glutamyl-cysteinyl-glycine; also known as GSH) is an endogenous antioxidant that plays a crucial role in cell defense mechanisms against oxidative stress. It is thus not surprising that this molecule can serve as a biomarker for oxidative stress monitoring. As capillary blood is a highly accessible target for biomarking, it is a valuable bodily fluid for diagnosing human GSH levels. This study focused on the optimization of GSH measurements from micro volumes of capillary blood prior to using electrochemical detection. The optimization of experimental parameters, including the sample volume and its stability, was performed and evaluated. Moreover, we tested the optimized method as part of a short-term study. The study consisted of examining 10 subjects within 96 h of their consumption of high amounts of antioxidants, attained from a daily dose of 2 g/150 mL of green tea. The subjects' capillary blood (5 μL) was taken at 0 h, 48 h, and 96 h for subsequent analysis. The short-term supplementation of diet with green tea showed an increase of GSH pool by approximately 38% (between 0 and 48 h) within all subjects.
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Intensive insulin therapy increases glutathione synthesis rate in surgical ICU patients with stress hyperglycemia.
Biolo, G, Massolino, B, Di Girolamo, FG, Fiotti, N, Mearelli, F, Mazzucco, S, Bertuzzi, C, Lazzarini, R, Colombatti, A, De Cicco, M
PloS one. 2018;(1):e0190291
Abstract
OBJECTIVE The glutathione system plays an essential role in antioxidant defense after surgery. We assessed the effects of intensive insulin treatment (IIT) on glutathione synthesis rate and redox balance in cancer patients, who had developed stress hyperglycemia after major surgery. METHODS We evaluated 10 non-diabetic cancer patients the day after radical abdominal surgery combined with intra-operative radiation therapy. In each patient, a 24-hr period of IIT, aimed at tight euglycemic control, was preceded, or followed, by a 24-hr period of conventional insulin treatment (CIT) (control regimen). Insulin was administered for 24 hours, during total parenteral nutrition, at a dosage to maintain a moderate hyperglycemia in CIT, and normoglycemic blood glucose levels in IIT (9.3±0.5 vs 6.5±0.3 mmol/L respectively, P<0.001; coefficient of variation, 9.7±1.4 and 10.5±1.1%, P = 0.43). No hypoglycemia (i.e., blood glucose < 3.9 mmol/L) was observed in any of the patients. Insulin treatments were performed on the first and second day after surgery, in randomized order, according to a crossover experimental design. Plasma concentrations of thiobarbituric acid reactive substances (TBARS) and erythrocyte glutathione synthesis rates (EGSR), measured by primed-constant infusion of L-[2H2]cysteine, were assessed at the end of each 24-hr period of either IIT or CIT. RESULTS Compared to CIT, IIT was associated with higher EGSR (2.70±0.51 versus 1.18±0.29 mmol/L/day, p = 0.01) and lower (p = 0.04) plasma TBARS concentrations (2.2±0.2 versus 2.9±0.4 nmol/L). CONCLUSIONS In patients developing stress hyperglycemia after major surgery, IIT, in absence of hypoglycemia, stimulates erythrocyte glutathione synthesis, while decreasing oxidative stress.
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Eryptosis and oxidative damage in hypertensive and dyslipidemic patients.
Pinzón-Díaz, CE, Calderón-Salinas, JV, Rosas-Flores, MM, Hernández, G, López-Betancourt, A, Quintanar-Escorza, MA
Molecular and cellular biochemistry. 2018;(1-2):105-113
Abstract
Arterial hypertension is a disease that often coexists with dyslipidemia. Both disorders can produce oxidative stress. Studies in vivo and in vitro have proven that oxidative stress can induce an increment of the erythrocyte apoptosis (eryptosis), through the rise of free intracellular calcium concentration ([Ca2+]i). Higher levels of eryptosis have not been described in patients with hypertension, dyslipidemia, or both combined. This study involved 81 men between 26 and 50 years old, assorted into four groups: normotensive with and without dyslipidemia, and hypertensive with and without dyslipidemia. Hypertensive and/or dyslipidemic patients had double mean lipid peroxidation and 30% less mean GSH concentration than the normotensive non-dyslipidemic patients. Mean [Ca2+]i in hypertensive patients was 100 and 200% higher, in patients without and with dyslipidemia, respectively, compared to normotensive patients. Dyslipidemic normotensive patients had three times higher mean PS externalization than the normotensive non-dyslipidemic patients, and the hypertension condition doubled this difference. Hypertensive patients had higher eryptosis associated with higher levels of [Ca2+]i and oxidative stress, suggesting that eryptosis participates in the pathophysiological mechanisms of hypertension. The quantitative analysis, when the dyslipidemic factor is included, shows that oxidative stress-[Ca2+]i-eryptosis do not follow a unique pattern in the different groups and suggests the existence of mechanisms of induction and molecular pathways alternative or additional to oxidative stress and [Ca2+]i, respectively.
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Eight weeks of resistance training in conjunction with glutathione and L-Citrulline supplementation increases lean mass and has no adverse effects on blood clinical safety markers in resistance-trained males.
Hwang, P, Morales Marroquín, FE, Gann, J, Andre, T, McKinley-Barnard, S, Kim, C, Morita, M, Willoughby, DS
Journal of the International Society of Sports Nutrition. 2018;(1):30
Abstract
BACKGROUND Supplementation of combined glutathione (GSH) with L-citrulline in response to a single bout of resistance exercise has been shown to increase plasma nitric oxide metabolites, nitrite and nitrate and cyclic guanosine monophosphate (cGMP), which may play a role in muscle protein synthesis. As a result, in response to resistance training (RT) these responses may establish a role for GSH + L-citrulline to increase muscle mass. This study attempted to determine the effects of an 8-week RT program in conjunction with GSH (Setria®) + L-citrulline, L-citrulline-malate, or placebo supplementation on lean mass and its association with muscle strength. The secondary purpose was to assess the safety of such supplementation protocol by assessing clinical chemistry markers. METHODS In a randomized, double-blind, placebo-controlled design, 75 resistance-trained males were randomly assigned to ingest GSH + L-citrulline (GSH + CIT), L-citrulline-malate, or cellulose placebo daily while also participating in 8 weeks of RT. The full dose of each supplement was delivered in capsules that were identical in weight, size, shape, and color. Participants completed testing sessions for body composition and muscle strength before and after 4 and 8 weeks of RT and supplementation. Venous blood samples were obtained before and after 8 weeks. RESULTS Leg press was increased with RT but was not significantly different between groups (p > 0.05); however, bench press strength was not increased with RT (p > 0.05). There were no significant changes in total body mass, fat mass, or total body water during 8 weeks of RT and supplementation. Lean mass increased in both GSH + CIT when compared to PLC; however, the increase was significant only after 4 weeks. Lean mass and strength were positively correlated (p < 0.05) in GSH + CIT, but not CIT-malate or PLC. Neither RT nor supplementation had any significant effects on blood clinical chemistry variables (p > 0.05). CONCLUSION Compared to PLC, supplementation of GSH + CIT during resistance training increased lean mass after 4 weeks of RT and was positively associated with muscle strength. However, after 8 weeks of RT there were no significant differences in any of the measured variables.
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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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Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase.
Sands, KN, Tuck, TA, Back, TG
Chemistry (Weinheim an der Bergstrasse, Germany). 2018;(39):9714-9728
Abstract
Selenium compounds play an important role in redox homeostasis in living organisms. One of their major functions is to suppress the harmful effects of hydrogen peroxide, hydroperoxides and downstream reactive oxygen species that lead to oxidative stress, which has in turn been implicated in many diseases and degenerative conditions. The glutathione peroxidase (GPx) family of selenoenzymes plays a key protective role by catalyzing the reduction of peroxides with glutathione. Considerable effort has been expended toward the discovery of small-molecule selenium compounds that mimic GPx. To date, ebselen has been the most widely studied such compound, including in several clinical trials. However, despite its proven lack of significant toxicity, it displays only moderate catalytic activity and very poor aqueous solubility. The cyclic seleninate esters and spirodioxyselenuranes have recently been investigated as potential next generation GPx mimetics, along with structurally related selenenate esters, diazaselenuranes and pincer selenuranes. Their catalytic activities, redox mechanisms and structure-activity relationships are described in this Review, along with a description and discussion of the relative merits of assays for measuring their activities.