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BACKGROUND/OBJECTIVES: Vitamin D, L-cysteine (LC) and glutathione (GSH) levels are lower in the blood of diabetic patients. This study examined the hypothesis that the levels of vitamin D and LC correlate with those of GSH in the blood of type 2 diabetic patients (T2D), and that vitamin D and LC upregulate glutamate-cysteine ligase (GCLC), which catalyzes GSH biosynthesis, in cultured monocytes. SUBJECTS/METHODS: Fasting blood was obtained after written informed consent from T2D (n = 79) and healthy controls (n = 22). U937 monocytes were pretreated with 1,25 [(OH).sub.2] vitamin D (0-25 nM) or LC (0-500 µM) for 24 h and then exposed to control or high glucose (25 mM) for 4 h. RESULTS: Plasma levels of vitamin D, LC, GSH and GCLC protein were significantly lower in T2D versus those in age-matched healthy controls. Multiple linear regression analyses and adjustment for body weight showed a significant positive correlation between plasma levels of vitamin D (r = 0.26, P = 0.05) and LC (r = 0.81, P = 0.001) and that of GSH, and between LC and vitamin D (r = 0.27, P = 0.045) levels. Plasma levels of GSH (r = -0.34, P = 0.01) and LC (r = -0.33, r = 0.01) showed a negative correlation with triglyceride levels. Vitamin D correlated inversely with [HbA.sub.1C] (-0.30, P = 0.01) and homeostatic model assessment insulin resistance (r = -0.31, P = 0.03), which showed a significant positive correlation with triglycerides (r = 0.44, P = 0.001) in T2D. Cell culture studies demonstrate that supplementation with vitamin D and LC significantly increased GCLC expression and GSH formation in control and high-glucose-treated monocytes. CONCLUSIONS: This study suggests a positive relationship between the concentrations of the micronutrients vitamin D and LC and that of GSH. Some of the beneficial effects of vitamin D and LC supplementation may be mediated by an increase in the levels of GSH and a decrease in triglyceride levels in T2D patients. European Journal of Clinical Nutrition (2014) 68, 1148-1153; doi: 10.1038/ejcn.2014.114; published online 25 June 2014, INTRODUCTION Reduced glutathione (GSH) is the most prevalent non-protein thiol found in mammalian cells. (1,2) GSH has a major role in the detoxification of a variety of electrophilic compounds, including [...]

Individuals with type 2 diabetes are at increased risk of acquiring melioidosis, a disease caused by Burkholderia pseudomallei infection. Although up to half of melioidosis patients have underlying diabetes, the mechanisms involved in this increased susceptibility are unknown. We found that B. pseudomallei-infected PBMCs from dia-betic patients were impaired in IL-12p70 production, which resulted in decreased IFN-γ induction and poor bac-terial killing. The defect was specific to the IL-12-IFN- γ axis. Defective IL-12 production was also observed during Mycobacterium tuberculosis infection, in which diabetes is likewise known to be a strong risk factor. In contrast, IL-12 production in diabetic cells was not affected upon Salmonella enterica infection or in response to TLR2, -3, -4, and -5 ligands. Poor IL-12 production correlated with a deficiency in intracellular reduced glutathione (GSH) concentrations in diabetic patients. Addition of GSH or N-acetylcysteine to PBMCs selectively restored IL-12 and IFN- γ production and improved bacterial killing. Furthermore, the depletion of GSH in mice led to increased susceptibility to melioidosis, reduced production of IL-12p70, and poorer disease outcome. Our data thus establish a link between GSH deficiency in diabetes and increased susceptibility to melioidosis that may open up new therapeutic avenues to protect diabetic patients against some intracellular bacterial pathogens., Introduction Type 2 diabetes mellitus has been described as a global epidemic fueled by population growth, aging, urbanization, and increasing obesity. It is estimated that the number of people diagnosed [...]

Background: There has been an increasing interest in the role of oxidative stress in the pathophysiology of bipolar disorder. To explore this further, we evaluated the activity of glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST), as well as 3-nitrotyrosine levels and carbonyl content in patients in the early (within 3 years of illness onset) and late (a minimum of 10 years of illness) stages of bipolar disorder. Methods: We matched 30 patients in the early stage and 30 patients in the late stage of bipolar disorder, diagnosed according to DSM-IV criteria, with 60 healthy controls (30 matched for each group of patients). We measured symptomatic status using the Hamilton Rating Scale for Depression and the Young Mania Rating Scale. Results: We found a significant increase in 3-nitrotyrosine levels among patients in the early (p < 0.010) and late (p < 0.010) stages of bipolar disorder. The activity of GR and GST was increased only among patients in the late stage of illness. Glutathione peroxidase activity and carbonyl content did not differ among the groups. Limitations: Limitations of our study include its cross-sectional design, which did not allow us to examine direct causative mechanisms or the effects of progression of illness, and the potential environmental bias introduced by comparing patient groups recruited from different regions of the world. Conclusion: Our data indicate a possible tyrosine nitration-induced damage in patients with bipolar disorder that is present from the early stage of illness. Our data also indicate that patients in the late stage of illness demonstrate enhanced activity of GR and GST, which could suggest the involvement of a compensatory system in bipolar disorder., Introduction Bipolar disorder is a chronic psychiatric illness characterized by recurrent episodes of mania, hypomania, mixed states and depression. It is a highly disabling condition that is estimated to affect [...]

The reactions of glutathione (GSH) with polychlorinated biphenyl (PCB) quinones having different degrees of chlorination on the quinone ring were examined. EPR spectroscopy and MS revealed 2 types of reactions yielding different products: (i) a nonenzymatic, nucleophilic displacement of chlorine on the quinone ring yielding a glutathiylated conjugated quinone and (ii) Michael addition of GSH to the quinone, a 2-electron reduction, yielding a glutathiylated conjugated hydroquinone. The [pK.sub.a] of parent hydroquinone decreased by 1 unit as the degree of chlorination increased. This resulted in a corresponding increase in the oxidizability of these chlorinated hydroquinones. The reaction with oxygen appears to be first-order each in ionized hydroquinone and dioxygen, yielding hydrogen peroxide stoichiometrically. The generation of semiquinone radicals, superoxide, and hydroxyl radicals was observed by EPR; however, the mechanisms and yields vary depending on the degree of the chlorination of hydroquinone/quinone and the presence or absence of GSH. Our discovery that chlorinated quinones undergo a rapid, nonenzymatic dechlorination upon reaction with GSH opens a different view on mechanisms of metabolism and the toxicity of this class of compounds. dechlorination | EPR | superoxide | semiquinone | hydrogen peroxide

The effects of a 7.3-y supplementation with garlic and micronutrients and of anti-Helicobacter pylori treatment with amoxicillin (1 g twice daily) and omeprazole (20 mg twice daily) on serum folate, vitamin B-12, homocysteine, and glutathione concentrations were assessed in a rural Chinese population. A randomized, double-blind, placebo-controlled, factorial trial was conducted to compare the ability of 3 treatments to retard the development of precancerous gastric lesions in 3411 subjects. The treatments were: 1) anti-H, pylori treatment with amoxicillin and omeprazole; 2) 7.3-y supplementation with aged garlic and steam-distilled garlic oil; and 3) 7.3-y supplementation with vitamin C, vitamin E, and selenium. All 3 treatments were given in a [2.sup.3] factorial design to subjects seropositive for H. pylori infection; only the garlic supplement and vitamin and selenium supplement were given in a [2.sup.2] factorial design to the other subjects. Thirty-four subjects were randomly selected from each of the 12 treatment strata. Sera were analyzed after 7.3 y to measure effects on folate, vitamin B-12, homocysteine, and glutathione concentrations. Regression analyses adjusted for age, gender, and smoking indicated an increase of 10.2% (95%CI:2.9-18.1%) in serum folate after garlic supplementation and an increase of 13.4% (95%CI: 5.3-22.2%) in serum glutathione after vitamin and selenium supplementation. The vitamin and selenium supplement did not affect other analytes and the amoxicillin and omeprazole therapy did not affect any of the variables tested. In this rural Chinese population, 7.3 y of garlic supplementation increased the serum folate concentration and the vitamin and selenium supplement increased that of glutathione, but neither affected serum concentrations of vitamin B-12 or homocysteine.

Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a [sigma]-donor/[pi]-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich 'piano-stool' ruthenium arene complexes [[([[eta].sup.6]-arene)Ru(azpy)l].sup.+] (where arene = p-cymene or biphenyl, and azpy = N,N-dimethylphenylor hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine [Ru.sup.11] complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential -0.2 to -0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. Intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione ([gamma]-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs. arenes | cytotoxicity | glutathione | redox reactions | ruthenium complexes

BACKGROUND: Exposure to toxic methylmercury (MeHg) through fish consumption is a large problem worldwide, and it has led to governmental recommendations of reduced fish consumption and blacklisting of mercury-contaminated fish. [...]

Cysteine synthesis from homocysteine is catalyzed by two pyridoxal 5'-phosphate (PLP)-dependent enzymes. This suggests that vitamin B-6 status might affect cysteine and glutathione homeostasis, but it is unclear whether this occurs in humans. We assessed the effects of vitamin B-6 status on static and kinetic parameters of cysteine and glutathione metabolism in healthy female (n = 5) and male (n = 4) volunteers (20-30 y) before and after 4 wk of dietary vitamin B-6 restriction ( KEY WORDS: * cysteine * glutathione * human * transsulfuration * vitamin B-6

Abstract The aim of this study was to investigate the effects of aqueous extract of Anoectochilus formosanus (AFE) on liver fibrogenesis in carbon tetrachloride (C[Cl.sub.4])-induced cirrhosis. Fibrosis was induced in [...]

Levels of glutathione in liver and kidney, and other nutrients in plasma were evaluated in male and female ascorbate-requiring osteogenic disorder Shionogi (ODS) rats fed semipurified diets in which the concentrations of ascorbate were gradually decreased from 1965 to 180 mg/kg. Plasma ascorbate levels in ODS rats were unaffected when ascorbate levels in the diet were decreased from 1965 to 768 mg/kg. However, plasma ascorbate levels decreased progressively when levels of ascorbate in the diet were decreased from 527 to 180 mg/kg. Plasma ascorbate levels decreased up to 77% when the dietary ascorbate concentration decreased from 1965 to 180 mg/kg. Ascorbate levels in liver and kidney fell as much as 60-70% when the dietary ascorbate levels were reduced from 1965 to 180 mg/kg. However, the glutathione levels in these tissues were not affected. Plasma retinol and vitamin E levels were not affected by decreasing dietary ascorbate intake. Total cholesterol levels increased significantly in female rats as dietary ascorbate intake declined. Levels of glycated hemoglobin decreased significantly when dietary ascorbate levels decreased from 1965 to 527 mg/kg. This study suggests that levels of vitamin E, retinol and glutathione are not affected by decreased dietary intake of ascorbate under nonscorbutic conditions, whereas elevated ascorbate intake is associated with a decrease in levels of plasma cholesterol in female ODS rats. However, excessive intake of ascorbate may be associated with elevated glycation of hemoglobin. To achieve the maximal health benefit of ascorbate supplementation, further studies are necessary to define optimal ascorbate intakes. KEY WORDS: ascorbate. vitamin E; vitamin A; glutathione; cholesterol; glycation; ODS rats

The antioxidant defense status of both symptomatic and asymptomatic individuals with human immunodeficiency virus-1 (HIV-1) infection was examined. The serum selenium levels as well as plasma thiol and glutathione (GSH) concentrations and erythrocyte glutathione peroxidase (GSH-Px) activity were measured quantitatively and assessed in relation to clinical stage and surrogate markers of HIV disease. The results indicated that the hallmarks of stages I-III of HIV disease include significant impairments of the antioxidative defenses of the infected individuals.

Byline: Syed. Ali, Sandeep. Danda, Syed Abdul. Basha, Asif. Rasheed, Osman. Ahmed, M. Ahmed Background: Ifosfamide (IFO) is widely used DNA-alkylating agents in cancer chemotherapy for management of solid tumors [...]

A glutathione reductase (GshR)-deficient mutant of Lactobacillus sanfranciscensis DSM2045[1.sup.T] is used to determine the functional characterization of a GshR in lactobacilli. It is indicated that GshR activity of L. sanfranciscensis contributes to the beneficial effects of sourdough fermentation on bread texture.

Objective: The objective of this study was to investigate the association between antioxidant nutrients and markers of oxidative stress with pulmonary function in persons with chronic airflow limitation. Design: Cross-sectional study exploring the association of antioxidant nutrients and markers of oxidative stress with forced expiratory volume in the first second (FEV[sub.1]%) and forced vital capacity (FVC%). Setting/Subjects: The study data included 218 persons with chronic airflow limitation recruited randomly from the general population of Erie and Niagara counties, New York State, USA. Results: After adjustment for covariates, multiple linear regression analysis showed that serum [beta]-cryptoxanthin, lutein/zeaxanthin, and retinol, and dietary [beta]-carotene, [beta]-cryptoxanthin, lutein/zeaxanthin, vitamin C, and lycopene were positively associated with FEV[sub.1]% (P [less than] 0.05, all associations). Serum vitamins [beta]-cryptoxanthin, lutein/zeaxanthin, and lycopene, and dietary [beta]-cryptoxanthin, [beta]-carotene, vitamin C, and lutein/zeaxanthin were positively associated with FVC% (P [less than] 0.05, all associations). Erythrocytic glutathione was negatively associated with FEV[sub.1]%, while plasma thiobarbituric acid-reactive substances (TBARS) were negatively associated with FVC% (P [less than] 0.05). Conclusion: These results support the hypothesis that an imbalance in antioxidant/oxidant status is associated with chronic airflow limitation, and that dietary habits and/or oxidative stress play contributing roles. European Journal of Clinical Nutrition (2006) 60, 991-999. doi: 10.1038/sj.ejcn.1602410; published online 15 February 2006 Keywords: forced expiratory volume, vital capacity, glutathione, glutathione peroxidase, oxidative stress, TBARS, Author(s): H M Ochs-Balcom [1, 2, 3]; B J B Grant [1, 4, 5]; P Muti [1]; C T Sempos [1]; J L Freudenheim [1]; R W Browne [6]; S [...]

A chemical and biochemical mechanism of action of the metallothionein (MT)/thionein (T) couple has been proposed. The mechanism emphasizes the importance of zinc/sulfur cluster bonding in MT and the significance of the two cluster networks as redox units that confer mobility on otherwise tightly bound and redox-inert zinc in MT. In this article, it is further explored how this redox mechanism controls the metabolically active cellular zinc pool. The low redox potential of the sulfur donor atoms in the clusters readily allows oxidation by mild cellular oxidants with concomitant release of zinc. Such a release by oxidants and the preservation of zinc binding by antioxidants place MT under the control of the cellular redox state and, consequently, energy metabolism. The binding of effectors, e.g., ATP, elicits conformational changes and alters zinc binding in MT. The glutathione/glutathione disulfide redox couple as well as selenium compounds effect zinc delivery from MT to the apoforms of zinc enzymes. This novel action of selenium on zinc/sulfur coordination sites has significant implications for the interaction between these essential elements. Tight binding and kinetic lability, modulation of MT by cellular ligands and the redox state, control of MT gene expression by zinc and many other inducers all support a critical function of the MT/T system in cellular homeostasis and distribution of zinc. J. Nutr. 130: 1455S--1458S, 2000. KEY WORDS: * zinc * metallothionein * redox regulation * ATP * glutathione