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Glutathione

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Title
Tissue glutathione, nutrition, and oxidative stress.
Author
Bray TM; Taylor CG
Address
Department of Nutritional Sciences, University of Guelph, ON, Canada.
Source
Can J Physiol Pharmacol, 71(9):746-51 1993 Sep
Abstract
glutathione, a cysteine-containing tripeptide, is the most abundant nonprotein thiol in mammalian cells. glutathione plays an important role in the detoxification of xenobiotic compounds and in the antioxidation of reactive oxygen species and free radicals. Because of its multiple functions in various tissues and its involvement in many diseases and malnutrition, a clear understanding of the interrelationships among tissue glutathione, nutrition, and oxidative stress is clinically relevant. The focus of this review is to discuss the regulation of tissue glutathione concentration by diet and nutritional status, and to apply this information to those diseases and malnutrition in which decreased tissue glutathione and increased oxidative stress are implicated. A potential strategy to rapidly restore glutathione for both antioxidant and immune defense systems before therapeutic treatment in malnourished patients is discussed.

Title
glutathione depletion in rats impairs T-cell and macrophage immune function.
Author
Robinson MK; Rodrick ML; Jacobs DO; Rounds JD; Collins KH; Saporoschetz IB; Mannick JA; Wilmore DW
Address
Laboratory for Surgical Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. 02115.
Source
Arch Surg, 128(1):29-34; discussion 34-5 1993 Jan
Abstract
Critical illness is associated with both immunosuppression and glutathione deficiency. We determined if in vivo depletion of glutathione would adversely affect immune status. Rats with normal glutathione levels and those with glutathione stores depleted by diethyl maleate underwent analysis of splenocyte function and mesenteric lymph node lymphocyte function. Lymphocytes of the spleen and mesenteric lymph nodes were tested for concanavalin A proliferative response and interleukin 2 production. Tumor necrosis factor and interleukin 6 secretion by splenic adherent cells was also measured. glutathione-depleted animals had significantly decreased lymphocyte proliferation and decreased production of tumor necrosis factor and interleukin 6 but unaltered interleukin 2 production. These findings indicate that in vivo glutathione deficiency impairs macrophage and T-cell function. Because glutathione depletion may occur in sepsis, trauma, and shock, treatments that help maintain glutathione levels may enhance immunocompetence and thus improve the ability of patients to recover from critical illness.

Title
Imbalance between oxidants and antioxidants in the lungs of HIV-seropositive individuals.
Author
Buhl R
Address
Pulmonary Department/ZIM, Frankfurt University Hospital, Germany.
Source
Chem Biol Interact, 91(2-3):147-58 1994 Jun
Abstract
Following the initial infection with HIV, there is evidence of immune dysfunction despite an apparent normal clinical state. In the context that the lung is a major site affected by opportunistic infection, and that some components of the immune system are activated during early HIV infection, we hypothesized that there may be activation of alveolar macrophages (AM), a key component of the pulmonary host defense system. Compared to cells from normal individuals, AM of asymptomatic HIV-seropositive (HIV+) individuals (CDC-stage II) spontaneously released significantly more superoxide anion (O2-.) (P < 0.002). The O2-. release by AM of HIV-infected individuals was comparable to the spontaneous O2-.-release by AM of cigarette smokers (P > 0.6), a condition often associated with chronic damage of respiratory tissues. The destructive effects of oxidants are normally suppressed by antioxidant defense systems. Evaluation of the concentrations of glutathione, a major component of the pulmonary antioxidant protective screen, demonstrated that the HIV+ state is also characterized by a significant glutathione deficiency in lung epithelial lining fluid (P < 0.001) and in venous plasma (P < 0.001). This suggests that the alveolar structures of HIV+ individuals are continuously exposed to increased amounts of toxic oxygen radicals without adequate protection, i.e. the reactive oxygen metabolites may cause sufficient tissue damage culminating in interstitial lung disease. Further, since many immune functions are susceptible to injury by extracellular oxidants, the consequences of an unsuppressed oxidant burden in the lung may amplify the extent of local immunocompromise. In addition, since glutathione plays an important role in modulating lymphocyte activation and effector functions independent of its antioxidant activity, the systemic glutathione deficiency may contribute to the progressive global immune dysfunction that characterizes HIV infection.

Title
Decreased levels of total and reduced glutathione in CD4+ lymphocytes in common variable immunodeficiency are associated with activation of the tumor necrosis factor system: possible immunopathogenic role of oxidative stress.
Author
Aukrust P; Svardal AM; MÍuller F; Lunden B; Berge RK; FrÍland SS
Address
Medical Department A, University of Oslo, National Hospital, Norway.
Source
Blood, 86(4):1383-91 1995 Aug 15
Abstract
We have previously shown chronic immune activation and enhanced generation of reactive oxygen species in common variable immunodeficiency (CVI). In the present study, we examined levels of glutathione, the dominant intracellular thiol, that play an important protective role against oxidative and inflammatory stress in plasma and in monocytes and lymphocyte subsets in 20 CVI patients and in 16 healthy controls. CD4+ lymphocytes from CVI patients had significantly lower levels of both total and reduced glutathione as well as a lower ratio of reduced to total glutathione compared with healthy controls. This decrease in glutathione levels in CD4+ lymphocytes was most pronounced in the CD45RA+ subset. Plasma levels of total glutathione were also significantly decreased in CVI. In contrast, monocytes from CVI patients exhibited increased levels of both total and reduced glutathione compared with blood donor monocytes. CVI patients had significantly raised serum levels of tumor necrosis factor alpha (TNF alpha) and TNF alpha concentration was strongly associated with glutathione depletion in CD4+ lymphocytes. Furthermore, the lowest levels of both total and reduced glutathione were found in a subgroup of CVI patients characterized by persistent immune activation in vivo, decreased numbers of CD4+ lymphocytes in peripheral blood, and splenomegaly. Finally, supplementation of cell cultures with glutathione-monoethyl ester did significantly enhance interleukin-2 production from peripheral blood mononuclear cells in CVI patients. These glutathione abnormalities in CVI indicate increased oxidative stress, particularly in CD4+ lymphocytes, and intracellular depletion of reduced glutathione of the demonstrated magnitude may have profound implications for CD4+ lymphocyte function and the immunodeficiency in CVI.

Title
Antioxidants and immune response in aged persons: overview of present evidence.
Author
Meydani SN; Wu D; Santos MS; Hayek MG
Address
Nutritional Immunology Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
Source
Am J Clin Nutr, 62(6 Suppl):1462S-1476S 1995 Dec
Abstract
The oxidant-antioxidant balance is an important determinant of immune cell function, including maintaining the integrity and functionality of membrane lipids, cellular proteins, and nucleic acids and controlling signal transduction and gene expression in immune cells. Optimal amounts of antioxidants are needed for maintenance of the immune response across all age groups. This need might be more critical, however, in aged persons. Age-associated dysregulation of immune response, particularly of T cell-mediated function, is well documented. The well-known age-related increase in free radical formation and lipid peroxidation contributes, at least in part, to this phenomenon. We summarize animal and human studies undertaken by ourselves as well as other investigators on the effects of antioxidants, vitamin E, beta-carotene, and glutathione on the immune response of aged persons. The underlying mechanisms for the antioxidant nutrients' effects as well as their health implications for aged persons are discussed.

Title
Prostaglandin E2 suppresses phytohemagglutinin-induced immune responses of normal human mononuclear cells by decreasing intracellular glutathione generation, but not due to increased DNA strand breaks or apoptosis.
Author
Yu CL; Liu CL; Tsai CY; Sun KH; Liao TS; Lin WM; Chen HL; Yu HS
Address
Department of Medicine, Veterans General Hospital-Taipei, Taiwan, Republic of China.
Source
Agents Actions, 40(3-4):191-9 1993 Nov
Abstract
Prostaglandin E2 (PGE2) at concentrations more than 1 x 10(-8) M markedly suppressed the cell proliferation and release of soluble molecules of interleukin-2 receptor (sIL-2R), CD4 (sCD4) and CD8 (sCD8) from phytohemagglutinin (PHA)-stimulated normal human mononuclear cells (MNC) in a dose-related manner. To further elucidate the subcellular mechanism of the inhibitory effect of PGE2 on PHA-stimulated MNC, intracellular concentration of glutathione (GSH) in PHA-stimulated MNC was sequentially measured from day 1 to day 3 by enzymic method. Furthermore, the effect of PGE2 on nuclear DNA including DNA strand breaks in alkali treatment and DNA fragmentation (apoptosis) of PHA-stimulated MNC were also measured. We found intracellular GSH levels were significantly decreased in the early stage of lymphocyte activation (day 1), but no evidence of increased DNA strand breaks or apoptotic process appeared in 3-day culture. In addition, butathione sulfoximine (a specific GSH inhibitor) and dibutyryl cyclic AMP also exhibited both proliferation inhibition and GSH-decreasing effects on PHA-stimulated MNC as well as PGE2. These results suggest that the immunosuppressive effect of PGE2 is mediated by the decreased generation of intracellular GSH, but not by the increased DNA strand breaks or apoptotic mechanism in the cells.

Title
The biological activity of undenatured dietary whey proteins: role of glutathione.
Author
Bounous G; Gold P
Address
Department of Surgery, Montreal General Hospital Research Institute, Quebec.
Source
Clin Invest Med, 14(4):296-309 1991 Aug
Abstract
This study compared the effects of different sources of whey protein concentrate (20 g/100 g diet) and of casein on the spleen, liver, and heart glutathione content of C3H/HeJ mice, and on the immune response of their spleen cells to sheep red blood cells. Body weight curves were similar in all dietary groups. Our data indicate that the humoral immune response is highest in mice fed a dietary whey protein concentrate exhibiting the highest solubility (undenatured conformation) and a greater relative concentration of the thermolabile bovine serum albumin and immunoglobulins. In addition, the mice fed this type of whey protein concentrate exhibit higher levels of tissue glutathione. The presence in the serum albumin fraction of glutamylcysteine groups (rare in food protein) and the specific intramolecular bond as related to the undenatured conformation of the molecule are considered to be key factors in the glutathione-promoting activity of the protein mixture.

Title
Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells.
Author
Kinscherf R; Fischbach T; Mihm S; Roth S; Hohenhaus-Sievert E; Weiss C; Edler L; BÍartsch P; DrÍoge W
Address
Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Source
FASEB J, 8(6):448-51 1994 Apr 1
Abstract
HIV-infected individuals and SIV-infected rhesus macaques have, on the average, decreased plasma cysteine and cystine concentrations and decreased intracellular glutathione levels. We show that the cysteine supply and the intracellular glutathione levels have a strong influence on the T cell system. A study of healthy human subjects revealed that persons with intracellular glutathione levels of 20-30 nmol/mg protein had significantly higher numbers of CD4+ T cells than persons with either lower or higher glutathione levels. Persons who moved during a 4-week observation period from the optimal to the suboptimal range (10-20 nmol/mg) experienced, on the average, a 30% decrease in CD4+ T cell numbers. This decrease was prevented by treatment with N-acetyl-cysteine (GSH). GSH caused this relative increase of CD4+ T cell numbers in spite of decreasing glutathione levels and not by increasing the glutathione level. Our studies suggest that the immune system may be exquisitely sensitive not only against a cysteine and glutathione deficiency but also against an excess of cysteine.

Title
Micronutrient profiles in HIV-1-infected heterosexual adults.
Author
Skurnick JH; Bogden JD; Baker H; Kemp FW; Sheffet A; Quattrone G; Louria DB
Address
Department of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103-2714, USA.
Source
J Acquir Immune Defic Syndr Hum Retrovirol, 12(1):75-83 1996 May 1
Abstract
There is compelling evidence that micronutrients can profoundly affect immunity. We surveyed vitamin supplement use and circulating concentrations of 22 nutrients and glutathione in 64 HIV-1 seropositive men and women and 33 seronegative controls participating in a study of heterosexual HIV-1 transmission. We assayed antioxidants (vitamins A, C, and E; total carotenes), vitamins B6 and B12, folate, thiamin, niacin, biotin, riboflavin, pantothenic acid, free and total choline and carnitine, biopterin, inositol, copper, zinc, selenium, and magnesium. HIV-infected patients had lower mean circulating concentrations of magnesium (p < 0.0001), total carotenes (p = 0.009), total choline (p = 0.002), and glutathione (p = 0.045), and higher concentrations of niacin (p < 0.0001) than controls. Fifty-nine percent of HIV+ patients had low concentrations of magnesium, compared with 9% of controls (p < 0.0001). These abnormal concentrations were unrelated to stage of disease. Participants who took vitamin supplements had consistently fewer low concentrations of antioxidants, across HIV infection status and disease stage strata (p = 0.0006). Nevertheless, 29% of the HIV+ patients taking supplemental vitamins had subnormal levels of one or more antioxidants. The frequent occurrence of abnormal micronutrient nutriture, as found in these HIV+ subjects, may contribute to disease pathogenesis. The low magnesium concentrations may be particularly relevant to HIV-related symptoms of fatigue, lethargy, and impaired mentation.

Title
Antioxidants in nutrition and their importance in the anti-/oxidative balance in the immune system
Author
Biesalski HK; Frank J
Address
Institut für Biologische Chemie und Ernährungswissenschaft, Universität Hohenheim.
Source
Immun Infekt, 23(5):166-73 1995 Oct
Abstract
Free radicals and reactive oxygen species can damage cells and tissues of biological organisms. Due to the fact that these compounds are generated continuously in living cells defense mechanisms must exist. This so-called antioxidative system ensures that the formation of free radicals during different physiological processes does not result in cellular damage. Free radicals (oxidants) are produced form the immune system. The purpose of this immune cell products is to destroy invading organisms and damaged tissue. Oxidants enhance IL-1, IL-8 and TNF production in response to inflammatory stimuli. Sophisticated antioxidant defense systems like enzymes or vitamins protect directly and indirectly the host against the damaging influence of oxidants. While endogenous systems can hardly be influenced, exogenous antioxidants, delivered by the diet, can be upregulated in the body. By this way the pro-/antioxidative capacity can be balanced or even unbalanced.

Title
glutathione increases interleukin-2 production in human lymphocytes.
Author
Chen G; Wang SH; Converse CA
Address
University of Glasgow, Department of Medicine, Royal Infirmary, U.K.
Source
Int J Immunopharmacol, 16(9):755-60 1994 Sep
Abstract
It is known that glutathione (GSH) has an immunological effect on several features of the immune system. The present study investigated the effects of GSH on interleukin-2 (IL-2) production from normal human peripheral blood lymphocytes (PBL). The results showed that both exogenous GSH and 2-mercaptoethanol (2-ME) significantly increased intracellular GSH levels after PBL were incubated with both agents. IL-2 production from PBL was markedly increased at the presence of exogenous GSH (0.5-8 mmol/l) or 2-ME (12.5-50 mumol/l) which corresponded to 1.57-2.82 nmol/10(6) cells and 1.41 - 1.80 nmol/10(6) cells of intracellular concentrations of GSH, respectively. However, IL-2 production seemed to reach a steady level when exogenous GSH concentrations in cell culture were between 2 and 8 mmol/l. The findings also showed that there was a positive correlation between the IL-2 concentrations and intracellular GSH levels. This study indicated that both exogenous GSH and 2-ME were able to elevate intracellular GSH levels and the increased intracellular GSH could increase IL-2 production in vitro. It is suggested that GSH may exert its effects on the immune system via the regulation of IL-2 synthesis.

 

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