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1
Favilli, Fabio, Patrizia Marraccini, Teresa Iantomasi, and Maria T. Vincenzini. "Effect of orally administered glutathione on glutathione levels in some organs of rats: role of specific transporters." British Journal of Nutrition 78, no. 2 (August 1997): 293–300. http://dx.doi.org/10.1079/bjn19970147.
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The present study reports data on absorption of orally administered glutathione (GSH) in rat jejunum and in other organs, and the possible role of specific transport systems of GSH and γ-glutamyltranspeptidase (EC 2.3.2.1; γ-GT) activity. GSH levels were measured simultaneously in various organs after oral GSH administration to untreated rats and rats treated with L-buthionine sulfoximine (BSO) or acivicin (AT125). BSO selectively inhibits GSH intracellular synthesis and AT125 is a specific inhibitor of γ-GT activity. GSH levels were also measured after oral administration of an equivalent amount of the constituent amino acids of GSH to untreated and BSO-treated rats. Significant increases in GSH levels were found in jejunum, lung, heart, liver and brain after oral GSH administration to untreated rats. GSH increases were also obtained in all organs, except liver, when GSH was administered to rats previously GHS-depleted by treatment with BSO. The analysis of all results allowed us to distinguish between the increase in GSH intracellular levels due to intact GSH uptake by specific transporters, and that due to GSH degradation by γ-GT activity and subsequent absorption of degradation products with intracellular resynthesis of GSH; both these mechanisms seemed to be involved in increasing GSH content in heart after oral GSH administration. Jejunum, lung and brain took up GSH mostly intact, by specific transport systems, while in liver GSH uptake occurred only by its breakdown by γ-GT activity followed by intracellular resynthesis.
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M. I, Abdelgadir, Omer F. I, Omer M. A, Awad ElGeed B. A, and Hassan MM. "Expected adverse health influences due to exposure to glyphosate-based herbicide (GBH) and its environmental outcomes using Wistar rats as experimental animals." International Journal of Medicine 11, no. 1 (September 6, 2023): 1–6. http://dx.doi.org/10.14419/ijm.v11i1.32315.
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A sum of 32 Wistar rats were divided into four equal groups, each containing 8 rats. Study animals were freely subject to normal rodent diet and tap water. One group was put as control. The applied agents were exposed to glyphosate-based herbicide (GBH-400 mg kg–1) GSH (nmol g–1 tissue), (GBH-600 mg kg–1) GSH (nmol g–1 tissue) and (GBH-850 mg kg–1) GSH (nmol g–1 tissue) once per day as oral gavage for 6 weeks. Study results clearly revealed that (GBH) significantly (p≤0.05) decreased the levels of GSH in liver, kidney, and brain tissues, due to many reasons including poor diet, chronic disease, infection and constant stress, besides aging. Biological negative influences of glyphosate herbicide through the scientific community, including government and non-government organizations have increased their interest in detecting and controlling the environmental agents responsible for damages to the human health and sustainability of the ecosystems.
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Tsan, M. F., J. E. White, and C. L. Rosano. "Modulation of endothelial GSH concentrations: effect of exogenous GSH and GSH monoethyl ester." Journal of Applied Physiology 66, no. 3 (March 1, 1989): 1029–34. http://dx.doi.org/10.1152/jappl.1989.66.3.1029.
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We studied the effects of exogenous glutathione (GSH) and GSH monoethyl ester (GSH-MEE) on the enhancement of endothelial GSH concentrations. The preparation of GSH-MEE used contained 91% GSH-MEE, approximately 9% GSH diethyl ester (GSH-DEE) and a trace amount of GSH. Both GSH and GSH-MEE markedly stimulated the intracellular concentrations of GSH in endothelial cells. GSH-MEE was more potent than GSH. The enhancement of endothelial GSH concentration by exogenous GSH was completely inhibited by buthionine sulfoximine (BSO), a potent inhibitor of gamma-glutamylcysteine synthase, or acivicin (AT-125), an inhibitor of gamma-glutamyl transpeptidase, suggesting that it was due to the extracellular breakdown and subsequent intracellular resynthesis of GSH. In contrast, the effect of GSH-MEE was largely resistant to BSO and acivicin, suggesting that it was primarily due to transport of GSH-MEE followed by intracellular hydrolysis. The GSH-MEE preparation, which contained 9% GSH-DEE, at concentrations of 2 mM or higher caused vacuolization of endothelial cells. The enhancement of GSH concentrations by exogenous GSH, but not by GSH-MEE, protected endothelial cells against H2O2-induced injury.
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Matteucci, Michael J., and Richard F. Clark. "GSH poisoning." Journal of Emergency Medicine 29, no. 3 (October 2005): 344–45. http://dx.doi.org/10.1016/j.jemermed.2005.06.004.
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García, Maria J., Candelario Palma-Bautista, Antonia M. Rojano-Delgado, Enzo Bracamonte, João Portugal, Ricardo Alcántara-de la Cruz, and Rafael De Prado. "The Triple Amino Acid Substitution TAP-IVS in the EPSPS Gene Confers High Glyphosate Resistance to the Superweed Amaranthus hybridus." International Journal of Molecular Sciences 20, no. 10 (May 15, 2019): 2396. http://dx.doi.org/10.3390/ijms20102396.
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The introduction of glyphosate-resistant (GR) crops revolutionized weed management; however, the improper use of this technology has selected for a wide range of weeds resistant to glyphosate, referred to as superweeds. We characterized the high glyphosate resistance level of an Amaranthus hybridus population (GRH)—a superweed collected in a GR-soybean field from Cordoba, Argentina—as well as the resistance mechanisms that govern it in comparison to a susceptible population (GSH). The GRH population was 100.6 times more resistant than the GSH population. Reduced absorption and metabolism of glyphosate, as well as gene duplication of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) or its overexpression did not contribute to this resistance. However, GSH plants translocated at least 10% more 14C-glyphosate to the rest of the plant and roots than GRH plants at 9 h after treatment. In addition, a novel triple amino acid substitution from TAP (wild type, GSH) to IVS (triple mutant, GRH) was identified in the EPSPS gene of the GRH. The nucleotide substitutions consisted of ATA102, GTC103 and TCA106 instead of ACA102, GCG103, and CCA106, respectively. The hydrogen bond distances between Gly-101 and Arg-105 positions increased from 2.89 Å (wild type) to 2.93 Å (triple-mutant) according to the EPSPS structural modeling. These results support that the high level of glyphosate resistance of the GRH A. hybridus population was mainly governed by the triple mutation TAP-IVS found of the EPSPS target site, but the impaired translocation of herbicide also contributed in this resistance.
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Liedschulte, Verena, Andreas Wachter, An Zhigang, and Thomas Rausch. "Exploiting plants for glutathione (GSH) production: Uncoupling GSH synthesis from cellular controls results in unprecedented GSH accumulation." Plant Biotechnology Journal 8, no. 7 (March 11, 2010): 807–20. http://dx.doi.org/10.1111/j.1467-7652.2010.00510.x.
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Hamilton, David, Jian Hui Wu, Moulay Alaoui-Jamali, and Gerald Batist. "A novel missense mutation in the γ-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production." Blood 102, no. 2 (July 15, 2003): 725–30. http://dx.doi.org/10.1182/blood-2002-11-3622.
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Abstractγ-Glutamylcysteine synthetase (γ-GCS) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis: the adenosine triphosphate (ATP)–dependent ligation of glutamate and cysteine. γ-GCS consists of a catalytic (γ-GCSH) and modifier (γ-GCSL) subunit. Hereditary deficiency of γ-GCS has been reported in a small number of patients and is associated with low erythrocyte levels of γ-GCS and GSH leading to hemolytic anemia. Here we report a novel γ-GCSH mutation, isolated from the cDNA of 2 related patients diagnosed with γ-GCS deficiency. Each was found to be homozygous for a C>T missense mutation at nucleotide 379, encoding for a predicted Arg127Cys amino acid change. Computerized structure modeling identified that the mutated amino acid lies within a cleft on the protein surface of γ-GCSH, and the border of this cleft was shown to contain Cys249, an evolutionarily conserved residue that has been proven to lie near the binding site of γ-GCSH. Transfection studies showed that the mutation is associated with decreased GSH production, and binding studies using purified recombinant protein showed that the mutant protein has markedly decreased enzymatic activity compared to wild type.
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Napolitano, Antonio, Daniela Longo, Martina Lucignani, Luca Pasquini, Maria Camilla Rossi-Espagnet, Giulia Lucignani, Arianna Maiorana, et al. "The Ketogenic Diet Increases In Vivo Glutathione Levels in Patients with Epilepsy." Metabolites 10, no. 12 (December 10, 2020): 504. http://dx.doi.org/10.3390/metabo10120504.
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The Ketogenic Diet (KD) is a high-fat, low-carbohydrate diet that has been utilized as the first line treatment for contrasting intractable epilepsy. It is responsible for the presence of ketone bodies in blood, whose neuroprotective effect has been widely shown in recent years but remains unclear. Since glutathione (GSH) is implicated in oxidation-reduction reactions, our aim was to monitor the effects of KD on GSH brain levels by means of magnetic resonance spectroscopy (MRS). MRS was acquired from 16 KD patients and seven age-matched Healthy Controls (HC). We estimated metabolite concentrations with linear combination model (LCModel), assessing differences between KD and HC with t-test. Pearson was used to investigate GHS correlations with blood serum 3-B-Hydroxybutyrate (3HB) concentrations and with number of weekly epileptic seizures. The results have shown higher levels of brain GSH for KD patients (2.5 ± 0.5 mM) compared to HC (2.0 ± 0.5 mM). Both blood serum 3HB and number of seizures did not correlate with GSH concentration. The present study showed a significant increase in GSH in the brain of epileptic children treated with KD, reproducing for the first time in humans what was previously observed in animal studies. Our results may suggest a pivotal role of GSH in the antioxidant neuroprotective effect of KD in the human brain.
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Aebi, S., and B. H. Lauterburg. "Divergent effects of intravenous GSH and cysteine on renal and hepatic GSH." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 263, no. 2 (August 1, 1992): R348—R352. http://dx.doi.org/10.1152/ajpregu.1992.263.2.r348.
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There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutathione (GSH) and cysteine on the cellular thiol status, thiols were administered intravenously to rats in doses ranging from 1.67 to 8.35 mmol/kg with and without pretreatment with 4 mmol/kg buthionine-[S,R]-sulfoximine (BSO), an inhibitor of GSH synthesis. One hour after administration of 1.67 mmol/kg GSH, the concentration of GSH rose from 5.2 +/- 1.0 to 8.4 +/- 0.9 mumol/g and from 2.5 +/- 0.5 to 3.7 +/- 0.7 mumol/g in liver and kidneys, respectively. After 8.35 mmol/kg, hepatic GSH did not increase further, but renal GSH rose to 6.7 +/- 1.8 mumol/g. Infusion of cysteine increased hepatic GSH to the same extent as intravenous GSH, but renal GSH did not increase after 1.67 mmol/kg and even significantly decreased to 0.6 +/- 0.2 mumol/g after 8.35 mmol/kg. In the presence of BSO, GSH resulted in a significant increase in renal but not hepatic GSH, suggesting that the kidneys take up intact GSH and indicating that the increment in hepatic GSH was due to de novo synthesis. The present data show that hepatic GSH can be markedly increased in vivo by increasing the supply of cysteine. Measurements of hepatic cysteine indicate that up to a concentration of approximately 0.5 mumol/g cysteine is a key determinant of hepatic GSH, such that the physiological steady-state concentration of GSH in the liver appears to be mainly determined by the availability of cysteine. At higher concentrations GSH does not increase further, possibly due to feedback inhibition of GSH synthesis or increased efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
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Hagen, T. M., G. T. Wierzbicka, A. H. Sillau, B. B. Bowman, and D. P. Jones. "Bioavailability of dietary glutathione: effect on plasma concentration." American Journal of Physiology-Gastrointestinal and Liver Physiology 259, no. 4 (October 1, 1990): G524—G529. http://dx.doi.org/10.1152/ajpgi.1990.259.4.g524.
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Plasma glutathione (GSH) concentration in rats increased from approximately 15 to 30 microM after administration of GSH either as a liquid bolus (30 mumol) or mixed (2.5-50 mg/g) in AIN-76 semisynthetic diet. GSH concentration was maximal at 90-120 min after GSH administration and remained high for over 3 h. Administration of the amino acid precursors of GSH had little or no effect on plasma GSH values, indicating that GSH catabolism and resynthesis do not account for the increased GSH concentration seen. Inhibition of GSH synthesis and degradation by L-buthionine-[S,R]-sulfoximine and acivicin showed that the increased plasma GSH came mostly from absorption of intact GSH instead of from its metabolism. Plasma protein-bound GSH also increased after GSH administration, with a time course similar to that observed for free plasma GSH. Thus dietary GSH can be absorbed intact and results in a substantial increase in blood plasma GSH. This indicates that oral supplementation may be useful to enhance tissue availability of GSH.
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Ahmad, Adel M., Hamdoon A. Mohammed, Tarek M. Faris, Abeer S. Hassan, Hebatallah B. Mohamed, Mahmoud I. El Dosoky, and Esam M. Aboubakr. "Nano-Structured Lipid Carrier-Based Oral Glutathione Formulation Mediates Renoprotection against Cyclophosphamide-Induced Nephrotoxicity, and Improves Oral Bioavailability of Glutathione Confirmed through RP-HPLC Micellar Liquid Chromatography." Molecules 26, no. 24 (December 10, 2021): 7491. http://dx.doi.org/10.3390/molecules26247491.
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The study aimed to develop a new glutathione (GSH) oral formulation to enhance the delivery of GSH and counter the nephrotoxicity of the anticancer drug, cyclophosphamide (CP). A nanostructured lipid carrier glutathione formulation (GSH-NLCs) composed of glutathione (500 mg), stearic and oleic acid (300 mg, each), and Tween® 80 (2%, w/v) was prepared through the emulsification-solvent-evaporation technique, which exhibited a 452.4 ± 33.19 nm spheroidal-sized particulate material with narrow particle size distributions, −38.5 ± 1.4 mV zeta potential, and an entrapment efficiency of 79.8 ± 1.9%. The GSH formulation was orally delivered, and biologically tested to ameliorate the CP-induced renal toxicity in a rat model. Detailed renal morphology, before and after the GSH-NLCs administration, including the histopathological examinations, confirmed the ameliorating effects of the prepared glutathione formulation together with its safe oral delivery. CP-induced oxidative stress, superoxide dismutase depletion, elevation of malondialdehyde levels, depletion of Bcl-2 concentration levels, and upregulated NF-KB levels were observed and were controlled within the recommended and near normal/control levels. Additionally, the inflammatory mediator marker, IL-1β, serum levels were marginally normalized by delivery of the GHS-NLCs formulation. Oral administration of the pure glutathione did not exhibit any ameliorating effects on the renal tissues, which suggested that the pure glutathione is reactive and is chemically transformed during the oral delivery, which affected its pharmacological action at the renal site. The protective effects of the GSH-NLCs formulation through its antioxidant and anti-inflammatory effects suggested its prominent role in containing CP-induced renal toxicity and renal tissue damage, together with the possibility of administrating higher doses of the anticancer drug, cyclophosphamide, to achieve higher and effective anticancer action in combination with the GSH-NLCs formulation.
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Sze, G., N. Kaplowitz, M. Ookhtens, and S. C. Lu. "Bidirectional membrane transport of intact glutathione in Hep G2 cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 265, no. 6 (December 1, 1993): G1128—G1134. http://dx.doi.org/10.1152/ajpgi.1993.265.6.g1128.
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Rat hepatocytes exhibit bidirectional carrier-mediated transport of reduced glutathione (GSH) across the plasma membrane. Transport of GSH has not been well characterized in human-derived cells. We examined Hep G2 cells as a possible human liver model for GSH homeostasis. Hep G2 cell GSH averaged 25.9 +/- 1.4 nmol/10(6) cells. When Hep G2 cells were incubated in buffer, no GSH appeared in the medium over 2 h. However, after pretreatment with acivicin to inhibit gamma-glutamyl transpeptidase activity, GSH efflux was unmasked and measured 30 +/- 4 pmol x 10(6) cells-1 x min-1, which is comparable to rat hepatocytes. GSH efflux was inhibited by sulfobromophthalein GSH adduct (BSP-GSH) and cystathionine, agents that inhibit sinusoidal efflux in the rat, and was stimulated by adenosine 3',5'-cyclic monophosphate-dependent agents. GSH uptake was measured after cells were pretreated with acivicin and buthionine sulfoximine to prevent breakdown of GSH and resynthesis of GSH from precursors, respectively. In the presence of 4 microCi/ml of [35S]GSH and 10 mM unlabeled GSH, GSH uptake was linear up to 45 min and did not require Na+ or Cl-. GSH uptake exhibited saturability with a maximal velocity of 4.15 +/- 0.23 nmol.mg-1 x 30 min-1, a Michaelis constant of 2.36 +/- 0.26 mM, and two interactive transport sites. BSP-GSH cis-inhibited GSH uptake in a dose-dependent manner with an inhibitory constant of 0.46 +/- 0.05 mM. Inhibition by BSP-GSH (1 mM) of GSH uptake was through a single inhibitor site and was overcome at > 10 mM GSH, which is consistent with competitive inhibition. Similar to the rat, 10 mM extracellular GSH trans-stimulated GSH efflux. These findings may be important in gaining better insights into GSH homeostasis in human liver cells.
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Goldfarb, R. D., and A. Singh. "GSH and reperfusion injury." Circulation 80, no. 3 (September 1989): 712–13. http://dx.doi.org/10.1161/circ.80.3.2766517.
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Lawyer, Lee. "The GSH Spring Symposium." Leading Edge 32, no. 5 (May 2013): 574–76. http://dx.doi.org/10.1190/tle32050574.1.
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Ogawa, Eri, Yuichiro Otsubo, Norihiro Taira, and Nihal S. Agar. "Uptake of dehydroascorbic acid in high-GSH and normal-GSH dog erythrocytes." Comparative Clinical Pathology 13, no. 3 (January 19, 2005): 137–41. http://dx.doi.org/10.1007/s00580-004-0529-z.
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Bai, C., L. A. Brown, and D. P. Jones. "Glutathione transport by type II cells in perfused rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 267, no. 4 (October 1, 1994): L447—L455. http://dx.doi.org/10.1152/ajplung.1994.267.4.l447.
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Glutathione (GSH) is an antioxidant that protects the lung against oxidative-injury. Most cells rely on synthesis of GSH to maintain intracellular supply and only a few cell types take up intact GSH. Although isolated type II cells from rat have a Na(+)-dependent uptake system that transports GSH into the cells against a concentration gradient, it is not known whether this occurs from the vasculature in the intact lung or whether other cell types in the lung also transport GSH. Based on the knowledge that gamma-glutamyl analogues of GSH are also transported by the Na(+)-GSH transporter, a method was developed and used to study the cell specificity of GSH uptake in perfused lung. A stable, fluorescent GSH S-conjugate (GSH-I14) was synthesized and separated from the original dye as analyzed by high-performance liquid chromatography. Studies with isolated alveolar type II cells showed that uptake of GSH-I14 was Na+ dependent and inhibited by GSH. In addition, uptake of GSH by the type II cells was inhibited by GSH-I14. After perfusion of the isolated rat lung with GSH-I14, the conjugate accumulated primarily in the alveolar type II cell as observed by fluorescence microscopy. This was confirmed by isolation of type II cells and measurement of GSH-I14 content. Thus these results show that specificity of GSH transport can be studied with the fluorescent derivative, GSH-I14, and that in the isolated perfused lung type II cells can transport and concentrate GSH-I14 from the perfusate. Quantitative fluorescence microscopy will be required to further determine relative transport activities by other cell types.
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Sen, C. K., M. Atalay, and O. Hanninen. "Exercise-induced oxidative stress: glutathione supplementation and deficiency." Journal of Applied Physiology 77, no. 5 (November 1, 1994): 2177–87. http://dx.doi.org/10.1152/jappl.1994.77.5.2177.
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Glutathione (GSH) plays a central role in coordinating the synergism between different lipid- and aqueous-phase antioxidants. We documented 1) how exogenous GSH and N-acetylcysteine (NAC) may affect exhaustive exercise-induced changes in tissue GSH status, lipid peroxides [thiobarbituric acid-reactive substances (TBARS)], and endurance and 2) the relative role of endogenous GSH in the circumvention of exercise-induced oxidative stress by using GSH-deficient [L-buthionine-(S,R)-sulfoximine (BSO)-treated] rats. Intraperitoneal injection of GSH remarkably increased plasma GSH; exogenous GSH per se was an ineffective delivery agent of GSH to tissues. Repeated administration of GSH (1 time/day for 3 days) increased blood and kidney total GSH [TGSH; GSH+oxidized GSH (GSSG)]. Neither GSH nor NAC influenced endurance to exhaustion. NAC decreased exercise-induced GSH oxidation in the lung and blood. BSO decreased TGSH pools in the liver, lung, blood, and plasma by approximately 50% and in skeletal muscle and heart by 80–90%. Compared with control, resting GSH-deficient rats had lower GSSG in the liver, red gastrocnemius muscle, heart, and blood; similar GSSG/TGSH ratios in the liver, heart, lung, blood, and plasma; higher GSSG/TGSH ratios in the skeletal muscle; and more TBARS in skeletal muscle, heart, and plasma. In contrast to control, exhaustive exercise of GSH-deficient rats did not decrease TGSH in the liver, muscle, or heart or increase TGSH of plasma; GSSG of muscle, blood, or plasma; or TBARS of plasma or muscle. GSH-deficient rats had approximately 50% reduced endurance, which suggests a critical role of endogenous GSH in the circumvention of exercise-induced oxidative stress and as a determinant of exercise performance.
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Curnow, E. C., J. Ryan, D. Saunders, and E. S. Hayes. "Bovine in vitro oocyte maturation as a model for manipulation of the γ-glutamyl cycle and intraoocyte glutathione." Reproduction, Fertility and Development 20, no. 5 (2008): 579. http://dx.doi.org/10.1071/rd08041.
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Glutathione (GSH) is the main non-enzymatic defence against oxidative stress and is a critical intracellular component required for oocyte maturation. In the present study, several modulators of intracellular GSH were assessed for their effect on the in vitro maturation (IVM) and intracellular GSH content of bovine metaphase (MII) oocytes. Of the five GSH modulators tested, only the cell-permeable GSH donor glutathione ethyl ester (GSH-OEt) significantly increased the GSH content of IVM MII oocytes in a concentration-dependent manner without adversely affecting oocyte maturation rate. The GSH level in IVM MII oocytes was greatly influenced by the presence or absence of cumulus cells and severely restricted when oocytes were cultured in the presence of buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. The addition of GSH-OEt to cumulus-denuded or BSO-treated oocytes increased the GSH content of bovine MII oocytes. Supplementation of the maturation medium with bovine serum albumin (BSA) or fetal calf serum (FCS) affected the GSH content of IVM MII oocytes, with greater levels attained under BSA culture conditions. The addition of GSH-OEt to the maturation medium increased the GSH content of IVM MII oocytes, irrespective of protein source. Spindle morphology, as assessed by immunocytochemistry and confocal microscopy, displayed distinct alterations in response to changes in oocyte GSH levels. GSH depletion caused by BSO treatment tended to widen spindle poles and significantly increased spindle area. Supplementation of the IVM medium with GSH-OEt increased spindle length, but did not significantly alter spindle area or spindle morphology. GSH-OEt represents a novel oocyte-permeable and cumulus cell-independent approach for effective elevation of mammalian oocyte GSH levels.
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Viña, Jose, Carmen Perez, Tadayasu Furukawa, Manuel Palacin, and Juan R. Viña. "Effect of oral glutathione on hepatic glutathione levels in rats and mice." British Journal of Nutrition 62, no. 3 (November 1989): 683–91. http://dx.doi.org/10.1079/bjn19890068.
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Administration of oral glutathione (GSH) increases hepatic GSH levels in fasted rats, in mice treated with GSH depletors such as diethyl maleate and in mice treated with high doses of paracetamol. An increase in hepatic GSH levels after administration of oral GSH does not occur in animals treated with buthionine sulphoximine, an inhibitor of GSH synthesis. Administration of oral GSH leads to an increase in the concentration of l-cysteine, a precursor of GSH, in portal blood plasma. Oral administration of l-methionine produced a significant decrease of hepatic ATP in fasted rats, but not in fed rats. Administration of N−acetylcysteine or GSH did not affect the hepatic ATP levels. The results show that the oral intake of GSH is a safe and efficient form of administration of its constituent amino acids in cases when GSH synthesis is required to replete hepatic GSH levels.
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Goto, Ikuo, N. S. Agar, and Yoshimitsu Maede. "Relation between reduced glutathione content and Heinz body formation in sheep erythrocytes." American Journal of Veterinary Research 54, no. 4 (April 1, 1993): 622–26. http://dx.doi.org/10.2460/ajvr.1993.54.04.622.
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Summary To clarify the oxidant defense functions of reduced glutathione (gsh) in erythrocytes, the effect of gsh deficiency on in vitro oxidant defense was studied, using gsh-deficient sheep erythrocytes (low-gsh cells). The formation of Heinz bodies in low-gsh cells was higher than that in high-gsh cells when the cells were incubated with an oxidant drug, acetylphenylhydrazine (aph). Artificial depletion of gsh by 1-chloro-2,4-dinitrobenzene in high-gsh cells resulted in increased Heinz body formation in these cells incubated with aph. Furthermore, high negative correlation was observed between Heinz body formation and gsh content in sheep erythrocytes exposed to aph. These results clearly indicate that erythrocyte gsh is indispensable for erythrocyte defense against oxidative damage induced by aph, and support the previous observations that sheep with low-gsh erythrocytes were more susceptible to oxidative agents than were sheep with high-gsh erythrocytes.
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Baek, Miri, and Soo-Jin Choi. "Effect of Orally Administered Glutathione-Montmorillonite Hybrid Systems on Tissue Distribution." Journal of Nanomaterials 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/469372.
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An ubiquitous tripeptide, glutathione (GSH), is assigned a role in detoxification, activation of immune system, intermediary metabolism, transport, and protection of cells against free radicals or reactive oxygen species. However, instability of orally administered GSH in gastrointestinal (GI) tract leads to low absorption and low bioavailability in tissues. In this study, we attempted to synthesize GSH-montmorillonite (MMT) hybrid systems by intercalating GSH into the interlayers of a cationic clay delivery carrier, MMT, to improve GSH bioavailability at the systemic level. Polymer coating of the hybrid with polyvinylacetal diethylaminoacetate (AEA) was further performed to obtain better stability. Synthetic condition of both GSH-MMT and AEA-GSH-MMT hybrids was optimized, and then GSH-delivery efficiency was evaluated in various organs after oral administration in normal as well as GSH-deficient mice. The present GSH-MMT hybrids remarkably enhanced GSH concentration in the plasma, heart, kidney, and liver, especially when AEA-GSH-MMT hybrid was administered under GSH-deficient condition. Moreover, both hybrids did not induce acute oral toxicity up to 2000 mg/kg, suggesting their great potential for pharmaceutical application.
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Meyer, D. J., E. Lalor, B. Coles, A. Kispert, P. Ålin, B. Mannervik, and B. Ketterer. "Single-step purification and h.p.l.c. analysis of glutathione transferase 8–8 in rat tissues." Biochemical Journal 260, no. 3 (June 15, 1989): 785–88. http://dx.doi.org/10.1042/bj2600785.
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GSSG selectively elutes two GSH transferases from a mixture of rat GSH transferases bound to a GSH-agarose affinity matrix. One is a form of GSH transferase 1-1 and the other is shown to be GSH transferase 8-8. By using tissues that lack this form of GSH transferase 1-1 (e.g. lung), GSH transferase 8-8 may thus be purified from cytosol in a single step. Quantitative analysis of the tissue distribution of GSH transferase 8-8 was obtained by h.p.l.c.
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Aw, T. Y., M. Ookhtens, C. Ren, and N. Kaplowitz. "Kinetics of glutathione efflux from isolated rat hepatocytes." American Journal of Physiology-Gastrointestinal and Liver Physiology 250, no. 2 (February 1, 1986): G236—G243. http://dx.doi.org/10.1152/ajpgi.1986.250.2.g236.
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The characteristics and kinetics of glutathione (GSH) efflux were examined in homogeneous suspensions of freshly isolated rat hepatocytes. GSH efflux was measured as its linear accumulation in the suspension medium. Appearance of GSH extracellularly was reflected in a quantitative loss in cellular GSH. However, the total GSH remained essentially unchanged, indicating minimal net synthesis of GSH under these experimental conditions. GSH efflux was sensitive to temperature, with a calculated Q10 value of 2.3. A wide range of cellular GSH concentration ranging from near complete and moderate depletion to severalfold the control values was achieved by treatment of animals or cells with various GSH depletors or inducers. At physiological (fed) and elevated (3-methylcholanthrene- and CoCl2-induced) cellular GSH, the rate of GSH efflux was near maximum. The rate fell dramatically to 50% maximum at a GSH concentration equaling 35 nmol/10(6) cells. A 48-h fast resulted in a 40% loss of cellular GSH, with a corresponding decrease in efflux rates. Addition of GSH to the incubation medium had no effect on efflux rates. The relationship of GSH efflux to cellular GSH concentration was characterized by apparent sigmoidal saturation kinetics. The data were fitted well by the Hill model with the following kinetic parameters: Vmax = 0.25 nmol X 10(6) cells-1 X min-1, Km = 3.5 mM, and n = 3. These results correspond very closely to our previous findings in the perfused liver.
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Fernandez-Checa, J. C., T. Maddatu, M. Ookhtens, and N. Kaplowitz. "Inhibition of GSH efflux from rat liver by methionine: effects of GSH synthesis in cells and perfused organ." American Journal of Physiology-Gastrointestinal and Liver Physiology 258, no. 6 (June 1, 1990): G967—G973. http://dx.doi.org/10.1152/ajpgi.1990.258.6.g967.
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The inhibition of efflux of intracellular reduced glutathione (GSH) by methionine was determined in isolated rat hepatocytes suspended either in Krebs-Henseleit buffer or in modified Fisher's medium. Methionine (1 mM) added to Krebs-Henseleit suspensions of isolated rat hepatocytes inhibited GSH efflux, with greater retention of GSH in the cells compared with control. Results were similar with methionine and 0.3 mM propargylglycine cystathionase inhibitor), suggesting no net synthesis of GSH from methionine. In Fisher's medium, the inhibitory effect of methionine on GSH efflux was masked due to increasing cellular GSH; however, the inhibitory effect of methionine was unmasked by propargylglycine, which prevented the utilization of methionine for GSH synthesis. The addition of serine (0.1 mM) to methionine in Krebs-Henseleit buffer raised cellular GSH, overcoming the inhibition of GSH efflux. In the perfused liver, infusion of 1 and 5 mM methionine initially inhibited GSH efflux, but the inhibition was reversed with continued methionine infusion. After removal of methionine, GSH efflux increased immediately. The reversal and rebound were blocked by propargylglycine, revealing concentration-dependent inhibition of sinusoidal GSH efflux by methionine. Thus, when methionine is utilized to promote GSH synthesis, its inhibitory effect on GSH efflux tends to be overcome.
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Curnow, E. C., J. P. Ryan, D. M. Saunders, and E. S. Hayes. "Developmental potential of bovine oocytes following IVM in the presence of glutathione ethyl ester." Reproduction, Fertility and Development 22, no. 4 (2010): 597. http://dx.doi.org/10.1071/rd09228.
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Glutathione (GSH) is synthesised during oocyte maturation and represents the oocyte’s main non-enzymatic defence against oxidative stress. Inadequate defence against oxidative stress may be related to poor embryo quality and viability. In the present study, bovine oocytes were matured in vitro in the presence of GSH ethyl ester (GSH-OEt), a cell permeable GSH donor, and its effects on subsequent fertilisation and embryo development were assessed. GSH-OEt significantly increased the GSH content of IVM oocytes without affecting fertilisation or Day 3 cleavage rates. Maturation in the presence of GSH-OEt did not significantly increase the blastocyst rate compared with control oocytes. However, 5 mM GSH-OEt treatment resulted in significantly higher blastocyst total cell number. The GSH level of IVM oocytes was significantly decreased in the absence of cumulus cells and when cumulus–oocyte complexes were cultured in the presence of buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. The addition of GSH-OEt to cumulus-denuded or BSO-treated oocytes increased the GSH content of bovine oocytes and restored the rate of normal fertilisation, but not embryo development, to levels seen in control oocytes. Thus, GSH-OEt represents a novel approach for effective in vitro elevation of bovine oocyte GSH and improvement in blastocyst cell number.
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Hagen, T. M., G. T. Wierzbicka, B. B. Bowman, T. Y. Aw, and D. P. Jones. "Fate of dietary glutathione: disposition in the gastrointestinal tract." American Journal of Physiology-Gastrointestinal and Liver Physiology 259, no. 4 (October 1, 1990): G530—G535. http://dx.doi.org/10.1152/ajpgi.1990.259.4.g530.
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Studies were performed in rats that had been fasted 24 h, fed a glutathione (GSH)-free semisynthetic diet (AIN-76), and fed the same diet supplemented with GSH. The results from the fasted rats and those fed GSH-free diet showed that the duodenum and jejunum contained 0.2-0.5 mumol of GSH/gram wet wt of luminal contents. The GSH contents of biliary juice was sufficient to maintain this amount of GSH in the intestinal lumen. Other analyses showed that cell sloughing, bacterial GSH content, and GSH secretion by epithelial cells of the jejunum were not sufficient to account for this content. GSH concentrations following consumption of a GSH-supplemented diet (5-50 mg/g AIN-76) showed a rapid increase in all regions of the small intestine and indicated that removal occurred primarily in the jejunum. However, the combined activities of brush-border gamma-glutamyltransferase and GSH uptake systems were not sufficient to remove all of the ingested GSH. Results from in situ vascular perfusions of small intestine showed that the upper jejunum is a principal site of GSH absorption. Measurements of the GSH-to-glutathione disulfide (GSSG) ratio in the lumen after ingestion of GSSG (5 mg/g diet) indicated that the upper small intestine also has a mechanism for reducing GSSG to GSH. The results therefore indicate that GSH is present in the lumen of the small intestine of rat under most if not all conditions. Although the physiological importance of luminal GSH remains unclear, it could potentially be used to detoxify reactive electrophiles in the diet or be absorbed for intracellular detoxication reactions.
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Braddon, S. A., C. M. McIlvaine, and J. E. Balthrop. "Distribution of GSH and GSH cycle enzymes in black sea bass (Centropristis striata)." Comparative Biochemistry and Physiology Part B: Comparative Biochemistry 80, no. 2 (January 1985): 213–16. http://dx.doi.org/10.1016/0305-0491(85)90198-1.
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Weldy, Chad S., Ian P. Luttrell, Collin C. White, Vicki Morgan-Stevenson, Theo K. Bammler, Richard P. Beyer, Zahra Afsharinejad, Francis Kim, Kanchan Chitaley, and Terrance J. Kavanagh. "Glutathione (GSH) and the GSH synthesis gene Gclm modulate vascular reactivity in mice." Free Radical Biology and Medicine 53, no. 6 (September 2012): 1264–78. http://dx.doi.org/10.1016/j.freeradbiomed.2012.07.006.
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Brophy, P. M., C. Southan, and J. Barrett. "Glutathione transferases in the tapeworm Moniezia expansa." Biochemical Journal 262, no. 3 (September 15, 1989): 939–46. http://dx.doi.org/10.1042/bj2620939.
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Four forms of GSH transferase were resolved from Moniezia expansa cytosol by GSH-Sepharose affinity chromatography and chromatofocusing in the range pH 6-4, and the presence of isoenzymes was further suggested by analytical isoelectric focusing. The four GSH transferase forms in the cestode showed no clear biochemical relationship to any one mammalian GSH transferase family. The N-terminal of the major GSH transferase form showed sequence homology with the Mu and Alpha family GSH transferases. The major GSH transferase appeared to bind a number of commercially available anthelmintics but did not appear to conjugate the compounds with GSH. The major GSH transferase efficiently conjugated members of the trans-alk-2-enal and trans, trans-alka-2,4-dienal series, established secondary products of lipid peroxidation.
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Zhang, Siyu, Cuina Wang, Weigang Zhong, Alyssa H. Kemp, Mingruo Guo, and Adam Killpartrick. "Polymerized Whey Protein Concentrate-Based Glutathione Delivery System: Physicochemical Characterization, Bioavailability and Sub-Chronic Toxicity Evaluation." Molecules 26, no. 7 (March 24, 2021): 1824. http://dx.doi.org/10.3390/molecules26071824.
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Glutathione (GSH) is a powerful antioxidant, but its application is limited due to poor storage stability and low bioavailability. A novel nutrient encapsulation and delivery system, consisting of polymerized whey protein concentrate and GSH, was prepared and in vivo bioavailability, antioxidant capacity and toxicity were evaluated. Polymerized whey protein concentrate encapsulated GSH (PWPC-GSH) showed a diameter of roughly 1115 ± 7.07 nm (D50) and zeta potential of 30.37 ± 0.75 mV. Differential scanning calorimetry (DSC) confirmed that GSH was successfully dispersed in PWPC particles. In vivo pharmacokinetics study suggested that PWPC-GSH displayed 2.5-times and 2.6-fold enhancement in maximum concentration (Cmax) and area under the concentration–time curve (AUC) as compared to free GSH. Additionally, compared with plasma of mice gavage with free GSH, significantly increased antioxidant capacity of plasma in mice with PWPC-GSH was observed (p < 0.05). Sub-chronic toxicity evaluation indicated that no adverse toxicological reactions related to oral administration of PWPC-GSH were observed on male and female rats with a diet containing PWPC-GSH up to 4% (w/w). Data indicated that PWPC may be an effective carrier for GSH to improve bioavailability and antioxidant capacity.
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Lee, Yechan, Sujeet Kumar, Sou Hyun Kim, Keum-Yong Seong, Hyeseon Lee, Chaerin Kim, Young-Suk Jung, and Seung Yun Yang. "Odorless Glutathione Microneedle Patches for Skin Whitening." Pharmaceutics 12, no. 2 (January 27, 2020): 100. http://dx.doi.org/10.3390/pharmaceutics12020100.
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Glutathione is a natural anti-aging substance that prevents the oxidation of protein thiols from reactive oxygen species. In the pharmaceutical industry, reduced glutathione (GSH) has been widely used for skin whitening due to its ability to inhibit tyrosinase. However, its poor permeability and foul odor limit its use in skin applications. Herein, we report a GSH-loaded dissolving microneedle (MN) patch prepared with hyaluronic acid (HA) that enables enhanced permeation across the skin and reduces the foul odor of GSH. HA was selected to prepare odorless GSH solutions and used for MN fabrications as a carrier of GSH. GSH-loaded MN (GSH-MN) arrays prepared from MN-forming solution containing up to 10% GSH showed good pattern uniformity and appropriate mechanical properties for insertion into the skin. The GSH-MNs with a loading capacity of 17.4% dissolve within 10 min following insertion into porcine skin and release the loaded GSH without being oxidized. This new approach combines functional biopolymers to reduce the characteristic GSH odor and advanced transdermal delivery based on MN technology to enhance skin permeation without pain. We believe this technique could expand the application of GSH in many cosmeceutical fields.
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Richie, J. P., P. Abraham, and Y. Leutzinger. "Long-term stability of blood glutathione and cysteine in humans." Clinical Chemistry 42, no. 7 (July 1, 1996): 1100–1105. http://dx.doi.org/10.1093/clinchem/42.7.1100.
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Abstract Glutathione (GSH) availability is an important factor in the maintenance of health. Accordingly, blood GSH has been proposed as an indicator of health status. To validate the use of blood GSH in population studies, we investigated the long-term intraindividual variation of blood GSH and cyst(e)ine (Cys and cystine) concentrations in healthy adults. In a longitudinal study of 10 subjects, GSH and cyst(e)ine were measured in blood samples collected weekly over 8 months. The average within-person CV for GSH was only 9.1% compared with an observed interindividual CV of 20%. Blood cyst(e)ine was more variable within individuals (mean CV 14.7%) than GSH, whereas the interindividual CV for cyst(e)ine was lower (8.6%). The results demonstrate the stability of blood GSH in free-living subjects and the utility of GSH measurements as an indicator of long-term GSH status.
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Bai, C., and D. P. Jones. "GSH transport and GSH-dependent detoxication in small intestine of rats exposed in vivo to hypoxia." American Journal of Physiology-Gastrointestinal and Liver Physiology 271, no. 4 (October 1, 1996): G701—G706. http://dx.doi.org/10.1152/ajpgi.1996.271.4.g701.
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The effects of hypoxia on glutathione (GSH) concentration and GSH-related enzyme and transport systems were studied in the small intestine of rats exposed to 8-10 days of 10.5% O2. Exposure to hypoxia resulted in a 40% lower GSH concentration in enterocytes and a 50% lower concentration in blood plasma. Activities of GSH-related detoxication enzymes in the intestinal epithelium were largely unaffected by hypoxic exposure. GSH degradation and synthesis rates in enterocytes isolated from hypoxic rats were comparable with rates in normoxic controls, but GSH uptake rate was decreased by 30%. Stimulation of absorption of GSH by phenylephrine, such as occurs in control rats, was not detectable in isolated, vascularly perfused intestines of hypoxic rats. Decreased GSH uptake was associated with enhanced transepithelial appearance of thiobarbituric acid-reactive substances in everted intestinal sacs incubated with peroxidized methyl linoleate. These results suggest that chronic hypoxia results in impaired uptake of GSH in the small intestine, and this may result in impaired GSH-related defense mechanisms in the small intestine.
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Brown, L. A., C. Bai, and D. P. Jones. "Glutathione protection in alveolar type II cells from fetal and neonatal rabbits." American Journal of Physiology-Lung Cellular and Molecular Physiology 262, no. 3 (March 1, 1992): L305—L312. http://dx.doi.org/10.1152/ajplung.1992.262.3.l305.
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Previous studies have demonstrated a correlation between intracellular glutathione (GSH) pools and sensitivity to oxidative injury. In the present study, we demonstrated that de novo GSH synthesis or GSH uptake could increase intracellular GSH by 7- and 19-fold, respectively, in type II cells from neonatal rabbits. This suggested that the rate of GSH uptake was against a concentration gradient and greater than the synthetic rate. This increased intracellular GSH was associated with protection from oxidant injury by paraquat or 80% O2. A relationship between GSH uptake and protection was further supported by blockage of both processes by gamma-L-glutamyl-L-glutamate, a GSH analogue. With a greater oxidative burden, both de novo synthesis and GSH uptake were required to maintain protection. Although the transport rate was only 6% of that for neonatal cells, cells from fetal animals transported GSH and were protected from oxidative injury. From these results we conclude there was a causal relationship between GSH transport and protection from oxidative injury in type II cells from neonatal and fetal animals.
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Taté, Rosarita, Michele Cermola, Anna Riccio, Graciana Diez-Roux, and Eduardo J. Patriarca. "Glutathione Is Required by Rhizobium etli for Glutamine Utilization and Symbiotic Effectiveness." Molecular Plant-Microbe Interactions® 25, no. 3 (March 2012): 331–40. http://dx.doi.org/10.1094/mpmi-06-11-0163.
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Here, we provide genetic and biochemical evidence indicating that the ability of Rhizobium etli bacteria to efficiently catabolize glutamine depends on its ability to produce reduced glutathione (l-γ-glutamyl-l-cysteinylglycine [GSH]). We find that GSH-deficient strains, namely a gshB (GSH synthetase) and a gor (GSH reductase) mutant, can use different amino acids, including histidine, alanine, and asparagine but not glutamine, as sole source of carbon, energy, and nitrogen. Moreover, l-buthionine(S,R)-sulfoximine, a GSH synthesis inhibitor, or diamide that oxidizes GSH, induced the same phenotype in the wild-type strain. Among the steps required for its utilization, glutamine uptake, occurring through the two well-characterized carriers (Aap and Bra systems) but not glutamine degradation or respiration, was largely reduced in GSH-deficient strains. Furthermore, GSH-deficient mutants of R. etli showed a reduced symbiotic efficiency. Exogenous GSH was sufficient to rescue glutamine uptake or degradation ability, as well as the symbiotic effectiveness of GSH mutants. Our results suggest a previously unknown GSH–glutamine metabolic relationship in bacteria.
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Ballatori, N., and A. T. Truong. "Glutathione as a primary osmotic driving force in hepatic bile formation." American Journal of Physiology-Gastrointestinal and Liver Physiology 263, no. 5 (November 1, 1992): G617—G624. http://dx.doi.org/10.1152/ajpgi.1992.263.5.g617.
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Indirect evidence suggests that transport of glutathione (GSH) across the canalicular plasma membrane into bile contributes to the formation of the bile acid-independent fraction of bile flow. To directly test this hypothesis, the present study measured bile flow in isolated perfused rat livers whose biliary GSH excretion rate was selectively modulated by administration of GSH monoethyl ester (50, 100, and 200 mumol infused over a 20-min interval), a high dose of GSH itself (550 mumol over 20 min), and the three amino acid components of GSH (70 mumol each) with and without methionine (35 mumol). Animals were starved overnight to decrease hepatic GSH levels, and livers were pretreated with acivicin to inhibit gamma-glutamyl transferase. Livers perfused single pass with Krebs-Henseleit buffer excreted bile acids at a relatively low rate of 1-3 nmol.min-1 x g-1, and this rate was unaffected by agents used to alter biliary GSH efflux. In comparison, basal biliary GSH efflux rates were 8-13 nmol.min-1 x g-1. Administration of the GSH ester produced a dramatic dose-dependent choleresis, a stimulation of biliary GSH excretion, and resulted in the biliary excretion of intact GSH ester. Changes in total biliary GSH excretion and bile flow were temporally and quantitatively related. Infusion of GSH and amino acid supplementation also resulted in higher rates of bile flow and biliary GSH excretion, but their effects were more modest.(ABSTRACT TRUNCATED AT 250 WORDS)
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Aw, T. Y., and M. W. Williams. "Intestinal absorption and lymphatic transport of peroxidized lipids in rats: effect of exogenous GSH." American Journal of Physiology-Gastrointestinal and Liver Physiology 263, no. 5 (November 1, 1992): G665—G672. http://dx.doi.org/10.1152/ajpgi.1992.263.5.g665.
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We previously found that mucosal glutathione (GSH) plays an important role in the intestinal metabolism of luminal peroxidized lipids [T. Y. Aw, M. W. Williams, and L. Gray. Am. J. Physiol. 262 (Gastrointest. Liver Physiol. 25): G99-G106, 1992]. To determine the effects of exogenous GSH on lipid hydroperoxide elimination under conditions in which mucosal GSH was initially depleted with buthionine sulfoximine (BSO), we infused peroxidized lipid solutions without or with GSH into the proximal intestine of rats and monitored the steady-state output of hydroperoxides in lymph and recovery of luminal hydroperoxides. GSH supplementation in BSO-treated rats resulted in a concentration-dependent attenuation of lymphatic output of peroxidized lipids that was correlated with increases in mucosal GSH. Compared with BSO control, the luminal lipid hydroperoxide contents were significantly lower in GSH-supplemented rats, consistent with enhanced elimination of peroxidized lipids by exogenous GSH. The effect of GSH was ameliorated by the inhibitors of GSH uptake, suggesting that the uptake of GSH is required for promotion of intestinal removal of luminal hydroperoxides. Other thiols, either at comparable or higher concentrations than GSH, were without significant effects on lymphatic transport or luminal recovery of lipid hydroperoxides, indicating that these thiols are poor substitutes for GSH. Overall, the data are consistent with exogenous GSH being a source for cellular reduction of peroxidized lipids. Results from these studies could directly impact on future consideration of therapeutic means to increase cellular antioxidant systems to promote intestinal hydroperoxide detoxication.
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Ballatori, N., and T. W. Clarkson. "Sulfobromophthalein inhibition of glutathione and methylmercury secretion into bile." American Journal of Physiology-Gastrointestinal and Liver Physiology 248, no. 2 (February 1, 1985): G238—G245. http://dx.doi.org/10.1152/ajpgi.1985.248.2.g238.
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The mechanism through which sulfobromophthalein (BSP) inhibits the biliary secretion of glutathione (GSH) and methylmercury was examined in male rats anesthetized with pentobarbital sodium. The biliary secretion rates of GSH and methylmercury were measured following the bolus intravenous administration of various doses of BSP, the GSH conjugate of BSP (BSP-SG), and phenol-3,6-dibromphthalein disulfonate (DBSP, a nonmetabolizable analogue of BSP). The effects of BSP on GSH secretion were dose dependent; at a dose of 120 mumol/kg the rate of GSH secretion fell close to zero. DBSP also inhibited GSH secretion, although the inhibition was not as complete as observed after BSP administration; at a dose of 180 mumol/kg GSH secretion fell to 18% of control. BSP-SG, in contrast, had no effect on GSH secretion into bile when given at a dose of 120 mumol/kg. At doses of 240 and 360 mumol BSP-SG/kg, there were only minor changes in the rate of GSH secretion. The changes in GSH secretion induced by these dyes were accompanied by proportional changes in glutathione disulfide (GSSG) secretion into bile, so that the molar ratio of GSSG to GSH in bile remained within the range of 0.07–0.18. In all experiments the changes in methylmercury secretion were parallel to the changes in GSH secretion. The results suggest that the BSP-induced inhibition of GSH, GSSG, and methylmercury secretion into bile is due to the direct inhibition of the biliary GSH transport process.
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Li, Shumin, Xun Li, Yu-Long Li, Chun-Hong Shao, Keshore R. Bidasee, and George J. Rozanski. "Insulin regulation of glutathione and contractile phenotype in diabetic rat ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 3 (March 2007): H1619—H1629. http://dx.doi.org/10.1152/ajpheart.00140.2006.
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Cardiovascular complications of diabetes mellitus involve oxidative stress and profound changes in reduced glutathione (GSH), an essential tripeptide that controls many redox-sensitive cell functions. This study examined regulation of GSH by insulin to identify mechanisms controlling cardiac redox state and to define the functional impact of GSH depletion. GSH was measured by fluorescence microscopy in ventricular myocytes isolated from Sprague-Dawley rats made diabetic by streptozotocin, and video and confocal microscopy were used to measure mechanical properties and Ca2+ transients, respectively. Spectrophotometric assays of tissue extracts were also done to measure the activities of enzymes that control GSH levels. Four weeks after injection of streptozotocin, mean GSH concentration ([GSH]) in isolated diabetic rat myocytes was ∼36% less than in control, correlating with decreased activities of two major enzymes regulating GSH levels: glutathione reductase and γ-glutamylcysteine synthetase. Treatment of diabetic rat myocytes with insulin normalized [GSH] after a delay of 3–4 h. A more rapid but transient upregulation of [GSH] occurred in myocytes treated with dichloroacetate, an activator of pyruvate dehydrogenase. Inhibitor experiments indicated that insulin normalized [GSH] via the pentose pathway and γ-glutamylcysteine synthetase, although the basal activity of glucose-6-phosphate dehydrogenase was not different between diabetic and control hearts. Diabetic rat myocytes were characterized by significant mechanical dysfunction that correlated with diminished and prolonged Ca2+ transients. This phenotype was reversed by in vitro treatment with insulin and also by exogenous GSH or N-acetylcysteine, a precursor of GSH. Our data suggest that insulin regulates GSH through pathways involving de novo GSH synthesis and reduction of its oxidized form. It is proposed that a key function of glucose metabolism in heart is to supply reducing equivalents required to maintain adequate GSH levels for the redox control of Ca2+ handling proteins and contraction.
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Kariya, Chirag, Heather Leitner, Elysia Min, Christiaan van Heeckeren, Anna van Heeckeren, and Brian J. Day. "A role for CFTR in the elevation of glutathione levels in the lung by oral glutathione administration." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 6 (June 2007): L1590—L1597. http://dx.doi.org/10.1152/ajplung.00365.2006.
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The cystic fibrosis transmembrane conductance regulator (CFTR) protein is the only known apical glutathione (GSH) transporter in the lung. The purpose of these studies was to determine whether oral GSH or glutathione disulfide (GSSG) treatment could increase lung epithelial lining fluid (ELF) GSH levels and whether CFTR plays a role in this process. The pharmacokinetic profile of an oral bolus dose of GSH (300 mg/kg) was determined in mice. Plasma, ELF, bronchoalveolar lavage (BAL) cells, and lung tissue were analyzed for GSH content. There was a rapid elevation in the GSH levels that peaked at 30 min in the plasma and 60 min in the lung, ELF, and BAL cells after oral GSH dosing. Oral GSH treatment produced a selective increase in the reduced and active form of GSH in all lung compartments examined. Oral GSSG treatment (300 mg/kg) resulted in a smaller increase of GSH levels. To evaluate the role of CFTR in this process, Cftr knockout (KO) mice and gut-corrected Cftr KO-transgenic (Tg) mice were given an oral bolus dose of GSH (300 mg/kg) and compared with wild-type mice for changes in GSH levels in plasma, lung, ELF, and BAL cells. There was a twofold increase in plasma, a twofold increase in lung, a fivefold increase in ELF, and a threefold increase in BAL cell GSH levels at 60 min in wild-type mice; however, GSH levels only increased by 40% in the plasma, 60% in the lung, 50% in the ELF, and twofold in the BAL cells within the gut-corrected Cftr KO-Tg mice. No change in GSH levels was observed in the uncorrected Cftr KO mice. These studies suggest that CFTR plays an important role in GSH uptake from the diet and transport processes in the lung.
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Cheung, P. Y., and R. Schulz. "Glutathione causes coronary vasodilation via a nitric oxide- and soluble guanylate cyclase-dependent mechanism." American Journal of Physiology-Heart and Circulatory Physiology 273, no. 3 (September 1, 1997): H1231—H1238. http://dx.doi.org/10.1152/ajpheart.1997.273.3.h1231.
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The actions of thiols on coronary vascular tone in the intact heart are unknown. Glutathione (GSH), glutathione disulfide (GSSG), and L-cysteine (10-1,000 microM each) and GSH ethyl ester (3-300 microM) were infused into isolated rat hearts perfused with Krebs buffer at a constant pressure by the Langendorff method. GSH, GSSG, and GSH ethyl ester, but not L-cysteine, caused a concentration-dependent increase in coronary flow with the following order of potency: GSH ethyl ester > GSH = GSSG. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (300 microM), prevented the increase in coronary flow with GSH and attenuated that with GSSG (300 microM each). The vasodilation with GSH or GSSG and the associated increase in myocardial guanosine 3',5'-cyclic monophosphate were abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (a specific inhibitor of soluble guanylate cyclase) at 1 and 3 microM, respectively. The vasodilator action of GSH was abolished by superoxide dismutase (50 U/ml). Inhibition of GSH reductase abolished GSSG-induced vasodilation. Neither glibenclamide (1 microM) nor indomethacin (4 microM) affected the vasodilator action of GSH and GSSG. We conclude that GSH and GSSG cause coronary vasodilation that is mediated by a nitric oxide- and guanylate cyclase-dependent mechanism, possibly mediated by the reaction between GSH and peroxynitrite to form S-nitrosoglutathione, a nitric oxide donor.
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Luo, Jia-Li, Folke Hammarqvist, Kerstin Andersson, and Jan Wernerman. "Surgical trauma decreases glutathione synthetic capacity in human skeletal muscle tissue." American Journal of Physiology-Endocrinology and Metabolism 275, no. 2 (August 1, 1998): E359—E365. http://dx.doi.org/10.1152/ajpendo.1998.275.2.e359.
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To gain insight into cellular metabolism underlying the glutathione (GSH) alterations induced by surgical trauma, we assessed postoperative skeletal muscle GSH metabolism and its redox status in 10 patients undergoing elective abdominal surgery. Muscle biopsy specimens were taken from the quadriceps femoris muscle before and at 24 and 72 h after surgery. GSH concentrations decreased by 40% at 24 h postoperatively compared with the paired preoperative values ( P < 0.001) and remained low at 72 h ( P < 0.01). The concentration of GSH disulfide (GSSG) did not significantly change throughout the study period, whereas the total GSH (as GSH equivalent) concentration decreased after surgery. Of the GSH constituent amino acids, the concentration of cysteine remained unchanged throughout the study period (from 28.2 ± 10.1 preoperatively to 29.4 ± 13.9 at 24 h postoperatively and to 28.3 ± 15.6 μmol/kg wet wt at 72 h postoperatively). Despite a reduction in glutamate concentration by 40% 24 h after surgery, no correlation was established between GSH and glutamate concentrations postoperatively. Activity of γ-glutamylcysteine synthetase did not change significantly after surgery, whereas GSH synthetase activity decreased postoperatively (from 66.4 ± 19.1 preoperatively to 41.0 ± 10.5 24 h postoperatively, P < 0.01, and to 46.0 ± 11.7 μU/mg protein 72 h postoperatively, P < 0.05). The decrease of GSH was correlated to the reduced GSH synthetase activity seen at 24 h postoperatively. These results indicate that the skeletal muscle GSH pool is diminished in patients after surgical trauma. The depletion of the GSH pool is associated with a decreased activity of GSH synthetase, indicating a decreased GSH synthetic capacity in skeletal muscle tissue.
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Kim, Seong-Jun, Wan-Kyu Ko, Gong-Ho Han, Daye Lee, Yuhan Lee, Seung-Hun Sheen, Je-Beom Hong, and Seil Sohn. "Chirality-Dependent Anti-Inflammatory Effect of Glutathione after Spinal Cord Injury in an Animal Model." Pharmaceuticals 14, no. 8 (August 12, 2021): 792. http://dx.doi.org/10.3390/ph14080792.
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Neuroinflammation forms a glial scar following a spinal cord injury (SCI). The injured axon cannot regenerate across the scar, suggesting permanent paraplegia. Molecular chirality can show an entirely different bio-function by means of chiral-specific interaction. In this study, we report that d-chiral glutathione (D-GSH) suppresses the inflammatory response after SCI and leads to axon regeneration of the injured spinal cord to a greater extent than l-chiral glutathione (L-GSH). After SCI, axon regrowth in D-GSH-treated rats was significantly increased compared with that in L-GSH-treated rats (*** p < 0.001). Secondary damage and motor function were significantly improved in D-GSH-treated rats compared with those outcomes in L-GSH-treated rats (** p < 0.01). Moreover, D-GSH significantly decreased pro-inflammatory cytokines and glial fibrillary acidic protein (GFAP) via inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway compared with L-GSH (*** p < 0.001). In primary cultured macrophages, we found that D-GSH undergoes more intracellular interaction with activated macrophages than L-GSH (*** p < 0.001). These findings reveal a potential new regenerative function of chiral GSH in SCI and suggest that chiral GSH has therapeutic potential as a treatment of other diseases.
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Deneke, S. M., and B. L. Fanburg. "Regulation of cellular glutathione." American Journal of Physiology-Lung Cellular and Molecular Physiology 257, no. 4 (October 1, 1989): L163—L173. http://dx.doi.org/10.1152/ajplung.1989.257.4.l163.
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In addition to its participation in a variety of other biochemical reactions, glutathione (GSH) is a major antioxidant. It is regularly generated intracellularly from its oxidized form by glutathione reductase activity that is coupled with a series of interrelated reactions. Synthesis of GSH also takes place intracellularly by a two-step reaction, the first of which is catalyzed by rate-limiting gamma-glutamylcysteine synthetase activity. Intracellular substrates for GSH are provided both by direct amino acid transport and by a gamma-glutamyl transpeptidase reaction that salvages circulating GSH by coupling the gamma-glutamyl moiety to a suitable amino acid acceptor for transport into the cell. Although the liver is a net synthesizer of circulating GSH, organs such as the kidney salvage GSH through the gamma-glutamyl transpeptidase reaction. Intracellular GSH may be consumed by GSH transferase reactions that conjugate GSH with certain xenobiotics. Elevation of cellular GSH levels in cultured cells in response to hyperoxia or electrophilic agents such as diethylmaleate is coupled with an increase in activity of the Xc- transport system for the amino acids cystine and glutamate. Strategies may be developed for protection against oxidant injury by enhancement of transport systems for precursor amino acids of GSH or by providing substrate that circumvents feedback inhibition of GSH synthesis.
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Amir, A., S. Chapman, Y. Gozes, R. Sahar, and N. Allon. "Protection by extracellular glutathione against sulfur mustard induced toxicity in vitro." Human & Experimental Toxicology 17, no. 12 (December 1998): 652–60. http://dx.doi.org/10.1177/096032719801701202.
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1 The present study characterizes the role of extracellularly added glutathione in protection against sulfur mustard (HD) toxicity in a macrophage monocyte cell line J774.2 Toxic effects of HD depend on dose and duration of exposure with an ED50of 50 and 75 mM for dividing and confluent cells respectively.3 Exposure to HD, 100-200 mM caused *15% decrease in the cellular glutathione (GSH) content 2 h after exposure, pretreatment with GSH, 0.2-10 mM, elevated cellular GSH *61.5.4 GSH pretreatment increased cell viability after HD 2-3-fold. Similar protective effects of GSH treatment were found in a human epidermoid carcinoma cell line (KB).5 Protection by post treatment with GSH was apparent even 60 min post HD exposure.6 No protection was afforded when the intracellular GSH concentration was elevated prior to exposure and the extracellular GSH had been washed out. However, GSH depleted cells were more sensitive to HD than normal cells, and were also protected by addition of GSH to the growth medium, although the intracellular GSH content remained low.7 We conclude that it is essential for the GSH to be present extracellularly in order to protect cells from HD toxicity.8 Our findings have therapeutic implications in particular for the protection of lungs after inhalation exposure to HD vapor.
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Khandaker, Morshed, Niyaf Alkadhem, Helga Progri, Sadegh Nikfarjam, Jiyoon Jeon, Hari Kotturi, and Melville B. Vaughan. "Glutathione Immobilized Polycaprolactone Nanofiber Mesh as a Dermal Drug Delivery Mechanism for Wound Healing in a Diabetic Patient." Processes 10, no. 3 (March 4, 2022): 512. http://dx.doi.org/10.3390/pr10030512.
Full textAbstract:
Glutathione (GSH) is an anti-inflammatory and antioxidant biomolecule. Polycaprolactone (PCL) nanofiber mesh (NFM) is capable of the attachment and release of biomolecules for prolonged periods and has the potential as a transdermal drug delivery system during wound healing for a diabetic patient. Our earlier study found that high levels of sugar in diabetic male mice were significantly decreased by daily doses of glutathione administered on the mice. Furthermore, oxidative stress found in diabetic male mice led to the total depletion of glutathione levels in the body’s organs (pancreas, spleen, epididymis, and testis). The objective of this study was to attach GSH with PCL NFM for the controlled release of GSH biomolecules for long periods of time from the fiber mesh into a diabetic body. This study produced PCL NFM using an electrospun technique and tested it on mice to evaluate its efficiency as a dermal drug delivery mechanism. This study dissolved GSH (2.5 mg/mL) with phosphate-buffered saline (PBS) and glutaraldehyde (GLU) solution to create GSH-PBS and GSH-GLU complexes. Each complex was used to soak PCL NFM for 24 h and dried to create PCL-GSH-PBS and PCL-GSH-GLU meshes. Fiber morphology, degradation, fibroblast cell proliferation, cytotoxicity, and GSH release activities from each mesh were compared. Fibroblast cell adhesion and cytotoxicity tests found excellent biocompatibility of both GSH-immobilized PCL meshes and no degradation until 20 days of the study period. The disk diffusion method was conducted to test the antibacterial properties of the sample groups. Release tests confirmed that the attachment of GSH with PCL by GSH-GLU complex resulted in a steady release of GSH compared to the fast release of GSH from PCL-GSH-PBS mesh. The disk diffusion test confirmed that PCL-GSH-GLU has antibacterial properties. The above results conclude that GSH-GLU immobilized PCL NFM can be a suitable candidate for a transdermal anti-oxidative and anti-bacterial drug delivery system such as bandage, skin graft for wound healing application in a diabetic patient.
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Li, Wenhua, Minghui Li, and Jing Qi. "Nano-Drug Design Based on the Physiological Properties of Glutathione." Molecules 26, no. 18 (September 13, 2021): 5567. http://dx.doi.org/10.3390/molecules26185567.
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Glutathione (GSH) is involved in and regulates important physiological functions of the body as an essential antioxidant. GSH plays an important role in anti-oxidation, detoxification, anti-aging, enhancing immunity and anti-tumor activity. Herein, based on the physiological properties of GSH in different diseases, mainly including the strong reducibility of GSH, high GSH content in tumor cells, and the NADPH depletion when GSSH is reduced to GSH, we extensively report the design principles, effect, and potential problems of various nano-drugs in diabetes, cancer, nervous system diseases, fluorescent probes, imaging, and food. These studies make full use of the physiological and pathological value of GSH and develop excellent design methods of nano-drugs related to GSH, which shows important scientific significance and prominent application value for the related diseases research that GSH participates in or responds to.
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Sexton, Daniel J., and Bulent Mutus. "Platelet glutathione transport: characteristics and evidence for regulation by intraplatelet thiol status." Biochemistry and Cell Biology 73, no. 3-4 (March 1, 1995): 155–62. http://dx.doi.org/10.1139/o95-019.
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The present study demonstrates the carrier-mediated uptake of intact glutathione (GSH) by human platelets. Platelet GSH uptake was characterized as being Na+independent and saturable. The KM, apparentand Vmax, apparentfor GSH uptake in platelet plasma membrane vesicles were 28.0 ± 8.4 μM and 263.5 ± 28.5 pmol/min per mg protein, respectively. The transport was inhibited by GSH analogs and enhanced by KCl-induced membrane depolarization. GSH transport may be regulated by the intracellular thiol status, since the depletion of intraplatelet GSH with 100 μM 1-chloro-2,4-dinitrobenzene (CDNB) increased GSH uptake by ~40%. The KM, apparentand Vmax, apparentfor GSH uptake in intact platelets changed from 99.5 ± 15 μM and 42 ± 7.5 pmol/min per 109platelets, respectively, to 33.7 ± 6.7 μM and 21.5 ± 6.9 pmol/min per 109platelets, respectively, on reducing intraplatelet GSH with 100 μM CDNB.Key words: glutathione, platelets, transport.
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Peacock, M. D., D. A. Schenk, R. A. Lawrence, J. A. Morgan, and S. G. Jenkinson. "Elimination of glutathione-induced protection from hyperbaric hyperoxia by acivicin." Journal of Applied Physiology 76, no. 3 (March 1, 1994): 1279–84. http://dx.doi.org/10.1152/jappl.1994.76.3.1279.
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Glutathione (GSH) administered intraperitoneally significantly prolongs the time to initial seizure and survival time of rats exposed to hyperbaric hyperoxia (HBO). Acivicin is an antitumor antibiotic that is an inhibitor of gamma-glutamyl transpeptidase (GGT), an enzyme necessary for the breakdown and transport across cell membranes of GSH. To determine whether acivicin treatment alters GSH-induced protection from HBO, rats were dosed with 25 mg/kg of acivicin or vehicle 1 h before O2 exposure at an inspired O2 fraction of 1.0 at 4 ATA. Immediately before exposure, rats received GSH (1 mmol/kg) or vehicle. Time to seizure and time to death were recorded during exposure by direct observation. In separate groups of rats on the same dosing schedule, plasma GSH, renal GGT, and brain GGT were measured 15 min after the GSH injection without HBO exposure and 100 min after the beginning of HBO exposure. Renal GGT was decreased to 2.5% of control and brain GGT to 37% of control in the acivicin-dosed rats. Plasma GSH increased 3-fold in rats given acivicin alone, 52-fold in rats given GSH alone, and 84-fold in rats receiving both acivicin and GSH. Rats dosed with GSH alone had significantly prolonged times to seizure and death compared with all other groups. Rats dosed with GSH after receiving acivicin were not protected from HBO despite the large increase in plasma GSH that occurred in these animals. GSH treatment did not increase tissue GSH in lung, liver, or brain at 160 or 200 min of exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
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Лановенко, І. І., and Г. П. Гащук. "Реактивність і взаємодія глутатіону еритроцитів і кисневотранспортної функції крові при гемічній гіпоксії гемолітичного генезу." Reports of the National Academy of Sciences of Ukraine, no. 4 (August 27, 2022): 106–14. http://dx.doi.org/10.15407/dopovidi2022.04.106.
Full textAbstract:
Глутатіон (GSH) є універсальним регулятором загального і кисневого гомеостазу. З огляду на поліпротекторні властивості GSH актуальними є дослідження його ролі в генезі гіпоксичних станів і особливо гемічної гіпоксії при анеміях. У статті висвітлені результати дослідження змін і взаємодії глутатіону еритроцитів та кисневотранспортної функції крові при гемічній гіпоксії гемолітичного генезу. В експерименті на щурах відтворювали модель гемічної гіпоксії (ГГ) гемолітичного генезу. В умовах ГГ застосовували вплив на метаболізм GSH: стимуляцію за допомогою його синергіста цистеаміну і донора GSH глутаргіну; пригнічення за допомогою його антагоніста GSH діетилмалеату. Визначали показники гемограми, мієлограми, обміну заліза, в еритроцитах крові — вміст відновленого (GSH) та окисненого (GSSG) глутатіону і активність глутатіонредуктази (GR), гемічну гіпоксію за показниками кисневотранспортної функції (КТФ) крові. Встановлено порушення КТФ крові (зменшення доставки і споживання О2, метаболічний ацидоз) і значне зниження вмісту (у 2,85 раза) глутатіону (GSH) і активності (у 4,89 раза) GR в еритроцитах крові. Пригнічення утворення GSH (за допомогою діетилмалеату) призводить до поглиблення недостатності GSH і порушень КТФ крові; стимуляція утворення GSH (за допомогою цистеаміну і глутаргіну) підвищує продукцію GSH, підсилює активність GR та відновлює КТФ крові. Обґрунтована можливість регуляції КТФ крові і корекції гемічної гіпоксії за допомогою регуляції метаболізму глутатіону.