Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem

Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Biological Chemistry (Impact Factor: 3.27). 02/2009; 390(3):191-214. DOI: 10.1515/BC.2009.033
Source: PubMed

ABSTRACT Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.

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Available from: Shujie Shi, Jun 12, 2014
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    • "Then, in order to assess the cellular antioxidant capacity, we determined the glutathione redox status. The ratio between oxidized and reduced glutathione serves as an important indicator for oxidative stress evaluation in cells and tissues (Ballatori et al., 2009). In this study, we observed a significant increase in GSSG/ GSH ratio in exposed population (p < 0.05; Table 1, Fig. 2F), result in agreement with several previous studies (Diouf et al., 2006; Liu et al., 2009). "
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    ABSTRACT: The purpose of the study was to determine Pb and Cd concentrations in humans and to assess the effect of co-exposure to these metals on biomarkers of oxidative stress and nephrotoxicity. Blood and urine levels of Pb and Cd, oxidative stress and urinary renal biomarkers were measured in 77 subjects neighboring a discharge and 52 in the control site. Exposed subjects showed significantly higher levels of lead and cadmium in blood and urine than the controls. Excessive production of reactive oxygen species induced by these metals in exposed subjects conducted to a decrease in antioxidant defense system (GPx, Selenium, GSH) and an increase in lipid peroxidation (MDA). Moreover, changes in markers of nephrotoxicity (high urinary concentrations of total protein, RBP and CC16, as well as GSTα and LDH increased activities) suggested the occurrence of discrete and early signs of impaired renal function for the discharge neighboring population. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Environmental Pollution 07/2015; 206:247-255. DOI:10.1016/j.envpol.2015.06.032 · 4.14 Impact Factor
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    • "K. Bačić Baronica et al. neurodegeneration (Ballatori et al. 2009, Al et al. 2013). GSTs are supergene family of enzymes which participate in GSH metabolism; beside their role in protecting the cells from damage caused by oxidized metabolites, GSTs are involved in cellular processes such as biotransformation , detoxification, steroidogenesis, and cell signaling (Armstrong 1997, Henderson et al. 1998, Watson et al. 1998). "
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    ABSTRACT: The impact of glutathione S-transferases (GSTs) detoxification pathway on complex pathogenesis and heterogeneity of clinical findings in multiple sclerosis (MS), particularly the exact correlation between indicators of clinical severity and different GST genotypes, has not yet been fully elucidated. The aim of the study was to assess the relationship between disability level in multiple sclerosis (estimated by Kurtzke Expanded Disability Status Scale), disease progression (estimated by Multiple Sclerosis Severity Score), the level of brain atrophy and lesion load (determined by MRI) and detoxification status (analyzing glutathione S-transferase P1, GSTP1, genotype profile), in a group of 58 MS patients and 68 age/gendermatched controls. The results present the first evidence on significantly higher frequency of GSTP1 C341T polymorphism (C-T transition) in healthy subjects compared to MS patients, suggesting it may act as a moderating factor in developing MS clinical phenotype. Gender-dependent distribution of the C341T polymorphism was found in both MS patients and controls, with higher frequency of C-T transition in females. In addition, preliminary data showed higher proportion of male MS patients with higher median MSSS scores, as well as lower brain atrophy level and lesion load in MS patients carrying the C341T mutation. Observed gender difference in distribution of the C341T polymorphism in MS patients, as well as in disease progression, suggests that GSTP1 detoxification pathway occurs in a gender-dependent manner and could therefore add to clinical severity in male MS patients.
    Acta neurobiologiae experimentalis 09/2014; 74(3):257-65. · 1.29 Impact Factor
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    • "GSH deficiency or a decrease in the [GSH]/[GSSG] ratio manifests itself largely through an increased susceptibility to oxidative stress, as observed in Parkinson's and Alzheimer's disease. Conversely, elevated GSH levels increase antioxidant capacity and resistance to oxidative stress, and this is observed in cancer cells [13], [14]. "
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    ABSTRACT: The imbalance of the intracellular redox state and, in particular, of the glutathione (GSH)/GSH disulfide couple homeostasis, is involved in the pathogenesis of a number of diseases. In many skin diseases, including psoriasis, oxidative stress plays an important role, as demonstrated by the observation that treatments leading to increase of the local levels of oxidant species ameliorate the disease. Recently, dehydrocostuslactone (DCE) and costunolide (CS), two terpenes naturally occurring in many plants, have been found to exert various anti-inflammatory and pro-apoptotic effects on different human cell types. These compounds decrease the level of the intracellular GSH by direct interaction with it, and, therefore, can alter cellular redox state. DCE and CS can trigger S-glutathionylation of various substrates, including the transcription factor STAT3 and JAK1/2 proteins. In the present study, we investigated on the potential role of DCE and CS in regulating inflammatory and proliferative responses of human keratinocytes to cytokines. We demonstrated that DCE and CS decreased intracellular GSH levels in human keratinocytes, as well as inhibited STAT3 and STAT1 phosphorylation and activation triggered by IL-22 or IFN-γ, respectively. Consequently, DCE and CS decreased the IL-22- and IFN-γ-induced expression of inflammatory and regulatory genes in keratinocytes, including CCL2, CXCL10, ICAM-1 and SOCS3. DCE and CS also inhibited proliferation and cell-cycle progression-related gene expression, as well as they promoted cell cycle arrest and apoptosis. In parallel, DCE and CS activated the anti-inflammatory EGFR and ERK1/2 molecules in keratinocytes, and, thus, wound healing in an in vitro injury model. In light of our findings, we can hypothesize that the employment of DCE and CS in psoriasis could efficiently counteract the pro-inflammatory effects of IFN-γ and IL-22 on keratinocytes, revert the apoptosis-resistant phenotype, as well as inhibit hyperproliferation in the psoriatic epidermis.
    PLoS ONE 09/2014; 9(9):e107904. DOI:10.1371/journal.pone.0107904 · 3.23 Impact Factor
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