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


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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    • "At previous studies reported that stimulation of antioxidant enzyme activities such as glutathione by ozone prepared the tissue against the effects of reactive oxygen species [21] [22]. GSH plays a particularly important role in the maintenance and regulation of the thiol-redox status of the cell [23]. Tissue GSH depletion is one of the primary factors permitting kidney tissue damage is associated with oxidative stress caused by Mtx in our study. "
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    ABSTRACT: Methotrexate is a chemotherapeutic agent used for many cancer treatments. It leads to toxicity with its oxidative injury. The purpose of our study is investigating the medical ozone preconditioning and treatment has any effect on the methotrexate-induced kidneys by activating antioxidant enzymes in rats. Eighteen rats were divided into three equal groups; control, Mtx without and with medical ozone. Nephrotoxicity was performed with a single dose of 20 mg/kg Mtx intraperitoneally at the fifteenth day of experiment on groups 2 and 3. Medical ozone preconditioning was performed at a dose of 25 mcg/ml (5 ml) intraperitoneally everyday in the group 3 and treated with medical ozone for five more days while group 2 was received only 5 ml of saline everyday for twenty days. All rats were sacrificed at the end of third week and the blood and kidney tissue samples were obtained to measure the levels of TNF-α, IL-1β, malondialdehyde, glutathione and myeloperoxidase. Kidney injury score was evaluated histolopatologically. Medical ozone preconditioning and treatment ameliorated the biochemical parameters and kidney injury induced by Mtx. There was significant increase in tissue MDA, MPO activity, TNF-α and IL-1β (P<0.05) and significant decrease in tissue GSH and histopathology (P<0.05) after Mtx administration. The preconditioning and treatment with medical ozone ameliorated the nephrotoxicity induced by Mtx in rats by activating antioxidant enzymes and prevented renal tissue.
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    • "Antioxidants are beneficial health substances because of their vital role against different diseases and disorders (Budhiyanti et al., 2011; Prasong, 2011; Saboo et al., 2011). Cellular concentration of glutathione may decreased in association with the processes of aging and pathogenesis of many diseases (Mahmoudabad et al., 2008) and on another hand, its level may affected by the growth, nutritional status and hormonal/stress levels (Ballatori et al., 2009). To our knowledge, there is no research conducted before to detect the oxidative stress on kidney tissue associated with osteoarthritis regulated with zerumbone administration. "
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    ABSTRACT: Abstract: The study aimed to assess histology of rat kidneys and explore the renal oxidative stress post treatment with zerumbone via evaluation of some renal metabolizing enzymes and assay of prostaglandin E2 in the serum. To conduct such research, fifty adult male Sprague Dawley rats were randomly assigned into five equal groups. Rats in the first and second groups were administered 2 mL kg–1 body weight of 0.2 and 0.4% w/v zerumbone, respectively. Third group were treated with Celecoxib and served as positive control and rats in the fourth group were received corn oil and served as negative control whereas rats of the fifth group were left without treatment as a basal normal group. Microscopic findings revealed normal picture of the renal tissue and no signs of morphological changes. Biochemical analysis showed that the microsomal content of Cytochrome P450 was significantly induced in the first three groups compared to fourth and fifth groups. Activity of cytosolic glutathione-S-transferase enzyme was induced significantly in zerumbone treated groups. Non significant induction of total glutathione enzyme in the animals treated with zerumbone or celecoxib was detected. Similarly, there was no significant elevation in the level of malondialdehyde in the first three groups compared to fourth and fifth groups. Significant reduction of prostaglandin hormone following four weeks of oral administration of zerumbone and celecoxib compared to the negative control group was observed. Interestingly the levels of hormone in second group showed comparable level to those measured in the normal group.
    Asian Journal of Cell Biology 09/2015;
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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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