The nature of antioxidant defense mechanisms: a lesson from transgenic studies. [1998](IR91)

The nature of antioxidant defense mechanisms: a lesson from transgenic studies. [1998](IR91)

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(Memo Item created on December 17, 2011 01:41 PM)
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The nature of antioxidant defense mechanisms: a lesson from transgenic studies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1533365/
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Environ Health Perspect. 1998 October; 106(Suppl 5): 1219–1228.
PMCID: PMC1533365
Copyright notice

Research Article

The nature of antioxidant defense mechanisms: a lesson from transgenic studies.

Y S Ho, J L Magnenat, M Gargano, and J Cao
Institute of Chemical Toxicology, Wayne State University, Detroit, MI 48201, USA. yho@wayne.edu

Abstract
Reactive oxygen species (ROS) have been implicated in the pathogenesis of many clinical disorders such as adult respiratory distress syndrome, ischemia-reperfusion injury, atherosclerosis, neurodegenerative diseases, and cancer. Genetically engineered animal models have been used as a tool for understanding the function of various antioxidant enzymes in cellular defense mechanisms against various types of oxidant tissue injury. Transgenic mice overexpressing three isoforms of superoxide dismutase, catalase, and the cellular glutathione peroxidase (GSHPx-1) in various tissues show an increased tolerance to ischemia-reperfusion heart and brain injury, hyperoxia, cold-induced brain edema, adriamycin, and paraquat toxicity. These results have provided for the first time direct evidence demonstrating the importance of each of these antioxidant enzymes in protecting the animals against the injury resulting from these insults, as well as the effect of an enhanced level of antioxidant in ameliorating the oxidant tissue injury. To evaluate further the nature of these enzymes in antioxidant defense, gene knockout mice deficient in copper-zinc superoxide dismutase (CuZnSOD) and GSHPx-1 have also been generated in our laboratory. These mice developed normally and showed no marked pathologic changes under normal physiologic conditions. In addition, a deficiency in these genes had no effects on animal survival under hyperoxida. However, these knockout mice exhibited a pronounced susceptibility to paraquat toxicity and myocardial ischemia-reperfusion injury. Furthermore, female mice lacking CuZnSOD also displayed a marked increase in postimplantation embryonic lethality. These animals should provide a useful model for uncovering the identity of ROS that participate in the pathogenesis of various clinical disorders and for defining the role of each antioxidant enzyme in cellular defense against oxidant-mediated tissue injury.
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(Memo Item created on December 17, 2011 01:47 PM)
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English to Chinese translation of some medical terms relevant to this paper
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ischemia-reperfusion injury

ischemia
【醫學】局部缺血

reperfusion
再灌注

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The central role of glutathione in the pathophysiology of human diseases [2007](IR91)

The central role of glutathione in the pathophysiology of human diseases.[2007](IR91)

The central role of glutathione in the pathophysiology of human diseases.[2007](IR91)

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The central role of glutathione in the pathophysiology of human diseases.

http://www.ncbi.nlm.nih.gov/pubmed/18158646
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Arch Physiol Biochem. 2007 Oct-Dec;113(4-5):234-58.

The central role of glutathione in the pathophysiology of human diseases.

Franco R, Schoneveld OJ, Pappa A, Panayiotidis MI.

Source
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.

Abstract
Reduced glutathione (L-gamma-glutamyl-L-cysteinyl-glycine, GSH) is the prevalent low-molecular-weight thiol in mammalian cells. It is formed in a two-step enzymatic process including, first, the formation of gamma-glutamylcysteine from glutamate and cysteine, by the activity of the gamma-glutamylcysteine synthetase; and second, the formation of GSH by the activity of GSH synthetase which uses gamma-glutamylcysteine and glycine as substrates. While its synthesis and metabolism occur intracellularly, its catabolism occurs extracellularly by a series of enzymatic and plasma membrane transport steps. Glutathione metabolism and transport participates in many cellular reactions including: antioxidant defense of the cell, drug detoxification and cell signaling (involved in the regulation of gene expression, apoptosis and cell proliferation). Alterations in its concentration have also been demonstrated to be a common feature of many pathological conditions including diabetes, cancer, AIDS, neurodegenerative and liver diseases. Additionally, GSH catabolism has been recently reported to modulate redox-sensitive components of signal transduction cascades. In this manuscript, we review the current state of knowledge on the role of GSH in the pathogenesis of human diseases with the aim to underscore its relevance in translational research for future therapeutic treatment design.

PMID: 18158646 [PubMed - indexed for MEDLINE]
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Glutathione dysregulation and the etiology and progression of human diseases {Major pathways of glutathione homeostasis in mammalian cells}[2009](IR92)

Glutathione dysregulation and the etiology and progression of human diseases {Major pathways of glutathione homeostasis in mammalian cells}[2009](IR92)

GSTs act by conjugating the thiol group from glutathione (GSH; g-glutamyl-cysteinyl-glycine) to compounds that possess an electrophilic center [2007]

[2011-09-24]

GSTs act by conjugating the thiol group from glutathione (GSH; g-glutamyl-cysteinyl-glycine) to compounds that possess an electrophilic center [2007]

Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91)

2011-09-24

Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91)

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Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91) (3_of_7).png

Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91) (4_of_7).png

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Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91) (6_of_7).png

Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91) (7_of_7).png

Keywords:

Glutathione, Acetaminophen Poisoning

Regulation of neuronal glutathione synthesis. [2008](IR91)

Regulation of neuronal glutathione synthesis. [2008](IR91)

Regulation of neuronal glutathione synthesis.
http://www.ncbi.nlm.nih.gov/pubmed/19008644

J Pharmacol Sci. 2008 Nov;108(3):227-38. Epub 2008 Nov 13.

Regulation of neuronal glutathione synthesis.
Aoyama K, Watabe M, Nakaki T.

Department of Pharmacology, Teikyo University School of Medicine, Itabashi, Tokyo, Japan.

Abstract
The brain is among the major organs generating large amounts of reactive oxygen species and is especially susceptible to oxidative stress. Glutathione (GSH) plays critical roles as an antioxidant, enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. GSH deficiency has been implicated in neurodegenerative diseases. GSH is a tripeptide comprised of glutamate, cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH synthesis within neurons. Most neuronal cysteine uptake is mediated by sodium-dependent excitatory amino acid transporter (EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous studies demonstrated EAAT is vulnerable to oxidative stress, leading to impaired function. A recent study found EAAC1-deficient mice to have decreased brain GSH levels and increased susceptibility to oxidative stress. The function of EAAC1 is also regulated by glutamate transporter associated protein 3-18. This review focuses on the mechanisms underlying GSH synthesis, especially those related to neuronal cysteine transport via EAAC1, as well as on the importance of GSH functions against oxidative stress.

PMID: 19008644 [PubMed - indexed for MEDLINE] Free full text

Molecular inflammation - Underpinnings of aging and age-related diseases [2009](IR91)

Molecular inflammation: Underpinnings of aging and age-related diseases [2009](IR91)

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(Memo Item created on March 4, 2011 04:33 PM)
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Molecular inflammation: underpinnings of aging and age-related diseases.

http://www.ncbi.nlm.nih.gov/pubmed/18692159
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Ageing Res Rev. 2009 Jan;8(1):18-30. Epub 2008 Jul 18.

Molecular inflammation: underpinnings of aging and age-related diseases.

Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C.
Department of Pharmacy, Longevity Science and Technology Institutes, Research Institute for Drug Development, Pusan National University, Geumjeong-gu, Busan 609-735, South Korea. hyjung@pusan.ac.kr

Abstract
Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) upregulation of pro-inflammatory mediators (e.g., TNF-alpha, IL-1beta, IL-6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-kappaB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity.

PMID: 18692159 [PubMed - indexed for MEDLINE]

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Biologic and pharmacologic regulation of mammalian glutathione synthesis [1999](IR90)

Biologic and pharmacologic regulation of mammalian glutathione synthesis [1999](IR90)

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Biologic and pharmacologic regulation of mammalian glutathione synthesis

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T38-3XT71JW-3&_user=10&_coverDate=11/30/1999&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1604517760&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3a6b923b86116ddca74640da64f79277&searchtype=a

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Free Radical Biology and Medicine
Volume 27, Issues 9-10, November 1999, Pages 922-935
doi:10.1016/S0891-5849(99)00176-8 | How to Cite or Link Using DOI
Copyright © 1999 Elsevier Science Inc. All rights reserved.    

Forums

Biologic and pharmacologic regulation of mammalian glutathione synthesis

Owen W. Griffitha, 2, ,
a Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA

Available online 4 November 1999.

Abstract
Glutathione (L-γ-glutamyl-L-cysteinylglycine, GSH) is synthesized from its constituent amino acids by the sequential action of γ-glutamylcysteine synthetase (γ-GCS) and GSH synthetase. The intracellular GSH concentration, typically 1–8 mM, reflects a dynamic balance between the rate of GSH synthesis and the combined rate of GSH consumption within the cell and loss through efflux. The γ-GCS reaction is rate limiting for GSH synthesis, and regulation of γ-GCS expression and activity is critical for GSH homeostasis. Transcription of the γ-GCS subunit genes is controlled by a variety of factors through mechanisms that are not yet fully elucidated. Glutathione synthesis is also modulated by the availability of γ-GCS substrates, primarily L-cysteine, by feedback inhibition of γ-GCS by GSH, and by covalent inhibition of γ-GCS by phosphorylation or nitrosation. Because GSH plays a critical role in cellular defenses against electrophiles, oxidative stress and nitrosating species, pharmacologic manipulation of GSH synthesis has received much attention. Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under conditions that would otherwise result in GSH depletion and cytotoxicity. Conversely, inhibitors of γ-GCS have been used to deplete GSH as a strategy for increasing the sensitivity of tumors and parasites (寄生生物) to certain therapeutic interventions.

Keywords: γ-Glutamylcysteine synthetase; Free radical; Oxidative stress; Transcriptional regulation; Cysteine availability; Feedback inhibition; Nitric oxide; Buthionine sulfoximine

Abbreviations: GSH, glutathione; GSSG, glutathione disulfide; NO, nitric oxide; γ-GCS, γ-glutamylcysteine synthetase; γ-GCSH, γ-GCS heavy subunit; γ-GCSL, γ-GCS light subunit; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; AP-1, activator protein-1; AP-2, activator protein-2; NF-κB, nuclear factor kappa B; ARE/EpRE, antioxidant and elctrophile response elements; Sp-1, PKA, cAMP-dependent protein kinase; PKC, protein kinase C; CMK, Ca2+/calmodulin-dependent protein kinase II; OTC, 2-oxothiazolidine-4-carboxylate; BSO, buthionine sulfoximine; L-SR-BSO, L-buthionine-S,R-sulfoximine; L-S-BSO, L-buthionine-S-sulfoximine; L-S-BSO-P, L-buthionine-S-sulfoximine phosphate

Article Outline

Introduction
The enzymes of synthesis
Modulation of cellular GSH levels—Overview
Control of GSH synthesis by regulation of γ-GCS expression
Control of glutathione synthesis by substrate availability
Feedback inhibition of γ-glutamylcysteine synthetase
Regulation of γ-GCS by post-translational modification
Pharmacologic control of γ-GCS
Acknowledgements
References



Address correspondence to: Owen W. Griffith, Ph.D., Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Tel: (414) 456-8435; Fax: (414) 456-6510

2 Dr. Owen W. Griffith earned his undergraduate degree in biochemistry from the University of California, Berkeley, and completed his graduate work at the Rockefeller University in New York City working on carnitine acetyltransferase with Dr. Leonard Spector. His work on γ-glutamylcysteine synthetase (γ-GCS) began in 1975 when he joined Dr. Alton Meister's group in the Department of Biochemistry at Cornell University Medical College. Dr. Griffith joined the faculty of that Department in 1980 and continued his work on the enzymes of glutathione metabolism and on carnitine-dependent enzymes. Among his contributions are the discovery of L-buthionine-S-sulfoximine as a highly selective, physiologically active γ-GCS inhibitor and numerous studies using that inhibitor to elucidate and pharmacologically control glutathione turnover. Other current interests include nitric oxide biology and microbial defenses against oxidative and nitrosative stress. Dr. Griffith is currently Professor and Chairman of Biochemistry at the Medical College of Wisconsin, a position he accepted in 1992.

Free Radical Biology and Medicine
Volume 27, Issues 9-10, November 1999, Pages 922-935
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