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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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)

Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91) (1_of_7).png

Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91) (2_of_7).png

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

Acetaminophen Poisoning - an Evidence-Based Consensus Guideline for Out-of-Hospital Management; Clinical Toxicology [2006](IR91) (5_of_7).png

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

我們的身體雖然奇妙, 卻只能拆拆裝裝, 沒有辦法無中生有。

2011-09-24
短文的標題：
「 我們的身體雖然奇妙，卻只能拆拆裝裝，沒有辦法無中生有。 」

短文的內容：
「 我們的身體雖然奇妙，但是她卻只會，視她當時的需要，把原子、離子或分子，拆拆裝裝重新組合，一面拆解，一面合成，也就是不斷地進行，新陳代謝的工作； 然而，她卻無法憑空生出一個分子、離子或是原子。也就是說，我們的身體無法做到，無中生有，這件事。也正因為，我們的身體無法無中生有，所以為了要維持身體的健康，我們不能只是光靠運動，我們也必須確保，身體所需要的各種營養分子、維生素、礦物質和能量，是足夠的，尤其是關鍵重要的營養素，例如，半胱胺酸（L-Cysteine）和各維生素、礦物質以及一些其他微量的營養素。

對於 青春永駐和長生不老 而言，維持 生體平衡，生物體內之新陳代謝的平衡，是一項非常重要的工作，因為它確保了我們的身體可以 青春永駐和長生不老。 而我要特別強調的是，為了要達到 青春永駐和長生不老 的目標，我們必須在，自己主觀的意識層次上，對於 維持生體平衡之極端重要性，有所認知與堅持。 因為透過這樣的認知與堅持，再加上我們自己持續不間斷地努力，我們才有可能讓自己可以 青春永駐，甚至於 長生不老。」

湯偉晉 （WeiJin Tang） 親手原創性地寫作於 西元 2011-09-24

對於我們身體的免疫系統, 我們每一個人都應該要虔誠地心存感激。

2011-09-24

短文的標題：

「 對於我們身體的免疫系統，我們每一個人都應該要虔誠地心存感激。 」

 

短文的內容：

「 每一個人的身體裡面都有一支，自己專用，而且是非常強悍的軍隊，隨時隨地分分秒秒持續而且非常積極地在保護我們，維護我們身體的健康，那就是我們的免疫系統。對於這一支，盡忠職守，專門為我們自己一個人效命的，免疫系統大軍，毫無疑問地，我們每一個人都應該要虔誠地心存感激； 因為沒有他們，我們根本無法存活在這個到處充滿各種微生物和危險物質，尤其是各種五花八門的人造污染物，的環境裡面。 」

 

湯偉晉 （WeiJin Tang） 親手逐字地寫於 西元 2011-09-24

 

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

Nobel Lecture by Paul A. M. Dirac; Theory of electrons and positrons [1933]

Nobel Lecture; The Nobel Prize in Physics 1933, {Theory of Electrons and Positrons}; by Paul A.M. Dirac; December 12, 1933

From our theoretical picture, we should expect an ordinary electron, with positive energy, to be able to drop into a hole and fill up this hole, the energy being liberated in the form of electromagnetic radiation. This would mean a process in which an electron and a positron annihilate one another. The converse process, namely the creation of an electron and a positron from electromagnetic radiation, should also be able to take place. Such processes appear to have been found experimentally, and are at present being more closely investigated by experimenters.

Nobel Lecture by Paul A. M. Dirac; Theory of electrons and positrons [1933].png

Google's salute to scientists and their great achievements (谷歌 (Google) 向 科學家們 和 他們的偉大成就 所表達的敬意) [2011-03-31]

Google's salute to scientists and their great achievements (谷歌 (Google) 向 科學家們 和 他們的偉大成就 所表達的敬意) [2011-03-31].png

 Figure saved by WeiJin Tang (湯偉晉) on [2011-03-31]

Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line.[2009](IR92)

Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line.[2009](IR92)
Background info (selected by WeiJin Tang (湯偉晉):
Telomeres (端粒) serve to maintain the structural integrity of chromosomes (染色體), yet each somatic cell (體細胞) division is associated with a decrease in telomere length. The cumulative decrease in telomere length can impose an upper limit for the number of cell divisions that can occur before a cell senesces (衰老).

Source:
Telomere Shortening in Hematopoietic Stem Cell Transplantation: A Potential Mechanism for Late Graft Failure?

Reference:
von Zglinicki T. Oxidative stress shortens telomeres. Trends
Biochem Sci. 2002;27:339-344.

Chronic oxidativestress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells [2004](IR92)

Begin of professional paper PP5CE113212B754B4D9A6DAED725631C:

Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line.[2009](IR92)

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Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line.

http://www.ncbi.nlm.nih.gov/pubmed/19463156
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BMC Neurosci. 2009 May 22;10:51.
Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line.

Pollicita M, Muscoli C, Sgura A, Biasin A, Granato T, Masuelli L, Mollace V, Tanzarella C, Del Duca C, Rodinò P, Perno CF, Aquaro S.
Department of Experimental Medicine and Biochemical Sciences, University Tor Vergata, Rome, Italy. michela.pollicita@uniroma2.it

Abstract

BACKGROUND: 
Oxidative stress plays a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV-1) infection causing apoptosis of astroglia cells and neurons. Recent data have shown that oxidative stress is also responsible for the acceleration of human fibroblast telomere shortening in vitro. In the present study we analyzed the potential relations occurring between free radicals formation and telomere length during HIV-1 mediated astroglial death.

RESULTS: 
To this end, U373 human astrocytoma cells have been directly exposed to X4-using HIV-1IIIB strain, for 1, 3 or 5 days and treated (where requested) with N-acetylcysteine (NAC), a cysteine donor involved in the synthesis of glutathione (GSH, a cellular antioxidant) and apoptosis has been evaluated by FACS analysis. Quantitative-FISH (Q-FISH) has been employed for studying the telomere length while intracellular reduced/oxidized glutathione (GSH/GSSG) ratio has been determined by High-Performance Liquid Chromatography (HPLC). Incubation of U373 with HIV-1IIIB led to significant induction of cellular apoptosis that was reduced in the presence of 1 mM NAC. Moreover, NAC improved the GSH/GSSG, a sensitive indicator of oxidative stress, that significantly decreased after HIV-1IIIB exposure in U373. Analysis of telomere length in HIV-1 exposed U373 showed a statistically significant telomere shortening, that was completely reverted in NAC-treated U373.

CONCLUSION: 
Our results support the role of HIV-1-mediated oxidative stress in astrocytic death and the importance of antioxidant compounds in preventing these cellular damages. Moreover, these data indicate that the telomere structure, target for oxidative damage, could be the key sensor of cell apoptosis induced by oxidative stress after HIV infection.

PMID: 19463156 [PubMed - indexed for MEDLINE]PMCID: PMC2694812Free PMC Article
Images from this publication.See all images (6) Free text

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Radical-free biology of oxidative stress; by Dean P. Jones [2008](IR92).png

Figure saved by WeiJin Tang (湯偉晉) on [2011-01-28]

Professor Dean P. Jones, Division of Pulmonary, Allergy and Critical Care Medicine, Clinical Biomarkers Laboratory, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia [2011-01-22](IR91).jpg

Radical-free biology of oxidative stress; by Dean P. Jones [2008](IR92).png

Potential hazardous substances in food. DDT, dichloro-diphenyl-trichloroethane [2009]

Potential hazardous substances in food. DDT, dichloro-diphenyl-trichloroethane [2009].png

The major route of acrylamide metabolism is conjugation to glutathione [2010]

The major route of acrylamide metabolism is conjugation to glutathione [2010].png

Classes of nutrients for human nutrition [2009]

January 28, 2011; 07:20:05 p.m. Taipei Time

Classes of nutrients for human nutrition [2009].png

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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