Depletion (耗盡) of reduced glutathione (穀胱甘肽) precedes inactivation of mitochondrial enzymes following limbic status epilepticus (癲癇持續狀態) in the rat hippocampus [2006](IR91)

Depletion (耗盡) of reduced glutathione (穀胱甘肽) precedes inactivation of mitochondrial enzymes following limbic status epilepticus (癲癇持續狀態) in the rat hippocampus [2006](IR91)

Depletion (耗盡) of reduced glutathione (穀胱甘肽) precedes inactivation of mitochondrial enzymes following limbic status epilepticus (癲癇持續狀態) in the rat hippocampus [2006](IR91)

穀胱甘肽

Depletion (耗盡) of reduced glutathione (穀胱甘肽) precedes inactivation of mitochondrial enzymes following limbic (邊緣的) status epilepticus (癲癇持續狀態) in the rat hippocampus (海馬（大腦中被認為是感情和記憶中心的部分)).

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Depletion (耗盡) of reduced glutathione (穀胱甘肽) precedes inactivation of mitochondrial enzymes following limbic status epilepticus in the rat hippocampus.

http://highwire.stanford.edu/cgi/medline/pmid;16290321?maxtoshow=&HITS=&hits=&RESULTFORMAT=1&andorexacttitle=and&fulltext=glutathione%2C+depletion%2C+epilepsy&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

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Depletion (耗盡) of reduced glutathione (穀胱甘肽) precedes inactivation of mitochondrial enzymes following limbic status epilepticus in the rat hippocampus.

H Sleven, JE Gibbs, S Heales, M Thom, and HR Cock
Neurochem Int, January 1, 2006; 48(2): 75-82.    

Abstract

Epilepsy Group, Centre for Clinical Neurosciences, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.

The time course and critical determinants of mitochondrial dysfunction and oxidative stress following limbic status epilepticus (SE) were investigated in hippocampal sub-regions of an electrical stimulation model in rats, at time points 4-44h after status. Mitochondrial and cytosolic enzyme activities were measured spectrophotometrically, and reduced glutathione (穀胱甘肽) (GSH) concentrations by HPLC, and compared to results from sham controls. The earliest change in any sub-region was a fall in GSH, appearing as early as 4h in CA3 (-13%, p<0.05), and persisting at all time points. This was followed by a transient fall in complex I activity (CA3, 16h, -13%, p<0.05), and later changes in aconitase (CA1,-18% and CA3, -22% at 44h, p<0.05). The activity of the cytosolic enzyme glyceraldehyde-3-phosphate-dehydrogenase was unaffected at all time points. It is known that GSH levels are dependent both on redox status, and on the availability of the precursor cysteine, in turn dependent on the cysteine/glutamate antiporter, for which extracellular glutamate concentrations are rate limiting. Both mechanisms are likely to contribute indirectly to GSH Depletion (耗盡) following seizures. That a relative deficiency in GSH precedes later changes in the activities of complex I and aconitase in vulnerable hippocampal sub-regions, occurring within a clinically relevant therapeutic time window, suggests that strategies to boost GSH levels and/or otherwise reduce oxidative stress following seizures, deserve further study, both in terms of preventing the biochemical consequences of SE and the neuronal dysfunction and clinical consequences.

Publication Types:

Journal article
Research support, non-u.s. gov't
MeSH Terms:

Animals
Chromatography, High Pressure Liquid
Electric Stimulation
Electroencephalography
glutathione (穀胱甘肽)
Male
Mitochondria
Rats
Rats, Sprague-Dawley
Status Epilepticus
PMID: 16290321

--------------------------------------------------------------------------------
MEDLINE data is licensed by HighWire Press from the National Library of Medicine. Some material in the NLM databases is from copyrighted publications of the respective copyright claimants. Users of the NLM databases are solely responsible for compliance with any copyright restrictions and are referred to the publication data appearing in the bibliographic citations, as well as to the copyright notices appearing in the original publications, all of which are hereby incorporated by reference.

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The Discovery of Glutathione by F. Gowland Hopkins and the Beginning of Biochemistry at Cambridge University [2002-06-14](IR90)

The Discovery of Glutathione by F. Gowland Hopkins and the Beginning of Biochemistry at Cambridge University [2002-06-14](IR90)

He was knighted in 1925 and received the Nobel Prize in Physiology or Medicine in 1929.

Sir Frederick Gowland Hopkins (1861–1947) was born in East Sussex, Great Britain. He founded the Department of Biochemistry (生物化學) at the University of Cambridge (劍橋) in 1914.

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The Discovery of Glutathione by F. Gowland Hopkins and the Beginning of Biochemistry at Cambridge University

http://www.jbc.org/content/277/24/e13.full
- - - End title or keyword:

Classic Article
"ON GLUTATHIONE"Hopkins, et al., 54:527-563.

The Discovery of Glutathione by F. Gowland Hopkins and the Beginning of Biochemistry at Cambridge University
Robert D. Simoni, Robert L. Hill and Martha Vaughan

On Glutathione. II. A Thermostable Oxidation-Reduction System
 (Hopkins, F. G., and Dixon, M. (1922) J. Biol. Chem. 54, 527–563)

Sir Frederick Gowland Hopkins (1861–1947) was born in East Sussex, Great Britain. He founded the Department of Biochemistry (生物化學) at the University of Cambridge (劍橋) in 1914. In 1920, the estate of Sir William Dunn provided funds for the establishment of a School of Biochemistry, a Chair of Biochemistry, and a new building for the Department at Cambridge. The Sir William Dunn Institute of Biochemistry was opened in 1924, and Hopkins was the first Sir William Dunn Chair (subsequent occupants of the Dunn Chair at Cambridge were A. C. Chibnall, Sir Frank Young, Sir Hans Kornberg, and, at present, Tom L. Blundell). Hopkins focused his own research on "accessory food factors," later termed vitamins, and his interests shaped the directions of research in this distinguished department.

Among the many contributions Hopkins made is the discovery and characterization of glutathione that is described in this Journal of Biological Chemistry (JBC) Classic Paper. It had been recognized that glutathione underwent reversible oxidation-reduction, which involved a disulfide linkage between two molecules of GSH in GSSG. In this paper, Hopkins cites the discovery of "coferment" of alcoholic fermentation by Harden, Young, and Meyerhof for his discovery of the factors necessary for respiratory oxidations as well as for the method of simple extraction of tissues with water to identify the factors necessary for a biochemical process. After studying chopped muscle tissue extracted with water, Hopkins concluded that "When a tissue is washed until it has lost its power to reduce methylene blue, the subsequent addition of glutathione to a buffer solution in which the tissue residue is suspended restores reducing power." By using boiled tissue, he demonstrated that the system was heat-stable and is non-enzymatic.

Although the discovery of glutathione certainly ranks among the major discoveries in biochemistry, Hopkins is unfortunately remembered for his error regarding the structure of glutathione, which he had concluded was a dipeptide of glutamic acid and cysteine. The structure of glutathione was controversial for several years. In 1927, Hunter and Eagles described a product, isolated using the same procedure employed by Hopkins, that had significantly less sulfur per mass than Hopkins had reported and was possibly a tripeptide (1). After seeing a preprint version of the Hunter and Eagles paper provided by the Editors of JBC with permission of the authors, Hopkins responded that their preparation of glutathione was impure and reasserted that glutathione was a dipeptide (2). In 1929, after developing a new procedure for preparing crystalline glutathione, Hopkins recognized that" Hunter and Eagles were right in doubting that the substance is a simple dipeptide of glutamic acid and cysteine...." (3). He then showed that glutathione is indeed a tripeptide of glutamic acid, glycine, and cysteine. Although he did not determine the precise structure, he suggested it was Glu-Cys-Gly. (The structure of glutathione is, in fact,γ -l-glutamyl-l-cysteinylglycine). In reference to the mistake, Hopkins wrote that "The grave discomfort involved in making an admission of previous error is mitigated by the circumstances that I am now able to describe a method, not without special interest in itself, which with ease and rapidity separates from yeast and red blood cells a pure crystalline thiol compound with a.... tripeptide structure" (3).

View larger version:
In this pageIn a new window
Download as PowerPoint SlideFrederick G. Hopkins. Photo courtesy of the National Library of Medicine.

His error on the structure of glutathione has not been forgotten many decades later. Hopkins is more appropriately remembered, however, as a giant of biochemistry. He was knighted in 1925 and received the Nobel Prize in Physiology or Medicine in 1929. In 1936, a young undergraduate student, Max Perutz, left his native Vienna, with the rise in anti-Semitism, and moved to Cambridge. He was attracted to Hopkins's department and Hopkins's work on vitamins and enzymes. Perutz worked with John Desmond Bernal in the Cavendish Laboratory and began his historic crystallographic analysis of the structure of hemoglobin.

The American Society for Biochemistry and Molecular Biology, Inc.

References
1.
Hunter, G., and Eagles, B. A. (1927) J. Biol. Chem. 72,133FREE Full Text
2.
Hopkins, F. G. (1927) J. Biol. Chem. 72,185FREE Full Text
3.
Hopkins, F. G. (1929) J. Biol. Chem. 84,269FREE Full

Related articles
ARTICLE:
F. Gowland Hopkins andM. Dixon
ON GLUTATHIONE: II. A THERMOSTABLE OXIDATION-REDUCTION SYSTEM
J. Biol. Chem. 1922 54: 527-563.
Full Text (PDF)
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Glutathione (穀胱甘肽) metabolism in brain - Metabolic interaction between astrocytes (【生】星細胞) and neurons (神經細胞) in the defense against reactive oxygen species [2000](IR92)

Glutathione (穀胱甘肽) metabolism in brain - Metabolic interaction between astrocytes (【生】星細胞) and neurons (神經細胞) in the defense against reactive oxygen species [2000](IR92)

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Glutathione (穀胱甘肽) metabolism in brain
Metabolic interaction between astrocytes (【生】星細胞) and neurons (神經細胞) in the defense against reactive oxygen species

http://www3.interscience.wiley.com/journal/119181433/abstract?CRETRY=1&SRETRY=0
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European Journal of Biochemistry
Volume 267 Issue 16, Pages 4912 - 4916
Published Online: 25 Dec 2001

Glutathione (穀胱甘肽) metabolism in brain
Metabolic interaction between astrocytes (【生】星細胞) and neurons (神經細胞) in the defense against reactive oxygen species

Ralf Dringen, Jan M. Gutterer and Johannes Hirrlinger
Physiologisch-chemisches Institut der Universität, Tübingen, Germany (德國)
Correspondence to R. Dringen, Physiologisch-chemisches Institut der Universität, Hoppe-Seyler-Strasse 4, D-72076 Tübingen, Germany (德國).
Fax: +49 7071 295360, Tel.: +49 7071 2973334 , E-mail: ralf.dringen@uni-tuebingen.de

Copyright FEBS, 2000

KEYWORDS
astrocytes (【生】星細胞) • brain • glutathione (穀胱甘肽) • neurodegeneration • neurons (神經細胞)

ABSTRACT
The cells of the adult human brain consume ≈ 20% of the oxygen utilized by the body although the brain comprises only 2% of the body weight. Reactive oxygen species, which are produced continuously during oxidative metabolism, are generated at high rates within the brain. Therefore, the defense against the toxic effects of reactive oxygen species is an essential task within the brain. An important component of the cellular detoxification of reactive oxygen species is the antioxidant glutathione (穀胱甘肽). The main focus of this short review is recent results on Glutathione (穀胱甘肽) metabolism of brain astrocytes (【生】星細胞) and neurons (神經細胞) in culture. These two types of cell prefer different extracellular precursors for glutathione (穀胱甘肽). glutathione (穀胱甘肽) is involved in the disposal of exogenous peroxides by astrocytes (【生】星細胞) and neurons (神經細胞). In coculture astrocytes (【生】星細胞) protect neurons (神經細胞) against the toxicity of reactive oxygen species. One mechanism of this interaction is the supply by astrocytes (【生】星細胞) of glutathione (穀胱甘肽) precursors to neurons (神經細胞).

(Received 5 January 2000, accepted 25 February 2000)

DIGITAL OBJECT IDENTIFIER (DOI)
10.1046/j.1432-1327.2000.01597.x About DOI

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Protein Misfolding; Oxidatively stressed and damaged mitochondria, and free radicals [2009-06-30](IR90)

Protein Misfolding; Oxidatively stressed and damaged mitochondria, and free radicals [2009-06-30](IR90)

 

Mitochondria and Free Radicals

 

Any given cell has hundreds of mitochondria. This illustration shows two—a healthy mitochondrion and an oxidatively stressed and damaged one. The arrows indicate the movement of free radicals, which can spread easily from damaged mitochondria to other parts of the cell.

 

http://www.nia.nih.gov/NR/rdonlyres/1460469B-C224-4259-9004-A6FAABB5F71D/10861/03_mitochondria_lg.jpg

 

Oxidatively stressed and damaged mitochondria, and free radicals [2009-06-30](IR90) - with source URL.jpg

 

 

Protein Misfolding

http://www.nia.nih.gov/Alzheimers/Publications/Unraveling/Part3/causes.htm#ProteinMisfolding

 

Researchers have found that a number of devastating neurodegenerative diseases (for example, AD, Parkinson’s disease, dementia with Lewy bodies, frontotemporal lobar degeneration, Huntington’s disease, and prion diseases) share a key characteristic—protein misfolding.

 

When a protein is formed, it “folds” into a unique three-dimensional shape that helps it perform its specific function. This crucial process can go wrong for various reasons, and more commonly does go wrong in aging cells. As a result, the protein folds into an abnormal shape—it is misfolded. In AD, the misfolded proteins are beta-amyloid (the cleaved product of APP; see "From APP to Beta-Amyloid Plaques" for more on the formation of beta-amyloid) and a cleaved product of tau.

 

Normally, cells repair or degrade misfolded proteins, but if many of them are formed as part of age-related changes, the body’s repair and clearance process can be overwhelmed. Misfolded proteins can begin to stick together with other misfolded proteins to form insoluble aggregates. As a result, these aggregates can build up, leading to disruption of cellular communication, and metabolism, and even to cell death. These effects may predispose a person to AD or other neurodegenerative diseases.

 

Scientists do not know exactly why or how these processes occur, but research into the unique characteristics and actions of various misfolded proteins is helping investigators learn more about the similarities and differences across age-related neurodegenerative diseases. This knowledge may someday lead to therapies.

 

...

...

 

The Aging Process

Another set of insights about the cause of AD comes from the most basic of all risk factors—aging itself. Age-related changes, such as inflammation, may make AD damage in the brain worse. Because cells and compounds that are known to be involved in inflammation are found in AD plaques, some researchers think that components of the inflammatory process may play a role in AD.

 

Mitochondria and Free Radicals

Any given cell has hundreds of mitochondria. This illustration shows two—a healthy mitochondrion and an oxidatively stressed and damaged one. The arrows indicate the movement of free radicals, which can spread easily from damaged mitochondria to other parts of the cell.

 

Other players in the aging process that may be important in AD are free radicals, which are oxygen or nitrogen molecules that combine easily with other molecules (scientists call them “highly reactive”). Free radicals are generated in mitochondria, which are structures found in all cells, including neurons.

 

Mitochondria are the cell’s power plant, providing the energy a cell needs to maintain its structure, divide, and carry out its functions. Energy for the cell is produced in an efficient metabolic process. In this process, free radicals are produced. Free radicals can help cells in certain ways, such as fighting infection. However, because they are very active and combine easily with other molecules, free radicals also can damage the neuron’s cell membrane or its DNA. The production of free radicals can set off a chain reaction, releasing even more free radicals that can further damage neurons (see illustration "Mitochondria and Free Radicals"). This kind of damage is called oxidative damage. The brain’s unique characteristics, including its high rate of metabolism and its long-lived cells, may make it especially vulnerable to oxidative damage over the lifespan. The discovery that beta-amyloid generates free radicals in some AD plaques is a potentially significant finding in the quest for better understanding of AD as well as for other neurodegenerative disorders and unhealthy brain aging.

 

 

持續不斷的研究是一個國家或一個公司得以長期成功的關鍵因素 [2009-06-18]

持續不斷的研究是一個國家或一個公司得以長期成功的關鍵因素。
Continuing research is the enabling key factor to a nation or a company's long-term success.

湯偉晉 (WeiJin Tang) 親手寫於 西元 2009-06-18

2009-06-18

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Keywords:
持續不斷的研究是一個國家或一個公司得以長期成功的關鍵因素

Number of attached files: 
2

致癌空窗期 [2009-05-21](IR90)

致癌空窗期 [2009-05-21](IR90)

2009-05-21
短文的標題：
致癌空窗期

思緒或靈感的來源：
「報紙在 2009-05-21 以頭版的方式報導，[蕭萬長副總統] 因為得了肺腺癌，所以在 [台北_榮總] 動手術，切除肺臟左下方之部位。 沒有吸煙、沒有抽香菸，也沒有喝酒，又經常運動，也十分重視養生，為什麼會得癌症？」

短文的內容：
[致癌空窗期]

[GSH/GSSG 的比值] 暫時性地失去平衡，因為缺乏 [L-Cystetne (半胱胺酸)] 這種，在製造 [穀胱甘肽 (Glutathione)] 的過程中，最具關鍵性的胺基酸，所以細胞來不及製造出 GSH (還原型的 穀胱甘肽 (Glutathione))，也因此細胞在情急之下只好把 GSSG 排出細胞之外，也就無法再把 GSSG 回收並且轉換成 GSH 了。

DNA 的直徑 大約是 2 nm ( 2 奈米 )。
穀胱甘肽 (Glutathione) 的大小 大約是 2.6 nm ( 2.6 奈米 )。
[L-Cystetne (半胱胺酸)] 的大小 大約是 1.2 nm ( 1.2 奈米 )。

平常被保護在 [細胞核] 內之[染色體] 中的 [DNA]，必須在多次遭受到 [多重性的攻擊 (multiple hits)] 之後，才有可能從 [正常穩定的狀態] 而被 [自由基] 竄改成為 (而突變成) [會致癌的狀態]。 [DNA] 從 [正常穩定的狀態] 因為突變，而被更改成為是 [會致癌的狀態]，這段敘述，就幾乎等同於是說，你得了癌症了！

結論：
人不可以過勞，不管你是多麼地年輕。 一旦細胞內部的 redox defense system 失去了平衡，甚至於被瓦解了，而使得細胞，相對於 過量之自由基的攻擊，呈現出 [致癌空窗期] 的狀態，這樣就會使 細胞和 DNA 處於十分危險的狀態。 這也就是為什麼，長期重複性短暫過勞 (例如 長期工作壓力過大的人)，或者是短期過勞 (例如 跑 長程馬拉松 的選手) 的人容易發生突發性的健康風險。

湯偉晉 (WeiJin Tang) 親手原創性地寫作於 西元 2009-05-21

湯偉晉 先生
WeiJin Tang
電子郵件
WeiJin.Tang@gmail.com
行動電話
0958-227-243
中華民國_台北市_天母_臥龍崗

「喜樂的心是一帖良藥」
聖經中的箴言

「助人為快樂之本」
青年守則

「我的恩典夠你用」
聖經中的箴言

「神賜給我們的乃是剛強、仁愛、謹守的心。」
聖經中的箴言

「真正的愛可以遮掩一切的過錯」
湯偉晉 曾經在 基督教 的書籍中看到過，而記下來的一句話。

[多層次及多方位的思維模式] 是 [湯偉晉先生] 所使用的思維模式。

教育從來就不是中立的 [2009-05-10](IR90)

教育從來就不是中立的 [2009-05-10](IR90)

教育從來就不是中立的；它不是讓人得以自由，就是讓人在不知不覺之中成為奴隸，卻不自知。

湯偉晉 (WeiJin Tang) 寫於 西元 2009-05-10

Inspired by a western educator, (I'm not sure what exactly his name is)


2009-05-26

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TextOnImage_教育從來就不是中立的_[2009-05-10](IR90)_[2009-05-26].gif

Number of attached files: 
1

 

The Secret of Life and Death - a Scientific Approach (生老病死的秘密 - 從科學的觀點切入) [2009-05-06]

The Secret of Life and Death - a Scientific Approach  (生老病死的秘密 - 從科學的觀點切入) [2009-05-06]

The Secret of Life and Death - a Scientific Approach
生老病死的秘密 - 從科學的觀點切入

Title of the presentation WeiJin Tang (湯偉晉) presented to the 5070退休樂活論壇 at Taipei on May 6, 2009

Nitric Oxide and Peroxynitrite in Health and Disease (IR93)[2007]; 我們應該高度讚賞和尊崇，這些科學家的勤奮與努力，和他們既傑出又驚人的偉大貢獻。

April 14, 2009; 03:58:07 p.m. Taipei Time

Nitric Oxide and Peroxynitrite in Health and Disease (IR93)[2007]; 我們應該高度讚賞和尊崇，這些科學家的勤奮與努力，和他們既傑出又驚人的偉大貢獻。

We should highly appreciate and respect the diligent efforts and phenomenal contributions of these scientists.
(我們應該高度讚賞和尊崇，這些科學家的勤奮與努力，和他們既傑出又驚人的偉大貢獻。)

湯偉晉 (WeiJin Tang) 親手逐字地寫於 西元 2009-04-14


Nitric Oxide and Peroxynitrite in Health and Disease (IR93)[2007] 001.PNG
Nitric Oxide and Peroxynitrite in Health and Disease (IR93)[2007] 002.PNG
Nitric Oxide and Peroxynitrite in Health and Disease (IR93)[2007] 003.PNG
Nitric Oxide and Peroxynitrite in Health and Disease (IR93)[2007] 01.PNG
Nitric Oxide and Peroxynitrite in Health and Disease (IR94)[2007] 02.PNG
Progression of heart failure and the role of oxidative stress and peroxynitrite [2007](IR88).PNG

盡心盡力地教導自己的部屬，讓他們也可以像自己一樣地成長和茁壯。

盡心盡力地教導自己的部屬，讓他們也可以像自己一樣地成長和茁壯。


只要你是一個移動的目標，你的部屬將永遠追不上你。所以，請您務必盡心盡力，好好地教導和幫助您的部屬，讓他們可以與您一起成長和茁壯。

湯偉晉 (WeiJin Tang) 親手逐字地寫於 西元 2009-04-29

盡心盡力地教導自己的部屬，讓他們也可以像自己一樣地成長和茁壯。
Version 1.00.01; Last Updated on [2009-04-29-AM-00-23-14]

2009-04-29

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Keywords:
盡心盡力地教導自己的部屬，讓他們也可以像自己一樣地成長和茁壯。

Number of attached files: 
1

Chemical Biology of DNA Damage Associated with Inflammation - Problems and Prospects of Using DNA Lesions as Biomarkers of Oxidative and Nitrosative Stress [2006](IR90)

April 14, 2009; 03:20:22 p.m. Taipei Time

Chemical Biology of DNA Damage Associated with Inflammation - Problems and Prospects of Using DNA Lesions as Biomarkers of Oxidative and Nitrosative Stress [2006](IR90) 01.PNG
Chemical Biology of DNA Damage Associated with Inflammation - Problems and Prospects of Using DNA Lesions as Biomarkers of Oxidative and Nitrosative Stress [2006](IR90) 02.PNG
Chemical Biology of DNA Damage Associated with Inflammation - Problems and Prospects of Using DNA Lesions as Biomarkers of Oxidative and Nitrosative Stress [2006](IR90) 03.PNG

Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)_FNKWs_{hydrogen peroxide, H2O2}

Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)

Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)_FNKWs_{hydrogen peroxide, H2O2}
http://www.vascularpath.org/projects.htm

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Essentially all risk factors for atherosclerosis result in the enhanced generation of hydrogen peroxide in the vessel wall by the activation of membrane bound NADPH oxidases (NOX). The NADPH oxidases generate superoxide in the extracellular space that both inactivates nitric oxide and is dismutated into hydrogen peroxide by extracellular superoxide dismutase (ECSOD).

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(Memo Item created on January 15, 2009 02:33 PM)
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Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S.

http://www.vascularpath.org/projects.htm
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Home | Projects | Lab Members | Publications | Links | Biographical Sketch | Contact

Projects

Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. The laboratory is seeking to understand the biochemical processes resulting in atherosclerosis in order to combat this pervasive disease.

Atherosclerosis is characterized by the development of necrotic/lipid cores within the intima of arteries at particular sites in the circulation. These necrotic/lipid cores form in the setting of a pre-existing intimal hyperplasia, characterized by the proliferation of smooth muscle-like cells within the intima. The laboratory is investigating both the mechanisms of signal transduction responsible for the formation of the pre-atherosclerotic intimal hyperplasia, as well as the factors stimulating the formation of intimal necrotic/lipid cores. Signal Transduction with Hydrogen Peroxide in Vascular Cells

Essentially all risk factors for atherosclerosis result in the enhanced generation of hydrogen peroxide in the vessel wall by the activation of membrane bound NADPH oxidases (NOX). The NADPH oxidases generate superoxide in the extracellular space that both inactivates nitric oxide and is dismutated into hydrogen peroxide by extracellular superoxide dismutase (ECSOD). These low physiologic levels of hydrogen peroxide are mitogenic, stimulating vascular cell growth and proliferation.

The mechanisms by which low endogenous levels of hydrogen peroxide stimulate cellular proliferation are currently poorly understood. The laboratory is using proteomic approaches with cultured vascular cells to identify signal transduction pathways activated by low physiologic levels of hydrogen peroxide. One target protein identified is the nuclear pre-mRNA binding protein hnRNP-C. Low physiologic levels of hydrogen peroxide stimulate the hyperphosphorylation of the acidic C-terminal domain of hnRNP-C, resulting in diminished ability of the protein to bind mRNA. The effect is mediate by protein kinase CK1 Other groups have previously shown that hnRNP-C is hyperphosphorylated during mitosis, and that CK1 entry into the nucleus is required for cell cycle progression. Proteomic Analyses of Intimal Hyperplasia from Atherosclerosis-Prone and Atherosclerosis-Resistant Human Arteries

Pre-atherosclerotic intimal hyperplasia forms at branch sites both in arteries prone to develop atherosclerosis, such as the internal carotid and coronary arteries and also in vessels remarkably resistant to the formation of atherosclerosis, such as the internal thoracic artery and the distal ulnar artery. The structural variations in intimal hyperplasia that may facilitate the development of atherosclerosis have been unclear. Proteoglycans have been implicated as playing a direct role in atherosclerosis, both by binding and retaining lipoproteins in the vessel wall and by regulating cell growth. One project in the laboratory has been to analyze by mass spectrometry the extracellular proteoglycans present in pre-atherosclerotic intimal hyperplasia from atherosclerosis-prone arteries as well as atherosclerosis-resistant arteries. This project has revealed the proteoglycan composition of human intimal hyperplasia to be more complex than previously realized with eight distinct proteoglycans present: perlecan, versican, aggrecan, biglycan, decorin, fibromodulin, lumican, and prolargin. Importantly, while most of the proteoglycans are present at similar levels in the two arterial types, there is a selective enhanced deposition of lumican proteoglycan in the pre-atherosclerotic intimal hyperplasia from the atherosclerosis-prone artery compared with the intimal hyperplasia from the atherosclerosis-resistant artery. This data suggests that lumican may play a central role in the development of atherosclerotic lesions in humans, and may partly account for site-specific susceptibility to atherosclerosis. Home | Projects | Lab Members | Publications | Links | Biographical Sketch | Contact

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©2007 James R. Stone Lab - Department of Pathology - Massachusetts General Hospital

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2009-03-17

File Index: 0001
Original file name (原始的檔案名稱):
Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)_FNKWs_{hydrogen peroxide, H2O2} 01.PNG
GUID file name:
FN_A2CF01CC1B6F4534A8DADDFEC29A9CE5.PNG

File Index: 0002
Original file name (原始的檔案名稱):
Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)_FNKWs_{hydrogen peroxide, H2O2} 02.png
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File Index: 0003
Original file name (原始的檔案名稱):
Atherosclerosis is the principal cause of heart disease and a leading cause of stroke, making it the most common cause of death in the U.S. [2008](IR92)_FNKWs_{hydrogen peroxide, H2O2} 03.png
GUID file name:
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Keywords:
Hydrogen peroxide, increased, glutathione (GSH), L-Cysteine, Atherosclerosis (【醫學】動脈粥狀硬化), cardiovascular (【醫學】心血管性的), stroke (中風)

Number of attached files: 
3

The major determinants (決定因素) of GSH synthesis are the availability of cysteine, and the activity of the rate-limiting enzyme, g-glutamylcysteine synthetase (GCS)[1999](IR90)

 

The major determinants (決定因素) of GSH synthesis are the availability of cysteine, and the activity of the rate-limiting enzyme, g-glutamylcysteine synthetase (GCS)[1999](IR90)

 

Regulation of hepatic glutathione synthesis: current concepts and controversies SHELLY C. LU

USC Liver Disease Research Center, the Division of Gastrointestinal (胃腸的) and Liver Diseases, Department of Medicine, University of Southern California School of Medicine, Los Angeles, California 90033, USA

 

ABSTRACT

 

Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol (【生物學】細胞溶質) of all mammalian (哺乳動物(的)) cells in a tightly regulated manner. The major determinants (決定因素) of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, g-glutamylcysteine synthetase (GCS). In the liver, major factors that determine the availability of cysteine are diet, membrane transport activities of the three sulfur amino acids cysteine, cystine and methionine, and the conversion of methionine to cysteine via the trans-sulfuration pathway. Many conditions alter GSH level via changes in GCS activity and GCS gene expression. These include oxidative stress, activators of Phase II detoxifying enzymes, antioxidants, drug-resistant tumor cell lines, hormones, cell proliferation, and diabetes mellitus (糖尿病). Since the molecular cloning (複製) of GCS, much has been learned about the regulation of this enzyme. Both transcriptional and post-transcriptional mechanisms modulate the activity of this critical cellular enzyme.

 

Lu, S. C. Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J. 13, 1169-1183 (1999)

 

Key Words:

g-glutamylcysteine synthetase , cysteine availability , detoxification , antioxidant