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 Posted: Sat Nov 22, 2008 1:16 am Post subject: Pro-oxidant shift in glutathione redox state during aging. |
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Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1545-52. Epub 2008 Jul
4.Click here to read Links
Pro-oxidant shift in glutathione redox state during aging.
Rebrin I, Sohal RS.
Department of Pharmacology and Pharmaceutical Sciences, University
of Southern California, Los Angeles, California 90089, USA.
The GSH:GSSG ratio, which is the primary determinant of the
cellular redox state, becomes progressively more pro-oxidizing during
the aging process due to an elevation in the GSSG content and a
decline in the ability for de novo GSH biosynthesis. The K(m) of
glutamate-cysteine ligase (GCL), the rate-limiting enzyme in de novo
GSH biosynthesis, significantly increases during aging, which would
adversely affect the ability for rapid GSH biosynthesis, especially
under stressful conditions. Experimental studies suggest that age-
related accumulation of homocysteine, an intermediate in the trans-
sulfuration pathway, may be responsible for causing the loss of
affinity between GCL and its substrates. Over-expression of GCL has
been shown to prolong the life span of Drosophila by up to 50%,
suggesting that perturbations in glutathione metabolism play a causal
role in the aging process.
PMID: 18652861 [PubMed - in process]
PMCID: PMC2585506 [Available on 10/01/09]
Related Articles
* Age-associated perturbations in glutathione synthesis in
mouse liver. [Biochem J. 2007]
* ReviewGlutathione metabolism during aging and in Alzheimer
disease. [Ann N Y Acad Sci. 2004]
* (R)-alpha-lipoic acid reverses the age-related loss in GSH
redox status in post-mitotic tissues: evidence for increased cysteine
requirement for GSH synthesis. [Arch Biochem Biophys. 2004]
* Redox analysis of human plasma allows separation of pro-
oxidant events of aging from decline in antioxidant defenses. [Free
Radic Biol Med. 2002]
* ReviewMechanisms of glutamate cysteine ligase (GCL)
induction by 4-hydroxynonenal. [Free Radic Biol Med. 2005]
» See Reviews... | » See All...
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| Posted: Sat Nov 22, 2008 9:47 pm Post subject: Re: Pro-oxidant shift in glutathione redox state during agin |
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Is SAM-e to the rescue? As per this abstract it might help, at least
in mice vs. gram negative bacteria. So it may be a good idea to keep
some SAM-e in the medicine cabinet and give it a try.
Arbor
Lab Invest. 2008 Oct;88(10):1121-9. Epub 2008 Aug 11.
Changes in S-adenosylmethionine and GSH homeostasis during endotoxemia
in mice.Ko K, Yang H, Noureddin M, Iglesia-Ara A, Xia M, Wagner C,
Luka Z, Mato JM, Lu SC.
Department of Medicine, USC Research Center for Liver Diseases, USC-
UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck
School of Medicine USC, Los Angeles, CA 90033, USA.
Endotoxemia participates in the pathogenesis of many liver injuries.
Lipopolysaccharide (LPS) was shown to inactivate hepatic methionine
adenosyltransferase (MAT), the enzyme responsible for S-
adenosylmethionine (SAMe) biosynthesis. SAMe treatment was shown to
prevent the LPS-induced increase in tumor necrosis factor-alpha, which
may be one of its beneficial effects. SAMe is also an important
precursor of glutathione (GSH) and GSH was shown to ameliorate LPS-
induced hepatotoxicity. The aims of this work were to examine changes
in SAMe and GSH homeostasis during endotoxemia and the effect of SAMe.
Mice received SAMe or vehicle pretreatment followed by LPS and were
killed up to 18 h afterward. Unexpectedly, we found hepatic SAMe level
increased 67% following LPS treatment while S-adenosylhomocysteine
level fell by 26%, suggesting an increase in SAMe biosynthesis and/or
block in transmethylation. The mRNA and protein levels of MAT1A and
MAT2A were increased following LPS. However, despite increased MAT1A
expression, MAT activity remained inhibited 18 h after LPS. The major
methyltransferase that catabolizes hepatic SAMe is glycine N-
methyltransferase, whose expression fell by 65% following LPS. Hepatic
GSH level fell more than 50% following LPS, coinciding with a
comparable fall in the mRNA and protein levels of glutamate-cysteine
ligase (GCL) catalytic (GCLC) and modifier subunits (GCLM). SAMe
pretreatment prevented the fall in GCLC and attenuated the fall in
GCLM expression and GSH level. SAMe pretreatment prevented the LPS-
induced increase in plasma alanine transaminases levels but not the
LPS-induced increase in hepatic mRNA levels of proinflammatory
cytokines. It further enhanced LPS-induced increase in interleukin-10
mRNA level. Taken together, the hepatic response to LPS is to
upregulate MAT expression and inhibit SAMe utilization. GSH is
markedly depleted largely due to lower expression of GCL.
Interestingly, SAMe treatment prevented the fall in GCL and helped to
preserve the GSH store and prevent liver injury.
PMID: 18695670
On Nov 21, 3:16 pm, timoth...@my-deja.com wrote:
[quote]Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1545-52. Epub 2008 Jul
4.Click here to read Links
Pro-oxidant shift in glutathione redox state during aging.
Rebrin I, Sohal RS.
Department of Pharmacology and Pharmaceutical Sciences, University
of Southern California, Los Angeles, California 90089, USA.
The GSH:GSSG ratio, which is the primary determinant of the
cellular redox state, becomes progressively more pro-oxidizing during
the aging process due to an elevation in the GSSG content and a
decline in the ability for de novo GSH biosynthesis. The K(m) of
glutamate-cysteine ligase (GCL), the rate-limiting enzyme in de novo
GSH biosynthesis, significantly increases during aging, which would
adversely affect the ability for rapid GSH biosynthesis, especially
under stressful conditions. Experimental studies suggest that age-
related accumulation of homocysteine, an intermediate in the trans-
sulfuration pathway, may be responsible for causing the loss of
affinity between GCL and its substrates. Over-expression of GCL has
been shown to prolong the life span of Drosophila by up to 50%,
suggesting that perturbations in glutathione metabolism play a causal
role in the aging process.
PMID: 18652861 [PubMed - in process]
PMCID: PMC2585506 [Available on 10/01/09]
Related Articles
* Age-associated perturbations in glutathione synthesis in
mouse liver. [Biochem J. 2007]
* ReviewGlutathione metabolism during aging and in Alzheimer
disease. [Ann N Y Acad Sci. 2004]
* (R)-alpha-lipoic acid reverses the age-related loss in GSH
redox status in post-mitotic tissues: evidence for increased cysteine
requirement for GSH synthesis. [Arch Biochem Biophys. 2004]
* Redox analysis of human plasma allows separation of pro-
oxidant events of aging from decline in antioxidant defenses. [Free
Radic Biol Med. 2002]
* ReviewMechanisms of glutamate cysteine ligase (GCL)
induction by 4-hydroxynonenal. [Free Radic Biol Med. 2005]
» See Reviews... | » See All...
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Guest
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| Posted: Sat Nov 22, 2008 9:52 pm Post subject: Re: Pro-oxidant shift in glutathione redox state during agin |
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I wrote:On Nov 22, 11:47 am, soowhatdouth...@hotmail.com wrote:
[quote]Is SAM-e to the rescue? As per this abstract it might help, at least
in mice vs. gram negative bacteria. So it may be a good idea to keep
some SAM-e in the medicine cabinet and give it a try.
Arbor
[/quote]
Sorry, I should have said: Is SAM-e to the rescue at least for the
young (which I am not but I am going to try it anyway)?
Arbor
[quote]
Lab Invest. 2008 Oct;88(10):1121-9. Epub 2008 Aug 11.
Changes in S-adenosylmethionine and GSH homeostasis during endotoxemia
in mice.Ko K, Yang H, Noureddin M, Iglesia-Ara A, Xia M, Wagner C,
Luka Z, Mato JM, Lu SC.
Department of Medicine, USC Research Center for Liver Diseases, USC-
UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck
School of Medicine USC, Los Angeles, CA 90033, USA.
Endotoxemia participates in the pathogenesis of many liver injuries.
Lipopolysaccharide (LPS) was shown to inactivate hepatic methionine
adenosyltransferase (MAT), the enzyme responsible for S-
adenosylmethionine (SAMe) biosynthesis. SAMe treatment was shown to
prevent the LPS-induced increase in tumor necrosis factor-alpha, which
may be one of its beneficial effects. SAMe is also an important
precursor of glutathione (GSH) and GSH was shown to ameliorate LPS-
induced hepatotoxicity. The aims of this work were to examine changes
in SAMe and GSH homeostasis during endotoxemia and the effect of SAMe.
Mice received SAMe or vehicle pretreatment followed by LPS and were
killed up to 18 h afterward. Unexpectedly, we found hepatic SAMe level
increased 67% following LPS treatment while S-adenosylhomocysteine
level fell by 26%, suggesting an increase in SAMe biosynthesis and/or
block in transmethylation. The mRNA and protein levels of MAT1A and
MAT2A were increased following LPS. However, despite increased MAT1A
expression, MAT activity remained inhibited 18 h after LPS. The major
methyltransferase that catabolizes hepatic SAMe is glycine N-
methyltransferase, whose expression fell by 65% following LPS. Hepatic
GSH level fell more than 50% following LPS, coinciding with a
comparable fall in the mRNA and protein levels of glutamate-cysteine
ligase (GCL) catalytic (GCLC) and modifier subunits (GCLM). SAMe
pretreatment prevented the fall in GCLC and attenuated the fall in
GCLM expression and GSH level. SAMe pretreatment prevented the LPS-
induced increase in plasma alanine transaminases levels but not the
LPS-induced increase in hepatic mRNA levels of proinflammatory
cytokines. It further enhanced LPS-induced increase in interleukin-10
mRNA level. Taken together, the hepatic response to LPS is to
upregulate MAT expression and inhibit SAMe utilization. GSH is
markedly depleted largely due to lower expression of GCL.
Interestingly, SAMe treatment prevented the fall in GCL and helped to
preserve the GSH store and prevent liver injury.
PMID: 18695670
On Nov 21, 3:16 pm, timoth...@my-deja.com wrote:
Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1545-52. Epub 2008 Jul
4.Click here to read Links
Pro-oxidant shift in glutathione redox state during aging.
Rebrin I, Sohal RS.
Department of Pharmacology and Pharmaceutical Sciences, University
of Southern California, Los Angeles, California 90089, USA.
The GSH:GSSG ratio, which is the primary determinant of the
cellular redox state, becomes progressively more pro-oxidizing during
the aging process due to an elevation in the GSSG content and a
decline in the ability for de novo GSH biosynthesis. The K(m) of
glutamate-cysteine ligase (GCL), the rate-limiting enzyme in de novo
GSH biosynthesis, significantly increases during aging, which would
adversely affect the ability for rapid GSH biosynthesis, especially
under stressful conditions. Experimental studies suggest that age-
related accumulation of homocysteine, an intermediate in the trans-
sulfuration pathway, may be responsible for causing the loss of
affinity between GCL and its substrates. Over-expression of GCL has
been shown to prolong the life span of Drosophila by up to 50%,
suggesting that perturbations in glutathione metabolism play a causal
role in the aging process.
PMID: 18652861 [PubMed - in process]
PMCID: PMC2585506 [Available on 10/01/09]
Related Articles
* Age-associated perturbations in glutathione synthesis in
mouse liver. [Biochem J. 2007]
* ReviewGlutathione metabolism during aging and in Alzheimer
disease. [Ann N Y Acad Sci. 2004]
* (R)-alpha-lipoic acid reverses the age-related loss in GSH
redox status in post-mitotic tissues: evidence for increased cysteine
requirement for GSH synthesis. [Arch Biochem Biophys. 2004]
* Redox analysis of human plasma allows separation of pro-
oxidant events of aging from decline in antioxidant defenses. [Free
Radic Biol Med. 2002]
* ReviewMechanisms of glutamate cysteine ligase (GCL)
induction by 4-hydroxynonenal. [Free Radic Biol Med. 2005]
» See Reviews... | » See All...
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trigonometry1972@gmail.co
Guest
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| Posted: Sun Nov 23, 2008 8:00 am Post subject: Re: Pro-oxidant shift in glutathione redox state during agin |
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Betaine, lecithin, and choline could also be useful in maintaining
the GSH:GSSG ratio. Anyway these provide lower cost
avenues to the same goal.
1: Am J Clin Nutr. 2007 Mar;85(3):702-8.
Choline-related supplements improve abnormal
plasma methionine-homocysteine metabolites and glutathione
status in children with cystic fibrosis.
Innis SM, Davidson AG, Melynk S, James SJ.
Department of Paediatrics,
University of British Columbia,
Vancouver, BC, Canada.
sinnis@cw.bc.ca
BACKGROUND:
Liver triacylglycerol accumulation and oxidative
stress are common in cystic fibrosis (CF) and
also occur in choline deficiency. Previously, we showed
an association between elevated plasma homocysteine,
reduced ratios of S-adenosylmethionine to S-adenosylhomocysteine
(SAM:SAH) and of phosphatidylcholine to phosphatidylethanolamine,
and phospholipid malabsorption
in children with CF.
OBJECTIVE:
he objective was to address a possible relation
between altered methionine-homocysteine metabolism and choline
metabolism in children with CF.
DESIGN:
Children with CF were assigned without bias to
supplementation with
2 g lecithin/d (n = 13),
2 g choline/d (n = 12), or
3 g betaine/d (n = 10) for 14 d.
Plasma concentrations of methionine, adenosine,
cysteine, cysteinyl-glycine, glutathione, glutathione
disulfide (GSSG), and fatty acids; SAM:SAH; and red
blood cell phospholipids were measured within each group
of children with CF before and after supplementation.
Plasma from healthy children without CF (n = 15) was
analyzed to obtain reference data. RESULTS:
Children with CF had higher plasma homocysteine, SAH,
and adenosine and lower methionine, SAM:SAH, and
glutathione:GSSG than did children without CF.
Supplementation with lecithin, choline, or betaine
resulted in a significant increase in plasma methionine,
SAM, SAM:SAH, and glutathione:GSSG and a decrease
in SAH (n = 35). Supplementation with choline or
betaine was associated with a significant decrease
in plasma SAH and an increase in SAM:SAH, methionine,
and glutathione:GSSG. Supplementation with lecithin or
choline also increased plasma
methionine and SAM.
CONCLUSION:
We showed that dietary supplementation with
choline-related compounds improves the low SAM:SAH
and glutathione redox balance
in children with CF.
PMID: 17344490 |
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David
Guest
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| Posted: Sun Nov 23, 2008 5:22 pm Post subject: Re: Pro-oxidant shift in glutathione redox state during agin |
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If anything, I>d expect that dumping more SAMe into the system would
*increase* homocysteine levels even as it raises GSH.
Seems like a much wiser strategy would be to take betaine (TMG) and
adequate folate/B12 to maintain low homocysteine levels while also
taking n-acetylcysteine, a proven supplement that significantly
increases GSH. |
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