Re: Glutathione depletion in autism and the spin-off for CFS

[Guest guest]

I read this and immediately thought of Bell's pediatric CFIDS

cases. Did they present as autism as well as CFIDS?

Helen

>

> Hi, all.

>

> As regular readers on this list will know, I have been emphasizing

> the importance of glutathione depletion in the pathogenesis of CFS

> for several years now, since Dr. Cheney first reported it in

> public talks early in 1999.

>

> I want to notify everyone here about some developments that I think

> are significant in this regard.

>

> About two weeks ago, on April 2, Dr. S. Jill of the

University

> of Arkansas gave a talk at the Experimental Biology 2005 conference

> in San Diego on the research she and he coworkers have done on

> autism. They have found that in kids with autism, the reduced form

> of glutathione is depleted by about 80%. This was reported in a

> paper they published earlier. In addition, they reported that they

> have now looked for single nucleotide polymorphisms (SNPs) in genes

> that may account for this glutathione depletion. They found that

in

> kids with autism, SNPs were elevated in the genes coding for the

> enzymes catechol-O-methyltransferase (COMT), glutathione-S-

> transferase M1, and transcobalamin II.

>

> Dr. suggested that autism occurs when there is a combination

> of a certain genetic makeup and an environmental insult that

> interacts with it. In autism, this environmental insult may be

> mercury, as from the thimerosol in vaccines, which many autism

> parents have suspected to be involved in causing autism in their

> children. As most readers will know, the body uses glutathione to

> rid itself of mercury. In children who are less able to maintain

> their glutathione levels for genetic reasons, mercury may be more

> toxic.

>

> I think that this is very exciting. I think that there could very

> well turn out to be many parallels between autism and CFS. The

> difference may be that autism occurs when glutathione depletion

> occurs early in life, while CFS occurs later in life, after the

> brain has had a chance to develop.

>

> I think that CFS research will benefit from these developments in

> autism. This talk got wide news coverage around the world. The

> autism parents are highly motivated, and many have resources. They

> are politically organized and capable of exerting considerable

> clout. I expect an increase to occur in research into glutathione

> depletion and into testing for relevant SNPs. I think this can

only

> help CFS research, since I believe that glutathione depletion is

> very important in CFS as well.

>

> All this is happening at the same time that a breakthrough has

> occurred in cystic fibrosis research that also involves glutathione

> (by Hudson at BYU in Utah). In cystic fibrosis, it appears

> that cells have difficulty in exporting glutathione. There is

> another highly motivated set of parents associated with this

> disease, and I expect that they will also be promoting research

into

> glutathione.

>

> We all know how difficult it has been to get scientific interest

and

> funding for research into CFS. I think we are now about to benefit

> from spin-offs from research into these other diseases. I think

> that this is a very interesting turn of events.

>

> Rich

[Guest guest]

this is a truly great post.

We are real lucky to have you here, Rich. I learn so much reading

your posts, and more importantly, they renew my hope that all our

suffering actually means something, may be of help to others if only

we can untangle its riddles.

This is a real gift.

Thanks,

>

> Hi, all.

>

> As regular readers on this list will know, I have been emphasizing

> the importance of glutathione depletion in the pathogenesis of CFS

> for several years now, since Dr. Cheney first reported it in

> public talks early in 1999.

>

> I want to notify everyone here about some developments that I

think

> are significant in this regard.

>

> About two weeks ago, on April 2, Dr. S. Jill of the

University

> of Arkansas gave a talk at the Experimental Biology 2005

conference

> in San Diego on the research she and he coworkers have done on

> autism. They have found that in kids with autism, the reduced

form

> of glutathione is depleted by about 80%. This was reported in a

> paper they published earlier. In addition, they reported that

they

> have now looked for single nucleotide polymorphisms (SNPs) in

genes

> that may account for this glutathione depletion. They found that

in

> kids with autism, SNPs were elevated in the genes coding for the

> enzymes catechol-O-methyltransferase (COMT), glutathione-S-

> transferase M1, and transcobalamin II.

>

> Dr. suggested that autism occurs when there is a combination

> of a certain genetic makeup and an environmental insult that

> interacts with it. In autism, this environmental insult may be

> mercury, as from the thimerosol in vaccines, which many autism

> parents have suspected to be involved in causing autism in their

> children. As most readers will know, the body uses glutathione to

> rid itself of mercury. In children who are less able to maintain

> their glutathione levels for genetic reasons, mercury may be more

> toxic.

>

> I think that this is very exciting. I think that there could very

> well turn out to be many parallels between autism and CFS. The

> difference may be that autism occurs when glutathione depletion

> occurs early in life, while CFS occurs later in life, after the

> brain has had a chance to develop.

>

> I think that CFS research will benefit from these developments in

> autism. This talk got wide news coverage around the world. The

> autism parents are highly motivated, and many have resources.

They

> are politically organized and capable of exerting considerable

> clout. I expect an increase to occur in research into glutathione

> depletion and into testing for relevant SNPs. I think this can

only

> help CFS research, since I believe that glutathione depletion is

> very important in CFS as well.

>

> All this is happening at the same time that a breakthrough has

> occurred in cystic fibrosis research that also involves

glutathione

> (by Hudson at BYU in Utah). In cystic fibrosis, it

appears

> that cells have difficulty in exporting glutathione. There is

> another highly motivated set of parents associated with this

> disease, and I expect that they will also be promoting research

into

> glutathione.

>

> We all know how difficult it has been to get scientific interest

and

> funding for research into CFS. I think we are now about to

benefit

> from spin-offs from research into these other diseases. I think

> that this is a very interesting turn of events.

>

> Rich

[Guest guest]

Rich,

The intimate relationship between GSH and inflammation is well

established and appears to be reciprocal.

Below is an interesting abstract regarding phase II response and the

endogenous nuclear factor E2-related factor 2 (Nrf2). Do a lit

search on Nrf2, you'll appreciate it.

Note that Nrf2 upregulates numerous cytoprotective genes including

the ones expressing glutathione-S-transferases. As they discuss,

this presents a therapeutic approach for treating chronic

inflammation. This therapy significantly increases intracellular

GSH and would be a good adjunct to GSH precursor supplementation.

I'm currently investigating some promising activators of Nrf2/ARE

pathway.

Curr Pharm Des. 2004;10(8):879-91.

Induction of cytoprotective genes through Nrf2/antioxidant response

element pathway: a new therapeutic approach for the treatment of

inflammatory diseases.

Chen XL, Kunsch C.

Discovery Research, AtheroGenics, Inc., 8995 Westside Parkway,

Alpharetta, GA 30004, USA. xchen@...

In the last decade, it has become recognized that reactive oxygen

species (ROS) play important roles in the multiple biological

processes involved in the pathophysiology of chronic inflammation

such as cell proliferation, adhesion molecule expression, cytokine

and chemoattractant production and matrix metalloproteinase

generation. Intracellular redox homeostasis is maintained by

balancing the production of ROS with their removal through cellular

antioxidant defense systems. The antioxidant response element (ARE)

is a cis-acting DNA regulatory element located in the regulatory

regions of multiple genes including phase II detoxification enzymes

as well as antioxidant proteins including glutathione-S-

transferases, NAD(P)H:quinone oxidoreductase-1, gamma-

glutamylcysteine synthase, ferritin, and heme oxygenase-1. Nrf2 is

the primary transcription factor that binds to the ARE, and through

heterodimerization with other leucine-zipper containing

transcription factors, activates the expression of these genes. It

is evident that activation of ARE-regulated genes contributes to the

regulation of cellular antioxidant defense systems. More

importantly, there is a growing body of evidence suggesting that

modulation of these cytoprotective genes has profound effects on

immune and inflammatory responses. Activation of cytoprotective

Nrf2/ARE-regulated genes can suppress inflammatory responses,

whereas decreased expression of these genes results in autoimmune

disease and enhanced inflammatory responses to oxidant insults.

Thus, coordinate induction of cytoprotective genes through Nrf2/ARE

pathway may represent a novel therapeutic approach for the treatment

of immune and inflammatory diseases.

PMID: 15032691

[Guest guest]

Here's a nice review.

Note the intimate relationship between Nrf2, NF-kappaB, and

PPARgamma. We simply can't overlook these important interactions.

IMO, this is why successful therapies for A-CIDs and other CIDs must

be comprehensive and why focusing on one facet such as ATII, Vit D,

or GSH, won't be very productive.

Annu Rev Pharmacol Toxicol. 2005;45:51-88.

Glutathione transferases.

JD, Flanagan JU, Jowsey IR.

Biomedical Research Center, Ninewells Hospital & Medical School,

University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.

john.hayes@...

This review describes the three mammalian glutathione transferase

(GST) families, namely cytosolic, mitochondrial, and microsomal GST,

the latter now designated MAPEG. Besides detoxifying electrophilic

xenobiotics, such as chemical carcinogens, environmental pollutants,

and antitumor agents, these transferases inactivate endogenous

alpha,beta-unsaturated aldehydes, quinones, epoxides, and

hydroperoxides formed as secondary metabolites during oxidative

stress. These enzymes are also intimately involved in the

biosynthesis of leukotrienes, prostaglandins, testosterone, and

progesterone, as well as the degradation of tyrosine. Among their

substrates, GSTs conjugate the signaling molecules 15-deoxy-delta

(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with

glutathione, and consequently they antagonize expression of genes

trans-activated by the peroxisome proliferator-activated receptor

gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor

2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene

expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic

human GST exhibit genetic polymorphisms and this variation can

increase susceptibility to carcinogenesis and inflammatory disease.

Polymorphisms in human MAPEG are associated with alterations in lung

function and increased risk of myocardial infarction and stroke.

Targeted disruption of murine genes has demonstrated that cytosolic

GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins

have proinflammatory activities. Furthermore, knockout of mouse

GSTA4 and GSTZ1 leads to overexpression of transferases in the

Alpha, Mu, and Pi classes, an observation suggesting they are part

of an adaptive mechanism that responds to endogenous chemical cues

such as 4-hydroxynonenal and tyrosine degradation products.

Consistent with this hypothesis, the promoters of cytosolic GST and

MAPEG genes contain antioxidant response elements through which they

are transcriptionally activated during exposure to reaction

acceptors and oxidative stress.

PMID: 15822171 [PubMed - in process]

>

> Rich,

>

> The intimate relationship between GSH and inflammation is well

> established and appears to be reciprocal.

>

> Below is an interesting abstract regarding phase II response and

the

> endogenous nuclear factor E2-related factor 2 (Nrf2). Do a lit

> search on Nrf2, you'll appreciate it.

>

> Note that Nrf2 upregulates numerous cytoprotective genes including

> the ones expressing glutathione-S-transferases. As they discuss,

> this presents a therapeutic approach for treating chronic

> inflammation. This therapy significantly increases intracellular

> GSH and would be a good adjunct to GSH precursor supplementation.

>

> I'm currently investigating some promising activators of Nrf2/ARE

> pathway.

>

[Guest guest]

Hi, Helen.

As far as I know, they did not. He reported that he rarely saw

sudden onset CFS in children younger than ten. He saw gradual onset

CFS at ages between five and ten. I believe that the cases Dr. Bell

treated were generally in children who were older than the ages at

which autism usually shows up, which is up to about three.

Rich

>

> I read this and immediately thought of Bell's pediatric

CFIDS

> cases. Did they present as autism as well as CFIDS?

>

> Helen