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TNF-alpha inhibits methioinine synthase transcription (is this the real culprit?)

FunkOdyssey

Senior Member
Messages
144
Mainstream autism doctors are coming around to XMRV and contributing useful perspectives:

More Evidence TNF-alpha Allows Viral Persistence

Dr. Jeff Bradstreet MD on 3/21/2011 said:
This comment came on one of my think tank blogs from researcher and professor Dick Deth:

“Viruses such as XMRV are suppressed by methylation, and the enzyme methionine synthase is a master controller of methylation. We observed very powerful and rapid inhibition of methionine synthase (MS) transcription by TNF-alpha (>90% decrease of MS mRNA). An examination of the promoter region of methionine synthase revealed a consensus site for NF-kappa-B binding which overlaps the normally promotional AP-1 site. Thus we can hypothesize that TNF-alpha decreases methylation activity via NF-kappa-B. This decrease will augment viral persistence and replication. Notably, MS is very sensitive to oxidative stress, implying that oxidative stress, initiated by any number of provocations, would increase susceptibility to viral infection. Persistent viral infection could in turn prolong/delay recovery from oxidative stress, leading to a persistent oxidative stress and persistent v (a self-reinforcing relationship). In other words we normally recover from an oxidative stress-producing event, but the presence of a viral infection can turn this into a chronic condition…”

This is exactly what we are observing in numerous conditions including XMRV, Autism and ME/CFS. The good news is these conditions can be treated.

This suggests that rather than some vague voodoo explanation that B12 is hijacked by toxins, the real culprit behind the decreased methionine synthase activity in our condition is elevated TNF-alpha.

Not to imply that B12/folate do not work to stimulate methionine synthase activity, because they clearly seem to, but this information suggests an alternate approach may exist: TNF-a inhibition. This can be done in a safe/moderate fashion (unlike anti-TNF antibody drugs) using pentoxifylline and various supplements.
 

dannybex

Senior Member
Messages
3,561
Location
Seattle
This suggests that rather than some vague voodoo explanation that B12 is hijacked by toxins, the real culprit behind the decreased methionine synthase activity in our condition is elevated TNF-alpha.

Not to imply that B12/folate do not work to stimulate methionine synthase activity, because they clearly seem to, but this information suggests an alternate approach may exist: TNF-a inhibition. This can be done in a safe/moderate fashion (unlike anti-TNF antibody drugs) using pentoxifylline and various supplements.

I'm no scientist at all, but could it be that TNF-alpha elevated in response to the various toxins released by the many different bacterial, viral and/or fungal infections that proliferate -- and once those are brought under control by balancing/strengthening immune function (starting in the gut?) then TNF-alpha will be reduced...?

Here's another link:

http://microbialinfluence.com/NFKB.html

d.
 

FunkOdyssey

Senior Member
Messages
144
Oh definitely, the TNF-a is elevated for a reason, and that is in response to an infection. But if the inhibition of methionine synthase activity by TNF-a is part of a vicious cycle which maintains the infection, then TNF-a inhibition may represent an effective intervention.
 
C

Cloud

Guest
My TNFA was 496 and then dropped to <14 after 6 months of AV tx. Normal levels: <27.
xmrv+
 

FunkOdyssey

Senior Member
Messages
144
My TNFA was 496 and then dropped to <14 after 6 months of AV tx. Normal levels: <27.
xmrv+

Wow, nice Cloud. What viruses were you positive for (besides XMRV) and what drug(s)/dose were you on for anti-viral treatment?
 
C

Cloud

Guest
Wow, nice Cloud. What viruses were you positive for (besides XMRV) and what drug(s)/dose were you on for anti-viral treatment?

I was on Vistide for CMV. It may also have helped to put the EBV back into remission. I am HHV6&7 negative, and have no other diagnosed infections (other than xmrv). Vistide is given IV. The dose is calculated by weight. I was on the regimen for 1 year exactly, but most change (labs, symptoms, etc.) happened by the 6 month mark. I also suspect that the Tx hit some undiagnosed enteroviruses because my GI system started functioning better as well.

My point being that since Vistide has no effect on xmrv, and it caused my TNFA to drop dramatically to normal levels, it seems unlikely xmrv was in any way responsible for my elevated TNFA.
 

Joopiter76

Senior Member
Messages
154
My TNFa isn t very high and I have had very severe CFS, now on recovery I guess. Methionine Synthase is very sensitive and can be blocked by any kind of oxidative stress, glutathione defency, nitric oxide nitrous oxide, heavy metals, mycotoxins, there are studies to all these and I guess there is much much more that can block methionine synthase activity. But what I wonder and maybe Rich can answer this is, why there is no megaloblastic anaemia in CFS when methionine synthase is blocked. It should be acording tho this study they say it. "severe inhibition of methionine synthase results in the development of megaloblastic anemia" http://www.fasebj.org/content/4/5/1450.short
 

Vegas

Senior Member
Messages
577
Location
Virginia
RE: Megaloblastic anemia

My TNFa isn t very high and I have had very severe CFS, now on recovery I guess. Methionine Synthase is very sensitive and can be blocked by any kind of oxidative stress, glutathione defency, nitric oxide nitrous oxide, heavy metals, mycotoxins, there are studies to all these and I guess there is much much more that can block methionine synthase activity. But what I wonder and maybe Rich can answer this is, why there is no megaloblastic anaemia in CFS when methionine synthase is blocked. It should be acording tho this study they say it. "severe inhibition of methionine synthase results in the development of megaloblastic anemia" http://www.fasebj.org/content/4/5/1450.short

Long before I had severe fatigue, at a time that I had mostly brain fog and p.e.m., my labs indicated I had megaloblastic anemia. This seems to have been an "early" finding, as the labs no longer reflect this condition. Unfortunately despite my family history of pernicious anemia and confirmatory labs, my doctors never said a thing about it.
 

richvank

Senior Member
Messages
2,732
My TNFa isn t very high and I have had very severe CFS, now on recovery I guess. Methionine Synthase is very sensitive and can be blocked by any kind of oxidative stress, glutathione defency, nitric oxide nitrous oxide, heavy metals, mycotoxins, there are studies to all these and I guess there is much much more that can block methionine synthase activity. But what I wonder and maybe Rich can answer this is, why there is no megaloblastic anaemia in CFS when methionine synthase is blocked. It should be acording tho this study they say it. "severe inhibition of methionine synthase results in the development of megaloblastic anemia" http://www.fasebj.org/content/4/5/1450.short

The thing that is actually the immediate or proximal cause of the megaloblastic anemia is a depletion in the cells of the bone marrow of the coenzyme forms of folate that are needed in the synthesis of DNA. I think it is possible to have inhibition of methionine synthase, and still have sufficient levels of these folate forms in the bone marrow cells if folate is coming in from the diet or supplementation or is being produced by bacteria in the gut, or a combination of these sources.

My observation from the test data I have received from various people is that some who test positive for a partial methylation cycle block do have large red blood cells (perhaps still within the reference range for CMV) and others do not. My guess is that those who don't have large red blood cells must have more folate in their bone marrow cells than those who don't.

Best regards,

Rich
 

richvank

Senior Member
Messages
2,732
This suggests that rather than some vague voodoo explanation that B12 is hijacked by toxins, the real culprit behind the decreased methionine synthase activity in our condition is elevated TNF-alpha.

Not to imply that B12/folate do not work to stimulate methionine synthase activity, because they clearly seem to, but this information suggests an alternate approach may exist: TNF-a inhibition. This can be done in a safe/moderate fashion (unlike anti-TNF antibody drugs) using pentoxifylline and various supplements.

Hi, Funk.

I can understand that B12 hijacking by toxins might sound "vague" and "voodoo," but there is actually support in the research literature for this notion:


Chem Res Toxicol. 2004 Dec;17(12):1562-7.
A new role for glutathione: protection of vitamin B12 from depletion by xenobiotics.

Watson WP, Munter T, Golding BT.

Syngenta Central Toxicology Laboratory, Alderley Park, Cheshire, SK10 4TJ, United Kingdom. william.watson@syngenta.com
Abstract

NADPH in microsomes reduces the hydroxocob(III)alamin form of vitamin B12 to cob(II)alamin and the supernucleophilic cob(I)alamin, which are both highly reactive toward xenobiotic epoxides formed by mammalian metabolism of dienes such as the industrially important chemicals chloroprene and 1,3-butadiene. With styrene, the metabolically formed styrene oxide is reactive toward cob(I)alamin but not cob(II)alamin. Such reactions in humans could lead to vitamin B12 deficiency, which is implicated in pernicious anemia, cancer, and degenerative diseases. However, glutathione inhibits the reduction of hydroxocob(III)alamin by formation of the 1:1 complex glutathionylcobalamin. This blocks reactions of the cobalamins with metabolically formed epoxides. The interaction between glutathione and vitamin B12 could protect against diseases related to vitamin B12 depletion.

PMID: 15606130


Nevertheless, I welcome Dick Deth's comment on the impact of TNF alpha on methionine synthase. I have thought for a long time, based on input from a large number of PWMEs/PWCs about the circumstances preceding their onsets, over the course of the past 15 years during which I have been studying ME/CFS, that there are many routes into this disorder. I think the fact that high dosages of B12 combined with active folates do help many people does argue that a functional depletion of B12 is involved in the pathophysiology of this disorder. I suppose it's possible that if TNF alpha is blocking methionine synthase, the high-dose B12 somehow counteracts that. Hopefully, time will tell. I'm not in love with B12 hijacking by toxins, but it seems to fit the available evidence so far.

Best regards,

Rich
 
C

Cloud

Guest
My MCV labs (red blood cell morphology) have always shown slightly enlarged rbc's.
 

aquariusgirl

Senior Member
Messages
1,732
funkodyssey (i think it was you who posted this).. can you say which site you saw the bradstreet comment on?
thanks
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Long before I had severe fatigue, at a time that I had mostly brain fog and p.e.m., my labs indicated I had megaloblastic anemia. This seems to have been an "early" finding, as the labs no longer reflect this condition. Unfortunately despite my family history of pernicious anemia and confirmatory labs, my doctors never said a thing about it.

Hi Vegas,

I had an experience a few years ago that may be relevant. My internist greeted me with the news that I no longer was being alerted for MCV. I had been sent the details and had observed that my MCV was unchanged. What had happened is that the alert level had been changed from >97 to >100. I called the lab and asked about it. I was told that it reflected the change in average MCV. Elevated MCV has now become NORMAL.
 

FunkOdyssey

Senior Member
Messages
144
Nevertheless, I welcome Dick Deth's comment on the impact of TNF alpha on methionine synthase. I have thought for a long time, based on input from a large number of PWMEs/PWCs about the circumstances preceding their onsets, over the course of the past 15 years during which I have been studying ME/CFS, that there are many routes into this disorder. I think the fact that high dosages of B12 combined with active folates do help many people does argue that a functional depletion of B12 is involved in the pathophysiology of this disorder. I suppose it's possible that if TNF alpha is blocking methionine synthase, the high-dose B12 somehow counteracts that. Hopefully, time will tell. I'm not in love with B12 hijacking by toxins, but it seems to fit the available evidence so far.

Best regards,

Rich

Thanks for the reply Rich. I didn't mean to insult by use of the word voodoo. I just feel like the relationship between TNF-a and methionine synthase seems a little more concrete and plausible given the elevated TNF-a frequently seen in this disease. If B12/Folate corrects it, it may not matter what the cause was.

I suppose it is also possible that suppressing TNF-a could have negative consequences if the elevated levels were not pathological but actually necessary for control of infections.
 

Vegas

Senior Member
Messages
577
Location
Virginia
Hi Vegas,

I had an experience a few years ago that may be relevant. My internist greeted me with the news that I no longer was being alerted for MCV. I had been sent the details and had observed that my MCV was unchanged. What had happened is that the alert level had been changed from >97 to >100. I called the lab and asked about it. I was told that it reflected the change in average MCV. Elevated MCV has now become NORMAL.

interesting. I had normal MCV & MCH, but high MCHC...although I'm not sure about the significance of this.
 

aquariusgirl

Senior Member
Messages
1,732
I just got my TNF alpha tested with VIPdx. Result was <14.. Normal is <27.
I do wonder if it was elevated at the beginning of my illness, but this is the first time I've tested, so who knows.
Point is, it's normal now.
Also, I just read this Richard Deth paper where he suggests chronic alcoholism leads to a block in methionine synthase by lowering GSH in "a cobalamin dependent manner."
So I'm going with Rich's theory on what sets up the vicious cycle.
The study is in rats fyi.
I can't find it, but if someone wants to go hunting it's in the Feb 2010 of Alcoholism: Clinical & Experimental Research. VOl 35. No2.