peroxynitrite more involved than realized ?

vortex

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I would like to put for the theory that peroxynitrite is a significant obstacle to
healing via methylation protocol in ways we havent realized by interfering
and or destroying much of our effort by the methylation protocol and some
degree of success in the methylation protocol comes from an inadvertent
co-treating and overcoming peroxynitrite.

In other words, peroxynitrite is contributing to keeping the mitochondria
shut down in more ways than is attributed in the current theory.

richvank theory mentions peroxynitrite inhibits methylfolate in #3 but leaves
out some important details of its real impact in other areas downstream.

http://forums.phoenixrising.me/inde...tion-cycle-block-hypothesis-for-me-cfs.15701/

Yes, peroxynitrite inhibits methylfolate but it also has its hand in shutting down other cycles
in the methylation cycle and glutathione cycle.

Peroxynitrite directly induces destruction of the tetrahydrobiopterin
http://www.ncbi.nlm.nih.gov/pubmed/20184376

Peroxynitrite Inactivation of Glutathione Peroxidase
http://www.sciencedirect.com/science/article/pii/S0003986197904070

But in #4 Rich attributes "Glutathione depletion lowers the affinity of the CblC"
as the start of the block/cause, theorizing this is shutting down "methionine synthase reaction" causing the block and focusing on this can fix things.

Although he then goes back to and mentions peroxynitrite in #7
"The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma"
he mentions it inhibits methylfolate which could contribute to some of this block but
then stops there and goes back to b-12. It almost seems like the peroxynitrite is incorporated
into this theory by mentioning it and saying its impact is that it inhibits methylfolate but then
stops short there.

He then goes back to b12 in #13 by saying the treatment should revolve
around the b-12

"dosage of B12 is necessary to compensate for the greatly lowered affinity for cobalamin of the CblC complementation group, so as to overcome the functional B12 deficiency,"


So if peroxynitrite can inhibit glutathione recycling and destruction of BH4 in addition to destruction of methylfolate which inhibits methionine synthase, who knows, this might be the real reason glutathione doesnt come back up and causes CFS instead of b-12. I think peroxynitrite is interfering with more steps than we realize and that by treating this with methylation boosters like methylfolate and methylcobalamin we arent just restoring methionine synthase reactions, but we may be treating peroxynitrite directly with the supplements we are using or indirectly by overdriving methionine synthase to compensate for peroxynitrite effects of destroying bh4 and glutathione peroxidase.

hydroxocobalamin is a peroxnitrite scavenger, which may explain why people are having a good response to this cobal over methylcobalamin which should be the only one that significantly boosts methionine synthase.

Also methylfolate is a peroxnitrite scavenger, so it makes you wonder how much methylfolate is going towards quenching peroxynitrite and how much is going towards methionine synthase ?

So it seems like peroxynitrite is destroying alot of our efforts and is like stepping harder on the gas while having the brakes on or turning the faucet on faster to try to fill the sink because the drain is partially open.

So I think that if this is true, then we should focus more on directly addressing peroxynitrite/nitrotyrosine scavenging directly so we dont have to put all the load on the methionine synthase reaction to overcome all of the destruction that peroxynitrite is causing.


So perhaps adding more peroxynitrite scavengers to the methylation protocol can help non-responders and or alter or reduce some of the doses of the methylation boosters so we dont have to compensate so much for all the destruction that peroxynitrite is doing to our efforts.

gamma tocopherol is a known peroxynitrite scavenger, can someone add to this list ?

This document by pall discusses some strategies to lower peroxynitrite
http://www.csom.ca/wp-content/uploa...g-was-Right-but-for-the-Wrong-Reason-25.3.pdf
 
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SOC

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@vortex, you might want to look into the work of Dr Martin Pall for more discussion on peroxynitrite in ME/CFS. Dr Pall is a biochemist who had/has ME/CFS and improved his own condition using his knowledge of biochemistry to select appropriate (to his thinking, anyway) supplements. His thinking has many similarities to Rich's and quite a few of the supplements they recommend are the same. Rich and Marty disagreed on the interpretation of how/why the supplements work for PWME, but not a lot on which supplements help.

This page might be a place to start. Here are several small snippets:
We do have several agents that are in that protocol, in part, to lower either peroxynitrite levels or help restore BH4 levels, but it is not clear that they work very well at the levels that can be easily obtained in the body from such oral supplements.
Carotenoids (alpha-carotene, bixin, zeaxanthin and lutein) -- lipid (fat) soluble peroxynitrite scavengers
Ascorbate is a peroxynitrite scavenger, although all of the evidence available suggests that it does not work very well at the normal levels typically found in the body or easily obtainable via oral ascorbate.However, IV ascorbate can generate levels 30 times or more higher and such levels should be much more effective in scavenging peroxynitrite.
This page about his Allergy Research Group supplement collection lists various components of the supplements and how Dr Pall believes they benefit ME/CFS. If you search the page for "peroxynitrite", it will be easy to find which supplements he believes are peroxynitrite scavengers.
 

vortex

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thanks for the info and link.

the last link I posted was a document from Dr. Pall you mentioned.

Since some of the supplements marty and rich recommend are the same, has anyone been helped by supplements that just help peroxynitrite and not methylation like gamma tocopherol ? Perhaps that could separate what is helping, methylation or peroxynitrite quenching.

I think it might be both, meaning supplements that boost methylation directly and quenching peroxynitrite at the same time that is helping people.

has anyone brought their nitrotyrosine levels down to normal range with the methylation protcol ?
 

Mimi

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I just want to add that I've been having great results with BH4 supplementation. I recently started taking L-tyrosine with it to make more dopamine after noticing the similarities between adult ADD/ADHD and ME/CFS. Turns out, low dopamine was one of the original theories of what causes ME/CFS, back when the first outbreaks happened and they were wondering if it was the same thing as Post-Polio Syndrome.
 

vortex

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I just want to add that I've been having great results with BH4 supplementation. I recently started taking L-tyrosine with it to make more dopamine after noticing the similarities between adult ADD/ADHD and ME/CFS. Turns out, low dopamine was one of the original theories of what causes ME/CFS, back when the first outbreaks happened and they were wondering if it was the same thing as Post-Polio Syndrome.
interesting, thanks for sharing that it is working, I have seen many
experts say they dont recommend using it, as it is too low a dose
and is not worth it, better to just take more methylfolate and make
more, but I have always wondered if that is true.

Can you share how you are taking the bh4 ?
what brand and how much ?

thanks
 

Mimi

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That's silly. How could they say if they haven't tried? BH4 is a cofactor, so you don't need much. I take 2.5 mg. Ecological Formulas along with 500 mg. tyrosine 2X. As for BH4 regeneration, I only take a little methylfolate and B6 as part of my Thorne Stress B-Complex, and I'm not currently taking NADH, although I will again soon.
 
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I agree with vortex. Except (and not everyone's the same) my nitric oxide is low confirmed medical test (with symptoms of chronic cold hands and feet) was always hot before CFS/ with superoxide and peroxide high which contradicts Dr. Pauls theory. This is a theory under some of the same pretenses but looking at low NO resulting in high peroxide as a cause of CFS through ATP damage. I have read palls work and find this to be much more conducive. Super interesting and compelling read. http://www.chronicfatiguetreatments...fatigue-syndrome-nitric-oxide/comment-page-1/
 
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I would like to put for the theory that peroxynitrite is a significant obstacle to
healing via methylation protocol in ways we havent realized by interfering
and or destroying much of our effort by the methylation protocol and some
degree of success in the methylation protocol comes from an inadvertent
co-treating and overcoming peroxynitrite.

In other words, peroxynitrite is contributing to keeping the mitochondria
shut down in more ways than is attributed in the current theory.

richvank theory mentions peroxynitrite inhibits methylfolate in #3 but leaves
out some important details of its real impact in other areas downstream.

http://forums.phoenixrising.me/inde...tion-cycle-block-hypothesis-for-me-cfs.15701/

Yes, peroxynitrite inhibits methylfolate but it also has its hand in shutting down other cycles
in the methylation cycle and glutathione cycle.

Peroxynitrite directly induces destruction of the tetrahydrobiopterin
http://www.ncbi.nlm.nih.gov/pubmed/20184376

Peroxynitrite Inactivation of Glutathione Peroxidase
http://www.sciencedirect.com/science/article/pii/S0003986197904070

But in #4 Rich attributes "Glutathione depletion lowers the affinity of the CblC"
as the start of the block/cause, theorizing this is shutting down "methionine synthase reaction" causing the block and focusing on this can fix things.

Although he then goes back to and mentions peroxynitrite in #7
"The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma"
he mentions it inhibits methylfolate which could contribute to some of this block but
then stops there and goes back to b-12. It almost seems like the peroxynitrite is incorporated
into this theory by mentioning it and saying its impact is that it inhibits methylfolate but then
stops short there.

He then goes back to b12 in #13 by saying the treatment should revolve
around the b-12

"dosage of B12 is necessary to compensate for the greatly lowered affinity for cobalamin of the CblC complementation group, so as to overcome the functional B12 deficiency,"


So if peroxynitrite can inhibit glutathione recycling and destruction of BH4 in addition to destruction of methylfolate which inhibits methionine synthase, who knows, this might be the real reason glutathione doesnt come back up and causes CFS instead of b-12. I think peroxynitrite is interfering with more steps than we realize and that by treating this with methylation boosters like methylfolate and methylcobalamin we arent just restoring methionine synthase reactions, but we may be treating peroxynitrite directly with the supplements we are using or indirectly by overdriving methionine synthase to compensate for peroxynitrite effects of destroying bh4 and glutathione peroxidase.

hydroxocobalamin is a peroxnitrite scavenger, which may explain why people are having a good response to this cobal over methylcobalamin which should be the only one that significantly boosts methionine synthase.

Also methylfolate is a peroxnitrite scavenger, so it makes you wonder how much methylfolate is going towards quenching peroxynitrite and how much is going towards methionine synthase ?

So it seems like peroxynitrite is destroying alot of our efforts and is like stepping harder on the gas while having the brakes on or turning the faucet on faster to try to fill the sink because the drain is partially open.

So I think that if this is true, then we should focus more on directly addressing peroxynitrite/nitrotyrosine scavenging directly so we dont have to put all the load on the methionine synthase reaction to overcome all of the destruction that peroxynitrite is causing.


So perhaps adding more peroxynitrite scavengers to the methylation protocol can help non-responders and or alter or reduce some of the doses of the methylation boosters so we dont have to compensate so much for all the destruction that peroxynitrite is doing to our efforts.

gamma tocopherol is a known peroxynitrite scavenger, can someone add to this list ?

This document by pall discusses some strategies to lower peroxynitrite
http://www.csom.ca/wp-content/uploa...g-was-Right-but-for-the-Wrong-Reason-25.3.pdf
This is also a interesting conversation of that topic http://forums.phoenixrising.me/inde...ent-of-mitochondrial-replication-in-cfs.9536/
 
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Scavengers include green tea tannin, flavonoids, and Uric acid a product of purines. Rich had a pretty interesting theory about low Uric acid in people with CFS but I can't find it specially, don't know if he ever made the connection but this could also be why PWC have problems low Uric acid = high peroxynitrite. Fix purine production > increase Uric acid> reduce peronxynitrite

How do CFS patients compare to metabolic syndrome patients? Given the heterogeneous findings for many of these tests in CFS its hard to definitively say. Some CFS patients in some studies have exhibited increased waist/hip ratios, increased sympathetic nervous system activity, low growth hormone levels, high lactic acid levels, higher c-reactive protein levels, altered electrolyte levels, increased fibrinogen, IL-6 and TNF-a. Other studies have shown differently with regard to SNS activity, growth hormone, lactic acid, fibrinogen, Il-6 and TNF-a. Dr. Cheney has stated that his patients have low, not high, uric acid levels. Virtually all studies that I am aware of have indicated increased oxidative stress in CFS. At this point there do appear to be some broad similarities between the two syndromes."- Rich
 

Hip

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In my peroxynitrite folder on my computer, I found the following list of peroxynitrite scavengers and inhibitors which I compiled a few years ago:

Inhibitors of Peroxynitrite Production

N-acetyl-cysteine
Curcumin

Peroxynitrite Scavengers

Alpha lipoic acid — potent
Ebselen (flavonoid) — potent
Melatonin — potent
Ellagic acid 1
Anthocyanins (anthocyanins are in blueberry, cranberry, bilberry, black raspberry, red raspberry, blackberry, blackcurrant, cherry)
Caffeic acid — found in coffee, especially decaf
Citrus juices — grapefruit juice is particularly effective
Folinic acid
Gamma tocopherol (a form of vitamin E)
Ginger
Green tea
Resveratrol
Rosmarinic acid (found in rosemary essential oil, and lemon balm essential oil )
Uric acid (note that the supplement inosine increases uric acid levels in the body)
Glutathione
Cysteine
Tryptophan
Lycopene
Luteolin
Curcumin
Echinacea purpurea
Selenium — behaves as an antioxidant and peroxynitrite scavenger when incorporated into selenoproteins
Jasmine tea
Sage
Slippery elm

Protection from Peroxynitrite Damage

Q10


This study found that the potency of peroxynitrite scavenging was in following order:
witch hazel bark > rosemary > jasmine tea > sage > slippery elm > black walnut leaf > Queen Anne's lace > Linden flower.

Another list of peroxynitrite scavengers is found here.

Note however this study, which found that the evaluation of the peroxynitrite scavenging abilities of certain supplements (such as caffeic acid) may be overstated, due to not accounting for the presence of bicarbonate, which reduces the scavenging ability.

Note that peroxynitrite is not without benefits: this study found peroxynitrite inhibits coxsackievirus.
 
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kyzcreig

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I've had some success following the advice of Rich and especially Marty Pall.

What confuses me however is my response to glutathione. I feel amazing when I get an IV of glutathione or vitamin C. In fact, if I dab a lot of topical glutathione on myself before sleeping I'm basically symptom free in the morning. But it doesn't last. Could something be inhibiting glutathione recycling? Maybe there is an underlying issue depleting glutathione? Is there any connection to peroxynitrite and iNOS?
 

JPV

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Thanks for posting this link. This article is probably one of the most important thing I've ever read on the subject and really deserves further attention.

I've been reading up lately on Jay Goldstein's (somewhat successful) experiments using NO donors such as Nitroglycerin. This article expands on and explains a lot about this mechanism and why it only partially works.

I'm really starting to think that disruption of the body's NO mechanism is the key to it all. The question is, what's the root cause and how can it be fixed.
 
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ahmo

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@JPV I'm finally gaining some comprehension of Martin Pall's work. Having done everything else I can to deal with my illness, it feels like peroxynitrite is what's left. In my understanding, Pall's work is about scavenging the peroxy, rather than increasing NO by other means. I've been implementing a lot of his suggestions over the past month or two. More info for you linked. The vid, from last year, is how I finally began to understand it. You can stop/start it. The first 25" is about the theory, then he discusses several conditions, and the last 20" are his supp recommendations, listed on slides. The forum I've linked is pretty dead, but you can address questions there. He has, in the past, answered. If not, the list owner is knowledgeable. Also, I've just written about my experiences on another thread, the first link below.

http://forums.phoenixrising.me/index.php?posts/558218/

Martin Pall website http://www.thetenthparadigm.org/therapy.htm
Martin Pall vid https://www.youtube.com/watch?x-yt-ts=1421914688&feature=player_detailpage&x-yt-cl=84503534&v=6A7r1gemjto

https://groups.yahoo.com/neo/groups/TenthParadigmSociety/info
 

JPV

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Thanks. Can I ask how much relief you have gained from following Pall's recommendations?

Also, what do you make of Dave Whitlock's theory that a lack of NO is problematic for CFS. He seems to be in contradiction with some aspects of Pall's work though both seem to agree that Peroxynitrite is a problem.

I'm very curious to try Whitlock's AO+ spray.
 
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ahmo

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Thanks. Can I ask how much relief you have gained from following Pall's recommendations?
I've only just now seen this...I guess the post was during the time I was offline.

On the one hand, I'm having good results using several things. OTOH, this peroxy issue seems to be very persistant. I don't know whether it's always been there, and my awareness is just greater now, or whether something has increased it. I'm inclined to think I've got greater awareness now, and so many of my other symptoms have resolved, that I'm now dealing with this as my major issue.

I'd started with olive leaf tea, per Pall's list. Thankfully I discovered that green tea does the same job, cheaper and from the grocery store. I switched my Vit E to Gamma form, per Pall. I've added resveratrol: I started w/ red wine, then red wine + Japanese knotweed. Eventually I recognized that red wine was pushing histamine reaction (duh :bang-head:), which then worsens peroxy. So I found a knotweed only resveratrol. Also astaxanthin. Nuts and seeds seems also very effective.

Until I began green tea, the thing my body wanted the most was carrots. I'm still using a lot of carrots, about 1 kg/day, but I've now decreased from 2 large juices + the pulp + extra carrots, to a single juice w/ pulp and some extra carrots through the day. The highest intake was while I was using the red wine extract.

Yes, I've read about Whitlock, but not gone into it. Because of the limits of my comprehension, I've not gone deeply into the low or high NO stuff. I'm just focusing on reducing peroxy. My understanding, (which is known to be wrong at times:lol:) is that reducing the peroxy will...increase? available NOS...Peroxy has seemed to me to be the only way I could affect anything in this cycle. I found Pall's list of some 37 cycles that are spinning in this vicious circle/cycle very compelling. After reading this thread again this AM (thanks @Hip) I'm considering again trying BH4. cheers:balanced::balloons:
 
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