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Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication...

Discussion in 'Other Health News and Research' started by anne_likes_red, Jan 1, 2014.

  1. Radio

    Radio *****

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    Viral Connection, NAD synthesis: Quinolinic / Kynurenine Pathway
    Viruses can affect the NAD Synthesis in the Kynurenine pathway. This is the reason why it's import to supplement to bypass the weak NAD synthesis. The key factor is the NAD+ deficiency, as well as the NADH recycling, anaerobic metabolism (ADP to ATP) imbalance.



    Kynurenine Pathway Metabolites in Humans: Disease and Healthy States

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195227/
    NAD synthesis , Tryptophan to quinolinate pathway
    http://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide


    Tryptophan Wikipedia
    http://en.wikipedia.org/wiki/Tryptophan


    [​IMG]

    http://forums.phoenixrising.me/index.php?threads/nt-factor-healed-my-cfs.27280/#post-416798
     
    Last edited: Jan 8, 2014
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  2. alex3619

    alex3619 Senior Member

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    High levels of quinolinic acid might imply that there is a failure to convert to NAD. This can be a big issue, and drive anaerobic metabolism. @Radio listed the pathway diagram, of how Tryptophan is converted to NAD via quinolinic acid.

    [My bolding]

    As the above abstract indicates, interferon gamma may drive quinolinic acid synthesis, and it is likely (see for example the recent immune study from NCNED) that we make too much gamma interferon. The gamma interferon works on both macrophages and microglia. Astrocytes are also implicated, though this is less certain.

    Quinolinic acid activates NMDA receptors, and NMDA activation has has been discussed extensively in ME research over the years. NMDA activation can drive NO synthesis so in conditions of oxidative stress give rise to peroxynitrite which is very damaging. These might be responsible for the elevated COX-2 enzyme activity in many disorders, and so in this case antiinflammatories might sometimes help.

    Quinolinic acid has been reported to be increased in Lyme disease.

    Here is a large diagram of NAD+ synthesis: http://jpet.aspetjournals.org/content/324/3/883/F3.large.jpg
     
    Last edited: Jan 2, 2014
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  3. Radio

    Radio *****

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    This is also one of the the main causes of schizophrenia and bipolar ADHD, I'm thinking the lithium dumping in autism is connected to this as well...
     
    Last edited: Jan 5, 2014
  4. alex3619

    alex3619 Senior Member

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    QPRtase = quinolinate phosphoribosyltransferase

    This enzyme has different forms, and different concentrations, and so is the first step in converting quinolinic acid to NAD. It is implicated in preventing apoptosis.

    http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08485.x/full

    [My bolding]

    Problems with QPRtase not detoxing quinolinic acid are being studied in MS and Alzheimers. Is it therefore a surprise this might be the case in ME?

    A defect in QPRtase is currently (tentatively) linked to seizures.
     
    Last edited: Jan 2, 2014
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  5. anne_likes_red

    anne_likes_red Senior Member

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    @dannybex, have you used curcumin? It's supposed to attenuate the neuroexcitotoxic (I may just have made that word up!!!) effects of QA.
    Epigallocatechin gallate too, from green tea....see http://www.australasianresearch.org/assets/252169

    Related maybe (?) and perhaps a good alternative to buying more bottles of supplements (?!) - a cancer researcher from McGill http://www.mcgill.ca/translational-research-cancer/researcher-biographies/beliveau has apparently been suggesting at his recent lectures that people brew 1 tsp green tea (such as Sencha which is high in ecgc), 1 tsp turmeric and a pinch of black pepper for ten minutes and drink it as an anti-cancer cocktail. :D
    I'll try some if you will! :p

    I wonder if high QA is a common finding in ME?

    Anne.
     
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  6. anne_likes_red

    anne_likes_red Senior Member

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    Very interesting Alex!!
     
  7. nandixon

    nandixon Senior Member

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    I thought I'd mention that I recently did a trial of a newer form of niacin/niacinamide (Vitamin B3) called "nicotinamide riboside" that is supposed to increase levels of NAD(+) and was first mentioned a few months ago on this thread by @kaffiend:
    http://forums.phoenixrising.me/index.php?threads/nad-controls-circadian-clock-in-mice.25398/

    (It's a patented compound and quite expensive:
    http://www.amazon.com/Niagen-Nicotinamide-Riboside-60-Caps/dp/B00ERPFBTE)

    A search on PubMed currently gives 108 hits:
    http://www.ncbi.nlm.nih.gov/pubmed/?term=nicotinamide riboside

    Various findings have been made including: "... current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis." (http://www.ncbi.nlm.nih.gov/pubmed/18429699/)

    I felt no effects from it whatsoever, even with 4 capsules at once (= total of 500mg). This is unusual for me because I usually have at least a negative effect to a majority of supplements. To have no effect is rare.

    By contrast, when I take 125mg of regular niacinamide there is a nice but brief (mentally) stimulating effect.

    If you can afford it, it might possibly be worth other people with ME/CFS also trialling this substance.
     
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  8. alex3619

    alex3619 Senior Member

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    In case anyone is wondering what c-Myc is, here is a page that discusses its function in conditions other than cancer:

    http://www.cell.com/abstract/S0092-8674(12)01101-4

    Basically c-Myc amplifies genetic expression of a gene, and does this for a wide range of genes.
     
  9. dannybex

    dannybex Senior Member

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    Anne -- curcumin and/or turmeric has been on my mind lately for inflammation, etc, despite my possible salicylate intolerance issues. I just might pick some up tomorrow…thanks!Radio -- if I fasted, I'd disappear. Waaaaay too skinny as it is.
     
  10. Radio

    Radio *****

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    Curcumin and/or turmeric is a MAO inhibitor, not a good idea in the long run.
     
    Last edited: Jan 3, 2014
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  11. dannybex

    dannybex Senior Member

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    I suppose it depends on one's genetic snps. I was told this herb acts as an anti‐inflammatory and helps with the CBS up‐regulation by slowing cysteine production and shifting to glutathione. And she knows I have the MAO+/+ defect.
     
  12. Radio

    Radio *****

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    Last edited: Jan 3, 2014
  13. alex3619

    alex3619 Senior Member

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    Hi, Radio is not talking about prolonged fasting, but about having twelve hours a day without food I think, a short break.

    I am also considering fasting, one day a week. I am not underweight though. This one day a week fasting has been used in CFS since 1993 at least, as that was when I first heard of it. It does not suit everyone. I do agree that someone who gets hypoglycaemia or is seriously underweight shouldn't consider it.

    The other thing is a fast is best undertaken with a little vegetable broth to sip on, low calorie but full of minerals. Also about ten grams of carbs are needed to prevent fasting from raiding protein stores. That is not a lot. To put it in perspective, a level teaspoon of sugar has about fifteen calories and four grams of carb. The vegetable broth may also provide this small amount of energy.

    Taking a little broth is important for us because the first place our bodies raid for protein is the gut, and we already have enough gut issues.
     
    Last edited: Jan 2, 2014
  14. Radio

    Radio *****

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    OK, Where do we go from here, How do we fix this metabolic dysfunction?

    The main cause of the metabolic dysfunction is the weak break down of tryptophan. We know quinolinic and interferon gamma are elevated and need to be reduced. The key factor is the NAD+ deficiency, as well as the NADH recycling, anaerobic metabolism imbalance. Ok, How do we fix this?
    The best approach would be to eat a low animal protein diet to compensate for the build up of quinolinic and interferon gamma from the lack of tryptophan conversion. The next step would be to supplement with either Free form Tryptophan, Nicotinamide, NAD+ or NADH with R- lipoic acid to compensate for the NAD+ deficiency. Riboflavin is needed for the monoamine oxidase enzyme, which functions in this metabolism. This could be the solution to the metabolic dysfunction and the missing link to CFS/ME.
     
    Last edited: Jan 7, 2014
  15. Radio

    Radio *****

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    I do like the idea of supplementing with green-tea-extract-phytosome, great TNF anti-inflammatory and you can benefit from the excitotoxicity inhibitor affect.

    http://www.vitacost.com/vitacost-greenselect-green-tea-extract-phytosome
     
  16. Little Bluestem

    Little Bluestem Senescent on the Illinois prairie, USA

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    @alex3619, So would increasing NAD increase one's anaerobic threshhold?
     
  17. Radio

    Radio *****

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    If we can increasing NAD+, balance the metabolism, bypass the metabolic dysfunction. We can increase one's anaerobic thresh-hold by generate less lactic acid and more ATP.
     
    Last edited: Jan 4, 2014
  18. alex3619

    alex3619 Senior Member

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    That is the theory, but it depends on the cause. As always reality trumps theory ... all this needs proper testing. I may say more later, I am about to catch some sleep.
     
  19. brenda

    brenda Senior Member

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    @Radio

    Hi! I am interested in what you are saying. I have had OAT results from a few years ago showing :

    Pyruvate 4.2 H (<6.4)
    L-LACTATE 16 H (3-46)
    Citrate >2000 H (56-987)
    Cis-Aconitate H 92 (18-78)
    Isocitrate 172 H (39-143)
    a-Keto 30.4 H (<35.0)
    Succinate 8.6 (<20.9)
    Fumarate 0.35 (<1.35)
    Malate 3.0 H (<3.1)
    Hydroxymethylgluterate 6.0 H(<5.1)
    Vanilmandelate 4.0 H (1.3-4.9)
    Homovanililate 8.5 H(1,6-10.9)
    5-Hydroxyindoleacetate 5.1 (1.6-9.80
    Kynurenate 0.6(<2.7)
    Quinolinate 4.1 (<5.8)
    Picolinate 6.2 (2.8-13.5)


    IgG low

    ADP conversion to ATP 1.38 (1.6-2.9) very low whole cell ATP.

    MAO-A R297R +/-

    I am not having much success with methylation supplements but would rather start on one or two supplements to show me that your protocol will help. What would you advise I start on? I have noticed that riboflavin has a very positive effect.
     
    Last edited: Jan 4, 2014
  20. alex3619

    alex3619 Senior Member

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    @brenda, it looks like you might have a block at Isocitrate dehydrogenase or alpha ketoglutarate hydrogenase, er even Succinyl-CoA synthase. The first two are NAD dependent enzymes, but the third is GDP dependent.

    GDP is guanosine diphosphate. If your problem is not NAD related, you might like to look at GDP. GDP is a precursor to GTP, which is similar to ATP.

    One of the things that can cause this is intracellular phosphate deficiency. Do you drink milk, or eat other dairy? Its high in phosphate, but if you cannot tolerate it you might need bone broth or something.

    About 2000 or so there were a couple of presentations at conferences showing some with CFS-like symptoms cannot retain phosphate. A combination of low phosphate diet and insufficient vitamin D appeared to be to blame, though there were implications that something genetic was involved.

    What are your phosphate and vitamin D levels like? Do check active vitamin D, 1,25. Also be aware that these people have normal serum phosphate, their cells deplete phosphate to keep serum phosphate stable. However they are always at the very low end of normal serum phosphate.

    Treatment is simple, and was effective within a week. Milk and vitamin D.

    Of course if the problem is in the first two enzymes I mentioned, then it might be NAD related.
     
    Last edited: Jan 4, 2014
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