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'Adding Pyruvate makes ME cells normal' - What questions does this prompt?

Discussion in 'General Treatment' started by AdamS, Apr 11, 2017.

  1. adreno

    adreno PR activist

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    More about HIF-1:

    It looks like HIF-1 signaling is impaired in neurodegenerative diseases, making it a potential treatment target:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213300/
     
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  2. AdamS

    AdamS Senior Member

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    Just found this...from 2000, but can be related to the findings of Fluge & Mella about PDH:

     
  3. msf

    msf Senior Member

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    Looks like we have had a similar reading list lately. Damn, I should have published in sections! Haha. I still feel I should put together what I have read recently into one blog/OP, unless of course you beat me to it!
     
    Last edited: Apr 25, 2017
  4. ljimbo423

    ljimbo423 Senior Member

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    Seems like we both might be on the same page! ;) I have not done a blog and would be very interested in one you might write. I think this is very good, important info. and I feel like the more people that have access to it the better!
     
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  5. kangaSue

    kangaSue Senior Member

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    Simple answer is inflammation. Inflammation causes hypoxia, hypoxia causes inflammation. If you've got gut issues, then you likely have inflammation causing hypoxia but incidently, inflammation is not necessarily overt enough to show up as an ESR or C-Reactive Protein issue.
    http://www.pnas.org/content/110/46/18351.full.pdf
     
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  6. nandixon

    nandixon Senior Member

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    I've posted elsewhere about this before. I'm pretty certain that the normalization with pyruvate in Ron Davis’ test device is excellent confirmation that the pyruvate dehydrogenase (PDH) complex is in fact being inhibited by the PDH kinases (PDK1, 2 & 4) as found by Fluge & Mella.

    Pyruvate is a potent inhibitor of the PDKs. Under the relatively simple test conditions Ron Davis is using I think it's most likely that the added pyruvate is simply de-inhibiting the PDH complex - by inhibiting the PDKs.

    This is because of the following:

    1.The activity of the PDH complex is under the complete control of the PDKs and the PDH phosphatases (PDPs). The reaction that the PDH complex performs in converting pyruvate to acetyl-CoA cannot be “driven” by adding additional pyruvate like you'd be able to do with many other enzymatic reactions.

    2.No other pathways utilizing pyruvate as an energy source come even close to the amount of ATP produced by injection of the acetyl-CoA made by the PDH complex into the Krebs Cycle.

    So the question is, what is causing the increased levels of PDKs? The unknown substance in the blood would presumably somehow be causing this.
     
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  7. nandixon

    nandixon Senior Member

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    The de novo synthesis of sphingolipids including ceramides requires acetyl coenzyme A. The major generator of acetyl-CoA is the pyruvate dehydrogenase (PDH) complex. With that complex being inhibited, that may be the simplest explanation for why Naviaux found the low levels of sphingolipids.
     
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  8. AdamS

    AdamS Senior Member

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    @nandixon Thanks a lot for your input, it's really helpful. I can't wait to see what the researchers find next, seems like we're getting close to a breakthrough.
     
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  9. AdamS

    AdamS Senior Member

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    Also @nandixon out of interest, do you know anything about dichloroacetate (DCA)?

    I was reading this and came across it, I didn't know if it would be relevant to ME patients though. I realise that it wouldn't actually be solving the root cause but wondered if it (or in fact any PDK inhibitor) could help symptoms at all. My guess is that it's not so simple though.

    From link above:
     
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  10. nandixon

    nandixon Senior Member

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    Dichloroacetate is certainly a theoretical possibility for inhibiting the PDKs in order to de-inhibit the PDH complex. But you'd need to take large quantities because it's not a very specific/efficient drug. And the older you are, i.e., older than a child, the more likely you are to develop the peripheral neuropathy problem it's infamous for. The neuropathy is usually reversible when the DCA is stopped but it's pretty well guaranteed to happen with the large doses of DCA that would be needed to make a difference in ME/CFS, I'm afraid.
     
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  11. Jesse2233

    Jesse2233 Senior Member

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    Do you think pulsing the Dichloroacetate in high doses would do any good?

    I'm meeting with a mitochondrial geneticist next month, and this is one of the drugs on my list to ask him about
     
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  12. nandixon

    nandixon Senior Member

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    I'm not sure. It looks like that's been tried in cancer with some success with both increased effectiveness and reduced toxicity, I think, but it requires administration by IV rather than orally.
     
  13. TreePerson

    TreePerson Senior Member

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    I apologise in advance if this is a really naive or stupid question and for taking up your time but you seem to be particularly knowledgeable. A Couple of times recently I have had an involuntary adrenaline burst due being in a very difficult or stressful situation. Both times I have noticed a really marked temporary increase in energy/capacity. Usually I feel considerably worse afterwards. Is there anything about adrenaline and or the receptors that could play a part in this pyruvate puzzle? Blocking or unblocking PDH and PDH kinase as you describe? Or is it simply that adrenaline massively opens up all energy pathways?
     
    Last edited: Apr 30, 2017
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  14. overtheedge

    overtheedge Senior Member

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    I've been thinking about trying some pyruvate out since mitochondrial supplements have done really well by me.

    Has anyone here supplemented pyruvate or know others who have?
     
  15. AdamS

    AdamS Senior Member

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    @overtheedge From what I understand, if PDK1 is raised then pyruvate is shunted away from the TCA cycle so supplementing it might not help. The issue seems to be with pyruvate utilisation not availability.
     
  16. Jesse2233

    Jesse2233 Senior Member

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    i wonder what effect supplementing acetyl co-A (if there were such a supplement) would have
     
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  17. pattismith

    pattismith Senior Member

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    "Symptoms similar to those of beriberi arise if an organism is exposed to mercury or arsenite (AsO33-). Both elements have a high affinity for neighboring sulfhydryls, such as those in the reduced dihydrolipoyl groups of the dihydrolipoyl dehydrogenase component of the pyruvate dehydrogenase complex (Figure 17.20). The binding of mercury or arsenite to the dihydrolipoyl groups inhibits the complex and leads to central nervous system pathologies."

    interestingly, Arsenic has a link to schizophrenia and is also an endocrine disruptor :thumbsup:
     
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  18. bertiedog

    bertiedog Senior Member

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    My recent Organic Acid test could not detect ANY pyruvate. The test was on the first morning void so basically after any overnight fast.

    No wonder I feel half dead till I have eaten some carbs on waking along with my steroid and thyroid meds.

    Pam
     
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  19. pattismith

    pattismith Senior Member

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  20. caledonia

    caledonia

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    It's also a known carcinogen.

    If you've eaten any chicken in the US between 1949 and 2016, you have arsenic. Yes, it was added to chicken feed for decades...
     
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