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Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS

Discussion in 'Latest ME/CFS Research' started by deleder2k, Dec 22, 2016.

  1. wastwater

    wastwater Senior Member

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    Sphingolipid is involved in gauchers disease and at an increased rate in Ashkenazi jews
     
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  2. Hip

    Hip Senior Member

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    For those interested in up-regulating mitochondrial fat burning, to try to compensate for the possible glucose energy metabolism blockage suggested by Fluge and Mella's study, the T2 thyroid hormone can do this. See this thread:

    Lesser Known T2 Thyroid Hormone Activates Mitochondria
     
  3. Wishful

    Wishful Senior Member

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    I was browsing old threads, followed some 'what does that do?' questions, and found that sphingolipids are produced on palmitoyl-CoA, which is part of the carnitine shuttle system. I've wondered why my symptoms get worse after consuming animal fats, unless I take an adequate amount of carnitine with them. While it's hardly proof of a link, I think my observations support the involvement of sphingolipids, and thus the PDH function.

    I also find a benefit from T2, but if it's from increasing fat burning, the effect is by triggering some other changes, because T2 only helps me with one dose every 21 days. It seems to trigger some change with a fairly precise and consistent 21 day lifespan.

    Just thought it was interesting enough to mention.
     
  4. rodgergrummidge

    rodgergrummidge Senior Member

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    love your work @Countrygirl !
     
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  5. rodgergrummidge

    rodgergrummidge Senior Member

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    nice explanation and insight @Hip !
     
  6. JaimeS

    JaimeS Senior Member

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    Marc_NL and Learner1 like this.
  7. rodgergrummidge

    rodgergrummidge Senior Member

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    sorry for the misquote @JaimeS . I am new to PR and still getting used to its 'clunky' format. Love your posts though. You have given some very nice insights into the biology of CFS!
     
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  8. rodgergrummidge

    rodgergrummidge Senior Member

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    The PI3K pathway, sometimes referred to as the PI3K/Akt/mTOR pathway, is recognized as being the most 'widely mutated pathway' in cancer. That is, more cancer-causing mutations (also known as oncogenic mutations) have been identified in components of the PI3K pathway (which includes Akt and mTOR) than any other known signalling pathway inside cells. Drugs that boost the long-term activity of PI3K, Akt or mTOR activity would be expected to increase the likelihood of cancer. Thus, it would be potentially very dangerous to try and pharmacologically boost Akt/mTOR as it might increase the chance of cancer as suggested by @adreno.

    It is for this reason that pharamceutical companies are very interested in developing drugs that inhibit PI3K, Akt and mTOR because of their potential to block the growth of cancers. To date, there are many drugs that inhibit the activity of PI3K, Akt and/or mTOR that have been examined in cancer clinical trial. Some have been approved for the treatment of specific cancers (e.g. I have discussed the use of mTOR inhibitors in the treatment of cancer and CFS elsewhere).
    \cheers
    Rodger
     
  9. rodgergrummidge

    rodgergrummidge Senior Member

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    Note @Tiger_Eyze that mitochondrial defects are inherited maternally. Just something to consider when CFS is found in families/relatives......
     
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  10. rodgergrummidge

    rodgergrummidge Senior Member

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    Hi @Hip , I was following your thread on using DCA in early 2017. Personally, I think it is potentially dangerous to self-medicate with DCA so it is not something I would consider myself. However, I am curious.

    Did you try it? What doses? Did you combine DCA with a specific diet? Did it change your capacity for either anaerobic or aerobic exercise? Did it affect your recovery time? If you exercise on day 0, did DCA change your aerobic or anaerobic exercise capacity on day 1 or 2? Did it change your blood glucose or blood ketones such as hydroxybutyrate?
    Very curious,
    Rodger
     
  11. Hip

    Hip Senior Member

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    I have not yet tried it, but will do at some point.
     
  12. knackers323

    knackers323 Senior Member

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    @Hip is thete anything else you know of that works like clarithromycin on these cytokines?
    I felt much better on it within a day also
     
    Last edited: Sep 26, 2017
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  13. Hip

    Hip Senior Member

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    I have tried plenty of supplements and drugs that inhibit IL-1β, TNF-α and IL-6, but usually without much success. However, a few things have helped. The supplement vinpocetine 40 mg (must be taken with food for proper absorption) I find helps a little for the blunted emotions of ME/CFS; it's a TNF-α inhibitor.

    Glucosamine is known to inhibit IL-1β, and I found N-acetyl-glucosamine (a version of glucosamine that can cross the blood-brain barrier) very effective for treating my generalized anxiety disorder, which I posit can be caused by chronic brain inflammation.

    But erythromycin is the only thing I've noticed that has these anti-PEM effects.
     
  14. JaimeS

    JaimeS Senior Member

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    'Blunted emotions' has never been a problem for me, but I took vinpo for awhile -- it significantly reduced the pain at the back of my neck. However, be aware it's a vasodilator, so those with POTS should be wary.
     
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  15. HowToEscape?

    HowToEscape? Senior Member

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    Is there anyone here who can write up a summary of this thread, with an outline and links to details/further reading? Even attempting 40 pages is no longer realistic for me.
     
  16. nandixon

    nandixon Senior Member

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    I've been meaning to provide an update for the hypothesis that I made in this thread, which was that the Fluge & Mella results were showing an under-activation of the critical enzyme mTOR/mTORC1, ever since Mark Davis’ work regarding the possibility of CD8+ T cell expansion in ME/CFS was revealed a couple months ago.

    If Mark Davis’ work is correct, and I have a feeling it probably is, then my hypothesis is going to be wrong, and it's going to be more likely that mTOR is actually over-activated in the type of cells that Fluge & Mella studied, i.e., PBMCs, and this would be the result of the activation/expansion (proliferation) process occurring in the T cell population of the PBMCs, namely their switch from oxidative phosphorylation to aerobic glycolysis to support that proliferative process.

    Note that this also means the impairment of the PDH complex Fluge & Mella found is with respect to the activated T cells and presumably is not happening in other cells in the body (although mitochondrial function in other cell types could very well be impaired by the cytokine signaling generated by the activated T cells).

    Neither under-activation nor over-activation of mTOR is a perfect fit for the Fluge & Mella results. The possibility of over-activation is made less likely by the high SIRT4 finding and by the normal HIF-1. Under-activation is made less likely by the high PDK4 finding.

    I went with under-activation because I thought there was real world confirmation of this in several different ways. For example, natural killer (NK) cell function tends to be low in ME/CFS and this almost certainly means mTOR is under-activated in those NK cells. What I didn't realize is that the high TGF-beta that is also commonly found in ME/CFS can cause impairment of mTOR. (Note that neither low NK cell function nor high TGF beta are diagnostic of ME/CFS but are found in a number of different disease states.)

    In other words, the activation of the T cells, which requires the activation of mTOR for the necessary switch to aerobic glycolysis in order for the T cells to expand/proliferate, also results in the production of TGF-beta which has an inhibitory downstream effect with respect to mTOR on other types of cells including NK cells. So under this scenario, mTOR is likely over-activated in at least one type of cell (i.e., the activated T cells) in the ME/CFS patient and simultaneously under-activated in other cells that are subject to TGF-beta signalling.

    Anyway, the new study posted on the thread entitled T-cells and metabolomics is likely relevant to the Fluge & Mella findings because it demonstrates how the amino acid profile they found might appear to support a general bodywide PDH impairment but yet actually be the result of the specific T cell expansion process Mark Davis may have uncovered.

    Also, my apologies in advance if Mark Davis’ T cell activation/expansion work turns out to be key (which, again, requires the over-activation of mTOR) to a poster whose username I can't remember, who had believed at one point in this thread that the Fluge & Mella work was likely showing this aerobic glycolysis.

    Lastly, some method of reducing the T cell activation and expansion might be helpful as a treatment if that is indeed what is happening in some people with ME/CFS. An obvious anti-proliferative agent to try might be rapamycin (sirolimus) itself.

    Edit: @Janet Dafoe (Rose49) would you mind showing Dr Davis (Ron) this? Thank you!
     
    Last edited: Oct 24, 2017
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  17. Murph

    Murph :)

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    Nothing more intellectually satisfying than seeing someone change their mind when new evidence comes out. Good one @nandixon. Does the paper out today from Tomas, Newton and Manning on metabolism in pbmcs shed any more light on these hypitheses, in your opinion?
     
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  18. nandixon

    nandixon Senior Member

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    If Mark Davis’ work is correct, then that study is seemingly again just showing the signature of the T cell activation/expansion process. To verify this, the next study that could be done is what Tomas et al actually propose at the end of their paper:


    They should find (assuming Mark Davis is on to something) that the “specific cell populations” are the same T cells involved in the expansion process that Mark Davis found - or so I would think.
     
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  19. A.B.

    A.B. Senior Member

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    Do antivirals reduce proliferation?

    https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/
     
  20. Gondwanaland

    Gondwanaland Senior Member

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    Tagging someone when editing won't notify the tagged person!
     
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