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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. Tunguska

    Tunguska Senior Member

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    They use Niacinamide in skin care because it helps with ceramides... https://www.ncbi.nlm.nih.gov/pubmed/10971324 (Niacinamide is heavily glucose-oxidation promoting, and fairly strong, and I've wondered if modulates mTor in any way; also lingering interest from Kimsie's posts, which recommended glutamine)

    I think transdermal was the only form I didn't try. But like you now, I focus more on brain health, out of necessity, with some indescribable but quite "physical" symptoms. The leucine+glutamine is worth a try for that, since crosses BBB, but I have my doubts it will match or work without something else (like ketamine/sarcosine/etc. mentioned earlier, or NMDA/AMPA in general) since I've already done high protein in general to death.
     
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  2. eljefe19

    eljefe19

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    Thanks for bringing this up. I am going to add Sarcosine and/or DXM for mTor on top of Leucine, glutamine, creatine, PA, and Ursolic Acid. Will report back.
     
  3. nandixon

    nandixon Senior Member

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    Thanks, I had also downloaded the raw data but have to do everything on a smartphone so wasn't sure if I'd missed it.

    Yes, I had noted that possibility in an earlier post:

    Everything fits for me. From my analysis, either low S1P or autoantibodies to one or more of its receptors seem nearly equally possible. The low S1P would be the block (i.e., impaired signaling), and low ceramides would be the immediate cause of the low S1P (or autoantibodies to S1P itself).

    (FWIW, non-autoimmune, low S1P has the additional advantage of explaining Julia Newton's cultured muscle cell results - because of S1P's "inside-out" manner of signaling to activate AMPK, this means no autoantibodies are required to explain her results. Also, Montoya supposedly found a "100%" mRNA gene expression match for ME/CFS with systemic inflammatory response syndrome/SIRS, and S1P is low in sepsis.)

    I think we need to know what the level of S1P is, and also of the precursor intermediate, sphingosine.

    If S1P is low, then presumably it's either because of the low ceramides or because it has autoantibodies directed against it. As to why ceramides might be low in this case, I'll make another post.

    If S1P is normal or high, then presumably it's because there are autoantibodies directed against one or more S1P receptors (e.g., S1P1 aka S1PR1), causing S1P production from ceramides to be upregulated to try to overcome this (and making ceramides low in the process).

    It makes me a bit mad to think that sphingosine-1-phosphate levels may have never been tested in our disease. It just shows how pitiful the funding has been for ME/CFS. It only requires a little extra sample preparation to run this analysis on LC-MS/MS, for example.


    Thanks, that's very good to know.
     
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  4. Hip

    Hip Senior Member

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    When my virus induced chronic recurrent body-wide paresthesias (pins and needles), that lasted for around 9 years (typically getting worse after exercise, and possibly a sign of some neuropathy), benfotiamine was one of the few treatments that had a (temporary) impact on this symptom.

    Since 2012, though, when I started taking high dose selenium and N-acetyl-glucosamine every day (and have taken these daily ever since), I have not had any recurrence of my viral paresthesias.
     
    Last edited: Jan 11, 2017
  5. nandixon

    nandixon Senior Member

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    Not sure. If it turns out there is impaired S1P signaling, and it has an autoimmune basis, then I guess there might be a chance of it being helpful. [Edit: Although fingolimod initially acts as an agonist to the S1P receptor it ultimately behaves as a functional antagonist, so definitely not what we want.]

    But if there's not an autoimmune basis, we'd want an agonist with a purer mode of action and fewer side effects, I think.

    S1P itself has an extremely short half-life in the blood. (Reference) So any agonist analogue has to improve upon that (like desmopressin for vasopressin or fludrocortisone for aldosterone).

    Alternatively, we might find something to inhibit one or more of the various enzymes that degrade S1P, especially S1P lyase (S1PL), which irreversibly degrades S1P.

    And of course there's rituximab (which may or may not be working by an autoimmune mechanism), but that's a different concept than a daily medication.
     
    Last edited: Jan 12, 2017
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  6. eljefe19

    eljefe19

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    I am considering Rituximab treatment actually.
     
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  7. alicec

    alicec Senior Member

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    Allithiamine is a natural form derived from garlic. Sulbutiamine is a synthetic analogue based on allithiamine structure. They act in the same way.

    They are described as fat soluble (even though allithiamine at least is very water soluble - presumably sulbutiamine is also) because their structure allows them to readily cross cell membranes, including the BBB. Lipophilic would be a better description.

    @Sidereal, perhaps the lack of effect of allithimine on the cognitive function is simply because the cause is not related to thiamine. Allithiamine certainly crosses the BBB.

    This capacity to readily cross the cell membrane means they are not limited by the slow uptake mediated by a specific transporter that applies to thiamine. High levels can be built up in cells.

    Note that benfotiamine is often claimed to be one of the allithiamine family. It is not. It has a different structure, does not have the same capacity to cross membranes and does not cross the BBB. It is not lipophilic.
     
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  8. junkcrap50

    junkcrap50 Senior Member

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    If your theory is correct and it is impaired S1P signalling, wouldn't it be fairly easy to measure and test? First, measure S1P levels sine neither Naviaux and Fluge seem to have done so. Second, add some (in increasing concentration/dose) S1P to cultured CFS/ME cells and see how they behave and if they act like they do when exposed to non CFS blood. Third, test for antibodies to S1P.

    Have you thought about writing a paper of your theory and sending it to Naviaux and Fluge & Mella or their contacts/representatives that are on Phoenix Rising? You seem to have a good grasp of the science and maybe they haven't thought of it yet.
     
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  9. J.G

    J.G

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    I actually test positive for anti-mitochondrial autoantibodies, albeit at a borderline titre (1:40).

    One possible interpretation is that, if one sees ME/CFS as a purposeful, adaptive response to a uncleared/unclearable pathogen (as Naviaux et al 2016 speculate), AMA could serve as a secondary mechanism to inhibit the Krebs cycle. I think of them as a non-essential annexe to whatever primary autoab and/or pathway up/downregulation suppresses PDH.

    If they'd been present in significant quantities in patient groups' serum we would have heard about that from the German-Norwegian nexus by now, I feel.
     
    Last edited: Jan 11, 2017
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  10. Hip

    Hip Senior Member

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    My own hunch is that it may be more the other way around: that ME/CFS is a purposeful state that is carefully organized and orchestrated by the pathogens that infect us, in order to prevent the body and immune system from destroying these pathogens, and clearing the infection.

    If you look at the numerous cunning techniques that infectious pathogens use to thwart the immune response (collectively called immune evasion), it becomes apparent that pathogens are masterful "hackers" of the human body and immune system; pathogens have evolved ways to control the bodies of the hosts they infect, in order to ensure they are not destroyed and cleared from the body.

    In this earlier post, I mention how the viral VP capsid protein from coxsackievirus B (a virus found active in the muscles of most ME/CFS patients) has a molecular similarity to mitochondrial translocator protein, and thus this virus appears to trigger an autoimmune attack on the mitochondria. This autoimmune attack has been observed in coxsackievirus B myocarditis, which is a disease involving viral infection and a low energy state of the heart muscle. This autoimmune attack on the mitochondria found in myocarditis may be the basis for the low energy state of ME/CFS as well.

    From the viruses' perspective, creating this low energy state via autoimmune attack may simply be an immune evasion survival strategy, that prevents the immune system from effectively clearing the virus.

    That's just speculation, but what I am saying is in general is that the state of ME/CFS may be more the result of viral immune evasion, rather than an adaptive response of the body to an unclearable pathogen. Although it might be a bit of both.
     
  11. nandixon

    nandixon Senior Member

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    I tagged @Ben Howell in a previous post a couple pages ago here, and this is @deleder2k's thread, who I believe is actually in the current Phase 3 rituximab trial in Norway, so hopefully he'll ask Fluge/Mella about testing for S1P levels and looking for autoantibodies to the S1P receptors and to S1P itself.
     
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  12. Learner1

    Learner1 Professional Patient

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    I'd posted this on another thread, but a couple of wise people suggested I also post it here...

    Investigating why I'm always so short of P5P, and what it's used for, I stumbled upon this:

    This describes PLP (P5P or B6) and it's importance in sphingolipids and immune function.

    http://www.folk.uib.no/mfapu/Pages/papers pdf/2013/paul_2013_nr_71-239.pdf

    I extracted this from the PDF:

    PLP-dependent metabolism of sphingolipids


    Reduced availability of PLP is associated with reduction
    in several components of the immune response, includ-
    ing significant decreases in lymphocyte numbers, espe-
    cially T-helper cells and IL-2 production in humans.6
    Lymphocytes isolated from vitamin B6-deficient subjects
    also show reduction of lymphoproliferative responses to
    mitogens that activate both T and B cells when grown in
    a culture medium containing adequate concentration of
    PLP.6 This has been attributed to the lower numbers of
    T-helper cells in the lymphocyte population from vitamin
    B6-deficient subjects. Maturation and egress of lympho-
    cytes, especially T-cells, from thymus and lymph nodes
    relies on the gradient of sphingosine-1-phosphate (S1P).
    PLP-dependent enzymes play a major role in the synthe-
    sis and breakdown of S1P, which is a potent metabolite
    that regulates inflammation and immune response pro-
    cesses such as cell growth, survival, differentiation, lym-
    phocyte trafficking, vascular integrity, and cytokine
    and chemokine production.58,59 PLP is required for the
    activity of serine palmitoyl transferase that catalyzes the
    condensation of serine and palmitoyl CoA into 3-keto-
    dihydrosphingosine, which is then converted to S1P
    in a series of reactions.58–60 PLP is also a cofactor for
    sphingosine-1-phosphate lyase, which irreversibly cleaves
    S1P to regulate its concentration.58,59,61 A gradient of S1P
    is required for lymphocyte egress from thymus and
    peripheral lymphoid organs, which is maintained by S1P
    lyase.62 Administration of vitamin B6 antagonist 4’ deoxy-
    pyridoxine interferes with the S1P gradient, results in
    accumulation of mature lymphocytes in the thymus, and
    depletes B- and T-lymphocytes from lymph causing lym-
    phopenia.62 These conditions can be reversed by provid-
    ing excess vitamin B6 in the diet.62 During inflammation,
    S1P concentration increases in the inflamed peripheral
    tissues,63 which functions as a chemoattractant for the
    inflammatory cells.
    One of the intermediate products during the synthe-
    sis of S1P from 3-keto-dihydrosphingosine is ceramide,
    which plays an important role in inflammatory processes.
    Ceramide functions as a second messenger mediating the
    effects of tumor necrosis factor-a and interferon-g on
    programmed cell death and regulating senescence.64,65 An
    increase in cellular ceramide concentration is observed in
    cystic fibrosis, experimental autoimmune encephalomy-
    elitis, and diet-induced insulin resistance, all of which are
    marked by chronic inflammation.66–68 The importance of
    ceramide in these diseases is demonstrated by the fact
    that manipulation of ceramide concentration via inhibi-
    tion of serine palmitoyl transferase or mutation of sph-
    ingomyelinase, reverses the pathology of the disease.66–68
    Ceramide-1-phosphate, which is derived from ceramide,
    activates mast cells that mediate inflammation.69
    Thus, it is possible that is a higher demand exists for
    PLP during inflammation due to the role of PLP in the
    synthesis of S1P and ceramide, and maintenance of S1P
    gradient.
     
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  13. lansbergen

    lansbergen Senior Member

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    Old veterinary knowledge: when you suspect a virusinfetion give them Vit B6. Better the whole B complex or B6-B12-B1-B2 together.
     
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  14. Ben Howell

    Ben Howell OMF Correspondent

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    Hey @nandixon

    This is an interesting discussion. I will certainly put this across. As for Naviaux I do not know.

    Thanks,

    B
     
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  15. Ben Howell

    Ben Howell OMF Correspondent

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    Hey @J.G

    One thing to point out is that with Naviaux, the belief is not that a pathogen is uncleared, but rather a response to a 'trigger' that has not 'reset' itself properly. The initial trigger may be long gone, but the maladaptive systemic response is the issue.


    B
     
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  16. Sidereal

    Sidereal Senior Member

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    Perhaps so but in my experience at least their effects in vivo are vastly different. Sulbutiamine does seem to improve cognition, it's just that its side effects are intolerable.

    I tend to think that all the symptoms of this illness are fundamentally caused by the same problem: lack of energy. Allithiamine didn't just improve the "fatigue"/exertional intolerance (while it lasted), it also cleared up other wacky problems frequently found in ME/CFS: alcohol intolerance, inability to catch normal infections like colds/flus, hypersensitivities to sound/light/movement/crowds/etc., hypokalemic reactions to methylation supplements etc.
     
  17. Snow Leopard

    Snow Leopard Hibernating

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    If there are autoantibodies involved in this disease, it is most likely subset(s) of GPCR that are targeted (some GPCR have already been studied by Carmen Scheibenbogen et al) - these receptors that tend to internalise after antibody binding and thus are less likely to lead to inflammitory immune complexes. The second aspect is targeting specific GPCR is a plausible explanation for the symptoms and symptom kinetics (PEM), as discussed in this thread.
     
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  18. Learner1

    Learner1 Professional Patient

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    Why B6?
     
  19. J.G

    J.G

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    Ben, thanks for pointing that out. Hit-and-run indeed seems the prevailing paradigm at the moment, but to my (limited!) understanding, the Naviaux paper doesn't make the argument either way (hit-and-run or latent/chronic pathogen). Maybe they've later clarified their position elsewhere, but in the paper, they simply say:
    That could go either way, adaptive or maladaptive. There's some anecdotal evidence suggestive of a persistent pathogen floating around these boards (success with antivirals/antibacterials; or maybe I'm just misunderstanding how/why they might help).

    I fully agree that hit-and-run is a cleaner, elegant, and scientifically more helpful hypothesis than chronic pathogen, since it is helping to direct our attention towards energy metabolism, gene expression, etc. rather than orchestrating pathogen hunts that are doomed to fail due to heterogeneity and the maladaptive (sub)group. But I think it's too early to discount the persistent infection hypothesis entirely. Agree to disagree, of course!
     
    Last edited: Jan 13, 2017
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  20. lansbergen

    lansbergen Senior Member

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    No idea. Its more than 30 years ago. i am pretty sure it was based on clinical observation. .
     

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