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Ponderings and speculations about purinergic signaling, in pursuit of a unified ME/CFS theory

Discussion in 'General ME/CFS Discussion' started by necessary8, Oct 29, 2017.

  1. anni66

    anni66 mum to ME daughter

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    This may be completely off the wall as i do not have a science background, so may be of no consequence, but does lack of intracellular magnesium affect signalling.
    My daughter' s ATP profile test showed a lack of magnesium bound ( so therefore capable of being used) ATP.
    Magesium as well as calcium ions are involved in many reactions and play key roles in some enzymatic functions.There is a proportional relationship required , so if this is disturbed what happens?

    Are magnesium levels impacted by calcium in/ outflows, and what effect does a lack of magnesium have ( impact on PH? / Affect on membrane potential? )
    Sorry if this is basic - my biochemistry stopped too many years ago to admit!
     
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  2. debored13

    debored13 Senior Member

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    http://www.sciencedirect.com/science/article/pii/S2319417016301287
    "
    Abstract
    Purinergic signalling plays a crucial role in immunity and autoimmunity. Among purinergic receptors, the P2X7 receptor (P2X7R) has an undisputed role as it is expressed to high level by immune cells, triggers cytokine release and modulates immune cell differentiation. In this review, we focus on evidence supporting a possible role of the P2X7R in the pathogenesis of systemic lupus erythematosus (SLE).

    Keywords
    Extracellular ATP
    P2X7R
    Systemic lupus erythematosus
    NLRP3 inflammasome
    Interleukin-1β"
    it's about purinergic signalling in lupus but figured it might be relevant
     
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  3. debored13

    debored13 Senior Member

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  4. nandixon

    nandixon Senior Member

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    Good catch @dreampop. I didn't realize Naviaux was viewing ME/CFS as rather the opposite of the CDR (and thus at least somewhat the opposite of autism in that respect).

    Interestingly, in the Light paper here, which you had also previously mentioned, it was found that mRNA expression of the P2X7 receptor (aka P2RX7) in ME/CFS was upregulated in leukocytes, whereas it was downregulated in Naviaux’ autism mouse model study (in cerebral synaptosomes). I wasn't aware of the Light finding, either, sorry to say.

    So there is perhaps the interesting situation where suramin might theoretically work in both seemingly opposite settings:

    In autism (a CDR case), suramin might reduce the amount of external ATP (by antagonizing various P2 receptors) and thus cause a compensatory upregulation of P2X7 expression.

    While in ME/CFS, suramin might directly antagonize P2X7 and thus effectively downregulate the activity of that (possibly) over-expressed receptor in that way. (A more specific P2X7 antagonist than suramin might be better to use, though.)

    I hope that makes sense, anyway.
     
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  5. debored13

    debored13 Senior Member

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    The plot thickens. Damn is this kind of stuff hard to understand from a laypersons perspective. Two thoughts. There are drugs that work probably by causing compensatory upregulation of that which they are antagonizing, such as low dose naltrexone, but id imagine that those kind of mechanisms are really hard to predict compared to the effects of an agonist. And there are also drugs or herbs that seem to cause regulatory effects on various chemicals or hormones--if it's too high it brings it down, and vice versa. Soviet scientists called these "adaptogens" and I believe that term is contested, but it does suggest that there are drugs that contribute to homeostatic effects rather than simply agonize or antagonize. This effect isn't very well understood. I wonder if part of the effect we are discussing relies on that
     
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  6. Ben H

    Ben H OMF Correspondent

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    Hi guys,

    Just to let you know I passed @necessary8 's theory on to Prof. Davis who found it interesting and is passing it onto members of his team. They were working on a similar theory around a year ago iirc.

    So keep working on the ideas, Prof. Davis really does listen and read them.


    Ben
     
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  7. Jesse2233

    Jesse2233 Senior Member

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    @Ben H great news! thank you! extremely gratifying to hear patients theories being taken seriously

    @nandixon still having benefit from Clemastine?
     
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  8. Aroa

    Aroa

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    Also tagging @dreamydays , I think he was trying it as well
     
  9. dreamydays

    dreamydays

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    Hi Aeoa, in a bit of a crash at the moment so will try in a few weeks.
     
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  10. nandixon

    nandixon Senior Member

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    It's still helping but I'm not sure why. As one possibility, it may be improving the quality/depth of my sleep, which has been a great problem ever since I developed ME/CFS.

    To be clear, it's not likely I would have even tried clemastine in the first place had I been aware of what I posted earlier here, especially since the Light study I mentioned, where increased gene expression of the P2X7 receptor was found in ME/CFS, appears to be consistent with the latest research by Mark Davis and Maureen Hanson indicating increased T cell activation in ME/CFS (my favorite line of research).

    The following study, in particular, seems to indicate this consistency:

    (Emphasis added)

    The potential ability of clemastine to further upregulate P2X7 (by making it more sensitive to lower concentrations of external ATP) would seemingly not be desirable then. (At the dose I'm currently taking in the evening of just half of a 1.34 mg tablet there may not be much of an effect on P2X7 anyway.)
     
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  11. debored13

    debored13 Senior Member

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    i've been trying to find an antihistamine that would be good for sleep with few side effects. i've heard cyproheptadine is good
     
  12. anni66

    anni66 mum to ME daughter

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    Another 3.30 am thought- given the many symbiotic ratio relationships with electrolytes- what does influx/ outflow of Ca, K, Na, P do to blood PH and buffering capacity/ energy gradients and signalling?
    Sorry if this is basic i am doing a lot of catch up
     
  13. wastwater

    wastwater Senior Member

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    I wondered does FOXO need upregulating and saw this Isothiazolonaphthoquinone small molecule activator of FOXO
     
  14. debored13

    debored13 Senior Member

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    guys I've been thinking about thyroid in this context. symptoms of hypothyroidism aren't exactly the same as cfs but some crossover. so then i thought "what's the connection between thyroid and purinergic signalling". not only do I not have a science background but I've been a lot worse illness wise lately, so sorry for the short, scattered post. this may yield some interesting stuff for any of you that understand the science better than me tho

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944044/





    https://www.hindawi.com/journals/jtr/2013/434727/



    @Hip @Learner1 @necessary8
     
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  15. Learner1

    Learner1 Forum Support Assistant

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    Thanks, @debored13 I'll have to chew on these awhile. ;)
     
  16. debored13

    debored13 Senior Member

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    I've gotta be careful to not go crazy with the research rn because I feel I'll bring on a crash...
    but had some labs that finally started to show some stuff--several low IgG subclasses, but also several high ones. dr levine didn't concentrate on the high ones much but I wonder if they have something to do with purinergic signalling and would fit into this theory. I can post my labs later


    also positive for high IgE antibodies. and several viruses, that levine said indicated recent infection
     
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  17. debored13

    debored13 Senior Member

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    Also was just rereading Naviaux's paper on the CDR, and saw this: "An important caveat to APT is that if the physical, chemical, or biological trigger of the CDR has not been eliminated or neutralized, treatments designed to inhibit a persistent CDR may have mixed effects." In my case I have viral loads which need to be treated, I feel less sure about whether I need to treat bacterial issues, but I would consider doing that more strongly before trying anti-purinergic therapy.
     
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  18. imitate-past-reign

    imitate-past-reign

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    Instead of treating this point in the cascade, with suramin, which has a Ki antagonism for anti-P2x which there is no evidence is occurring in CFS patients more than every illness, why not take the direction of the original authors of a similar theory, or treat with NK or T-cells? Suramin is a "small-molecule" drug with a bevy of moeities that cause multiple interactions throughout innumerable binding to proteins, which will at minimum lead to adverse drug reactions at large enough receptor occupancy.

    Or treat the problem upstream with better anti-infectives, since it is contingent on that milieu. Moreover, suramin is broad-spectrum effective against viruses d/t its interaction with helicases.

    The point is, even if purinergic signaling is a component of the problem, why is this point in the cascade being targeted?
     
  19. debored13

    debored13 Senior Member

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    is there something upstream of purinergic signalling?

    sincerely,
    a total noob
     
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  20. debored13

    debored13 Senior Member

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    On the other hand, rather than focusing on every infection and sensitivity and allergy, I've been thinking about the big picture of a disordered response to things, recently. lots of people get lyme and are alright (although 20% of people get PTLDS to varying degrees, actually a high percentage). Lots of people get viruses and are alright. What's the problem with my system that I respond in such a way?
     
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