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ME/CFS: In Free Fall Through the Looking Glass
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Xpr1 is an Atypical G-protein Coupled Receptor that Mediates Xenotropic and ...

Discussion in 'XMRV Research and Replication Studies' started by Deatheye, Nov 16, 2011.

  1. greenlantern81

    greenlantern81

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    We honestly have no idea if systemic administration of forskolin would have a positive effect in an xeno / polytropic retrovirus-infected organism, especially given that the drug would be hitting all sorts of unaffected tissues and cells. Our work is preliminary and there is no direct evidence of Xpr1 disfunction in in humans, so treatment with forskolin would be premature. None of the authors are MDs either, so we cannot and don't give medical advice.
  2. Rrrr

    Rrrr Senior Member

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    thanks for your thoughts.

    i did look it up, and it is not a drug, but an over the counter supplement.

    best,
    rrrr
  3. anne_likes_red

    anne_likes_red Senior Member

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    It's also part of Andy Cutlers protocol. Not a "basic" first tier supplement but recommended for specific symptoms. He suggests it's useful (along with other things) if your heavy metal toxicity is compounded by autoimmune problems, allergies, asthma. There are a ton of references to it in his books.
    Anne.



  4. alex3619

    alex3619 Senior Member

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    I have been keeping quiet on this paper since it leaked. In 2002 I was working on a CFS model (not calling it ME back then, though sometimes ME/CFS) which was a twist on my earlier hypercitricemia model. In it I postulated a failure of the cAMP/Ca++ axis as a cause of CFS, but this was never published - though it was discussed in a private online research forum. I also looked at forskolin, but I was not sufficiently happy with the safety profile to use myself as a guinea pig. Essentially there was an hypothesis that we have hypercitricurea. A UK study then couldnt find it. Everyone took that as evidence it was wrong. However, the results they got were entirely predicted by the prevailing model (and mine), they just misunderstood the model. They made the presumption that citrate was constantly elevated, and couldnt find it, but the evidence from the researchers was that it was elevated during late sleep, not during waking hours, and could even be low during waking. I am not sure if this was published however.

    My hypothesis, the second version (there is a third version too, more recent, again not public), was that there was a citrate burst during sleep. (Version 3 also has this.) This resulted in massive depletion of calcium, which led to disproportionate release of calcium in compensation, from internal stores. Ionic calcium is in balance with cAMP, and this would lead to a daily disturbance in the cAMP/Ca++ balance. This would give rise to early morning abnormalities of vascular regulation such as described by Vance Spence (who I had talked to at the time).

    I am not saying this is right, but its worth thinking about, if not in relation to ME then in relation to any Ca++/cAMP disturbance. Its an axis is my understanding, which means the balance regulates hormone synthesis, since these are critical regulatory chemicals inside cells.

    Version three is the same model but not trying to show causality, just pathology (version 2 attempted to show a causal model). Essentially it was postulated that certain signals of oxidative stress might release a citrate burst during sleep. This would flush the cells of metals, including free iron. The cells cannot tell what is causing the oxidative stress, only that it is present, so flush with citrate to try to correct it. I called this the Citrate Flush Hypothesis.

    These are both old models, I have not worked on them in nearly 9 years. I raise them only for debate, not because I think they are right.

    Bye
    Alex

    PS A critical predictor, never tested, was that the calcium-cAMP disturbances would vary between early morning and later in the day. It might indicate that timing of tests in the patient's own circadian pattern was important.
  5. Rrrr

    Rrrr Senior Member

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    alex, thanks for all this work! and for telling us. i'm not very smart when it comes to science. does this mean our calcium levels should be "off"? mine are not.

    rrrr
  6. greenlantern81

    greenlantern81

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    hey Alex, is any of that published? I'd love to read it.
  7. alex3619

    alex3619 Senior Member

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    Hi greenlantern81, Rrrr, no it wasnt published. My health was in full decline, I had just finished my biochemistry degree, and my finances hit rock bottom. I did discuss it with some docs and researchers, but that is about it. An earlier (incorrect) version (version 1), my first attempt, was presented at the 1999 CFS conference in Sydney as a poster. I was also unable to pursue my Ph.D. (for a second time, on this my second degree) due to falling health - I had a potential opportunity to work on certain aspects of oxidative stress in beetles (alas not humans), although the chemistry would have been similar for humans.

    The hypothesis was speculative, trying to explain the data known at that time. The common view of the hypercitricuria claim was that it was for a constant elevated urinary citrate, but none of the people involved in the research itself seemed to hold that claim, it was a common misconception so far as I know. One doctor who had patients with elevated early morning urinary citrate put them on twenty four hour urinary citrate testing and found their levels were low.

    Citrate is a calcium chelator - in fact a divalent cation chelator. I am not sure it will modify whole body citrate (that would require excretion), and in particular it will only have a real impact on ionized calcium (Ca++) not other forms of calcium. We release melatonin during sleep, which is a powerful antioxidant. I postulated (version 3) that we might release a spike of citrate from the mitochondria via similarly induced or even connected mechanisms, to flush the mitochondria and even the cell. Divalent cations would be bound. Since Ca++ is an intracellular messenger, this would have immediate impact. Since Ca ++ and cAMP tend to be inversely proportional inside a cell (and I have not looked into this sufficiently to be certain of this, and it was a decade ago, I don't know current developments) this would knock out hormone balance. Essentially hormone production (and I am primarily concerted with para- and auto-crine hormones here) would be skewed.

    If there was intracellular ionized calcium depletion, then a trigger (such as acetylcholine) might induce a larger than normal ionized calcium burst - this has been observed in situations with high cellular citrate. Indeed, I advised Vance Spence that citrate was a known cause of the kinds of things he was discussing at the time, a fact I got from aluminium toxicity research (which involved using citrate, with observed exagerated acetylcholine responses). Essentially he saw excessive micro-vasodilation. Calmodulin is triggered proportional to the level of ionized calcium it is exposed to - and can remain activated for up to six hours. This means the problem would be a six hour spike in the morning. This was a critical predictor of my model, which I was trying to confirm but no researcher I talked to at the time had been collecting data that could provide evidence for or against this. However, one orthostatic intolerance knowledgeable cardiologist claimed that he was much more likely to provoke a strong tilt table response in the first so many hours after sleep. Late afternoon rarely induced a response.

    I never pursued this, put it on the back burner while the science evolved, hoping I would regain more capacity. Instead, my cognitive capacity has been in decline, although my finances are now stable.

    I am happy to discuss this further, but I am very out of date on this science now (much would have changed in the last ten years).

    In response to Rrrr, no it might not impact whole body calcium levels, though I think it might put a drain on divalent cations such as calcium this depends also on other factors such as dietary intake and excretion regulation (e.g. vitamin D).

    Bye, Alex

    PS An implication of this might be that mitochondrial testing will also show a circadian variation, a potential cause of confounding data.

    PPS At least one of the researchers I was discussing this with at the time is a member of PR, but I leave it to him to disclose who he is since it was confidential at the time.

    Oh, almost forgot, welcome to the forums greenlantern81!
  8. MDL

    MDL

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    We have to look at the role of hydrogen sulfide

    You will want to note the mention of forskolin in this first article" Vasoconstrictive effect of hydrogen sulfide involves downregulation of cAMP in vascular smooth muscle cells": http://www.ncbi.nlm.nih.gov/pubmed/18787076

    A second reference "Hydrogen sulfide regulates cAMP homeostasis and renin degranulation..." (which brings me back to the low aldosterone finding in ME/CFS) focuses on kidney cells, but it does seem to me to be relevant to the discussion : http://ajpcell.physiology.org/content/early/2011/09/19/ajpcell.00341.2010.abstract

    What do you think? Does this fit, Alex and GreenLantern81? Ecoclimber? Anybody else?
  9. greenlantern81

    greenlantern81

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    I'll have to look into this more, as I haven't really thought about the possibility of global deregulation of cAMP / Ca2+ in the context of our work. What we're seeing seems to be very cell-type specific, i.e. only neurons are affected. I've only considered cAMP in terms of it being the second messenger transducing the "pro-survival" signal (or not, in infected cells) in neurons.
  10. MDL

    MDL

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    Thank you for that suggestion. Here is another reference (which I find difficult to follow), but maybe you could put it into context: "H2S protects hippocampal neurons from anoxia-reoxygenation through cAMP-mediated PI3K/Akt/p70S6K cell-survival signaling pathways":http://www.ncbi.nlm.nih.gov/pubmed/20967511

    There is much to explore on the calcium side. For example: "Hydrogen sulphide regulates calcium homeostasis in microglial cells" http://www.ncbi.nlm.nih.gov/pubmed/16718684

    Please let me know what you think, and thank you!
  11. alex3619

    alex3619 Senior Member

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    Hi MDL, anything that modifies cAMP modifies Ca++ levels, and since they are the two key intracellular messengers, together they regulate everything else to some extent. So this could be important, or not. Its certainly interesting. This whole area of intracellular messengers in ME research deserves more attention from researchers. Bye, Alex
  12. alex3619

    alex3619 Senior Member

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    Hi, I looked at ways to improve hypoxia tolerance back in the late 90s. I think two aminos stood out, glycine and alanine. At the time no mechanism was known, at least to me, as to why this helped. It was just an empirical observation with hypoxia researchers. This all ties in with H2S and NO of course, its all connected. Unravelling the connections is the trick - they exist but are they relevant in all ME patients, just a subset, or none? It just begs for more research. So much of our hypothetical biochemistry is like that: this is real chemistry, but is it relevant? My mantra has always been: we need more research.

    One critical factor, again empirical, that I was very interested in, was that massive amounts of arachidonic acid are released during reperfusion injury events. Arachidonate stimulates a massive oxidative stress burst from the mitochondria (mechanism unknown in 2000 or so). It also induces inflammatory hormone synthesis, way too much. This mechanism is probably why alchohol poisoning kills, as arachidonate is released at high alcohol concentrations (biologically high, as in very drunk). When this is blocked with drugs, alcohol poisoning becomes nonfatal.

    Bye
    Alex
  13. MDL

    MDL

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    Hi Alex,

    I do believe in the underlying hypoxia/oxidative stress theories of ME/CFS, (which is not to say oxygen is toxic), and I think that H2S may go a long way toward explaining these findings. As for oxygen, rather than it being toxic, it may be a big part of the solution.

    What I like about your comments is that you assume that ME/CFS is related to the gases, which is not a commonly held view! In fact, it is a pretty radical view, but one which, I think, eventually, will come to be accepted. It is my hypothesis that disturbances in H2S metabolism and homeostasis are the key to this disease. Life began with H2S, and there is a reason why H2S has been conserved in our mitochondria as a substrate alternative to oxygen since then. Emerging research on redox will eventually bear this out, I think, but we shall see.

    Regarding arachidonic acid, I have always wondered about this, and yes, H2S plays a role, which tells us something about its effect on fatty acid metabolism, another problem evident in PWC. In the reperfusion/arachidonic cascade process, a recent study suggests that H(2)S could activate PLA(2), which in turn releases arachidonic acid leading, initially, to vasoconstriction followed by vasodilation mediated by cytochrome P450-derived metabolites.: http://www.ncbi.nlm.nih.gov/pubmed/21228064 The study goes on to say that H2S may act through the Endothelium-Derived Hyperpolarizing Factor (EDHF), which is involved in the hyperpolarization and relaxation of vascular smooth muscle cells.

    Another article (http://www.ncbi.nlm.nih.gov/pubmed/21980127) confirms this finding and explains how it works: H(2)S is a major EDHF that causes vascular endothelial and smooth muscle cell hyperpolarization and vasorelaxation by activating the ATP-sensitive, intermediate conductance and small conductance potassium channels through cysteine S-sulfhydration. It goes on to say Because EDHF activity is a principal determinant of vasorelaxation in numerous vascular beds, drugs influencing H(2)S biosynthesis offer therapeutic potential. I second that idea!

    BTW, it is also of note that that EDHF plays a key role in celiac disease: http://www.celiac.com/articles/2252...al-Inflammation-in-Celiac-Patients/Page1.html. This should not pass unnoticed!

    As for specific amino acids, that is a very complex subject. Does an excellent profile and analysis of ME/CFS amino acids patterns exist anywhere? That would be useful. I believe cysteine deserves far more attention, read NAC and P-5-P.

    Just to bring this discussion full-circle, EDHF is involved in cAMP (a few posts back). http://www.pnas.org/content/99/9/6392.full

    From the few posts Ive made, I think it is obvious that there are many, many reasons to look seriously at hydrogen sulfide metabolism and its role in ME/CFS. I'd like to hear more about blocking arachidonic acid.

    All best,
    Marian
  14. alex3619

    alex3619 Senior Member

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    Hi Marian, there is no doubt H2S is involved as are many factors. The question, as always, is involved to what extent? Most of the theories that have cropped up over the last several decades involve real processes. They are there. The issue is: are they important in ME?

    At least two factors increasing arachidonic acid release in ME have been known for a long time, H2S makes three.

    I am aware of de Meirleir's research in severe ME patients, showing that H2S levels are proportional to severity. It follows that one of three things must be true (or all three):

    A. H2S is involved in ME chemistry.
    B. H2S is a marker of ME severity.
    C. H2S is causally involved in ME chemistry.


    Of course this presumes that de Meirleir's results are typical - they need replication. The claims go from duh, its obvious, to maybe. I call this kind of list (and it could be made longer, with more steps) a ladder of evidence. As we learn more we move up the ladder. Most of the modern interesting models of ME have moved a long way up the ladder - but it requires a lot more evidence to reach the top.

    There are drugs that block arachidonic acid, one of which is used in alcohol poisoning ( I forget the name at the moment). I favour simple dietary changes for baseline control, using mechanisms of competitive inhibition and mass action - using fish oil (EPA) and extra virgin olive oil. A second layer is about inflammatory mechanisms. This has included hormones and nitric oxide. Now it seems it includes H2S. Then we have drugs for acute crises, which include cortisol.

    Essentially we will have a big clue when we can emprically block a pathway to eliminate ME symptoms - some or all. That requires testing, first in the lab then in clinical trials.

    So while I do not support the view that H2S is causally involved, I am aware of it and I think its an important open question that needs to be answered - we need strong evidence one way or another. If the evidence can show it is causally involved I will be ecstatic.

    The other confounding factor is loops or cycles. We are still learning about body chemistry. In 1993 I was introduced to the idea of vicious cycle mechanisms in CFS (ME definitions were not used), involving in this case arachidonic acid. As we learn more chemistry, the number of loops multiplies. So all these factors play a part - but is it a combination of loops or one critical loop? And which loop?

    Best wishes,
    Alex

    PS One last point: a driving force could be behind all the loops of course. That include pathogens.
  15. MDL

    MDL

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    Hi Alex,

    First of all, if you think that there is value in pursuing the arachidonic cascade, I would really encourage you to put it forward. We are all looking for answers and you obviously know a lot about this disease.

    As for H2S, I think that it has the potential to serve as a unifying hypothesis for the underlying mechanism of the disease, in that most specific findings can be explained. In attempting to address specific findings, I have tried to shed light on the greater whole.

    For example, I wrote today on the thread "Boosting Mitochondria May Not Only Increase Energy, But Also Lead to Complete Viral Clearance about the coxsackie virus, a common suspect in ME/CFS:

    In China, where interest in H2S is high, scientists recently infected mice with coxsackievirus B-3 virus and looked at CSE: In the myocarditis group, the serum H2S content and H2S production rates in cardiac tissues were significantly higher than those in the control group 4 and 10 days after injection (P<0.05). The expression of CSE protein in the heart in the myocarditis group was also significantly higher than that in the control group The authors concluded that CBS and its downstream production of H2S increase in mice with acute viral myocarditis. From this, they postulated that the increased expression of CSE/H2S pathway might be involved in the pathogenesis of viral myocarditis. http://www.ncbi.nlm.nih.gov/pubmed/20849728 and, on glutathione...

    Further, as far as glutathione in the mitochondria is concerned, hydrogen sulfide again comes into play. In fact, Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria.
    http://www.ncbi.nlm.nih.gov/pubmed/19852698

    It seems to me that these are not idle observations, but instead could hold the seeds of real understanding.
    As always, I appreciate your thoughtfulness.
    Marian
  16. MDL

    MDL

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    Absolutely!

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