Novel characterization of endogenous transient receptor potential melastatin 3 ion channels from Gulf War Illness participants 2024 Marshall-Gradisnik

Discussion in ''Conditions related to ME/CFS' news and research' started by Andy, Jun 26, 2024.

  1. Andy

    Andy Committee Member

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    Abstract

    Gulf War Illness (GWI) is a chronic condition characterized by multisystem symptoms that still affect up to one-third of veterans who engaged in combat in the Gulf War three decades ago. The aetiology of GWI is mainly explained by exposure to multiple toxic agents, vaccines, and medications. As there is a significant overlap in symptoms between GWI and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), the objective of this study was to investigate a biomarker widely reported in Natural Killer (NK) cells from ME/CFS patients, the Transient Receptor Potential Melastatin 3 (TRPM3) ion channel.

    NK cells from 6 healthy controls (HC) and 6 GWI participants were isolated, and TRPM3 function was assessed through whole-cell patch-clamp. As demonstrated by prior studies, NK cells from HC expressed typical TRPM3 function after pharmacomodulation. In contrast, this pilot investigation demonstrates a dysfunctional TRPM3 in NK cells from GWI participants through application of a TRPM3 agonist and confirmed by a TRPM3 antagonist. There was a significant reduction in TRPM3 function from GWI than results measured in HC. This study provides an unprecedented research field to investigate the involvement of TRP ion channels in the pathomechanism and potential medical interventions to improve GWI quality of life.

    Open access, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0305704
     
  2. Andy

    Andy Committee Member

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    For my own 'amusement', I discovered that the phrase "gold standard" was used 3 times in this paper in reference to the method of testing.
     
  3. John Mac

    John Mac Senior Member (Voting Rights)

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    Widely reported mostly by themselves. Have they reached a dead end with this finding in ME and are now just moving on to new diseases? What next TRMP3 in Lyme disease, TRMP3 in Long Covid?
     
    Last edited: Jul 2, 2024
  4. Kitty

    Kitty Senior Member (Voting Rights)

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    They've got the whole FND field to go at too.
     
  5. Hutan

    Hutan Moderator Staff Member

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    Does anyone know, has any other group ever tried to replicate this finding?

    NCNED got a fair chunk of the NHMRC AUD3 million funds, back in, what was it, 2021? to get on with things. But, they have never scaled things up. And now they are doing the same small study in a different disease.

    I haven't read this paper yet and I forget if we have discussed the TRPM3 finding in ME/CFS and dismissed it. But why doesn't NCNED cooperate with some other lab to replicate their finding? They've been claiming that they have solved ME/CFS for years, you'd think they would want someone else to say 'yep, it really looks like they have'.
     
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  6. Hutan

    Hutan Moderator Staff Member

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    Oops, I take some of that back.
    Authors:
    • Sonya Marshall-Gradisnik ,
    • Etianne Martini Sasso ,
    • Natalie Eaton-Fitch,
    • Peter Smith,
    • James N. Baraniuk,
    • Katsuhiko Muraki
    Looks as though the Baraniuk lab has got on board. Perhaps they had some Department of Defence GWI funding sloshing around. The paper could be worth checking out to see if it holds up.
     
  7. Hutan

    Hutan Moderator Staff Member

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    Introduction
     
  8. Hutan

    Hutan Moderator Staff Member

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    Methods
    So, it's looking as though it was done in the NCNED lab.

    Data about their symptoms was collected.

    Whole blood sample
    (We get told a lot of detail in some places, but I didn't see anything about how quickly the blood was processed)
    Peripheral blood mononuclear cells centrifuged out
    NK cells isolated by immunomagnetic selection

    Samples of NK cells didn't differ in purity.


    :)
    There were a lot of salts and other things in the solutions.

     
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  9. Hutan

    Hutan Moderator Staff Member

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    Results

    GWI and control groups matched on age and BMI.
    No differences in full blood counts between the groups

    WHODAS
    Electrophysiology experiments
    Figure 2
    Screen Shot 2024-06-26 at 11.00.53 pm.png
    It does look interesting. Hopefully someone familiar with the approach can tell us if it all holds together.
     
    Last edited: Jun 26, 2024
  10. Hutan

    Hutan Moderator Staff Member

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    Discussion


    (There's quite a lot of typos in the paper)

    Conclusion
    So, I guess the authors are suggesting GWI is a channelopathy, as is ME/CFS and Long Covid. Unfortunately, it looks as though we still don't have replication in a lab that isn't NCNED.

    But, maybe they are right? How would new NK cells be being produced with the channelopathy?
     
  11. Hutan

    Hutan Moderator Staff Member

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    The following paper has some background on TRPM3. But the paper is from 2008, and so surely more is known. I'd be interested to know why Sonya Marshall-Gradinisk has focussed on TRPM3 - was work done on a whole range of ion channels in ME/CFS and this was the one that wasn't working properly, or was there some reason that this particular ion channel was selected for investigation?

    Herbal Compounds and Toxins Modulating TRP Channels, 2008

     
  12. Nightsong

    Nightsong Senior Member (Voting Rights)

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  13. Hutan

    Hutan Moderator Staff Member

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    Transient receptor potential (TRP) channels: a clinical perspective, 2013
    A slightly more recent paper

    From the paper:

    TRPM3
    Endogenous agonists:
    Pregnenolone sulphate Wagner et al. (2008) [as used in this Marshall-Gradinisk study, with the GWI NK cells not responding to the stimulation]
    D-erythro-sphingosine Grimm et al. (2005)

    Endogenous antagonist:
    Progesterone Majeed et al. (2012) [interesting given female preponderance of ME/CFS, but not sure how it fits with reported improvements in pregnancy and a seeming lack of change in symptoms post-menopause]

    Exogenous antagonist:
    Rosiglitazone Majeed et al. (2011a)
    Mefenamic acid Klose et al. (2011)
    Naringenin, hesperetin, ononetin, eriodictyol Straub et al. (2013)
    TM3E3 (polyclonal antibody) Naylor et al. (2008)


    So, I'm imagining these molecules sitting in the cell membrane, with loops sticking out of the cell that can capture the molecules it is made to sense. Interesting about the possibility of multiple TRPs joining together and that they may have distinct pharmacological properties when they do that. This paper has a picture of a standard TRP:
    Screen Shot 2024-06-27 at 7.12.09 am.png

    I think this Marshall-Gradisnik GWI paper was suggesting that these channels might also be operating on the surface of organelles i.e. within the cell.

     
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  14. Hutan

    Hutan Moderator Staff Member

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    So, I guess the question I have is why hasn't the report of faulty TRPM3 in ME/CFS got more attention? The answer might be in forum threads on the older papers. Certainly the small size of studies and the lack of replication have contributed.

    But, it doesn't seem like a particularly difficult thing to attempt a replication of. Why haven't other labs had a look at this? Perhaps with Baraniak's involvement in this paper, there will be more attention and followup.
     
  15. Sid

    Sid Senior Member (Voting Rights)

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    :rolleyes:
     
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  16. forestglip

    forestglip Senior Member (Voting Rights)

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    ABC (Australia): Griffith University researchers believe cellular door dysfunction is the cause of long-misunderstood Gulf War Illness
    By Janelle Miles and Emma Pollard

    "In a world first, Australian researchers have identified a significant defect in the cells of Gulf War participants they believe explains an array of mystery health issues that have plagued many of the veterans for decades.

    The discovery, by Griffith University scientists, has given hope to the veterans that their often-debilitating symptoms will finally be recognised as Gulf War Illness by the medical profession and the Australian government.

    It may also have international ramifications, with almost a million people serving in the US-led coalition of countries against Iraq in 1990-91, including more than 1,800 Australians.

    Up to a third are estimated to suffer Gulf War Illness."

    ---

    "In a laboratory on the Gold Coast, the Griffith University study's lead researcher Sonya Marshall-Gradisnik and her team have identified faulty cell function in veterans which she suspects is caused by their exposure to hazardous biological and chemical agents during their Gulf War service.

    They compared the natural killer cells, a type of immune cell, in six Gulf War veterans with six healthy participants of similar age and gender in a pilot study recently published in the scientific journal, PLOS ONE.

    The team has since replicated their findings in another 10 veterans."

    ---

    "Professor Marshall-Gradisnik said the Australian scientists are the first to identify ion channel impairment as a potential explanation for Gulf War Illness.

    She said the scientists have found the same "faulty doors" in patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

    The specific ion channels, or faulty doors, are also known as threat receptors."

    ---

    "Clinical trials of low dose naltrexone on patients with ME/CFS and long COVID are planned after "rigorous" experiments in Queensland showed the drug can repair the "faulty doors" of their cells in the test tube.

    In new laboratory experiments, the Griffith University scientists are also testing whether naltrexone, a medication used to decrease cravings in people who are alcohol dependent, and other drugs, can restore calcium ion channel function in the damaged cells of veterans with Gulf War Illness."
     
    Last edited: Jul 14, 2024
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  17. Art Vandelay

    Art Vandelay Senior Member (Voting Rights)

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    Gulf War Syndrome is not recognised in Australia:

    Wessely given a platform yet again:

     
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  18. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Are you sure Simon? Or is that just wishful thinking?

    You mean by denying them disability payments, societal support and embrace, recognition of harm, and even the very potential of medical treatment and cure. Sure, good job.
     
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  19. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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  20. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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