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Anti-purinergic therapy restores itaconate/IFNa (Dr. Phair's theory) and Dr. Prusty's proposed abnormalities in ME/CFS

serg1942

Senior Member
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Spain
@serg1942 Could inosine and adenosine also be exacerbating the problem?
That's a very good question. On the contrary, the purinergic receptors for adenosine (P1 receptors) are mostly anti-inflammatory, and compensate for the inflammatory tone set by the receptors for ATP and ADP (P2).

In fact, adenosine agonists are been trialed for all kind of chronic inflammatory diseases and even for cancer.

This is why I like the idea of breaking ATP with an enzyme into adenosine to lower the extracellular ATP and increase the adenosine levels. There's an experimental drug known as APT102 that does this, but unfortunately it hasn't been trialed in humans yet.

A similar way to achieve this would be to increase the expression of the membrane-bound CD39 enzyme, which also degrades ATP into ADP. For example bilirrubin has shown to do this, and the animals studies are very interesting in this regard. Again, bilirubin is not available for human consumption.

However, it seems that inhaling carbon monoxide in very low therapeutic doses, might increase the CD39 expression. And this is something that I'll be trying soon.
Actually, anything that increases the expression of heme oxidase 1 will probably increase the CD39 expression, by increasing bilirubin and carbon monoxide levels.

So yes, perhaps the adenosine receptors might be very important when it comes to design an anti-purinergic therapy approach.

Best wishes,
Sergio
 
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serg1942

Senior Member
Messages
543
Location
Spain
This is interesting. I have CFS and also gout/high uric acid, which I am controlling with allopurinol. Can you suggest some links to read up on probenecid in relation to CDR?
Please excuse the late reply.

Switching to probenecid is a really good idea!

Here are some papers that I have compiled on probenecid, that you might like:

Probenecid, an Old Drug with Potential New Uses for Central
Nervous System Disorders and Neuroinflammation
https://www.mdpi.com/2227-9059/11/6/1516

PROBENECID PROTECTS AGAINST CEREBRAL
ISCHEMIA/REPERFUSION INJURY BY INHIBITING
LYSOSOMAL AND INFLAMMATORY DAMAGE IN RATS
https://pubmed.ncbi.nlm.nih.gov/26047730/

Probenecid arrests the progression
of pronounced clinical symptoms in
a mouse model of multiple sclerosis
https://pubmed.ncbi.nlm.nih.gov/29222419/

Probenecid Improves Cardiac Function in Patients With Heart Failure
With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium
Sensitivity In Vitro
https://pubmed.ncbi.nlm.nih.gov/29331959/
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
Another big link I think:

Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. https://pubmed.ncbi.nlm.nih.gov/17093123/

Orexin/receptor pathways play vital regulatory roles in many physiological processes, especially feeding behavior, sleep–wake rhythm, reward and addiction and energy balance.

Electrophysiological experiments have been used to identify factors that regulate orexin neurons. Recordings from transgenic mice expressing GFP in orexin neurons demonstrate that agonists of ionotropic glutamate receptors activate orexin neurons, while glutamate antagonists inhibit their activity. These results indicate that orexin neurons are tonically activated by glutamate. In addition, monoamine neurotransmitters such as dopamine, noradrenaline, and serotonin (5-HT) hyperpolarize and inhibit orexin neurons via alpha 2-adrenergic and 5-HT1A receptors. Other factors that reportedly influence the activity of orexin neurons include corticotrophin-releasing factor, ATP, neuropeptide Y, and physiological fluctuations in acid and carbon dioxide levels. It should be noted that factors involved in feeding (such as glucose, ghrelin, and leptin) inhibit the activity of orexin neurons https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345701/

The studies showed that orexins may directly excite serotonin (5-HT) neurons by activating K+ leak currents or Na+-dependent NSCCs https://pubmed.ncbi.nlm.nih.gov/11166339/ Unexpectedly, at higher concentrations, orexins indirectly inhibit 5-HT neurons by exciting GABAergic interneurons https://pubmed.ncbi.nlm.nih.gov/12417670/

Adenosine and INF(a) synergistically increase ifn-gamma (y) production of human NK cells. Here we show that the adenosine A(3) receptor agonist iodobenzyl methylcarboxamidoadenosine potently inhibited proliferation, IFN-gamma production, and cytotoxicity of activated human lymphoid cells. Stimulation of the A(3) receptor also caused apoptosis of activated PBMC. However, when PBMC were stimulated with IFN-alpha, adenosine did not decrease, but synergistically increased, the IFN-gamma production of NK cells. https://pubmed.ncbi.nlm.nih.gov/19095736/

Adenosine A3AR stimulation inhibits the respiratory burst, interleukin (IL) 1β, TNF-α, chemokine macrophage inflammatory protein (MIP) 1α, interferon regulatory factor 1, iNOS (inducible nitric oxide synthase), and CD36 gene expression. However, adenosine reduced the expression of adhesion molecules on monocytes and decreased cytokine production, effects that were potentiated by an A3AR antagonist. In addition, A3AR stimulation increased TNF-α production in activated macrophages https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756520/

Orexin A strongly ameliorated ongoing EAE, limiting the infiltration of pathogenic CD4+ T lymphocytes, and diminishing chemokine (MCP-1/CCL2 and IP-10/CXCL10) and cytokine (IFN-γ (Th1), IL-17 (Th17), TNF-α, IL-10, and TGF-β) expressions in the CNS. https://pubmed.ncbi.nlm.nih.gov/30894198/
 
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serg1942

Senior Member
Messages
543
Location
Spain
Is there any evidence that the CDR actually exists? Purinergic receptors and metabolism is altered in lots of diseases but the concept of CDR I believe is completely conceptual
Yes, it is very well studied state. It had been described in parts, with different names such as integrated stress response, among others . Dr Naviaux put all the different alterations together and coined a name for it.
 

serg1942

Senior Member
Messages
543
Location
Spain
Purinergic signalling is a great topic. Key purine is also the key energy molecule: ATP. If we're signalling with it, we're not making energy with it.

I want to say 3 things about how it may apply.

1. sleepiness is brought on by the accumulation of adenosine. adenosine is part of the purine metabolism, it gets made as we break down other purines. There's some signals of adenosine being too high in mecfs in the old naviaux metabolite paper. Are we leaking too much atp and building up adenosine too easily /too soon? is that why we need naps?!

2. @necessary8 has a long thread on purinergic signalling that's worth a look. The basic idea is that cells use ATP for energy, so when they spit them out as a danger signal, it's a highly credible signal. They wouldn't spit it out unless they had to. Then the body perhaps fails to break down those ATP (via cd38) so they signal for longer than they are supposed to. Also, ATP doesn't hit the circulation, it just stays in a "halo" around the cell it came from, signalling to nearby cells and back to the cell itself. So you can't expect blood tests to find it.
https://forums.phoenixrising.me/thr...rsuit-of-a-unified-me-cfs-theory.55801/page-6

3. My own obsession is vasodilation and POTS and how that ties in with me/cfs. If blood vessels aren't dilating properly to let red blood cells through, one way they signal to the blood vessel is by squirting out ATP.
This happens mechanically: they just get squashed by trying to jostle down the narrow tube. Out comes ATP. Seems to me blood vessel dilation has gone wrong in pots-mecfs. Whether the red blood cells have stiff membranes so no atp is coming out, or whether the vessels are unresponsive so red blood cells are exhaustign their atp load, I don't know. but I bet there's something going on there.

in summary i'm very keen for more purinergic research!!
Hi Murph, thank you for your message.

1.Yes, as far as I understand it the more extracellular ATP, the more extracellular adenosine. This is a compensatory mechanism. For this to be true the enzymes that break down ATP know as CD39 and CD73 should be substrate-driven.

In deed, according to this study, the soluble recombinant CD39 does increase its activity when doses of ATP increase up to a point, and then it is inhibited. This makes sense.
https://ui.adsabs.harvard.edu/abs/2023NatSR..13.8958V/abstract

2. Yes, ATP is a very valuable coin!! And yes, ATP is located forming a halo, so as you say, perhaps directly measuring ATP in blood might not reflect the excessive CDR our cells might display. That's why I am measuring my IL1-beta levels as a proxy to estimate the effectiveness of the purinergic therapy I will be taking.

2. Regarding the vasodilation problem we normally have, I remembered a paper I read time ago with human arterioles in vitro from patients with hypertension, where inhibiting the pannexin-1 channel (that allows ATP to get out of the cell) with spironolactone caused vasodilation. So, I guess that the CDR might be involved in this process (although this might be just part of the picture, as the autoimmunity and neurological component is for sure important as well).

Here's this study:

https://pubmed.ncbi.nlm.nih.gov/29237722/

Take care!
Sergio
 

Violeta

Senior Member
Messages
2,843
That's a very good question. On the contrary, the purinergic receptors for adenosine (P1 receptors) are mostly anti-inflammatory, and compensate for the inflammatory tone set by the receptors for ATP and ADP (P2).

In fact, adenosine agonists are been trialed for all kind of chronic inflammatory diseases and even for cancer.

This is why I like the idea of breaking ATP with an enzyme into adenosine to lower the extracellular ATP and increase the adenosine levels. There's an experimental drug known as APT102 that does this, but unfortunately it hasn't been trialed in humans yet.

A similar way to achieve this would be to increase the expression of the membrane-bound CD39 enzyme, which also degrades ATP into ADP. For example bilirrubin has shown to do this, and the animals studies are very interesting in this regard. Again, bilirubin is not available for human consumption.

However, it seems that inhaling carbon monoxide in very low therapeutic doses, might increase the CD39 expression. And this is something that I'll be trying soon.
Actually, anything that increases the expression of heme oxidase 1 will probably increase the CD39 expression, by increasing bilirubin and carbon monoxide levels.

So yes, perhaps the adenosine receptors might be very important when it comes to design an anti-purinergic therapy approach.

Best wishes,
Sergio
Thank you, Sergio.

I was wondering if AMP would also be involved in this topic, I had to look up whether it affected P1 receptors and found this:

"Adenosine activates four distinct G protein-coupled receptors, the so-called P1 purinergic receptors: adenosine A1 receptor (A1R,2 ADORA1), adenosine A2A receptor (A2AR, ADORA2A), adenosine A2B receptor (A2BR, ADORA2B), and adenosine A3 receptor"

That is from this study:

AMP Is an Adenosine A1 Receptor Agonist​

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285310/

So this would mean that AMP would be helpful, too, is that correct?

Would ATP be broken down to AMP in the extracellular space? Or is that just intracellular?

Just found this, AMP does exist in extracellular space.

Extracellular AMP Suppresses Endotoxemia-Induced Inflammation by Alleviating Neutrophil Activation

https://www.frontiersin.org/articles/10.3389/fimmu.2020.01220/full

"The effects of extracellular AMP were abolished by an adenosine 1 receptor (A1R) antagonist but were not influenced by inhibiting the conversion of AMP to adenosine (ADO), indicating that AMP inhibited inflammation by directly activating A1R."

Do you think AMP would be an antipurinergic?
 
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datadragon

Senior Member
Messages
389
Location
East Coast, USA
ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity. Extracellular ATP acts as a “danger” signal and stimulates immune responses, i.e. by inflammasome activation. Its degradation product Ado on the other hand acts rather anti-inflammatory, as it down regulates functions of dendritic cells (DCs) and dampens T cell activation and cytokine secretion. https://www.frontiersin.org/articles/10.3389/fimmu.2018.02581/full

The IFN-induced differentiation of DCs (dendritic cells) is irreversible and, in contrast to that driven by GM-CSF and IL-4, persists upon removal of the cytokines. IFN-DCs produced lower levels of IL-12p70 and higher levels of IFN-alpha, IL-4, and IL-10 than IL-4-DCs. As a consequence of this different pattern of cytokine secretion, IFN-DCs induced T cells to produce type 1 (IFN-gamma) and type 2 (IL-4 and IL-10) cytokines, and as expected, IL-4-DCs induced only Th1 differentiation. IFN-α can bridge innate and adaptive immunity through its effects on DC differentiation/activation, skewing DC functions towards the priming and expansion of protective antitumor immune responses https://pubmed.ncbi.nlm.nih.gov/14525963/ In addition to IFN-α, the combination of GM-CSF and IFN-β turned out to be very efficient in inducing monocyte differentiation into DCs endowed with phenotypic features very similar to those observed in the presence of IFN-α https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073125/ Side note: The irreversible differentiation is an additional potential lead to the longer term effects separate from loss of orexin neurons or lowering of orexin.

IFN-α induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350004/ It also lowers orexin, however there are other pathways that lead to orexin.

type I IFNs can exhibit beneficial effects, including antitumor and antiviral activities, but also adverse effects leading to auto-reactive CD8+ T cell responses or immune suppression by inhibiting virus-specific CD4+ T cell responses. Notably, this peculiar type of IFN-induced inhibitory effect, which may apparently be in contrast with the general role of type I IFNs as enhancers of protective immune responses, is associated with high serum levels and sustained IFN signature occurring during persistent virus infections or after prolonged IFN therapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073125/

in the fecal metabolome, the % butyrate was increased in the NoPEM group compared with both the PEM and control groups
... Importantly, histone deacetylase 2 (HDAC2) was ~four fold higher and HDAC3 was ~two-fold higher, in ME/CFS cases compared with controls https://www.mdpi.com/2075-4418/9/3/70/htm

Perhaps try sodium butyrate, Butyrate also inhibits histone deacetylase activity (HDAC) https://www.ncbi.nlm.nih.gov/pubmed/12840228 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333934/

Previously, a molecular switch from Th2 to Th1 cell phenotype by restoring the histone acetylation at the Ifnγ and Tbx21 loci was observed for human T cells treated with HDAC inhibitors https://www.nature.com/articles/s41598-018-32860-x Low butyrate levels may even impact energy production by decreasing the conversion of pyruvate to acetyl-CoA – the main substrate for aerobic energy production in the Krebs cycle.

Elevated levels of systemic IL-10 have been associated with several chronic viral infections, including HCV, EBV, HCMV and LCMV. In the chronic LCMV infection model, both elevated IL-10 and enhanced infection of dendritic cells (DCs) are important for viral persistence. This report highlights the relationship between enhanced viral tropism for DCs and the induction of IL-10 in CD4 T cells, which we identify as the most frequent IL-10-expressing cell type in chronic LCMV infection. Here we report that infected CD8αneg DCs express elevated IL-10, induce IL-10 expression in LCMV specific CD4 T cells, and suppress LCMV-specific T cell proliferation. DCs exposed in vivo to persistent LCMV retain the capacity to stimulate CD4 T cell proliferation but induce IL-10 production by both polyclonal and LCMV-specific CD4 T cells. Our study delineates the unique effects of direct infection versus viral exposure on DCs. Collectively these data point to enhanced infection of DCs as a key trigger of the IL-10 induction cascade resulting in maintenance of elevated IL-10 expression in CD4 T cells and inhibition of LCMV-specific CD4 and CD8 T cell proliferation. https://pubmed.ncbi.nlm.nih.gov/24613988/

@serg1942
 
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datadragon

Senior Member
Messages
389
Location
East Coast, USA
@datadragon very interesting that you would post that as I intend to try Butyrate
Yes, see the post above this one. also
Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. https://www.sciencedirect.com/science/article/pii/S1347861321000384
 

SlamDancin

Senior Member
Messages
509
@datadragon Have you read about Tributynin? It’s ostensibly a more bioavailable butyrate prodrug. I think that will be what I try specifically. I too have been wanting to find a good class 1 HDAC inhibitor
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
@datadragon Have you read about Tributynin? It’s ostensibly a more bioavailable butyrate prodrug. I think that will be what I try specifically. I too have been wanting to find a good class 1 HDAC inhibitor

I have only ever tried sodium butyrate. There is this patented form that claims will have better delivery to the intestine which could be tried if the normal capsules more easily available cant do the job well enough. It says - it is preferable that butyric acid is in the form linked to sodium due to its high lipophilicity and cellular exchange capacity. Sodium butyrate is a very active molecule but with a high degree of dissociation ( pKa 4.82 ), which in the absence of adequate protection would not reach the intestine, in particular the colon / rectum
https://www.butyrose.it/butyrose-lsc-microcaps https://www.viafarmaciaonline.it/butyroser-30-capsule-da-600-mg.html

Tributyrin is the triglyceride form of butyric acid (the other form being sodium butyrate.) Tributyrin is essentially a triacylglyceride (TAG), which is an ester derived from glycerol and 3 fatty acids (triglyceride). Tributyrin requires lipase to release the butyrate attached to the glycerol. https://www.allaboutfeed.net/animal-feed/feed-additives/sodium-butyrate-or-tributyrin/ The only reason I didnt try being that blood type A often has the lowest levels of critical intestinal enzymes known as phosphatases - lipase is needed to assist in fat breakdown - which I guessed might be an issue for type A's. https://dadamo.com/dangerous/2023/04/01/do-we-need-a-different-digestive-enzyme-for-each-blood-type/ https://pubmed.ncbi.nlm.nih.gov/30530634/

Miyarisan was another but I believe that is gut bacteria that make butyrate, need butyrate since acetyl coa may be low. https://cfsremission.com/2015/10/19/miyarisan-clostridium-butyricum-revisited/

Butyrate is metabolized to acetyl-coa which should help fix the low acetyl-coa leading to the itaconate shunt https://www.cell.com/molecular-cell/fulltext/S1097-2765(12)00777-0
 
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Osaca

Senior Member
Messages
344
Hey @serg1942 have you had a look at Suramin (PAX-101) by PaxMedica? Apparently there's a clinical trial running in South Africa for Long-Covid (I can't find much official information on this) and there's apprarently also interest in ME/CFS. Target are the P2X- and P2y purinergic receptors. I haven't really looked into it, but thought it might be interesting for you if you haven't looked into it yet (which you probably have).
 

aquariusgirl

Senior Member
Messages
1,732
I have only ever tried sodium butyrate. There is this patented form that claims will have better delivery to the intestine which could be tried if the normal capsules more easily available cant do the job well enough. It says - it is preferable that butyric acid is in the form linked to sodium due to its high lipophilicity and cellular exchange capacity. Sodium butyrate is a very active molecule but with a high degree of dissociation ( pKa 4.82 ), which in the absence of adequate protection would not reach the intestine, in particular the colon / rectum
https://www.butyrose.it/butyrose-lsc-microcaps https://www.viafarmaciaonline.it/butyroser-30-capsule-da-600-mg.html

Tributyrin is the triglyceride form of butyric acid (the other form being sodium butyrate.) Tributyrin is essentially a triacylglyceride (TAG), which is an ester derived from glycerol and 3 fatty acids (triglyceride). Tributyrin requires lipase to release the butyrate attached to the glycerol. https://www.allaboutfeed.net/animal-feed/feed-additives/sodium-butyrate-or-tributyrin/ The only reason I didnt try being that blood type A often has the lowest levels of critical intestinal enzymes known as phosphatases - lipase is needed to assist in fat breakdown - which I guessed might be an issue for type A's. https://dadamo.com/dangerous/2023/04/01/do-we-need-a-different-digestive-enzyme-for-each-blood-type/ https://pubmed.ncbi.nlm.nih.gov/30530634/

Miyarisan was another but I believe that is gut bacteria that make butyrate, need butyrate since acetyl coa may be low. https://cfsremission.com/2015/10/19/miyarisan-clostridium-butyricum-revisited/

Butyrate is metabolized to acetyl-coa which should help fix the low acetyl-coa leading to the itaconate shunt https://www.cell.com/molecular-cell/fulltext/S1097-2765(12)00777-0
I tried miyarsan a couple of times..and anything more than one pill caused terrible brain inflammation. Any thoughts?
 

datadragon

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I tried miyarsan a couple of times..and anything more than one pill caused terrible brain inflammation. Any thoughts?

Miyarsan = Clostridium butyricum. It may be because of numerous SCFAs generated by C. butyricum, include not only butyric acid but also acetic acid and propionic acid. Conversion may be compromised as well as due to the state you are in. Increased propionic acid and decreased butyrate imbalanced states typically found under inflammation conditions may be better to use only butyrate in that state (using a capsule that will deliver it to the intestine (delayed release capsule) and not lost to stomach acid, or also by removing the inflammation such as with Palmitoylethanolamide as one example has shown that allows restoration of the downstream effects of the inflammation like the leaky gut barrier and modulation of the microbiome and SCFA profile leading to those issues. Example: https://www.sciencedirect.com/science/article/pii/S0889159118305488?via=ihub

Maybe if the same thing happened taking only butyrate than I could post some of the butyric acid effects on the body
 
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serg1942

Senior Member
Messages
543
Location
Spain
Hey @serg1942 have you had a look at Suramin (PAX-101) by PaxMedica? Apparently there's a clinical trial running in South Africa for Long-Covid (I can't find much official information on this) and there's apprarently also interest in ME/CFS. Target are the P2X- and P2y purinergic receptors. I haven't really looked into it, but thought it might be interesting for you if you haven't looked into it yet (which you probably have).
Hi! Thank you for let me know about this trial! Yes, I knew about it, and I got really excited when I read it. I think it will be a success if they get the dose right, and I hope suramin gets again the attention I think it deserves among the ME/CFS community.. Well see!
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
@serg1942 and all,

Hi! Thank you for let me know about this trial! Yes, I knew about it, and I got really excited when I read it. I think it will be a success if they get the dose right, and I hope suramin gets again the attention I think it deserves among the ME/CFS community.. Well see!

We know that the inflammation/cytokines lead to the negative symptoms and so first thought was to reduce them via inhibiting the NLRP3 inflammasome at minimum in earlier phases which would therefore stop all the subsequent downstream cascade of effects by blocking the cytokines. That is where palmitoylethanolamide, doxycycline, and colchicine which all inhibit the NLRP3 inflammasome that have shown benefits may be effective before all the major downstream issues set in. Suramin happens to be another NLRP3 inhibitor and why its helpful in inflammatory conditions including autism and likely ME/CFS in earlier phases. I have lists of dozens of them, but those also happen to have potential additional effects on other areas known to be related to ME/CFS and some have reported benefits.

Extracellular ATP can cause P2X receptors to activate the NOD-like receptor 3 (NLRP3) inflammasome and cause IL-1β and IL-18 maturation and release. https://pubmed.ncbi.nlm.nih.gov/23434541/ The NLRP3 inflammasome is present primarily in immune and inflammatory cells, including mast cells, neutrophils, and macrophages, following activation by inflammatory stimuli and is a good target to stop downstream effects that can lead to ME/CFS.

Consistently, apyrase (extracellular ATP scavenger), suramin (P2 receptor inhibitor), TNP-ATP (P2X receptor antagonist), and 5-BDBD (P2X4 inhibitor) downregulate NLRP3 expression https://www.nature.com/articles/s41401-022-00886-7

Viruses can trigger a biochemical pathway, known as the immune complement system...Complement activation then elicits secretion of both IL-1β and IL-18 via activation of the NLRP3 inflammasome https://pubmed.ncbi.nlm.nih.gov/23817414/

These articles were discussing the activation of the NLRP3 inflammasome in regard to COVID-19 which is not the same
https://www.sciencedirect.com/science/article/pii/S0024320520308651
Palmitoylethanolamide inhibits NLRP3 inflammasome expression (such as mentioned here expressed by sars-cov-2 spike protein). However it also helped with the gut barrier, restructuring the gut bacteria and short chain fatty acid profile, and inhibits STING so that was my first thought over some of the other options that appear to help from their NLRP3 inhibition which I can provide a list I started awhile ago.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472716/ And of course sodium butyrate in later stages should help with the pem and energy as another thought I've mentioned so far in addition to inflammation and perhaps helping to restore TH1.

Regarding Dr Phairs latest video about IL-1a, which they suggested as a potential target:

This article confirms IL-1 can induce production and release of more IL-1, a process described as an autoinflammatory loop. Anakinra is a bio-engineered form of the naturally occurring interleukin-1 receptor antagonist (IL-1ra) that blocks the action of interleukin-1. It is routinely used in patients with autoimmune and inflammatory disorders and MAS. Within the IL-1 family of cytokines, several inhibitory mechanisms are in place to prevent runaway inflammation induced by IL-1α or IL-1β. The main mechanism is the IL-1 receptor antagonist (IL-1Ra), which blocks the IL-1R1 and prevents binding of IL-1α and IL-1β. In contrast to JAKinibs, anakinra will not directly block the IFN-STAT1/STAT2 pathway critical for host defense against viral infections. Third, in contrast to tocilizumab (an IL-6 inhibitor), it targets and inhibits the core mechanism in the pathogenesis of MAS, namely the hyperactive inflammasome loop https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03166-0

This one metions neutralization of IL-1α inhibits the antiviral activity of IFN-γ by 90%, whereas no inhibition of type I IFN activity was observed. Indeed, the antiviral activity of IFN-γ depends largely on the basal level of NF-κB, which is maintained by constitutively expressed IL-1α. https://www.sciencedirect.com/science/article/pii/S1568997221000227#s0070
 
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datadragon

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East Coast, USA
Actually Anakinra has been tried before for CFS, and it didn't work: https://pubmed.ncbi.nlm.nih.gov/28265678/

Thanks @bob800 The paper says Several studies in inflammatory and noninflammatory illnesses have assessed the effect of IL-1 inhibition on fatigue severity, and most have found positive effects. Studies using daily anakinra injections (100 mg) found decreased fatigue within 4 weeks of treatment. To investigate the role of proinflammatory activity in CFS, we conducted a randomized, placebo controlled trial in female patients with CFS using the IL-1 receptor antagonist anakinra. All patients had severe fatigue leading to functional impairment. a decision was made to exclude patients with illness lasting more than 10 years - Median illness duration (range), mo 44 (7–109).

So its possible here that this treatment can work on earlier states of ME/CFS where the inflammation level is still currently high as would things like NLRP3 inflammation inhibition to a greater degree which would help prevent further deterioration. However in the later phase it does not appear that IL-1 inhibition alone at that point ( at least via anakinra that may not be able to reach the brain) can recover the subsequent lasting alterations that happen from the chronic inflammatory state and requires a different treatment approach as expected, which is important to note the two phases patients can be in.
 
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