Research: SMPDL3B a novel biomarker and therapeutic target in ME

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Wishful

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That's a finding I can accept. It could explain why my symptoms have been affected by fatty acid intake. It fits neurological symptoms. I don't know the time frame for the reactions, but it certainly could explain rapid switching of state. I hope this gets proper development.
 
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datadragon

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These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. SMPDL3B, when membrane-anchored, exerts a dual regulatory function in innate immune signaling by inhibiting TLR4 activation [8] while simultaneously enhancing TLR3 signaling [9]. In the TLR4 pathway, membrane-bound SMPDL3B modulates lipid raft composition, reducing membrane fluidity and limiting receptor clustering. This structural regulation dampens inflammatory responses, thereby curbing excessive release of pro-inflammatory cytokines such as TNF-α and IL-6. Conversely, SMPDL3B promotes TLR3 activation by stabilizing the receptor complex within specialized membrane microdomains, enhancing type I interferon (IFN-β) production and supporting antiviral immunitY
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Interesting. This appears as a first thought to be another downstream effect after a switch to an inflammatory state by the body such as after an infection, inflammation, nlrp3 activation etc and may help explain secondary effects. Divalent metal ions, Ca2+, Mg2+, Mn2+, and Zn2+ (zinc), are inhibitory at 2–10 mM and high concentrations of NaCl show significant inhibition of Pi-Plc naturally. https://meassociation.org.uk/2025/0...novel-biomarker-and-therapeutic-target-in-me/

The active form of Vitamin B6 (PLP) also serves as a cofactor in sphingolipid synthesis and is thereby important for myelin formation which also is affected by zinc status that is both put into the cell and absorption lowered during inflammation/infection states. Sphingomyelin that appears to increase SMPDL3B is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons.
https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.91144/post-2451651
https://pubmed.ncbi.nlm.nih.gov/17260529
https://pubmed.ncbi.nlm.nih.gov/12686137
https://pubmed.ncbi.nlm.nih.gov/6342384

The mechanism by which wasf3 levels are causing the pem is the main focus https://www.healthrising.org/blog/2023/08/16/nih-mitochondria-chronic-fatigue-syndrome/
And can be helped for many with nlrp3 inhibitors or ifn-y inhibitors, but then it’s not just er stress but infection inflammation glucose fructose heavy exercise etc all happen to converge to increase wasf3 levels via nlrp3 activation or increase in ifn-y.

The additional issue I’ve mentioned before has been that several nutrients go deficient during an infection/inflammation state or that nlrp3 activation such as zinc for example gets placed into the cell and its absorption is lowered both so it’s not easily restored without using a chelated form. . From there this can cause problem with vitamin b6 and other nutrients in a further cascade where it’s needed with b6 for example to convert it to the active form and get it into the cell, otherwise b6 would be more inflammatory and fuel serine production rather than it’s usual anti inflammatory effects. So yes we may need an extra step like a chelated zinc that is not glycinate due to glycine effect on NMDA glutamate receptors and cause insomnia, although I was hoping the lowering of inflammation would restore the zinc metabolism and lessen its additional requirement in some people. Here’s a few of the nlrp3 inhibitors
https://forums.phoenixrising.me/threads/bcaas-reducing-pem.34719/post-2480567
 
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Violeta

Violeta

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datadragon said:
Interesting. This appears as a first thought to be another downstream effect after a switch to an inflammatory state by the body such as after an infection, inflammation, nlrp3 activation etc and may help explain secondary effects. Divalent metal ions, Ca2+, Mg2+, Mn2+, and Zn2+ (zinc), are inhibitory at 2–10 mM and high concentrations of NaCl show significant inhibition of Pi-Plc naturally. https://meassociation.org.uk/2025/0...novel-biomarker-and-therapeutic-target-in-me/

The active form of Vitamin B6 (PLP) also serves as a cofactor in sphingolipid synthesis and is thereby important for myelin formation which also is affected by zinc status that is both put into the cell and absorption lowered during inflammation/infection states. Sphingomyelin that appears to increase SMPDL3B is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons.
https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.91144/post-2451651
https://pubmed.ncbi.nlm.nih.gov/17260529
https://pubmed.ncbi.nlm.nih.gov/12686137
https://pubmed.ncbi.nlm.nih.gov/6342384

The mechanism by which wasf3 levels are causing the pem is the main focus https://www.healthrising.org/blog/2023/08/16/nih-mitochondria-chronic-fatigue-syndrome/
And can be helped for many with nlrp3 inhibitors or ifn-y inhibitors, but then it’s not just er stress but infection inflammation glucose fructose heavy exercise etc all happen to converge to increase wasf3 levels via nlrp3 activation or increase in ifn-y.

The additional issue I’ve mentioned before has been that several nutrients go deficient during an infection/inflammation state or that nlrp3 activation such as zinc for example gets placed into the cell and its absorption is lowered both so it’s not easily restored without using a chelated form. . From there this can cause problem with vitamin b6 and other nutrients in a further cascade where it’s needed with b6 for example to convert it to the active form and get it into the cell, otherwise b6 would be more inflammatory and fuel serine production rather than it’s usual anti inflammatory effects. So yes we may need an extra step like a chelated zinc that is not glycinate due to glycine effect on NMDA glutamate receptors and cause insomnia, although I was hoping the lowering of inflammation would restore the zinc metabolism and lessen its additional requirement in some people. Here’s a few of the nlrp3 inhibitors
https://forums.phoenixrising.me/threads/bcaas-reducing-pem.34719/post-2480567
Click to expand...
Excellent, thank you.
 
Violeta

Violeta

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andyguitar said:
Looks interesting. Easy to see if either of the two drugs mentioned work. Look forward to seeing what happens with this.
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Those two drugs DDP-4 inhibitors. (DDP-4 breaks down GLP-1)
Ozempic is a GLP-1 agonist.

They both are used for diabetes T2. Just different methods.
I don't know what that means for if a GLP-1 agonist (for example, berberine) would work for this issue or not.
 
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Violeta

Violeta

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3,451
Violeta said:
Those two drugs DDP-4 inhibitors.
Ozempic is a GLP-1 agonist.

They both are used for diabetes T2. Just different methods.
I don't know what that means for if a GLP-1 agonist (for example, berberine) would work for this issue or not.
Click to expand...
In recent years, research has revealed a potential link between berberine, a natural alkaloid, and its interaction with the enzyme sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), particularly within the context of metabolic and renal health.
 
Violeta

Violeta

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PS: DPP-4 is an enzyme that rapidly degrades GLP-1, thus limiting its effects.
Berberine's role in metabolism and potential impact on SMPDL3B

  • Berberine is known to activate AMP-activated protein kinase (AMPK), a key regulator of metabolism.
  • AMPK activation can potentially impact SMPDL3B's role in lipid and glucose metabolism and could be a factor in conditions like diabetic kidney disease (DKD) where SMPDL3B levels are elevated.
 
O

Oliver3

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1,116
Violeta said:
Those two drugs DDP-4 inhibitors. (DPP-4 is an enzyme that rapidly degrades GLP-1, thus limiting its effects.)
Ozempic is a GLP-1 agonist.

They both are used for diabetes T2. Just different methods.
I don't know what that means for if a GLP-1 agonist (for example, berberine) would work for this issue or not.
Click to expand...
I've posted recently about the marked difference berberine has made to my quality of life. There's definitely smthg to what you're saying
 
O

Oliver3

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1,116
Chromium picolante also gave me astounding clarity of thought but its renal safety makes me hold off for now.
Many people with heart disease are very deficient in chromium
 
O

Oliver3

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Just one last reflection on berberine.
The change was immediate. Within a few hours. I felt oxygenated and my dysautomnia lessened.
More interesting was that pain meds started to work again. Paracetamol had stopped having any effect. With berberine it works, although not as well as when I first started it.
More remarkably, I stopped taking my antidepressants. Not on purpose, just my mood improve and I didn't remember to take them.
I've been on sertraline ( zoloft) for about 15 years and any attempt to get off them just was impossible.
I've taken two 100 milligram tablets in the last four months. This happened directly after starting berberine and also using nicotine ( which I'm tapering off). I still get given 34 mg of diaezepam a month, and again when I do take it, the synergy with berberine gives a better effect.
I've read that taken together, both drugs have a fairly strong influence on insulin.
Just thought I'd mention it.
 
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Oliver3

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1,116
kushami said:
And berberine is a vasodilator – I must give it a try. Every time I think I've looked at every class, a new one pops up.

And GLP-1 agonists too, if I read correctly?
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Make sure its a ' clean berberine'.
I'm uk based but I only buy stuff that's is 3rd party tested by the ' soil association '
 
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