Research: SMPDL3B a novel biomarker and therapeutic target in ME

[Wishful]

Thought it was a few cells in the brain.

Not incompatible theories. The effects of the enzyme most likely vary with the type of cells. Neurons with really long axons would have more myelin to be affected. So, even if there was a brain-wide alteration in this enzyme or its metabolites, it might have significant effects on a few neurons while others are insignificantly affected.

ME doesn't seem to affect all brain cells equally. One can have serious brainfog, but not have impaired vision due to visual cortex neurons failing to the same degree. Some people suffer hypersensitivities in one sense, while others have it in a different sense, and others have none.

The theory of ME involving a small number of specific cells is more an explanation for why there's no obvious marker (all brain cells showing signs of mitochondrial dysfunction, or whatever).

I'm wondering whether a much larger percentage of the population has the ME root mechanism, but it'--by random chance--not affecting the part of the brain that leads to the common constellation of ME symptoms. Some people could be suffering from some ME symptoms, via the ME mechanism, but don't fit the ME criteria, so they're stuck with symptoms from a mysterious cause. Maybe chronic fatigue is ME with part of the mechanism not active.

 

[Oliver3]

Still zero evidence.. just the same old sane old...not new, exciting, blue sky thinking. Just tragic. Keep trolling boi

 

[datadragon]

Vitamin D produced a significant reduction in tissue DPP-4 concentration. It was reported that upon correction of Vit D insufficiency or deficiency, serum DPP-4 activity decreased significantly. https://www.sciencedirect.com/science/article/abs/pii/S0041008X22004690. The study mentioned the goal was to inhibit pi-plc to restore more membrane bound smpdl3b and they suggested the dpp-4 inhibitors to do so. So perhaps a nlrp3 inhibitor for the wasf3 increase and vitamin d, chelated zinc not zinc glycinate, magnesium sulfate or a dpp-4 inhibitor combo. Keep in mind vitamin d may have different oils they are carried in the pill to consider secondary effects such as now vs carlson for example.

Dpp-4 inhibitors Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form

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

 

[Violeta]

Vitamin D produced a significant reduction in tissue DPP-4 concentration. It was reported that upon correction of Vit D insufficiency or deficiency, serum DPP-4 activity decreased significantly. https://www.sciencedirect.com/science/article/abs/pii/S0041008X22004690. The study mentioned the goal was to inhibit pi-plc to restore more membrane bound smpdl3b and they suggested the dpp-4 inhibitors to do so. So perhaps a nlrp3 inhibitor for the wasf3 increase and vitamin d, chelated zinc not zinc glycinate, magnesium sulfate or a dpp-4 inhibitor combo. Keep in mind vitamin d may have different oils they are carried in the pill to consider secondary effects such as now vs carlson for example.




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

Amazing research, @datadragon!

I think information gives a good way to deal with the problem without taking a DDP-IV inhibitor. (If that is incorrect, someone let me know.)

DPP-IV (dipeptidyl peptidase IV) is an enzyme that can aid in the digestion of gluten and casein. It's often found in digestive enzyme supplements designed to help individuals with gluten or dairy sensitivities break down these proteins. DPP-IV specifically targets proline-rich peptides, which are common in gluten and casein.
Vildagliptin has side effects! The main adverse drug events which have been reported with the use of vildagliptin include nausea, peripheral edema, weight gain, headache, dizziness, upper respiratory infection, back pain and diarrhea.Oct 23, 2017

 

[datadragon]

@Violeta yes SMPDL3B, when membrane-anchored, exerts a dual regulatory function in innate immune signaling as mentioned and it was the enhanced cleavage of the membrane-bound SMPDL3B by PI-PLC. That is the issue and lowering this by a dpp4 inhibitor that may fix that problem. That i s why I mentioned some natural to start like vitamin d or even zinc and magnesium that is not glycinate due to the potential effect on nmda glutamate receptors related to the effect on lowering pi-plc.. Of course pem is related to the increase in wasf3 levels to deal with if experiencing pem that I found wasf3 is increased not just by er stress but also what people mention like a virus, glucose, fructose, heavy exercise etc.

 

[datadragon]

As a side note to tie in some earlier research of mine

SMPDL3B requires zinc ions for its activity, with two zinc ions coordinated by specific amino acid residues in the active site.https://www.sciencedirect.com/science/article/pii/S0021925820346755

The Zinc Finger Protein Gfi1 Controls TLR4-Mediated Inflammatory Response by Directly Antagonizing NF-κB Transcription Factor​

https://www.sciencedirect.com/science/article/pii/S0006497119477677

The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding​

https://www.nature.com/articles/s41423-019-0265-6

Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Zinc inhibits iNOS-dependent nitrite accumulation in endothelial cells. Zinc decreases cytokine-induced iNOS expression in endothelial cells. Zinc inhibits iNOS promoter activity. NF-kB silencing abolishes cytokine-induced iNOS expression. Zinc inhibits the transactivation activity of NFκB.https://www.sciencedirect.com/science/article/pii/S2213231714000834 There is your switch for nitric oxide. from: https://forums.phoenixrising.me/threads/is-there-bh4-supplement-medicine.22480/post-2452006

Zinc is both brought into the cell and absorption is lowered during inflammation/infection states so this can be a downstrem effect of inflammation/infection and making it a bit harder to restore metabolism without chelated forms as ive covered before and have the research.

 

[annaloecher]

Is anybody trying Vildagliptin already or is it hopeless due to the high concentration that would need to be reached?