Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis (Kaczmarek 2023)

[Wishful]

Can these miRNAs be suppressed in just the brain without showing noticeable decline in muscle strength and stamina?

To answer my own question: maybe. Maybe a decade ago, I read a paper that said that neural DNA was slightly different from DNA in the rest of the body. I never found that paper again, so I don't recall the details, but the implication is that it is at least possible to have a DNA disorder that affect the brain without affecting the body, or vice-versa.

 

[SWAlexander]

Was it this one?
Literature reveals that 70% of known miRNAs are expressed in the brain [50].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936914/

 

[Wishful]

I think the one I read was well before 2014. It mentioned that there were differences between either the DNA or mitochondrial DNA in the brain vs the body. I'm not sure how that would work: maybe when the embryo reaches a certain point, the cell that divides into the first neural cell undergoes some editing. Maybe it was just that researcher's unproven belief. At the time I just accepted it as a possible explanation for why I had neurological symptoms but not physical ones.

 

[pattismith]

I think zinc is good to take anyways, but it won't do anything about the VEGF suppression. None of these dysfunctions can be treated directly, actually. Because this is miRNA, suppression on the translational level is nearly impossible to overcome with a drug. For treatment, we'd need to do more invitro experiments to find out the full downstrem effects of these changes, and in what tissues they occur, and treat those (symptomatic treatment), or find out what's upstream of the shit in miRNA, and treat that (root cause treatment).

Thank you so much for this impressing work!

And thank you for coming on PR to share your thoughts with us!

Do you think Curcuma may be curative for this low VGEFA?

I mean Intravenous form or transcutaneous essential oil, because oral curcuma is poorly absorbed.

I am currently using curcuma essential oil on my skin, and I found it powerful to improve my low ferritin level (I suppose by hepcidin dowregulation).

I also read about it may suppress HIF1A and VEGFA under some curcunstancies

https://pubmed.ncbi.nlm.nih.gov/22739211/

 

[necessary8]

Do you think Curcuma may be curative for this low VGEFA?

No, definitely not. Bear in mind drugs mainly work by binding to receptors and eliciting intercellular actions indirectly. Transnational suppression by miRNA doesn't care about receptors. It cannot be directly overcome by any drugs or phytochemicals. The only two ways would be to either have some big-ass molecule that's binding to the miRNAs and selectively sponging them up (some lncRNAs do this, but I don't know of any drug that would), or to figure out what's upstream of this miRNA shift and hit that. Otherwise you can't move this with any pharmacology, AFAIK.

 

[Murph]

Lol, my next study is about metabolomics actually. XD

I'm sure you've seen this study that combines a few mtabolomics studies.

https://forums.phoenixrising.me/thr...-cohorts-brydges-che-lipkin-fiehn-2023.90957/

I think their methodology seems good, you may like to borrow from them. the weakness is they used relatively few studies as inputs.

 

[necessary8]

I think their methodology seems good, you may like to borrow from them. the weakness is they used relatively few studies as inputs.

Their methodology is interesting, tho mine will probably be completely different.

 

[Violeta]

The miRNA suppression of VEGFA in ME/CFS would imply an impaired ability to adapt to hypoxia.

Wow, this is exactly what I was looking for this morning. I expected to find suppression of HIF-1!

 

[Violeta]

I wonder how many of the genes in the other categories are induced by VEGFa, which is to say, downstream.

I found 2 so far, BCL-2 and CREB1.

 

[necessary8]

I wonder how many of the genes in the other categories are induced by VEGFa, which is to say, downstream.

I found 2 so far, BCL-2 and CREB1.

Well it's a good thing I mapped out every single known, high-confidence direct interaction between all of them then

Fig 3:

As you can see, for the most part VEGF is the one being induced by the rest of them, not the other way around. This is why it scores so highly as the most inhibited one. Because it's not just inhibited directly by some miRNAs, it's also induced by many other genes that are inhibited by other miRNAs. It basically only induces IGF1R directly.
The limitation of this data is that it will not track long indirect interactions that pass through intermediate genes not present in the target list, which is why you don't see the BCL2 and CREB1 connections here.
I was tempted to try to map those out as well, but that gets extremely messy and noisy once you go down that route.

 

[Violeta]

Well it's a good thing I mapped out every single known, high-confidence direct interaction between all of them then

Fig 3:
View attachment 53275

As you can see, for the most part VEGF is the one being induced by the rest of them, not the other way around. This is why it scores so highly as the most inhibited one. Because it's not just inhibited directly by some miRNAs, it's also induced by many other genes that are inhibited by other miRNAs. It basically only induces IGF1R directly.
The limitation of this data is that it will not track long indirect interactions that pass through intermediate genes not present in the target list, which is why you don't see the BCL2 and CREB1 connections here.
I was tempted to try to map those out as well, but that gets extremely messy and noisy once you go down that route.

Thank you, saves me a bit of time.

 

[necessary8]

Btw I should mention, hypoxia in ME/CFS is more complicated than just VEGF suppression. I do think VEGF is important but the whole picture is way more complex. I will have a full paper on that somewhere in the next few years probably (taking me a long time cause the paper is huge and there are a few computational studies I want to try completing before finalizing it).

 

[Violeta]

Btw I should mention, hypoxia in ME/CFS is more complicated than just VEGF suppression. I do think VEGF is important but the whole picture is way more complex. I will have a full paper on that somewhere in the next few years probably (taking me a long time cause the paper is huge and there are a few computational studies I want to try completing before finalizing it).

I was thinking that the poor response to VEGF is just a complication, but not the cause.

If you have any bullets about hypoxia, I would appreciate it.

I am thinking viscosity is part of the upstream cause, but then again, it's not the root.

 

[SlamDancin]

Research Summary: From the Desk of Alain Moreau, PhD, Director of the OMF ME/CFS Collaborative Research Center at the University of Montreal & Corinne Leveau, MSc, Lead Author & PhD student at the OMF ME/CFS Collaborative Research Center at the University of Montreal:

​

“In this talk, I discussed the effects of post-exertional malaise (PEM) on people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our team developed a standardized test lasting 90 minutes to induce PEM in ME/CFS patients using a mechanical arm stimulation with an inflatable cuff. We included both people with ME/CFS and sedentary healthy individuals in our study. Both groups had blood drawn and underwent cognitive testing before and after the PEM test.

Our initial findings indicate that ME/CFS participants experienced cognitive impairment after the PEM test, although a significant variation in individual responses was observed. This prompted us to divide the participants into three subgroups based on their cognitive responses.

These subgroups align with specific microRNAs (miRNAs), which are small molecules that regulate genes. Interestingly, these same miRNAs are linked to other neurological disorders, suggesting their potential role in cognitive function. Our future research will involve looking for more miRNAs and other molecules related to various aspects of cognition (like attention, memory, and executive function) in the context of ME/CFS. These results will contribute to a better understanding of the disease, particularly its impact on brain fog and other types of cognitive impairment.”

Latest OMF update…

 

[Violeta]

I was thinking that the poor response to VEGF is just a complication, but not the cause.

If you have any bullets about hypoxia, I would appreciate it.

I am thinking viscosity is part of the upstream cause, but then again, it's not the root.

Does anyone know if this herpes virus activity with heparan sulfate would raise blood viscosity?

There are at least five viral envelope glycoproteins involved in a virus’s attempt to invade a host cell. They can recognize homologous receptors on the surface of host cell, such as heparan sulfate, and this specific recognition facilitates membrane fusion.

Adherence to heparan sulfate is mainly mediated by glycoprotein gC in HSV-1 and glycoprotein gB in HSV-2.

After adsorption, the four glycoproteins (gD, gH, gI, and gB; gD being the most important glycoprotein in viral penetration) interact synergistically with the herpes virus entry medium (HVEM), nectin-1, nectin-2, and 3-O sulfated heparan sulfate proteoglycan (HSPG). This process triggers the conformational change in the virus and plasma membrane results in membrane fusion. Then the virus enter the cytoplasm and complete the invasion step.

https://www.sciencedirect.com/science/article/pii/S0753332220306624?via=ihub

 

[Rufous McKinney]

viscosity

YES, THAT

 

[SlamDancin]

YES, THAT

I think this may be getting slightly off topic but I looked up blood viscosity and saw something interesting. Apparently blood viscosity increases by 2% for every 1 degree C drop in body temp. I’m not sure about all pwME but my temp was consistently 1-2 degrees F low. So if there are changes in viscosity it could be a direct result of lowered metabolism

 

[Violeta]

I think this may be getting slightly off topic but I looked up blood viscosity and saw something interesting. Apparently blood viscosity increases by 2% for every 1 degree C drop in body temp. I’m not sure about all pwME but my temp was consistently 1-2 degrees F low. So if there are changes in viscosity it could be a direct result of lowered metabolism

Yes, my temp has been 1-2 degrees below normal for years.

 

[Violeta]

Does anyone know if this herpes virus activity with heparan sulfate would raise blood viscosity?

There are at least five viral envelope glycoproteins involved in a virus’s attempt to invade a host cell. They can recognize homologous receptors on the surface of host cell, such as heparan sulfate, and this specific recognition facilitates membrane fusion.

Adherence to heparan sulfate is mainly mediated by glycoprotein gC in HSV-1 and glycoprotein gB in HSV-2.

After adsorption, the four glycoproteins (gD, gH, gI, and gB; gD being the most important glycoprotein in viral penetration) interact synergistically with the herpes virus entry medium (HVEM), nectin-1, nectin-2, and 3-O sulfated heparan sulfate proteoglycan (HSPG). This process triggers the conformational change in the virus and plasma membrane results in membrane fusion. Then the virus enter the cytoplasm and complete the invasion step.

https://www.sciencedirect.com/science/article/pii/S0753332220306624?via=ihub

So far I've found this about heparan sulfate:
Heparan sulfate (HS) is a sulfated glycosaminoglycan abundant on the cell surface and in the extracellular matrix and has several biological activities including anticoagulation and anti-inflammation. Liver ischemia reperfusion injury is associated with coagulation and inflammatory responses.

So the virus adheres to the heparan sulfate and then the virus enters the cytoplasm.

It seems as though that would negate the effectivity of heparan sulfates' anticoagulation and anti-inflammation.

I am thinking viral adhesion to heparan sulfate would disable it's action on cell adhesion.

Heparan sulfate proteoglycans at the cell surface and in the extracellular matrix act as receptors and coreceptors, with profound effects on growth factor action, cell adhesion, and tissue architecture.

Ah ha! "Heparin was discovered as the first anti-herpetic drug in 1964 [37]."

 

[Violeta]

Inhibitory effect of heparin on herpes simplex virus.

https://journals.asm.org/doi/abs/10.1128/jb.87.5.1060-1066.1964

Abstract​

Nahmias, André J. (Boston University School of Medicine, Boston, Mass.), and Sidney Kibrick. Inhibitory effect of heparin on herpes simplex virus. J. Bacteriol. 87:1060–1066. 1964.—A substance inhibitory to herpes simplex virus was observed during experiments with leukocyte cultures. The component in the cultures responsible for this inhibition was identified as heparin. The minimal inhibitory concentration required to inhibit 30 to 300 tcd50 of the virus in human amnion tissue culture was found to be 1 to 2 units per ml (10 to 20 μg/ml). This effect was confirmed with other strains of herpes simplex virus, other tissue-culture systems, and other media. The inhibitory activity of the heparin was found to be related to the sulfate groupings on the molecule. The effect of heparin appears to be on the virus, rather than on the cell. The virus is not inactivated, however, and the heparin-virus “complex” is readily dissociable on dilution. Heparin was shown to affect viral infection in its earliest phase, probably at the primary electrostatic attachment of virus to cell. The import of these and related observations on common virological laboratory procedures and the possible biological significance of our findings are discussed.