Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Owl42]

I've seen you've been discussing on THC and CB1. I'm in an awful cognitive state to follow or theorise but I created a thread to talk about the endocannabinoid system role in CFS/ME if you want to discuse it there.

http://forums.phoenixrising.me/inde...noid-system-role-in-me-cfs.48387/#post-797212

I don't know what increasing CB1R expression really means. I know I can modulate it through inhibition of the enzymes that metabolize it, adding endocannabinoids (anandamide that is found in some legal foods), anandamide precursors or PEA as someone said.

I'm more interested in the CB2 receptor from an experimental point of view, I'am trying to rise 2-AG levels in my brain through inhibition of MAGL

 

[FMMM1]

So the levels of PDK1 enzyme and the mRNA which regulates its production are both elevated. Others have pointed out that this is a potential blood diagnostic test.

Does anyone know:

• if the normal levels for PDK1 enzyme and this mRNA have been established i.e. for people without ME/CFS?
• the cost of tests measuring the the PDK1 enzyme and/or this mRNA?

High throughput automated analysers measuring enzyme levels in blood have been available for 30 + years; I'm guessing that these are also available for measuring mRNA's. Therefore large scale testing should be deliverable if the test proves to be valid.

 

[Snow Leopard]

@Snow Leopard Are you alluding to G-protein-coupled receptor desensitization?

No. I am not talking about nondiscriminate desensitation of GPCR (eg by GRK/arrestins)

I am alluding that specific GPCR are being disrupted due to signals ultimately of extracellular origin. (endocrine or paracrine). (if not a GPCR then another receptor...)

So the levels of PDK1 enzyme and the mRNA which regulates its production are both elevated. Others have pointed out that this is a potential blood diagnostic test.

It is not a potential diagnostic test because the findings are not sensitive enough.

 

[Murph]

So @nandixon, if you were to play devil's advocate on this s1p theory, what's the best argument against it? What conditions would falsify it?

 

[nandixon]

So @nandixon, if you were to play devil's advocate on this s1p theory, what's the best argument against it? What conditions would falsify it?

That's a great question. I'm not sure. I've been trying to find problems with it but haven't been able to. And that's the first time I haven't found any real inconsistencies with a theory in nearly 20 years.

We really need to have a researcher measure S1P levels (and also measure the precursor, sphingosine).

If S1P is low, then that's probably because ceramides and sphingomyelin are low (both of which Naviaux found). Then the question of course is what's the real problem causing the low ceramides.

If S1P is high (or possibly normal), then it may be because autoantibodies against a S1P receptor are present.

 

[Murph]

[please read the below as it is intended: helpful and scientific. it's not meant to be mean, dismissive or grumpy, but I sense a risk even as I type that it may come across rather ... brusque]

@nandixon I love the theory but in the name of rigorousness I have to say this: you mention measurement, but your mental model expressed above allows for s1p to be the problem whether it is measured high, low or normal.

I'm neither clever nor educated enough to figure out how to falsify the theory, but any theory without a clear path to falsification is one I'd be inclined to stay skeptical of!

I don't say this as a way of saying that I think you're wrong, or that I don't appreciate your thinking. I think the s1p theory is an awesome candidate. It really seems to fit. And I'm sure you are smart enough to determine the conditions that would falsify the theory. I just think being clear with yourself and others on what those conditions are is important!

 

[nandixon]

@Murph I'm not giving the low and high (and possibly normal) options to make it impossible to falsify the hypothesis, but rather to provide reasons for why the S1P signaling axis might be impaired with those findings for the level of S1P.

 

[Snow Leopard]

So @nandixon, if you were to play devil's advocate on this s1p theory, what's the best argument against it? What conditions would falsify it?

Normal functioning compared to well matched controls would falsify the hypothesis.

You'd not just measure S1P levels, but ideally, to get a fuller picture: gene expression of S1P and the receptors and try to measure the activity of the S1PRs (with the serum eg if there are any autoantibodies or other factors that may be blocking the regular activity of the receptor to S1P).

I admit confirmation bias is a powerful thing. When looking at the literature, we tend to over-focus on well-characterised biological factors, ignoring the less well known (eg perhaps the central pathway is one that is not yet well understood). My personal perspective, this is just one of the hypotheses that I've found interesting (I was interested in the S1PR last September after looking at possible causes for my eye pain and noted the altered sphingolipid levels found by Naviaux).

 

[Owl42]

About S1P I've found this article on its rellation to Endocannabinoid system. I am foucsed on this because ECS modulation has helped me and many other people I know to handle this disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128475/

 

[eljefe19]

@Owl42 that article is over my head but I'm interested in the ECS system. How have you modulated it positively?

 

[Owl42]

@Owl42 that article is over my head but I'm interested in the ECS system. How have you modulated it positively?

I'm currently trying to stop my wasting of endocannabinoid through MAGL and FAAH inhibitio. I use nutmeg for this. But I have the problem I'm kind of addict to chocolate and it interferes with my experiments.

 

[eljefe19]

lol I am a chocolate addict myself. What dosage of nutmeg? What benefits in ME/CFS symptoms?

 

[Bdeep86]

I started investigating PPAR dysfunction a few months back after a discussion with an herbalist in Colorado about marijuana CBDs. The dysfunction of nuclear receptors became to compelling to ignore and It pulled me out of my CFS research hiatus, I have been working on this ever since. I have used alcohol and antibiotics as two major biomarkers in my research and after seeing them mentioned here I can't just sit back and not at least provide some insight of what I believe is happening.

I decided to start of health blog, I have been wanting to do for some time. With recent research revelations and the unnecessary passing of my uncle last night from needless disease. I think it is time. My first entry is my theory involving Farnesoid X Receptor over activation in the Ilium. I don't think i'll post the full theory directly on to Phoenix Rising as anytime someone does that it tends to turn into to some sort of battle that I don't feel like engaging in. If you would like to see it you can visit https://naturalresetorg.wordpress.com/

This is a temporary URL.

I feel there is a dysfunctional communication taking place between the intestines and the liver. This is being mediated via the FXR receptor in the intestines. Overactivation of the FXR receptor in the gut leads to upregulation of PDK4, this is how it is able to metabolically reprogram energy homeostasis via the liver. A form of liver dysfunction starts to feed into this as proper bile flow becomes compromised. When this occurs dysbiosis sets in which increases overgrowth of bacteria that promote deconjugation of bile acids, this causes reduced levels of tauro beta muracholic acid which is a potent intestinal FXR antagonist. This creates sustained hyperactivation of intestinal FXR which continually communicates to the liver to shut down certain functions that pertain to bile synthesis which has many profound effects on the body including immune system dysfunction. I have a more elaborate explanation on my blog but even then I will have to write more and plan on doing a series to explain what I feel is happening.

So basically when you guys are describing using anti-biotics or anti-parasite medications, what I think is happening is it is knocking down overgrowth that is causing the rapid deconjugation. There is a temporary increase in Tauro Beta Muricholic acid and you get a subsequent increase in FXR activation. When people find relief upon acute alcohol consuption, you are flat out antagonizing the FXR receptor in the gut, this is why you see increased bile synthesis during acute alcohol consumption. This is the most basic way I can put these things, it all feeds into this giant system of dysfunction.

Hopefully this sparks some minds, i'll be on here the next couple of days. Check out my blog at https://naturalresetorg.wordpress.com/ for the longer explanation.

 

[Chocolove]

This might make sense as in an energy deficient state the body might be converting much of it to lactate.

One of the first features of thiamine deficiency is a rise in lactic acid and then other changes including decline in the activity of dependent enzyme transketolase, which is needed for carbohydrate as well as lipid and amino acid metabolism and the maintenance of the protective myelin nerve sheaths.

The mineral magnesium is an important co-factor for thiamine-dependent enzymes and nerve conduction and sometimes co-existing deficiency limits the response to the correction of thiamine deficiency.

 

[Bdeep86]

@nandixon, thank you so much. It looks great. I don't understand much of it, but I am sure they'll reply. You can also send the e-mail to dr. Mella.


Some are sensitive to alcohol, but why do I almost feel 100% recovered when drinking a lot of alcohol? Less dizzy, lactic acid is gone, significantly reduced pain, less cracking in my joints. It looks like alcohol effects all my symptoms. Haukeland says that some can't drink alcohol at all. A glass of wine is enough to make them feel poisoned. I need to drink a bottle of wine to feel better. A few years ago, when my ME wasn't that bad 2-3 glasses of wine improved my symptoms. Now I need more to get the same effect.

I do suffer from some sort of endothelial dysfunction. I am also 99% certain that my flow-mediated dilatation test will show reduced blood flow under stress.

The relief in your symptoms may have to do with acute alcohol ingestion antagonizing FXR receptors in the intestines.

 

[eljefe19]

The relief in your symptoms may have to do with acute alcohol ingestion antagonizing FXR receptors in the intestines.

Great write up! Do you think Sevelamer would help people with ME?

 

[Bdeep86]

Great write up! Do you think Sevelamer would help people with ME?

Since i've gone public with this and I would like to be able to speak with people i'm not sure whether I can say directly. But I will say that I have entertained that thought. I however would not recommend trying this on your own, it could have serious consequences. To restore this system a few different things need to be in place, so much interplay between systems. I have a program in mind but like I said I need to look into the legality of releasing that information. The study I linked involves mice but I do feel that it is an FXR antagonist in the intestines for humans as well. It is possible that this could yield some very powerful results should my theory be correct. I have a whole plan to correct this issue, I just need to make sure I'm not putting myself in a legal situation as it involves a combination of certain agents and diet.

I forgot to mention also that FXR signaling has a relationship with mTOR which I have seen come up on here. I haven't investigated that deeply but I know it exists.

Also @eljefe19 i've been meaning to compliment your profile pic. I haven't come across many Cage fans in CFS research interactions.

 

[eljefe19]

@Bdeep86 haha yes! Something about CFS always pushed me towards the angrier music. I'll PM you to avoid derailing this great thread

 

[Bdeep86]

@Bdeep86 haha yes! Something about CFS always pushed me towards the angrier music. I'll PM you to avoid derailing this great thread

That is actually very relevant. There is a major emotional body component to this condition. It is something that will need to be addressed for full restoration for some. Obviously it is no secret that glucorticoids have a profound impact on this condition (glucocorticoid receptors are part of the nuclear receptor family) however our minds through conditioning can get locked into certain brainwave patterns that lock us into a stressed state. This is where much of the initial liver dysfunction takes place. And where much of the miscommunication begins. That is also I guess another discussion.

 

[eljefe19]

Interesting, I was always an angry child and had a ton of emotional trauma and stress before getting sick. I wouldn't be surprised if there was a connection in early sickness.