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

[ScottTriGuy]

Tagamet

Turns out I have some from 5 or so years ago (pre-ME) when I was in the US and had heartburn.

Before starting my own experiment with Tagamet, I'd be interested to know your constellation of symptoms and see how they align with my own.

Currently, because I limit my activity to avoid pem, my most limiting symptoms include walking more then 10 minutes on flat ground or walking up more then 1 flight of stairs (even 1 flight causes my heart to pound).

Using my arms to lift or reach above my head will make me feel very unwell, light headed, nauseous until I get horizontal for 20 minutes or so. I do not have POTS (no change in my bp for 10 mins), but something is messed up with my blood pressure. Trying to get NMH testing.

I do not have pain or brain fog (if I'm to believe the cognitive testing I had done, because there sure have been instances when my mind has been blank searching for words). My body temperature is low but labs normal but synthroid helps with feeling cold (though I'm still very sensitive to cold temperatures, and love the sun / heat).

I've done better (in terms of less nausea) cutting way back on sugar and carbs.

Recently I had a bad week (dizzy, extra cold, blood pooling abdomen) that I am attributing to not taking acetyl-L-carnitine.

I do not seem to get colds or the flu in the last few years. (In Oct I was in a room with others for a week long meeting - almost everyone got a cold, some worse than others, that lasted for weeks, but I only had very mild symptoms.)

Thanks @nandixon - and others on this thread, for sharing, and making accessible to the lay person, this important technical info.

 

[nandixon]

Turns out I have some from 5 or so years ago (pre-ME) when I was in the US and had heartburn.

Before starting my own experiment with Tagamet, I'd be interested to know your constellation of symptoms and see how they align with my own.

Cimetidine (Tagamet) has a shelf life of only about 2 years, so I'm afraid it will be rather degraded after 5 years. The problem with expired drugs is that they can not only be much less effective but also potentially have degraded into undesirable substances. (I used to be a pharmaceutical/medicinal chemist and this drug in particular I would not try old lots of.)

A post where I give my symptoms is here.

Good luck!

 

[ScottTriGuy]

Cimetidine (Tagamet) has a shelf life of only about 2 years, so I'm afraid it will be rather degraded after 5 years.

Thanks for that info. I'll have to delay my n=1 experiment.

 

[eljefe19]

Thanks for that info. I'll have to delay my n=1 experiment.

I'm going to take my first dose today

 

[adreno]

@nandixon

http://www.sciencedirect.com/science/article/pii/S0014579302038826

Abstract
We show here for the first time that sphingosine-1-phosphate (Sph-1-P) stimulates cortisol secretion in zona fasciculata cells of bovine adrenal glands. This effect was dependent upon protein kinase C (PKC) and extracellular Ca2+, and was inhibited by pertussis toxin. Sph-1-P activated phospholipase D (PLD) through a pertussis toxin-sensitive mechanism, also involving extracellular Ca2+ and PKC. Primary alcohols, which attenuate formation of phosphatidic acid (the product of PLD), and cell-permeable ceramides, which inhibit PLD, blocked Sph-1-P-induced cortisol secretion. In conclusion, Sph-1-P stimulates cortisol secretion through a mechanism involving Gi/o protein-coupled receptors, extracellular Ca2+, PKC and PLD.

So S1P stimulates cortisol secretion. This fits well with the general ME picture, which often show low cortisol. However it says here that ceramides inhibited this, thru blocking PLD. I thought that according to your model ceramides stimulate S1P. Am I misunderstanding something?

 

[nandixon]

So S1P stimulates cortisol secretion. This fits well with the general ME picture, which often show low cortisol. However it says here that ceramides inhibited this, thru blocking PLD. I thought that according to your model ceramides stimulate S1P. Am I misunderstanding something?

S1P is made from ceramides in two steps:

ceramides--> sphingosine--> S1P

Ceramides and S1P generally have opposite cellular actions, so if ceramides were to accumulate too much relative to how much are converted to S1P then the ceramides could interfere with S1P's actions. But the Naviaux study showed that ceramides were low in ME/CFS patients.

 

[kangaSue]

Using my arms to lift or reach above my head will make me feel very unwell, light headed, nauseous until I get horizontal for 20 minutes or so. I do not have POTS (no change in my bp for 10 mins), but something is messed up with my blood pressure. Trying to get NMH testing.

@ScottTriGuy You were mentioning getting a vascular ultrasound done in another thread, are they going to be looking for gastrointestinal compression syndromes too? Nutcracker Syndrome can screw up your b.p. through the renin-angiotensin system.
http://forums.phoenixrising.me/inde...ith-pots-and-childhood-cfs.48793/#post-803537

There is a kidney/brain pathway that is activated by renal ischemia too.
https://www.ncbi.nlm.nih.gov/pubmed/28030955

 

[ScottTriGuy]

Thanks @kangaSue

See my reply on this thread: http://forums.phoenixrising.me/inde...ith-pots-and-childhood-cfs.48793/#post-803537

 

[adreno]

I keep reading bad things about ceramides:

Generation of ceramide by sphingomyelinases might contribute to disturbed barrier function seen in diseases such as inflammatory, infectious, toxic or radiogenic bowel disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171303/

 

[nandixon]

I keep reading bad things about ceramides:

Yes, ceramides are bad when their levels are too high. But if too low then there's not enough starting material available to make S1P (and also sphingomyelins).

The same situation exists, for example, with respect to cholesterol. If it's too high then it's bad, but if too low then there's not enough starting material for steroid synthesis and hormones.

 

[bel canto]

@nandixon - I don't know that this will have any relevance to this discussion, but I ran into a mention of defective mTor signalling in a Castleman's (rare autoimmune disease) patient. His theory is that his disease is due to overactive signaling of this pathway, but I thought I'd provide the link.

 

[kangaSue]

Interesting paper finding increased ceramides in IBS patients in a small study.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797663/ Elevated pro-inflammatory and lipotoxic mucosal lipids charecterise irritable bowel syndrome.
[In the present study, lipids - particularly lysophosphatidylcholines (lysoPCs) and ceramides - were the most upregulated molecules in IBS patients. Mounting data suggest that certain lipids, including phospholipid derivatives and ceramides, play a role in modulating and enhancing pain sensitivity[27,28], which could be one explanation for their involvement in IBS pathophysiology. LysoPCs have not previously been associated with IBS, but studies indicate elevated levels of lysoPCs or phospholipase A2, an enzyme involved in lysoPC formation, in inflammatory bowel disease (IBD)[29,30]. A high lysoPC concentration has been suggested to impair mucosal barrier function and increase gastrointestinal permeability in vivo and in vitro[31-34]. The role of permeability defects in IBS is not fully elucidated, but a recent review by Camilleri and Gorman concludes that there appears to be at least one IBS subgroup with increased gut permeability[35]. Interestingly, lysoPCs have also been associated with vascular inflammation, endothelial dysfunction, and coronary atherosclerosis[36], implying that lysoPCs might also play a role in the subtle type of mucosal inflammation present in IBS.]

 

[eljefe19]

@kangaSue interesting! I had been diagnosed with IBD-D for 10 years until 2 weeks at OMI they diagnosed me with MCAS. I have intense stomach ache cramps going on 15 years (I'm 26). So maybe my ceramides aren't high. I need this tested.

 

[kangaSue]

I have intense stomach ache cramps going on 15 years (I'm 26).

Is this made worse shortly after eating, half an hour or so?

 

[eljefe19]

Exactly. Although sometimes it wakes me up first thing in the morning too.

 

[Tiger_Eyze]

@eljefe19
@kangaSue

LysoPCs are the result of phospholipase A2 cleaving phosphatidyl choline in the plasma membrane of a cell to make AA. Phospholipase A2 can be activated by several things, including LPS. AA is a major precursor to a bunch of prostaglandins/leukotrienes (most of which promote inflammation & angiogenesis) synthesized by Cox1/2, LoX5 & some others.

Some exciting alternative lipid products of this cascade called Lipoxins & resolvins are like the naturally occurring "off switch" to the inflammatory prostaglandin cascade.
Lipoxins block nfKB, lower TNF-a, increase activated neutrophil death & removal, etc. At least in asthma, it appears there is defective or insufficient lipoxins to shut down the inflammation.

USC has a synthetic Lipoxin analogue in clinical trials called Benzo-lipoxin. It's a mouth was for gingivitis inflammation. There r a few others being tested out.
I want!

But in the meantime, statins+aspirin+EPA support can supposedly increase epi-Lipoxins (possibly the true reason for the protective effects in atherosclerosis) via funneling metabolites towards lipoxins.

Additionally, leukotrienes can cause inflammation. Not sure if Singulair would be of use or not or if LOX5 inhibitors like boswallic acid would reduce both leukotrienes and lipoxins equally, or yield a net anti-inflammation effect.

---------------------
The Pyruvate dehydrogenase block in ME/CFS was associated with high PDK1, which is a major player in the PI3K/Akt/mTORC1 pathway. Another study looking at metabolites showed a block in the TCA cycle at aconitase as well, and a few other studies have found higher lactate production from pyruvate during exercise in ME pts.

Turns out HIF1-a increases PDK1 (blocks PDH), blocks aconitase, elevates Lactate dehydrogenase (converts pyruvate to lactic acid), and increases VEGF.

Apparently Pyruvate can also be converted to alanine by ALT?

HIF1-a can be induced in normoxic conditions by the NFKB pathway. Hif1-a + high VEGF leads to abnormal vessel proliferation & vessel leakiness.

Not sure where I was going with that...apparently it's time for bed.

I can post refs in AM for anyone who would like them.

 

[ScottTriGuy]

@nandixon

This article mentions the mTOR pathway - any relevance to your hypothesis?

(BTW, I'll have Tagamet soon to try)

"If Dr. Fajgenbaum could get his body to shut down that communication line — known as the mTOR pathway — he might be able to stop his immune system from overreacting and prevent a relapse."

https://www.nytimes.com/2017/02/04/...?action=click&contentCollection=Business&_r=0

 

[temple88]

I ran into an article discussing mTOR and macrolides earlier today. Not sure if it's been posted yet. Click to download the file if you want.

https://www.researchgate.net/public...ivation_by_direct_modulation_of_mTOR_activity

 

[kangaSue]

Exactly. Although sometimes it wakes me up first thing in the morning too.

Same here. I asked because I know what causes my problem, it's intestinal ischemia and abdominal pain about 30 minutes after eating is the most prevalent symptom you get with it. (It has various names, I have Chronic Mesenteric Ischemia in the form of Non-occlusive Mesenteric Ischemia)). It started as just a dull background abdominal pain but once it started to hurt after eating too, it got to be severe at times and not let up for hours which meant a trip to the ER for some serious pain relief.

This was first diagnosed as Gastroparesis and all the symptoms that go with that, early satiety and/or have little to no appetite and can occur with nausea and vomiting too.

Gastrointestinal mast cell activity is increased with intestinal ischemia but I don't know how or if that would tie in with MCAS.

Whatever the cause, when you delve into the literature, intestinal ischemia is way more prevalent than indicated by any statistics as relatively few doctors even suspect it to go looking to rule it out. That and the fact that there isn't a test specific for it when it is non-occlusive.

 

[Tiger_Eyze]

Same here. I asked because I know what causes my problem, it's intestinal ischemia and abdominal pain about 30 minutes after eating is the most prevalent symptom you get with it. (It has various names, I have Chronic Mesenteric Ischemia in the form of Non-occlusive Mesenteric Ischemia)). It started as just a dull background abdominal pain but once it started to hurt after eating too, it got to be severe at times and not let up for hours which meant a trip to the ER for some serious pain relief.

This was first diagnosed as Gastroparesis and all the symptoms that go with that, early satiety and/or have little to no appetite and can occur with nausea and vomiting too.

Gastrointestinal mast cell activity is increased with intestinal ischemia but I don't know how or if that would tie in with MCAS.

Whatever the cause, when you delve into the literature, intestinal ischemia is way more prevalent than indicated by any statistics as relatively few doctors even suspect it to go looking to rule it out. That and the fact that there isn't a test specific for it when it is non-occlusive.

If you don't mind my asking, how was your ischemia diagnosed? Did you end up having a vessel blockage that they found on a CT or elevated lactic acid in your blood? Or was your ischemia more of an SMA Syndrome type picture that is hard to pick up with standard testing?