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i think i figured it out (the cause of cfs ) i will pass on the baton

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chronic fatigue syndrome is an upregulation of the antioxidant system in the brain and muscle. there was an a strong stressor (mental , physical or emotional ) of high intensity and long duration . This stress requires higher amounts of atp , the higher amounts of atp production creates more potential for oxidative stress , in order to protect itself from this oxidative stress, the cell upregulates the antioxidant system.

PKM2 is upregulated in the muscle cell and the brain cell . Pyruvate kinase involved in glycolysis and production of pyruvate .Normally PKM1 is dominant expression in brain and muscle . The upregulation of PKM2 allows for diversion of glucose in the pentose phosphate pathway (important for the antioxidant system). The upregulation of PKM2 affects gene expression and activity of other enzymes . Chronic fatigue patients have higher activity of nfkb and lower activity of p53. PKM2 may be what is causing lower activity of p53 . Lower activity of P53 (big problem ) , p53 affects glycolysis and oxidative phosphorylation. we need normal activity of p53 for normal activity of oxidative phosphorylation and fatty acid oxidation (important for atp i.e. energy) . PKM2 binds p53 and lowers its activity. nrf2 may induce expression of PKM2 . nrf2 affects glutamine metabolism .

cfs patients have lower resting lactate levels compared to healthy people because glucose is diverted into the pentose phosphate pathway . When physically or mentaly active cfs patient make more lactate compared to healthy people . This might be due to expression different isoforms of lactate dehydrogenase , but more importantly the lower activity of p53 inhibits oxidative phosphorylation and fatty acid oxidation .During physical activity , in order to try to meet atp demands glycolysis is upregulated , so we depend more on glycolysis for energy (because oxidative phosphorylation is inhibited ) and we produce more lactate.

Unlike PKM1 which is readily active, PKM2 activity depends on allosteric regulators . fructose 1,6 bisphosphate (FBP) is activator of PKM2 . When there is a build up of FBP PKM2 can be activated , so when we have a build up of FBP we can use glycolysis for our atp needs , but as glycolysis is activated the levels of FBP goes and the ability to activate PKM2 lessens and our ability to get energy from glycolysis lessens . so the cfs patient can only depend on glycolysis for awhile because we express PKM2 .

We need to cause increased activity of p53 and upregulation expression of PKM1 . PKM2 has three forms with different levels of activity , monomeric , dimeric and tetrameric . Monomeric and dimeric forms can bind and lower p53 activity . monomeric and dimeric PKM2 can translocate to nucleus and affect gene transcription and expression . Increasing p53 increases oxidative phosphorylation . There are synthetic molecules that can increase activity of PKM2 and keep it in tetrameric form. Tetrameric PKM2 doesn't lower activity of P53 . Dimeric and monomeric KM2 can translocate to the nucleus to lower activity of p53. but I think the synthetic molecules are only in research , there are some other substances that can effect PKM2 found naturally in plants called naphthoquinones .

Naphthoquinones inhibit PKM2 and may increase activity of p53 . Shikonin is a naphtoquinone used in cancer research , it inhibit aerobic glycolysis and increases p53 . it causes cancer cell death . but I don't think it'll cause the same problems in healthy cells. One of the ways shikonin may work is through inhibition of phosphorylation of PKM2 . phosphorylation of PKM2 allows formation of monomeric PKM2 , monomeric PKM2 can translocate to the nucleus and inhibit p53 activity . So by inhibiting PKM2 phosphorylation there is less monomeric PKM2 , so less monomeric PKM2 to interfere with p53 activity . We need p53 for normal oxidative phosphorylation .

I think shikonin is a hopeful substance to use, maybe some other naphthoquinones as well. Shikonin is found in family of boraginacaee plants . These plants have some toxic substances namely pyrrolizidine alkaloids which can cause liver damage and other problems . If we want to use shikonin and shikonin derivatives found in these plants we have to find a way to seprate out the toxic substances .

I think there test are that can prove my guesses here ( besides muscle and brain biopsy to test for increased PKM2 expression) . I think if we check the blood( probably serum) we will see at least these two abnormalities that has to do with what i'm talking about . If we check the blood or serum I think we will see increased levels of PKM2 , and higher levels of 2,3dpg . If we do muscle biopsy we may higher levels of total glutathione because is upregulation of antioxidant system . Because of PKM2 is lower activity than PKM1 in cfs patients muscles , there is a rise in 3PGA , the rise in 3PGA promotes higher levels of 2,3dpg , by phosphatase inhibition and synthase activation .

The higher levels of 2,3 dpg is released into the blood stream and is taken up by other cells , maybe red blood cells and pbmc ( peripheral mononuclear cells ) and causes abnormalities when researchers like Ron Davis test them. 2,3 dpg is the substance in the serum that we've been looking for . 2,3 DPG (2,3 diphosphoglycerate )when taken up by mononuclear cells inhibits HK, PFK and GAPD , this affects glycolysis , probably lowering the glycolytic intermediates and the production of pyruvate (leaving less pyruvate available for oxidative phosphorylation ).

But what we're seeing in mononuclear cell test is only the downstream effects of what is happening in muscle and brain . Even if we clean up all the 2,3dpg from the blood stream its not gona fix cfs . 2,3dpg is the substance causing the abnormalities in Ron Davis study but 2,3dpg is not the cause of cfs . The Stanford study did test outside of the serum that didn't have the high 2,3dpg in it , this resulted in higher levels of atp production( probably from higher glycolysis) compared to healthy controls, it might've been due to adaptation of glycolytic enzymes in cells from cfs patients from inhibition by 2,3dpg so that when you remove them from the 2,3dpg they have higher activity than healthy control cells of healthy patients who had normal 2,3dpg leves in their blood , serum .

The key is to fix whats happening in muscle cells and brain . I think increasing p53 to increase oxidative phosphorylation and I think we should look into shikonin
 
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this is one cause of fatigue , other people who have fatigue maybe misdiagnosed with medical conditions that already been discovered , example chemcical toxicity , prediabetes and hormonal problems , sjorgren syndrome and blood pressure type things among other things. I know I didn't write organized but i'm completely exhausted
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Interesting but at least incomplete. It helps to break up long arguments into smaller paragraphs.

My first paper on ME was about 2,3 dpg, in 1999, though my primary focus was hypercitricemia.

However I was trying to explain why it was low in one study, and later it was shown to be high. Investigation has moved on since then.

There does not appear to be evidence of higher glutathione. The data suggests its low.

The substance Stanford is looking for is very high molecular weight, or at least size. So a single molecule is too small to be the substance, but this does not allow for clumping . . . I have just never heard of it clumping.

We also find using invasive CPET high levels of RBC oxygen in venous blood.

I wonder if you should take into account blood pH? While we have acidic spikes due to lactate and hence an acidic shift, in general we seem to be alkaline . . . some kind of buffering or compensation. So the pH adjustment might well see low 2,3 DPG, something has to be pushing levels up. I hope I have not gotten the pH impact wrong, tis been about 18 years since I looked at this.

However I can confirm, though perhaps unpublished, that 2,3 dpg is likely to be high. It would be interesting to see if other markers you predict can be found.

I have not worked on this idea since about 2002.
 
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2,3 dpg is what is causing the abnormal study in Ron Davis test , it is being released into the bloodstream by muscle and brain , and taken up by mononuclear cells. 2,3dpg inhibit hk ,pfk, and gadp glycoltic enzymes , causing lower glycolytic intermediates , lower glycolysis and less pyruvate production . Less pyruvate is available for oxidative phosphoporylation . In the Stanford study they found higher levels of atp production , this is because they did the tests without patient serum with high 2,3dpg . The mononuclear cells in the Stanford study were adapted to a high 2,3dpg environment in the serum and glycolylytic enzyme inhibition , when they were taken out of this high enzyme environment (patient serum) this resulted in higher levels of glycolysis and more atp from glycolysis pathway . Getting 2,3dpg to normal levels is not gona fix cfs . High 2,3dpg is the result of what is happening in muscle cells and brain cells .In the muscle there is an ongoing upregulation of the antioxidant system . nrf2, pkm2 (high), pkm1(maybe low) and p53(low) is what is abnormal there .
 
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ALEX my main point is the ongoing upregulation of the antioxidant system inside muscle and brain . If they look there they would higher total glutathione not lower . Higher expression of PKM2 expression and lower P53 activity in muscle and brain is what is causing cfs . 2,3dpg is only a downstream product
 
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PKM2 exist in 3 activity levels . monomeric dimeric and tetrameric . In cfs patient muscle is the lower activity of PKM2 in comparison to Pkm1 that causes a build up a build up glycolytic intermediates (2,3dpg) . 2,3dpg is released into blood and taken up by mononuclear cells
 
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Alex glutathione maybe low in certain places (maybe red cells). but in muscle where I think there is an upregulation of the antioxidant system , the total glutathione would be high
 

HABS93

Senior Member
Messages
485
Alex glutathione maybe low in certain places (maybe red cells). but in muscle where I think there is an upregulation of the antioxidant system , the total glutathione would be high
I know this is a simple question compared to those paragraphs of knowledge. Wouldn't you be able to have an idea of your gultithione levels through the OAT ? Or is in the muscle a totally different level?
 
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there's higher levels of oxidative stress in muscle cells of cfs patients, how the muscles protect themselves from oxidative stress through upregulation of the antioxidant system , and antioxidant enzymes expression PKM2 , normally PKM1 is expressed the dominant form in muscles .PKM2 allows diversion of glucose into the antioxidant pathway. so if glutathione is high it would be in there . but we don't need to be trying to raise glutathione , its not gona fix cfs mainly the fatigue
 
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you need to normalize whats happening inside the muscles, mainly PKM2 . PKM2 inhibits p53. p53 activity is needed for oxidative phosphorylation ( production of atp). the cfs patient (at rest) usually has lower lactate levels than healthy people but when they physically active they have higher lactate levels than healthy people (this is because they are producing energy from aerobic glycolysis and not enough from oxidative phosphorylation. lower levels of p53 activity results in lower oxidative phosphorylation ( less mitochondrial atp production) . p53 is necessary for (sco2 ) cytochrome c oxidase 2 , mitochondrial complex iv . electron transport chain
 
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HABS93 I don't even what OAT is . i'm just a patient trying to figure things out , but I believe I have most complete and probably the only correct guess out here right now . as far as explaining the mechanism of cfs I think I've gone farther than any researcher all around the world even Ron Davis . Ron Davis is searching for the that's causing abnormality in mononuclear cell ( I think its 2,3dpg) . 2,3dpg inhibits glycolytic enzymes causing the abnormality he sees
 

WantedAlive

Senior Member
Messages
158
@phillybadboy I recently proposed involvement of PKM2 in my thread along with OAT testing, see here:
https://forums.phoenixrising.me/thr...ults-do-we-all-show-the-warburg-effect.80662/

The impairment of glycolysis is an interesting and unproven hypothesis in ME/CFS. So far I think only one researcher (McGregor) is supporting it, while many others have demonstrated impairment of PDH but without impairment to glycolysis. I'm confused by this because impairment of PDH is typically associated with high pyruvate or lactate, whereas OAT tests of PwME typically show low pyruvate and lactate. In my thread to date, you'll see all but one OAT result contributor show this result, so based on this short survey I'm in the camp that supports something isn't right with glycolysis.

As explained in my thread, PKM2 is the rate limiting step of glycolysis and ubiquitously expressed in sepsis and cancer. Its plausible therefore PKM2 is a good candidate for involvement in ME/CFS if glycolysis is impaired.
 
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no glycolysis is not impaired , at rest the lactate levels are are low , but during physical activity the lacate levels are higher than normal people . if glycolysis was impaired you wouldn't have high lactate levels . It is actually oxidative phosphosphorylation that is inhibited . so we try to make energy by aerobic glycolysis similar to how cancer cells do . the reason this abnormality is PKM2 expression in muscle cells ( normally PKM1 is expressed in muscle cells ) PKM2 helps you with antioxidant system . but PKM2 inhibits p53 activity , p53 is very important for oxidative phosphorylation (sco2) .
 

JES

Senior Member
Messages
1,340
as far as explaining the mechanism of cfs I think I've gone farther than any researcher all around the world even Ron Davis

Not really. You presented a hypothesis, an explanation requires a demonstration that the idea in fact is valid and should also be subject to scrutiny. Only when every reasonable attempt at falsifying the hypothesis fails should it considered to be true or likely true. Have you tried getting in contact with some researcher? I'd suggest you contact OMF, but especially Davis gets bombarded with emails, so he's probably not the best target.
 

Mohawk1995

Senior Member
Messages
287
as far as explaining the mechanism of cfs I think I've gone farther than any researcher all around the world even Ron Davis

I would caution against this line of thinking with ME/CFS. It has been this type of thinking in medicine that has created many issues with patient care (PACE for instance). There is a difference between having an explanation of a mechanism in a disease and actually understanding the root cause of the disease. Not denying that what you have proposed may be accurate, but it is a description of a mechanism at play in ME/CFS and not the root cause. The ultimate question is why does this system become mal-adaptive in some and not in other people who experience the same distress (disease, trauma, emotional stress, etc....). When we know that answer, then perhaps we can boast just a little. :)
 
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Mohawk good point if true , but I believe all people are capable of getting cfs if the stressors are intense enough and of enough duration . I believe the mechanism that I describe happens in healthy people too , when they demand for antioxidant system , say if healthy people were to run a marathon , I think this mechanism would upregulate to protect them from oxidative stress , then after some days of rest , the system downregulates itself , and the enzymes involved downregulate . This is is a normal mechanism that happens to protect cells from oxidative stress . but in cfs we're stuck in cycle of high ROS (reactive oxygen spieces , signaling) and the upregulation of the antioxidant system . The normal downregulation isn't happening . i'm looking into compounds that can reverse this mechanism
 
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Mohawk i'm also looking blood, serum, or urine testing for PKM2 and 2,3dpg , finding both at the same , together , would add support to my guess . Hopefully these are available commercially and a doctor would be able to order
 
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Wantedalive glycolysis is impaired or inhibited in mononuclear cells . 2.3dpg is inhibiting glycolysis is inhibiting glycolysis in mononuclear cells . But in muscles glycolysis is not inhibited , oxidative phosphorylation is inhibited , cfs patients depend on aerobic glycolysis for our energy that's why during physical activity we produce more lactate than healthy people.
 
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