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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
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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