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From brain fog to clarity in 30 minutes

frozenborderline

Senior Member
Messages
4,405
I'm having really good success with BCAA's and pantethine. 2 of the 3 BCAA's, isoleucine and leucine are converted to Acetyl CoA and feed the krebs cycle.

The third, Valine, feeds into the krebs cycle directly. Pantethine (co-enzyme B-5) is the precursor to CoA, which is converted to Acetyl CoA and feeds the krebs cycle, like isoleucine and leucine.

Both BCAA's and pantethine feed the krebs cycle after the pyruvate dehydrogenase enzyme.
BCAAs have helped me too. Since I was sort reckless and also too tired to do much measuring I went with a high dose to try them, two teaspoons, about 6 g. This helped me feel better, less pain, more energy, warmth, etc, but I got diarrhea bad on the fourth time I tried this dodse.
 

frozenborderline

Senior Member
Messages
4,405
BCAAs have helped me too. Since I was sort reckless and also too tired to do much measuring I went with a high dose to try them, two teaspoons, about 6 g. This helped me feel better, less pain, more energy, warmth, etc, but I got diarrhea bad on the fourth time I tried this dodse.
but yes, didn't fluge and mella show that the BCAAs were used better than the amino acids that feed pyruvate or ?? I forget this specific step but they showed increased utilization of some amino acids that entered into the kreb's cycle at a different point than the pyruvate oxidation
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
but yes, didn't fluge and mella show that the BCAAs were used better than the amino acids that feed pyruvate or ?? I forget this specific step but they showed increased utilization of some amino acids that entered into the kreb's cycle at a different point than the pyruvate oxidation

Yes. This diagram is from the Fluge and Mella study. The red box shows the amino's that are reduced in ME/CFS. Because they are being used to make Acetyl-CoA to feed the Krebs cycle instead of Pyruvate.

Because of the PDH inhibition. The amino's are Isoleucine, leucine, Lysine, Phenylalanine, Tryptophan and Tyrosine. The purple boxes also show reduced amino's that feed the krebs cycle directly.

upload_2018-10-6_10-3-19.jpeg
 

ljimbo423

Senior Member
Messages
4,705
Location
United States, New Hampshire
BCAAs have helped me too. Since I was sort reckless and also too tired to do much measuring I went with a high dose to try them, two teaspoons, about 6 g. This helped me feel better, less pain, more energy, warmth, etc, but I got diarrhea bad on the fourth time I tried this dodse.

You might want to try splitting the dose into 2-3 doses instead of one and take a lower dose. Taking them with food might also help.

I also get loose stool but from higher doses of 15 grams or more. Maybe start with just one gram twice a day and see if you can slowly increase the dose, over time, without side effects.
 

frozenborderline

Senior Member
Messages
4,405
A user on another forum, named travis, made this very interesting post after I showed him the Naviaux and fluge/mella stuff on metabolism being impaired in CFS and asked what he would try specifically:
"I can't think of anything besides thiamine, unless of course you'd find a way to increase the expression of the enzyme. Yet there could be a way to do this: Since pyruvate dehydrogenase is under negative regulation by hypoxia inducible factor-1—via transcribing-for pyruvate dehydrogenase kinase—then taking baicalein and/or lapachol should ultimately act to increase it. These phytochemicals are the two most powerful natural glyoxalase-1 inhibitors (Kᵢ ≈ 5–7 μM), acting to increase methylglyoxal by inhibiting its degradation to lactate. Methylglyoxal is very powerful because it selectively reacts with exposed arginyl side-chains on proteins, irreversibly converting them into hydroimidazolone rings. By reacting with 'hot spot' arginine residues is how methylglyoxal been shown to regulate transcription (Yao, 2007), and the transcription factor HIF-1 is also inactivated in this manner (Bento, 2010). Taking a glyoxalase inhibitor such as baicalein could be expected to: increase intracellular methylglyoxal, decrease intracellular lactate, inhibit 15-lipoxygenase (Deschamps, 2006), inactivate hypoxia inducible factor-1α (Bento, 2010) thereby increasing pyruvate dehydrogenase expression. Methylglyoxal had acquired a pathological reputation because it reacts with extracellular proteins in diabetes, yet this only occurs in states where glucose cannot get into the cell where it belongs. Methylglyoxal also forms inside the cell mainly from carbohydrates, and appears to be the biochemical signal for their metabolic rate. Intracellular methylglyoxal has also acquired reputation for powerfully inhibiting cancer, and very likely the reason why baicalein and lapachol have been so successful at treating it.



Kim, Jung-Whan. "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia." Cell metabolism (2006)



'Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1a null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.' ―Jung-Whan



Bento, C. F. "The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal." PloS one (2010)



'Methylglyoxal has recently been shown to modify HIF-1α on arginine residues [22], probably leading to changes in protein conformation. Indeed, immunoprecipitation experiments showed that methylgloxal-modified lysine and arginine residues of HIF-1α, increasing its immunoreactivity against N-carboxymethyl-lysine and Nα-acetyl-Nδ(5-hydro-5-methyl)-4-imidazolone (MG-H1) antibodies, respectively. Thus, we hypothesized that modification by methylgloxal might stimulate proteasome-dependent degradation of HIF-1α, as a result of post-translational modifications.' ―Bento



Yao, Dachun. "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry (2007)



'Our studies demonstrate for the first time that methylglyoxal causes post-translational modification of a coregulator protein and that this modification affects gene expression. The extent of this modification reflects the net effect of a variety of intracellular processes, including metabolic flux and reactive oxygen formation, and may thus function as a new integrating signal to coordinately regulate distinct patterns of gene expression.' ―Yao"
 

sb4

Senior Member
Messages
1,659
Location
United Kingdom
It is an interesting idea but I have supplemented lapodin previously and not noticed a diference. Perhaps because I seem to be a DCA non responder, or I didn't take a high enough dose for long enough.
 

frozenborderline

Senior Member
Messages
4,405
It is an interesting idea but I have supplemented lapodin previously and not noticed a diference. Perhaps because I seem to be a DCA non responder, or I didn't take a high enough dose for long enough.
I've tried lapodin and it seemed to help a lot at the time but I was a little less severe, and it could have been from the emodin, not the lapachone.

Baicalein looks promising, because it has additional effects besides what travis was talking about--effects on GABA and estrogen antagonism.
 

Chris

Senior Member
Messages
845
Location
Victoria, BC
Noone has tried the combo of DCA and phenylbutyrate proposed by the Ferriero essay, which seems to imply that the combo might be a partial substitute for Suramin, which seems to be the only current drug that inhibits all the PDKs? I feel tempted to try my doc with a request for low dose Phenylbutyrate, but know that the response would be a polite "no unless you can provide me with good evidence..."--but it would be great if one had access to the stuff as one has access to DCA, and could try the combo out, starting of course with very low doses of both....ah well, guess we will just have to wait.