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"
