Coffee and homocysteine

Filtered or unfiltered coffee increases homocysteine levels in healthy individuals whereas caffeine has a much weaker effect on homocysteine levels. Stopping drinking coffee reduces homocysteine levels.

Increased homocysteine levels point to decreased levels of L-cysteine which is synthesized from homocysteine. With decreased synthesis of L-cysteine iron-sulfur cluster formation could be dysregulated which could upset many biological processes. Increased homocysteine levels could could affect DNA methylation. In schizophrenia there is a positive association between plasma homocysteine and DNA methylation. Difficulties due to coffee could take years to develop due to hypermethylation of genes taking years to develop.

The Major Histocompatibility Complex, HFE and schizophrenia

The Major Histocompatibility Complex (MHC) has been associated with schizophrenia. The hemochromatosis gene, HFE, which regulates iron levels is linked to the MHC on chromosome 6. In cells that express HFE IRP1 and IRP2 binding increases as the labile iron pool decreases with increased HFE expression. IRP1 and IRP2 are regulated by iron levels. Genetic studies that have associated the MHC region with schizophrenia frequently conclude that this is evidence for an infectious etiology to schizophrenia as the MHC is involved in immunity. What genetic associations of the MHC to schizophrenia could be picking up is associations of HFE with schizophrenia where such associations arise due to dysregulations in iron metabolism.

Treating the negative symptoms of schizophrenia

The negative symptoms of schizophrenia are at least partly due to a shortage of coenzyme A which is used by the E2 unit of the 2-oxoglutarate dehydrogenase complex and the E2 unit of the pyruvate dehydrogenase complex in the citric acid cycle. What is needed is to increase levels of coenzyme A which can be done by supplemental pantothenic acid.

Why are coenzyme A levels low in schizophrenia? L-cysteine is required to synthesize coenzyme A. Due dysregulation of the transsulfuration pathway in schizophrenia, as explained in my paper Treatment-resistant schizophrenia: focus on the transsulfuration pathway, intracellular levels of L-cysteine can be low in schizophrenia which will decrease synthesis of coenzyme A.

Supplementation with L-carnitine from carnitine tartrate is needed as L-carnitine reverses the inhibition of pantothenic kinase by coenzyme A and acetyl-coenzyme A. Pantothenic kinase is the rate-limiting enzyme in coenzyme A synthesis. Supplementation with acetyl-l-carnitine is avoided as palmitonylcarnitine , which is what actually reverses the inhibition of pantothenic kinase, is synthesized from L-carnitine not acetyl-L-carnitine. For reasons I will not go into here the L-carnitine must be L-carnitine from L-carnitine tartrate. L-carnitine fumarate must be avoided.

Supplementation with sulbutiamine will also be helpful in the treatment of the negative symptoms of schizophrenia. Sulbutiamine is a fat-soluble form of thiamine which can greatly increase thiamine diphosphate levels . Thiamine diphoshpate is used by the E1 unit of the 2-oxogularate dehydrogenase complex and the E1 subunit of the pyruvate dehydrogenase complex.

Supplementation with sublingual biotin would be useful. The sodium-dependent multivitamin transporter (SMVT) transports pantothenic acid, biotin and lipoate. Biotinyalition of histones associated with with the sodium-dependent multivitamin transporter silences transcription of the sodium-dependent multivitamin transporter gene. High dosages of pantothenic acid could competitively biotin transport in the gut but this would be avoided with sublingual biotin. Very surprisingly coenzyme Q10 must be taken when biotin is supplemented. Biotin apparently can have a large effect on the TCA cycle. If the TCA cycle hangs up at the succinate dehydrogenase step supplemental biotin is not of assistance.

Acetyl-coenzyme A can be synthesized from fatty acids. EPA + DHA where EPA makes up 65 to 70% of the EPA + DHA combination will be helpful. A EPA + DHA combination has been extensively studied and has good safety profile.

Supplemental coenzyme Q10 is also required. Succinate dehydrogenase which is an iron-sulfur protein in the citric acid cycle, requires coenzyme Q10. Biotin is not useful without coenzyme Q10. If the citric acid cycle gets hung up at the succinate dehydrogenase step biotin is not helpful.

Activities of the E3 subunits of the pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex, which have NAD+ as substrates, unstimulated by supplements are  completely acceptable as is.

If niacin, niacin derivatives,  riboflavin and/or lipoic acid are supplemented pantothenic acid and thiamine will not work against the negative symptoms of schizophrenia.  A B-50 supplement is a terrible supplement. What not to supplement with is as important as what to supplement with.  Lipoic acid increases l-cysteine levels by reducing cystine to L-cysteine but cystine must be present to enter cells by way of the cystine/glutamate antiporter. Once in cells cystine is rapidly reduced to L-cysteine.  In any case lipoic acid is synthesized on lysine residues of proteins so supplemental lipoic acid would not boost activities of the  E2 subunit of the pyruvate dehydrogenase complex and E2 subunit of the 2-oxoglutarate complex. Do not supplement with pantethine. Pantethine depletes cystine.

The supplements must be taken with food. Taking the supplements with food makes a huge difference.

Can pantothenic acid, sulbutiamine, sublingual biotin, EPA + DHA, coenzyme Q10 and l-carnitine be effective against  the negative symptoms of schizophrenia when taken alone? I don’t know. Minimally, to be avoided supplements and polyphenol containing drinks as listed on the Treatment page should be avoided.

A new disease class – Epigenetic Disorders

There are infectious diseases subdivided into bacterial and viral diseases, there is cancer where there are many sorts of cancer, there is heart disease, lung disorders  etc. There could be a new disease class. There could  be epigenetic disorders where there is common origin for a wide range of epigenetic disorders. With epigenetic mechanisms  dysregulated many different diseases can arise as there are many different ways genes and histones can become inappropriately methylated.  My idea is that a dysregulation of aconitase 1 can dysregulate iron metabolism and decrease 2-oxogularate synthesis which will in turn dysregulate TET enzymes, which demethylate DNA,  and dysregulate Jumonji domain-containing proteins, which demethylate histones.   Dysregulation of  TET enzymes and dysregulation of Jumonji domain-containing proteins  can play out many different ways in terms of inappropriate DNA methylation and inappropriate histone methylation whereby many different diseases can arise. Though many different diseases can arise from dysregulations of aconitase 1, iron metabolism and 2-oxoglutarate synthesis prevention of a range of illnesses could be achieved by the same treatment. For example, a treatment than prevents schizophrenia could also prevent Alzheimer’s disease and Parkinson’s disease. The Treatment presented in the Treatment section is not ready for home use, however, a Moon shot would not be necessary to get the treatment to a state where family doctors could prescribe a treatment which would prevent a range of chronic illnesses from schizophrenia, to Alzheimer’s disease, to Parkinson’s disease. What is needed is a launch ten weather balloons into the high atmosphere then collect and analyze data kind of effort.