Branched-chain amino acid degradation, beta-oxidation and biotin

On this blog I have argued that the sodium-dependent multivitamin transporter (SMVT) is dysregulated in bipolar depression. . The SMVT transports biotin. Biotin-dependent enzymes, methylcrotonoyl-CoA carboxylase and propionyl-CoA carboxylase are involved in the degradation of branched-chain amino acids.. Methylcrotonoyl-CoA carboxylase and propionyl-CoA carboxylase in the branched-chain amino acid pathway are very closely associated with enzymes that are also involved in beta-oxidation.

Enoyl-CoA hydratase is involved in both the degradation of branched-chain amino acids and beta-oxidation. 3-hydroxyacyl-CoA dehydrogenase is involved in both the degradation of branched-chain amino acids and beta-oxidation. Acetyl-CoA acyltransferase is involved in both the degradation of branched-chain amino acids and beta-oxidation. Acyl-Coenzyme A dehydrogenase is an enzyme involved in both the degradation of branched-chain amino acids and beta-oxidation. These four enzymes are one on two enzymes away from biotin-dependent enzymes in the branched-chain amino acid degradation pathway.

The upshot of this in that dysregulation of biotin-dependent enzymes in the branched-chain amino acid degradation pathway will also dysregulate the beta-oxidation pathway. In conjunction with other supplements olive oil, which will increase beta-oxidation, can be a helpful supplement.

Any reprogramming of youthful methylation patterns in humans would require that TET enzymes be re-regulated first

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Sinclair et al. using the eye as a model CNS tissue, showed that ectopic expression of Oct4, Sox2 and Klf4 genes in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2.

However, I have been arguing in papers (see Treatment-resistant schizophrenia: focus on the transsulfuration pathway and A disease-modifying treatment for Alzheimer’s disease: focus on the transsulfuration pathway) and on this blog that TET enzymes are the very enzymes that are dysregulated in many chronic illnesses, which results in various chronic illnesses possessing a range of phenotypic expressions. Ectopic expression of OCT4, KLF4 and SOX2 alone would not work in aged humans and/or ill humans as TET enzymes are dysregulated in aged and/or ill humans.

TET enzymes are iron and 2-oxoglutarate dependent dioxyegenases. Fixing TET enzymes could be a key part of the treatment of a range of chronic illness and would be a lot simpler and safer than systematic ectopic expression of OCT4, KLF4 and SOX2 in humans. A lot of methylation changes acquired during aging must be beneficial. Systematically turning back the clock to 18 or so would not be desirable .’Just’ fixing TET enzymes would allow desirable methylations to occur but would allow DNA demethylations of undesirable DNA methyations. Clearly fixing TET enzymes would be a required first step prior to any genetic engineering of humans to restore youthfulness given that such genetic engineering was feasible and desirable.

A unitary theory of sadness in all depressions

The thyroid may still yet have large undiscovered lands. There are many ways that individuals can feel below par.. Sadness in depressions is different than malaise, fatigue are lethargy though malaise, fatigue and lethargy are very frequently associated with depression.

Sadness in all depressions could be due to dysregulation of iodide transporters. Thyroid hormone levels can be normal while thyroid hormone homeostasis can be upset resulting in sadness though thyroid tests show patients as apparently euthyroid. In all instances of intense sadness iodide transporters could be dysregulated even intense sadness due to mourning.. A reasonable period of mourning would, of course, not call for pharmaceutical treatment.

There is an upside to this and a downside to this. Sadness is all depressions except due to mourning, could be highly pharmaceutically treatable. Sadness can pop up in almost any illness and everywhere depression as sadness pops could be due to dysregulation of iodide transporters. Sadness in all depressions could be treated by iodide from kelp, l-tyrosine and Se-methylselenocysteine. Iodide from kelp, L-tyrosine and Se-methylselenocysteine would not treat all states associated with depression only sadness. Kelp and L-tyrosine have to be taken three or four times a day. Thyroid tests must be obtained. The goal is most definitely not high thyroid hormone levels. Iodide from potassium iodide apparently reacts with too many substances. The effect of iodide from potassium iodide is not dependable. Approximately 1000 micrograms of iodide from kelp have to be taken each dosage. Iodide from kelp and L-tyrosine are taken three times a day . L-tyrosine taken without iodide is not helpful. L-tyrosine is taken on an empty stomach. Se-methylselenocysteine is supplemented. Selenium is required for thyroid hormone homeostasis. 200 micrograms of Se-methylselenocysteine is taken once a day. More Se-methylselenocysteine is not better.

The downside of this is that iodide from kelp, L-tyrosine and Se-methylselenocysteine would only treat sadness. Individuals could still feel way below par even though their intense sadness had been addressed . The SMVT besides transporting iodide also transports biotin, lipoate and pantothenic acid.. Supplemental iodide would not necessarily re-regulate the SMVT. At this point treatment becomes much more complex. Under no grounds should lipoic acid ever be supplemented as lipoate is synthesized on residues and supplemental lipoic acid would only block the SMVT. Iodide from kelp, L-tyrosine and Se-methylselenocysteine can do a lot but far from everything.

A fundamental rule of nutrition

Supplements or drinks with tricarboxylic acid cycle intermediates should be avoided though supplements with alpha ketoglutarate could be helpful. TET enzymes are 2-oxoglutarate dependent.enzymes that demethylate DNA. JmjC domain-containing proteins are 2-oxoglutarate dependent.enzymes that demethylate histones .Fumarate and succinate inhibit TET and JmjC domain-containing proteins. This could lead to DNA hypermethylation and histone hypermethylation. Malic acid could inhibit fumarate dehydratase by end product inhibition and lead to a build up of fumarate.

Accumulation of succinate and fumarate are associated with cancer due the inhibition of 2-oxoglutarate-dependent dioxygenases, such as TET and JmjC-domain containing proteins. Citrate is a competitive inhibitor of oxaloacetate for citrate synthase. Citrate synthase also produces coenzyme A which is needed by the 2-oxoglutarate complex. Citric acid from soft drinks could dysregulate the the 2-oxoglutarate complex. There is a lot of circumstantial evidence that citric acid has goofy effects on individuals witness Mountain Dew ads.

A lot of supplements contain tricarboxylic acid cycle intermediates. Calcium citrate contains citrate. Magnesium succinate contains succincate. Carnitine fumarate contains. fumarate. Citruline malate contains malate, TCA intermediates are everywhere is supplements.

But as always the key selling point of supplements is ‘better absorption’ and minerals, for example, minerals bound to citrate, can be well absorbed. A huge and very frequently deleterious factor not usually considered is what supplements are bound to. ‘Better absorption’ is the siren call of supplements. Chelated minerals are also avoided.

Schizophrenia, anosognosia and Se-methylselenocysteine

Lack of insight or lack of awareness of illness in schizophrenia is termed anosognosia with some 30% of individuals with schizophrenia having anosognosia.

What is the cardinal feature of anosognosia? The cardinal feature is not elaborate delusions rather the cardinal feature of anosognosia is confusion and disorganization. Individuals with agonosgnosia are having terrible cognitive difficulties.

Se-methylselenocysteine treats cognitive symptoms of schizophrenia. Supplemental Se-methylselenocysteine could be a treatment for anosognosia. Se-methylselenocysteine would be taken with iodide from kelp. Sadness can pop up in almost any illness and everywhere depression as sadness pops could be due to dysregulation of iodide transporters. Sadness in all depressions could be treated by iodide from kelp, l-tyrosine and Se-methylselenocysteine. L-tyrosine is involved in the synthesis of thyroid hormones. Patients might not be responsive to treatment for anosognosia with Se-methylselenocysteine if they are intensely sad..

Iodide from kelp, L-tyrosine and Se-methylselenocysteine would not treat all states associated with depression only sadness. Kelp and L-tyrosine have to be taken three or four times a day. Thyroid tests must be obtained. The goal is most definitely not high thyroid hormone levels. Iodide from potassium iodide apparently reacts with too many substances. The effect of iodide from potassium iodide is not dependable. Approximately 1000 micrograms of iodide from kelp have to be taken each dosage. Iodide from kelp and L-tyrosine are taken three times a day . L-tyrosine taken without iodide is not helpful. L-tyrosine and kelp are taken away from food.

Se-methylselenocysteine is supplemented. Selenium is also required for thyroid hormone homeostasis. 200 micrograms of Se-methylselenocysteine is taken once a day. More Se-methylselenocysteine is not better. Deiodinases, which are selenoproteins, can both activate and deactivate thyroid hormones. Selenium taken alone could stress the thyroid.

sT4 – active, T3 very active, rT3 not active, ID1 – deiodinase I, ID2 – deiodinase II, IDIII – deiodinase III.

Patients on Se-methylselenocysteine, iodide from kelp and L-tyrosine could have ahedonia but there would be an awareness of illnesses. More organized delusions though with an awareness of illness could be a feature of the treatment. I hold more can be done to treat schizophrenia, however, Se-methylselenocysteine, iodide from kelp and l-tyrosine can readily tested as a treatment for agonosgnosia.

Can deleterious epigenetic changes be reversed by supplemental alpha ketoglutarate?

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TET enzymes are 2-oxoglutarate dependent.enzymes that are instrumental in DNA demethylation. JmjC domain-containing proteins, which are 2-oxoglutarate dependent.enzymes, demethylate histones.

Research indicates that 2-oxoglutarate by affecting TET and Jmjc domain-containing proteins can have epigenetic effects reversing epigenetic changes arising from dysregulation of the tricarboxylic acid (TCA) cycle. The TCA cycle synthesizes 2-oxoglutarate.

I have been stressing in this blog that with a dysregulation of iron-sulfur cluster formation there is a dysregulation of aconitase which is an iron-sulfur protein early in the TCA cycle With aconitase dysregulated the TCA cycle is dysregulated. Another enzyme in the TCA cycle, succinate dehydrogenase, also has iron-sulfur clusters.

Could deleterious epigenetic changes in humans, due to dysregulation of the TCA cycle, be reversed by supplemental alpha-ketoglutarate? That has not yet been established.

2-oxoglutarate-dependent dioxygenases are involved in aging, 2-oxoglutarate could be a longevity supplement. A rule of thumb in regards to longevity supplements is never take a longevity supplement for longevity that does not have immediate positive benefits as absent immediate positive benefits knowing whether one is going in the correct direction is unknowable . If 2-oxoglutarate proves to be useful in the treatment of various neurological illnesses but also increases longevity so much the better.

An exclusive focus on absorption of minerals is at odds with the gut being a key to various illnesses

The gut has become a primary focus of a lot of research on various illnesses. The gut has become a focus in research on major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder, autism, anxiety, Parkinson’s disease, Alzheimer’s disease, osteoporosis, amyotrophic lateral sclerosis etc.

Yet the key selling point of most mineral supplements is increased absorption with increased absorption demanding that the gut be bypassed. Moreover almost all clinical studies done on humans employ inorganic forms of minerals rather than chelated organic forms of minerals. ‘Zinc gluconate human‘ turned up 560 results in Pubmed whereas ‘zinc methionine human, turned up 11 results where there were two human trials with an equivocal result in one of the trials and a positive result on a narrow measure of reduced acne in the other.

Individuals taking organic chelated mineral supplements are venturing into unknown lands and I think dangerous lands. Chelated minerals are highly absorbed but that is a bug not a feature.

The Gene: An Intimate History by Siddhartha Mukherjee

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The Gene is a popular introductory book on the gene. This is not a criticism as each new generation has to be introduced to a subject and this an acceptable popular introductory book.. With the field not at all crowded The Gene is a welcome popular introductory book on the gene.

The major criticism I have is that Mukherjee slights epigenetics in terms of behavior, is much too sanguine about genetic engineering to cure what are held to be polygenetic illnesses and is much too sanguine about genetic engineering to instill beneficial polygenetic traits. Geneticists apparently repeatedly assured Mukherjee that geneticists will one day be able treat polygenetic illnesses and moreover will be able to instill beneficial polygenetic traits most likely via some sort of embryo selection. Mukherjee took the geneticists at their word. Genetic determinism is almost a religion among geneticists as determinism is almost a religion in academia.

Medical horrors are apparently inadvertently being planned for the wealthy. Now the wealthy depressed are taking ketamine which can cause a schizophrenia-like psychosis. 10 years from now the wealthy could be selecting embryos on the basis of very abstruse calculations where if something goes wrong the advising geneticist will say ‘the odds slightly favored a favorable outcome. Look at these calculations. You must understand probabilities.’

Selenium and the thyroid gland

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The human thyroid gland has the highest selenium content per gram of tissue among all organs.The iodothyronine deiodinases (DIO1,2,3), are selenoproteins. Glutathione peroxidase and thioredoxin reductase are selenoproteins that are involved in protection of the thyroid from hydrogen peroxide.

The first step in the synthesis of thyroid hormones is catalyzed by thyroid peroxidase which requires hydrogen peroxide. Hydrogen peroxide used by thyroid peroxidase is produced by dual oxidase 1 and dual oxidase 2. Hydrogen peroxide is both required for thyroid hormone synthesis but also can be toxic to the thyroid gland. Selenium is required both for thyroid hormone synthesis and protection of the thyroid from hydrogen peroxide needed to synthesize thyroid hormones. .

Biohack mental illness now!

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A lot of biohacking does not appear to be safe. For example, trying to alter at home one’s genetic makeup via CRISPR seems beyond unsafe.

A lot of biohacking is undertaken to achieve increased longevity. Biohacking for increase longevity requires that one wait around for decades to see the results. One has to wait 30 or 40 years to see whether one selected a right mix of supplements and then in all probability if one lives to a healthy 100 years of age one would not know exactly which supplements were the key supplements. Knowledge as to what increases longevity would still be lacking. One could be interviewed with questions asked as to how longevity was achieved and a laundry list of supplements would then be detailed. Someone listening to the interview could say, ‘I will eat 3 strips of bacon every morning. The other guy eats three strips of bacon every morning and is an alert, healthy 102 year old.’

A lot of specialty nootropics taken for cognitive enhancement have unclear effects and have not been widely tested in clinical trials . Moreover most nootropics are likely manufactured in China which does not have a reputation for tight controls on drug manufacture. What is more there would be a huge mainstream market for nootropics given noontropics worked. Individuals with mental illnesses very frequently could use some cognitive enhancement but nootropics are not being prescribed. After decades of use and study use of nootropics appears to be a very sketchy practice.

The appeal now of becoming part cyborg is 98% aesthetic. Becoming part cyborg now does not result in cognitive enhancements or health enhancements.

Biohacking mental illness

I hold that a lot of mental illness can be biohacked now, this week. 600 milligrams of carbonyl iron taken once a day at bedtime can treat psychosis. 200 micrograms of Se-methylselenocysteine taken once a day in the morning. can treat disorganization. 1,000 micrograms of iodide from kelp taken three times a day with 1000 milligrams of L-tyrosine taken three times a day can treat depression which is presents as sadness. Iron interacts with lots of substances, coffee and tea being two examples. The point of taking the carbonyl iron at bedtime is to take the iron and iodide away from substances that can interfere with iron metabolism in the gut. The last cup of coffee or cup of tea of the day should be drunk at least 6 or 7 hours before carbonyl iron is taken.

300 milligrams of thiamine is taken 4 times a day can decrease fatigue.

No other supplements would be taken.

Cons

I hold that iron-sulfur proteins are dysregulated in schizophrenia and that 600 milligrams of carbonyl iron taken once a day at bedtime can address the psychosis of schizophrenia. There is no direct clinical evidence that iron-sulfur proteins are dysregulated in schizophrenia. Given iron-sulfur proteins were dysregulated in schizophrenia this would cause major difficulties where psychosis could be one such difficulty.

There is no clinical evidence Se-methylselenocysteine effectively treats cognitive symptoms of schizophrenia.

Everyone who is treated for depression has had their thyroid hormone levels checked. A search of PubMed using ‘thyroid major depressive disorder’ turns up 999 articles. Thyroid hormones have not proven efficacious in treating major depressive disorder. Yet I hold that major depressive disorder is partly due to thyroid dysregulation. Conceivably doctors when prescribing T3 never asked the correct question. The correct question would be ‘Are you still sad?’ Not ‘Has your depression remitted?’

Why such high dosages of thiamine are needed is not clear. 25 milligrams of vitamin B6 twice a day. could also be helpful.

T4 could work better than iodide and L-tyrosine. T4 is fully iodinated and with T4 one would still be working with natural mechanisms for the production of T3 ,which is the active hormone. T3 could be too much. With T4 the question to ask would be ‘has the sadness passed? not ‘has the depression remitted?’

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No other supplements should be taken.

Iodide from kelp and L-tyrosine only treats depression as sadness. Frequently malaise and apathy are associated with major depressive disorder which iodide and L-tyrosine would likely not address. Iodide and L-tyrosine are not going to address all symptoms of major depressive disorder.

Pros

Dirt simple and very quick. Very safe for at least a week. If the treatment has not worked at the end of week the treatment would be stopped. If the treatment is effective then safety of the supplements can be studied further and necessary tests obtained.

A lot of research cited on this website points to iron-sulfur cluster formation and selenoprotein metabolism being dysregulated in various neurological illnesses. Dysregulation of thyroid hormones can certainly result in depressive illnesses.