Bone mineral density and major depression

Decreased bone mineral density is associated with major depression. There are also low vitamin D levels in individuals who are depressed. Ahedonia in major depression could be due to hidden osteomalicias. Taurine, vitamin D and vitamin K could treat hidden osteomalacias present in major depression. Supplements used to treat hidden osteomalicias, would not be effective for intense sadnesses that frequently occur with major depressions.

Bipolar disorder and inflammation


Bipolar disorder is associated with inflammation. See also this paper.

Inflammation is increased by ecosanoids derived from arachidonic acid, however, inflammation can be reduced by the sythesis of eicosanoids derived from eicosapentaenoic acid (EPA) and dihomo-γ-linolenic acid (DGLA). DGLA is synthesized from gamma-linolenic acid (GLA), which is in evening primlrose oil, while EPA is in fish oils. Cyclooxygenases and lipoxygenases can act on DGLA, EPA and/or arachidonic acid. DGLA and EPA competitively inhibit synthesis of inflammatory eicosanoids from arachidonic acid,

To stop inflammation in bipolar disorder supplmentation with GLA and EPA could be of assistance. GLA and and EPA are synthesized from linolenic acid and alpha-linoleic acid respectively. Linoleic acid is an omega-6 fatty acid while alpha-linolenic acid is an omega-3 fatty acid both of which are essential fatty acids. Eicosanoid homeostasis is upset when GLA and EPA are not available more or less second by second. Both GLA and EPA must be supplemented as the difficulty in eicosanoid homeostasis arises from difficulties in absorbing essential fatty acids due to defiencies in taurine.

IRP1 and neuropathy


Hypoxia-inducible factor 1alpha (HIF-1α) induces transcription of thiamine transporter 2 by binding to the promoter of thiamine transporter 2. HIF-1α and hypoxia-inducible factor 2alpha bind to the same hypoxia responsive elements is promoters of hypoxia regulated genes. Hypoxia-inducible factor-2alpha is also called endothelial PAS domain-containing protein 1 (EPAS1).

EPAS1 mRNA has an iron response element in the 5′ untranslated region. When iron regulatory proteins (IRPs) bind to an iron response elements in the 5′ untranslated region of mRNA transcripts mRNA transcripts are destabilized reducing translation of iron responsive genes.

EPAS1 could like HIF-1α bind to promoters of the gene for thiamine transporter 2. However increased activity of IRP1 could destabilize EPAS1 mRNA transcripts reducing transcription of thiamine transporter 2 in response to hypoxia.

Neuropathy could result from increased activity of IRP1. With increased activity of IRP1 there could be low levels of EPAS1. Overtime with hypoxia not inducing thiamine transporter 2 the gene for thiamine tranpor 2 could become hypermethylated. Taking only RDA amounts of thiamine is then no longer sufficuent.

For neuropathy a combination of iron from carbonyl iron, thiamine and biotin could be of assistance. Iron decreases IRP1 activity which would stabilize mRNA transcipts of EPAS1 so thiamine transporter 2 can be induced by EPAS1. Thiamine and biotin supplementation can treat mutations in thiamine transporter 2.

When biotin is supplemented biotin is supplemented three times a day while pantothenic acid is supplemented once a day also but away from biotin.  Intestinal absorption of biotin is via the sodium-dependent multivitamin transporter (SMVT) where the SMVT also transports pantothenate. High dosages of pantothenic acid taken at the same time as biotin could inhibit transport of biotin. Biotinylation of the SMVT locus inhibits transcription of the SMVT gene so biotin cannot be taken at the same time as pantothenic acid.

The SMVT also transports lipoic acid. Supplementing with lipoic acid must be avoided as lipoic acid supplementation would competitively inhibit the transport of biotin and pantothenic acid by the SMVT.

There is no genetic defect nor is there a systematic thiamine deficiency where there is neuropathy arises due to high levels of IRP1. Only some thiamine transporter 2 genes are hypermethylated. Localized thiamine deficiencies do not have the symptoms of generalized thiamine deficiences, however, one of the symptoms of localized thiamine deficiencies could be neuropathy.

Synthesis of thiamine diphosphate by thiamine pyrophosphokinase requires ATP. Creatine buffers ATP. Creatine taken four times a day can be of asssistance in the treatment of neuropathy due to high levels of IRP1 as long as creatine is taken with iron from carbonyl iron, thiamine and biotin.

Vitamin B6 will worsen a neuropathy due to increased levels of IRP1 likely due to an effect on glutamic–pyruvic transaminase and serine-pyruvate transaminase which can not be supported due to dysregulation of aconitase 1 in the TCA cycle. Supplemental vitamin B6 could be of assistance given iron from carbonyl iron is supplemented.

Supplemental carbonyl iron, thiamine, biotin and pantothenic acid could be a more effective treatment for a lot of cases of neuropathy where supplemental vitamin B6 could also be assistance. Supplements and drinks on the list of ‘too be avoided supplements and drinks’ on the Treatment Page would have to be avoided.

Iron, amyloid precursor protein, and Alzheimer’s

amyloid beta plaques

Amyloid precursor protein (APP) mRNA has an iron response element (IRE) in the 5′ untranslated region. Iron regulatory 1 (IRP1) and and iron regulatory protein 2 (IRP2) when bound to the IRE in the 5′ untranslated region destablize transcripts of iron regulated proteins. IRP1 and IPR2 when bound to the IRE in amyloid precursor protein mRNA decrease translation of APP. Iron decreases levels of IRP1 and IRP2. A point of iron chelators in Alzhemeir’s disease is by decreasing iron levels to increase levels of IRP1 and IRP2 thereby decreasing transcripition of APP.

APP is the precusor of amybloid beta protein. Amyloid beta can form plaques which are associated with Alzheimer’s disease. Iron chelators by decreasing APP levels would decrease levels of amyloid beta protein which was thought for decades to be a very good thing. Very effective treatments for Alzheimer’s appeared imminent.

A very serious difficulty arose. Drugs that reduce levels of amyloid beta do not treat or slow the progression of Alzheimer’s disease.

APP can looked at from a different angle. Amyloid precursor protein when ablated increases iron retention in cells by decreasing iron export. Loss of tight control of APP translation not high levels of APP could be what is causing iron retention in neurons.

What I have been arguing is that IRP1 is dysregulated in a range of neurological illnesses, such as Alzheimer’s and that this can lead to iron accumulation in neurons and cell death. Tight control of iron levels, not reducing iron levels via iron chelation, could be part of a treatment for various neurological illnessse such as Alzheimer’s disease.

A meta-analysis indicate that serum iron is significantly lower in Alzheimer’s patients than in controls. Supplmental iron carbonyl given three time a day could be part of a treatment for Alzheimer’s disease. The goal, of course, would not be high iron levels but rather tightly regulated levels of IRP1 and IRP2. Iron homeostasis could be upset in Alzheimer’s disease which is a much different way of loooking at iron than ‘iron is toxic’ in Alzheimer’s disease.

Iron and α-synuclein in Parkinson’s disease

synuclein protein in Parkinson’s disease

Alpha synuclein mRNA has an iron responive element in the 5′ untranlated region. Iron responive elements in the 5′ untranlated region of mRNA when bound by iron responsive protein 1 (IRP1) or iron responive protein 2 (IRP2) destabilize transcripts of iron-regulated proteins. Increasing iron levels would decrease levels of IRP1 and IRP2 and increase levels of alpha synuclein which is held to be very bad.

Alpha synuclein can act as a ferrireductase reducing iron 3+ to iron 2+. Overexpressing human α-synuclein in nigral dopaminergic neurons demonstrated a correlation between α-synuclein expression and ferrireductase activity, however, in Parkinson’s patients there is a reduction of ferrireductase activity in brains.

What if the key fact about alpha synuclein in Parkinson’s patients is alpha synuclein aggregates form only after decreases in ferrireductase activity in Parkinson’s patients. High, constant but normal iron levels where iron levels are tightly regulated throughout the day could keep ferrireductase activity constant throughout the day preventing alpha synuclein aggregates from forming.

Supplemental iron from iron carbonyl could keep iron levels constant keeping ferrireductase activity of alpha synuclein constant preventing alpha synuclein aggregates from forming. There is no significant differences in serum iron levels between controls and Parkinson’s patients. There are serious difficulties with iron in PD patients but these difficulties could stem from a loss of iron homeostasis which could be re-regulated by iron from iron carbonyl given three times a day.

This idea would, of course, have to be tested in rats before being tested in humans

DNA methylation of genes which code for proteins in protein pathways that have fallen into disuse

Could there be epigenetics changes to genes when protein pathways become non-fuctional? Say there is decreased activity in a rate limting enzyme in a protein pathway. Do other genes coding for proteins is the pathway keep producing proteins in the pathway even though those proteins now no longer serve any purpose?’

The Central Dogma of Biology according to James Watson – DNA makes RNA makes protein.

The Central Dogma of biology is at the same time a non-sequitur, strictly false and though simple is simpler than possible. What genes are transcribed matters a very great deal and what genes are transcribed is due to epigenetic changes on those genes so the Central Dogma is a non-sequitur is terms of activites of protein pathways and behaviors of organisms. The Central Dogma is strictly false as RNA viruses can change DNA. The Central Dogma is also simpler than possible. Very many genes code for proteins that are splice variants. The production of splice variants of genes is regulated by a system of trans-acting proteins that bind to cis-acting sites on primary transcripts.

Why bring up the the Central Dogma? The Central Dogma of biology is so 1960’s. The genetic determinism of the Central Dogma of biology is still an undercurrent that gets in the way of appreciating the epigenetic basis of many chronic illnesses.

If transcription of genes for proteins in protein pathways in specific organs can fall together this could give rise to unique illnesses where the basis of such illnesses would be due to epigenetic changes, which at first could be isolated to specific organs but which could spread over time worsening such illnesses in relatively predictable ways. With epigenetics, protein pathways falling into disuse can affect only specific organs though over time there could be a spreading effect which fits with how chronic diseases develop.

Another implication of genes becoming hypermethylated when proteins that those genes code for become unused is that optimum nutrition could result in increased numbers of healthy years lived. I would say that as of now there is very, very litttle useful information on what opimum nutrition is in terms of increasing number of healthy years lived. Preventive medicine in terms of nutrition has been one mistep after another. Huge errors have been made. For example, increasing free antioxidants by taking vitamin E, vitamin C and beta-carotene in more than RDA amounts has been a terrible disaster. The only path in terms discovering what optimum nutrition is would be to work back from nutrional strategies than cure diseases rather than are speculations on diet as to how to prevent diseases developing decades and decades later. Pilot studies are very, very frequently misleading. Supplements are now a minefield.

Taurine chloramine downregulates the production of proinflammatory mediators

Taurine chloramine produced from taurine under inflammation provides anti-inflamnatory and cytoprotective effects

Chaekyun Kim  1 Young-Nam Cha


Taurine is one of the most abundant non-essential amino acid in mammals and has many physiological functions in the nervous, cardiovascular, renal, endocrine, and immune systems. Upon inflammation, taurine undergoes halogenation in phagocytes and is converted to taurine chloramine (TauCl) and taurine bromamine. In the activated neutrophils, TauCl is produced by reaction with hypochlorite (HOCl) generated by the halide-dependent myeloperoxidase system. TauCl is released from activated neutrophils following their apoptosis and inhibits the production of inflammatory mediators such as, superoxide anion, nitric oxide, tumor necrosis factor-α, interleukins, and prostaglandins in inflammatory cells at inflammatory tissues. Furthermore, TauCl increases the expressions of antioxidant proteins, such as heme oxygenase 1, peroxiredoxin, thioredoxin, glutathione peroxidase, and catalase in macrophages. Thus, a central role of TauCl produced by activated neutrophils is to trigger the resolution of inflammation and protect macrophages and surrounding tissues from being damaged by cytotoxic reactive oxygen metabolites overproduced during inflammation. This is achieved by attenuating further production of proinflammatory cytokines and reactive oxygen metabolites and also by increasing the levels of antioxidant proteins that are able to scavenge and diminish the production of cytotoxic oxygen metabolites. These findings suggest that TauCl released from activated neutrophils may be involved in the recovery processes of cells affected by inflammatory oxidative stresses and thus TauCl could be used as a potential physiological agent to control pathogenic symptoms of chronic inflammatory diseases.

Taking supplemental taurine lowers blood pressure in humans

Taurine lowers blood pressure in humans by increasing synthesis of hydrogen sulfide, which is a vasodilator, through increasing activities of cystathionine beta-synthase and cystathionine gamma-lyase, the two enzymes in the transsulfuration pathway. Cystathionine beta-synthase and cystathionine gamma-lyase synthesize hydrogen sulfide. A meta-analysis indicates that taurine lowers blood pressure in clinically relevant amounts. Taurine also decreases homocysteine levels in humans. There is also lots of evidence from animals than taurine lowers total cholesterol. Research points to taurine as being the factor for Japanese longevity which could be due to taurine lowering various cardiovascular risk factors. The actions of taurine are more pronounced when taurine is taken on an empty stomach.