Bone mineral density and negative symptoms of schizophrenia

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A meta-analysis points to bone mineral density being significantly decreased in individuals with schizophrenia compared to healthy controls. Bone mineral density in schizophrenia could be decreased in individuals with schizophrenia due to deficiencies in taurine stemming from dysregulation of the transsulfuration pathway. Taurine is synthesized from L-cysteine which is synthesized via the transsulfuration pathway.

Taurine is required for intracellular calcium homeostasis. Various bile acids are synthesized from taurine. Bile acids are required for absorption of fat soluble vitamins. Vitamin D and vitamin K are fat soluble vitamins involved in bone formation. With deficiencies of taurine calcium homeostasis can be upset and there can also be deficiencies of vitamin D and vitamin K which could lead to low bone mineral density in schizophrenia.

Low bone mineral density in schizophrenia point to there being a kind of osteomalicia in schizophrenia. With taurine deficiencies intracellular calcium homeostasis can be upset, though extracellular calcium levels could be normal, leading to a hidden osteomalicia.

Dysregulation of the transsulfuration pathway can result in epigenetic changes whereby there could be localized osteomalacias. Given osteomalacia due to taurine deficiencies develops in the neck and back of the head negative symptoms of schizophrenia could develop due to compressions of cerebellums whereas given osteomalacia due to taurine deficiencies develops in lower backs then there could be ‘only’ lower back pains.

There are range of symptom in schizophrenia besides negative symptoms of schizophrenia. To treat the range of symptoms seen is schizophrenia due to dysregulations of the transsulfuration pathway supplements, beyond supplements that treat hidden oesteomalicias, are required.

Bipolar disorder and inflammation

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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 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.

Friedreich’s ataxia and tight iron utilization

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Friedreich’s ataxia is a genetic disease, where there are expansions of GAA trinucleotide repeats in intron 1 of both frataxin alleles. Gait and limb ataxia, dysarthria and loss of lower limb reflexes are clinical features Friedrich’s ataxia.

Mice models of Friedreich’s ataxia have been developed in which the gene for frataxin in is mutated, where the mice exhibit a progressive Friedreich’s ataxia-like pathology. Frataxin binds iron which assists in iron-sulfur cluster biogenesis.

Giving mice, with ataxia due to mutations in genes for frataxin, iron from iron carbonyl by gavage three times a day could be a treatment for such an ataxia as iron carbonyl given by gavage three times a day could tightly regulate iron utilization, making iron constantly available thereby making the frataxin protein less required or even redundant. As the iron chelator, desferal decreases expressiot of frataxin, carbonyl iron given by gavage three times a day to mice could also increase expression of the gene for frataxin.

As deferiprone, an iron chelator, can worsen ataxia in patients with Friedreich’s ataxia iron carbonyl given three times a day to humans could be part of a treatment for Friedreich’s ataxia. Prior to any clinical trials in humans, carbonyl iron, given by gavage three times a day from birth to mice with mutated frataxin genes, would have to stop a Friedreich’s ataxia-like pathology from developing and/or treat in mice, a Friedreich’s ataxia-like pathology after mice with mutated frataxin genes develope a Friedreich’s ataxia-like pathology.

Homocystinuria due to cystathionine beta-synthase mutations

cystathionine beta-synthase

Mutations in cystathionine beta-sythase (CBS) can result in homocystinuria, which is very high levels of homocysteine. Severe illnesses can occur where there are mutations in CBS.

Lowering homocysteine levels is now the main focus of treatment where there are mutations in CBS with very high homocysteine levels. However, many of the difficulties associated with mutations in CBS could be due to dysregulations in pathways downstream from the transsulfuration pathway.

The treatment presented on the Treatmemt Page could be tested on rats with CBS mutations that result in very high levels of homocsyteine. Along with treatments to lower homocysteine levels treatments to address dysregulations in pathways downstream of the transsulfuration pathway could be of terrific assistance to individuals with mutations in CBS with very high homocysteine levels.

Se-methylselenocysteine and cancer

Selenium compounds as establishd by in vitro and in vivo experimental models show than that selenium is an effective anticancer agent. Clinical trials, however, have not shown that selenium supplementation in humans is an effective way to prevent cancer.

The transsulfuration pathway metabolizes L-selenomethionine which is the food form of selenium. L-selenomethionine is stored in the body through replacing L-methionine in proteins. Selenium not exiting L- selenomethionine can explain why selenium supplemenation, heretofore, has not been an effective way to prevent cancer in humans.

Tte transsulfuration pathway metabolizes homocysteine. High homocsyteine levels point to the transsulfurtation pathway being dsyregulated. High homocysteine levels are associated with cancer. High homocysteine levels in cancer would then point to the transsulfuration pathway being dysregulated in cancer. With the transsulfuration pathway dysregulated in cancer L-selenomethionine is not metabolized. As L-selenomethione is not metabolized selenium supplementation in the form of L-selenomethionine is not an effective way to prevent cancer in humans.

Se-methylselenocysteine is a very effective anti-cancer agent. Se-methylselenocysteine is a form of selenium that is not metabolized via the transsulfuration pathway but rather is metabolized by kynurenine aminotransferase, which is not an enzyme in the transsulfuration pathway, so formation of selenoproteins from Se-methylselenocysteine is not stopped by dysregulation of the transsulfuration pathway. Se-methylselenocysteine could be an effective anti-cancer agent in experimental models and also in humans.

Choosing an appropriate dosing scheduls is a key to effective selenium supplementation. Supranutrional selenium can increase activity of thioredoxin reductase. There is an end of dosarge effect with selenium apparently due to declines, during the day, in activity of thioredoxin reductase. For the prevention of cancer 100 micrograms of Se-methylselenocysteine taken twice a day would be a more effective selenium supplmentation schedule than 200 micrograms of of selenium from Se-methylselenocysteine taken once a day.

IRP1 and neuropathy

thiamine

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.

Major depressive disorder and taurine

Ketamine is being used in the treatment of major depressive disorder. Ketamine is a glutamate NMDA receptor antagonist. A ‘modulating ‘effect of ketamine on NMDA receptors has been stated as giving rise an antidepressant effect of ketamine in major depressive disorder.

Glutamate toxicity due to calcium influx through L-, P/Q-, N-type voltage-gated calcium channels and NMDA receptor calcium channels is inhibited by taurine with taurine having a neuroprotective effect. The treatment presented on the Bipolar Depression page, which includes taurine, would address glutamatergic neurotransmission and could be effective for major depressive disorder.

Addressing glutamatergic neurotransmission via taurine is much preferable to addressing glutamatergic neurotransmission via ketamine. Research points to supplemental taurine as reducing homocysteine levels (Ahn, 2009), reducing cholesterol levels in animals (Guo et al., 2017; Chen et al., 2012) having an anti-obesity effect, as being negatively associated with ischemic heart disease, as ameliorating diabetes and points to taurine deficiencies as resulting in premature aging. Research on rats points to the neurotoxic effects of repeated ketamine exposure as being due to changes in purine metabolism and glycerophospholipid metabolism in the prefrontal cortex that persist even after ketamine withdrawal.

Regulation of iron metabolism by the transsulfuration pathway

top – ACO1; bottom – iron regulatory protein 1 bound to an mRNA

Iron metabolism is regulated by hepicidin, ferroportin and iron regulatory proteins. Aconitase 1 (ACO1) is a dual function protein that serves as an aconitase, which is an enzyme in the TCA cycle, when ACO1 has a 4Fe-4S iron sulfur cluster and as iron regulatory protein 1 when ACO1 looses a 4Fe-4S cluster. The sulfur for iron-sulfur clusters is derived from L-cysteine.

L-cysteine is synthesized from homocyteine via the transsulfuration pathway. Dysregulation of the transsufuration pathway by dysregulating L-cysteine synthesis could dysregulate iron-sulfur cluster formation thereby dyseregulating iron regulatory protein 1 and iron homestasis.

High homocysteine levels are present in a lot of illnesses, for example, schizophrenia, Parkinson’s disease, Alzheimer’s disease and bipolar disorder. A key part of the difficulties that arise from high homocysteine levels could be due to dysregulation of iron homeostasis.