Iron increases glutamate secretion by increasing cytosolic aconitase activity. The synthesis of isocitrate by cytosolic aconitase is the the first step in a three step synthesis of glutamate. Glutamate, arising from increases in cytosolic aconitase due to increases in iron, is secreted via the cystine/glutamate antiporter where at the same time cystine is imported into cells increasing glutathione levels in cells.
With iron supplementation in schizophrenia via iron carbonyl taken three times a day there could be increased glutamatergic neurotransmission via increases is secreted glutamate where at the same time there would be increases in cystine in cells and thereby increases in glutathione levels in cells. Supplementation with iron from iron carbonyl could be part the treatment of schizophrenia.
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 regiondestablize 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 betacan 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 ablatedincreases 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.
Alpha synuclein mRNAhas an iron responive element in the 5′ untranlated region. Iron responive elementsin 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 patientsthere 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 differencesin 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
The following paragraph is from From Schizophrenia in 2020: Trends in diagnosis and therapy by Wolfgang Gaebeland Jürgen Zielasek
“The number of risk‐associated loci in schizophrenia is estimated to be at about 850 loci. All of these genetic risk markers may explain around 10% of all schizophrenia cases. Some rare copy number variations, especially those involving partial deletions of the long arm of chromosome 22 (22q11.2), show a high penetrance in schizophrenia, but these cases only amount to approximately 0.2–0.3% of all patients with schizophrenia. Genome‐wide association studies in schizophrenia have added new risk loci and recently increased the number of probably relevant genetic polymorphisms into the range of n = 8500, but also increasing the explained variance of liability to about 32%.”
Genetics of schizophrenia has become uninteresting.
There are conflcting reports about selenium levels in prostate cancer. Rearch indicates that there are reduced levels of selenoprotein P in prostate cancer. High levelsof selenoprotein P are also associcated with low risk of high grade prostate cancer. Other research indicates that circulating selenium levels are high in advanced prostate cancer.
I have been arguing that in many illnesses that the transsulfuration pathway is dysregulated. Besides synthesizing L-cysteine from homocysteine the transsulfuration pathway also metabolizes L-selenomethioninewhich is the food form of selenium. L-selenomethionineis stored in the body via replacing methionine in proteins. If selenium never makes it out of selenomethionine there could be both high selenium levels and low selenoprotein levels. High levels of circulating selenium in advanced prostate cancer could paradoxcially indicate that there are selenoprotein deficiencies in prostate cancer which appears to be the case both for selenoprotein P and glutathione peroxidase. Glutathione peroxidase, another selenoprotein, is also reduced in prostate cancer.
Se-methylselenocysteine is a form of selenium that is not metabolized via the transsulfuration pathway so formation of selenoproteins from Se-methylselenocysteine would not be impeded by dysregulation of the transsulfuration pathyway. While supplemental selenomethionine apparently does not reduce the risk of prostate cancer supplemental Se-methylselenocysteine could reduce the risk of prostate cancer. The advantage of Se-methylselenocysteine as a cancer preventive could be exactly due to metabolism of Se-methylselenocysteine not depending on the transsulfuration pathway.
Research indicates that estrogen stops bone resorption by inhibiting IL-1 and IL-6.Taurine also inhibts IL-1 and IL-6 formation. Post-menopause taurine levels decline. Increased bone resorption post-menopaus could partly be due to reductions is taurine levels which increase IL-1 and IL-6. Supplemental taurine could have an estrogen-like effect on bone.
Hidden oosteomalacia due to dysregulation of intracellular calcium homeostasis arising from low levels of taurine stemming from dysregulation of the transsulfuration pathway .could be wide spread. In individuals with schizohpenia there could be hidden osteomalacia that do not show as back pain but could affect necks compressing cerebellums leading to severe psychological effects. Calcium blood levels could be low normal or slightly low.
Some x-ray studies of bones is the neck region are called for in schizophrenia. If cerebellums are being compressed by a hidden osteomalacia treatmens for a range of psychological symptoms in schizophrenia could be much, much different. Taurine, vitamin D, vitamin K and calcium carbonate could treat the hidden osteomalicia addressing structural and functional brain abnormalties in schizophrenia. Bone mineral densities are lower in older indivduals with schizophrenia compared to indivduals without schizophrenia. Early diagnosis would be a key.
With cerebellums compressed there could negative symptoms of schizohrenia. Negative symptoms are are deficit symptoms where such deficits could be due to deficits in the ability of the cerebellum to function due to being compressed from hidden osteomalacia.
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.
There is lots and lots of research on how to increase absorption of minerals. The supplement industry following up on this has formulated mineral supplements to be better absorbed.
My idea that minerals must be available both in the enteric system and systematically to be useful in treating illnesses does not conflict with any biological findings but it goes against what is held as common sense. Every one just knows that the goal with mineral supplements is to increase and enhance absorption. Minerals that are not formulated for increased abosorption can be absorbed and can effectively treat diseases associated with mineral deficiencies. Most of the clinical trials of minerals do not use amino acid chelates.
The assumption with minerals formulated for increased absorption is that somehow proteins in the enteric system watch minerals pass by unused and hold that is totally acceptable. Proteins in the enteric system are willing to go the end of the line and wait for minerals to get back to them. The common sense idea is that the gastrointestinal tract is like a busy 4 way intersection.
Metal proteins in the enteric system could set the stage for metal proteins throughout the body. Systematically metal proteins might not work effectively unless the stage is set by metal proteins in the enteric system working.
Increasing levels of free antioxidants via supplmentation could be much worse than useless. Before iron can be absorbed iron must be reduced from Fe3+ to Fe2+. Antioxidants like vitamin C, vitamin E , beta-carotene and quercetin could one way or other promote the reduction of Fe3+ to Fe2+ in the gastrointestinal tract which would increase absorption. The goal, however, is to delay iron absorption as long as feasible.
There is oxidant stress in lots of illnesses but this could be due to dysregulation of selenoproteins and dysregulation of iron metabolism which would not be fixed by increasing levels of free antioxidants with supplemental vitamin C, vitamin E , beta-carotene, quercetin etc.
Supplementing with free antioxidants could be associated with very subtle but serious mineral dysregulations which would basically be undiagnosable.