ALKB is involved in base excision repair. ALKB is a 2-oxoglutarate and Fe dependent enzyme that requires vitamin C. Re-regulating TET enzymes with iron and vitamin C taken at different times where the vitamin C is also taken away from other antioxidants would also re-regulate ALKB enhancing base excision repair.
EDTA binds copper and iron and has been frequently used to chelate minerals.. Chelation trials for autism were halted in 2008. Walmart and Amazon still have a selection of EDTA products in the health sections. Compounds that bind to minerals are everywhere in the food supply and generating huge unrecognized medical difficulties. A fundamental fact about nutrition is that minerals have to be available in the gut as well as systematically. Trace minerals should be supplemented only at bedtime and away from food, drinks and other supplements, such as vitamin C, to maximize availability in the gut as well as systematically. Iron, copper and manganese can compete for the same transporter, DMT1, but this is to be much preferred to minerals being chelated or complexed by food, drinks and/or supplements.
There is a place for chelation in terms of proven metal toxicites. Chelation therapy would only be done in a hospital under close medical supervision Purchasing EDTA suppositories at Walmart and then waiting around to be cured is very ill advised. Chelated mineral supplements are a sort of DIY chelation therapy for the gut which is very much a negative.
One group of guinea pigs would be given vitamin C by gavage two times a day, another group of guinea pigs would be given vitamin C and slow release iron sulfate by gavage two times a day with the vitamin C and slow release iron given at the same time and a third group of guinea pigs would be given vitamin C two times a day and and slow release iron once a day with the slow release iron given away from the vitamin C and as the last supplement given each day. . Slow release iron is used where the slow release iron is given last in the day to insure that iron is available or at least has a chance to be available in the gut. A fourth group of guinea pigs would be a control group. Rats synthesize vitamin C, however, guinea pigs do not not so guinea pigs rather than rats are used in the experiment
In six months time the gut epigenomes of the guinea pigs could be investigated. I think there would be large differences in the gut epigenomes of the various groups of guinea pigs. The guinea pigs given vitamin C and iron together and vitamin C alone would show high levels of DNA methylation in the gut as with vitamin C iron is well absorbed and not available in the gut. TET enzymes and JmjC domain-containing proteins require both vitamin C and iron. The guinea pigs given vitamin C and slow release iron at different times would show low levels of DNA methylation in the gut as then both iron and vitamin C would be available in the gut for TET enzymes and JmjC domain-containing proteins
Vitamin C is being investigated as a way to reprogram the gut epigenome in terms of treating cancer. A test of the effects of vitamin C and vitamin C and iron on the gut epigenome could be a preliminary experiment in terms of eventually reprogramming the epigenome in terms of treating cancer with vitamin C. Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells. This could be due to increased DNA demethylation of colon cancer cells.
Sodium dependent transport in very common with the sodium-dependent multivitamin transporter only one example. Sodium is also required for the transport of vitamin C by sodium-dependent vitamin C transporter 1 and sodium dependent vitamin C transporter 2 .
Why would sodium-dependent transport in the gut be especially prone to dysregulation? Sodium-dependent transport is regulated transport. When the gut epigenome goes awry regulated transport can become dysregulated and a large part of regulated transport in the gut is sodium-dependent. With regulated transport there is an opening for DNA hypermethylation to have a large effect. Transport by passive diffusion may not be so susceptible to dysregulation when the gut epigenome goes awry.
The first order of business would be to re-regulate the gut epigenome. TET enzymes and JmjC domain proteins are vitamin C and iron dependent enzymes. Both iron and vitamin C would be required to re-regulate TET enzymes and JmjC domain proteins in the gut.
Vitamin C and iron, however, cannot be taken at the same time. Vitamin C complexes with iron which would make iron unavailable in the gut even though iron absorption can be increased by vitamin C. Iron from iron carbonyl would be taken at bedtime five or so hours after the last vitamin C dosage of the day. Vitamin C can also interfere with copper absorption so copper from copper gluconate would also be taken at bedtime. Only trace minerals that are available in the gut can be supplemented. There are some excellent chelated minerals on the market all of which must be avoided.
One of the difficulties in any epigenetic approach to illnesses is to select which hypermethylated genes are the relevant hypermethylated genes. In a range of illnesses there could be excess DNA hypermethylation of genes associated with sodium dependent transport. Given this is the case this would clearly be relevant to the etiology such illnesses..
I have repeatedly stressed in this blog what happens in the gut is key. TET2 is highly expressed in the gut. TET3 is also highly expressed in the gut. There are a lot of JMJC domain containing proteins and a lot of them are highly expressed in the gut. For some examples see the Human Protein Atlas.
Reprogramming the gut epigenome via immediate release vitamin vitamin C and iron from iron carbonyl taken at bedtime away from vitamin C could have a large effect on the gut and therefore have large systematic effects. Copper from copper gluceonate would be taken at bedtime too as vitamin C can decrease copper absorption. Even with normal levels of iron iron from iron carbonyl would be supplemented at bedtime. as iron must be available in the gut as well as absorbed.
Unless the epigenome can be reprogrammed one ends up playing whack a mole. Upon addressing one symptom successfully other symptoms become prominent. Address one symptom successfully and one .can still be very ill. Ameliorating .one symptom then does not feel like much of a victory. A minimal program would be vitamin C taken during the day and iron and copper taken at bedtime. Mineral levels would be checked.
Linus Pauling brought vitamin C to the world’s attention
Vitamin C has been repeatedly investigated since Linus Pauling focused on vitamin C. TET enzymes and JmjC domain-containing proteins are vitamin C and iron dependent enzymes which demethylate DNA and histones respectively. .Vitamin C is being investigated as a way to reprogram the epigenome..
There are various difficulties with supplementation with vitamin C. First of all vitamin C is poorly absorbed. Secondly vitamin C can affect mineral absorption. The adverse affects on mineral absorption of vitamin C has not been sufficiently stressed as an important limiting factor in vitamin C supplementation. As iron must be available in the gut forming vitamin C-iron complexes in the gut may not be desirable.
Getting vitamin C to work could be as easy as not taking trace minerals such as iron and copper at the same time as vitamin C. What one would be looking for is whether activity of TET enzymes and JmjC domain-containing proteins could be be increased by supplemental vitamin C and carbonyl iron taken at different times of the day. Activity of TET enzymes and JmjC domain-containing proteins in the gut would be investigated. A combination of immediate release vitamin C and liposomal vitamin C where the vitamin C is taken away from trace minerals could be optimal.
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.
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.
Many illnesses, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and bipolar disorder are associated with oxidant stress. Yet, increasing levels of free antioxidants by supplementing with more than RDA amounts of vitamin E, beta-carotene and vitamin C does not treat these illnesses.
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.
Calcium citrate contains a whole lot of citrate. The formula of calcium citrate is Ca3(C6H5O7)2. Calcium citrate is about 85% citrate. Citric acid can be purchased on Amazon. 4 ounces of food grade citric acid can be purchased on Amazon for $4.99. 4 ounces should be more than enough for the experiment. 600 millgrams of calcium from calcium citrate would have 4000 milligrams of citrate.
A citric acid drink with say 4000 milligrams of citric acid could be drunk 3 or 4 times a day for 3 or 4 days. The drink would only contain water and citric acid. The hypothesis being tested is whether citric acid can befuddle thinking. I am not actually recommending anyone do this experiment but as I stated for the experimentally inclined.
Citric acid should increase iron absorption still I think the adverse effects of citric acid are due to an iron interaction with citric acid in the gut which makes iron unavailable in the gut with very significant negative effects. Iron chelated to citric acid in the gut is not bioavailable in the gut. Iron must be available in the gut as well as systematically. Enhancers of iron absorption can have negative effects on iron metabolism in the gut.
In defense of a calcium citrate calcium supplement but not Mountain Dew the citrate in calcium citrate could largely be be chelated to calcium rather than to iron.
How are Mountain Dew focus groups actually run? Do individuals running the focus groups give indivduals in the focus groups Mountain Dew to drink then riff in ads on postive reactions to Mountain Dew and the individuals who gave those postive reactions?