@Mauritio said:

NMN increases butyrate producing bacteria and Akkermansia as well as the thickness and permeability of the mucosa . It also affected bile acids a lot.
https://pubmed.ncbi.nlm.nih.gov/34395502/

That's tricky to derive an adequate HED from because of the non-linearly dose-dependent effects: The treatment group G2 (0.2mg NMN/mL drinking water) is the odd one out and clearly deviating from the control, the lower-dosed G1 and the higher-dosed G3 and G4 group wrt to most markers. G2 even showed lower body weight gain, i.e. stunted growth.
The authors focused on G1 vs CON comparisons without addressing that odd G2 group.

@herenow said:

You could end up with an effect similar to Rx medications by combining weak inhibitors and the drugs seem to have toxicity. It could be an issue over time.

Do you mean that the the non-Rx substances would, especially in combination, clearly be safer and similarly effective than taking Rx medications?
Or do you mean that the non-Rx substances could show similar toxicities like Rx over the course of time?

There seems to be a sweet dosage range for best effects. Overdoing the inhibitors could deplete stem cells through ↑cell differentiation , ↓ proliferation and ↑ apoptosis.
As in the case with those butyrate-sensitive ISCs which are meant to be particularly protected at the bottom of special intestinal crypts.

@herenow said:

The only established application for the drugs that I could find is cancer treatment and I did not yet find many off label uses.

Yes the medical guidelines and practices are very restrictive about them. Even if you look up the cancer applications you'll see those Rx inhibitors are only being allowed to patients after a failed first-line round of chemotherapy and then only in combination with another bout of chemotherapy.

But the hints and references to epigenetically engrained alterations are everywhere.
Not least in psychology and psychiatry where it's known that e.g. in depression epigenetic expression and methylation patterns are all over the place in significant deviation from "healthy" controls.

In the vitamin D study linked above e.g. they wrote of dibenzazepine as stimulating specific lines of cell differantion [to goblet cells in the case of the GI system], which is interesting because that whole dibenzazepine drug class includes (ox)carbamazepine and a hole range of tryclic neuroleptic and antidepressants and constitutes one of the cornerstone of hit-and-miss psychiatric medications with a very wide range of effects and oven irresponsibly prescribed to "reset" incomprehensible brain metabolism.

And many probably know of the countless rodent experiments in which animals were stressed in various ways and various developmental stages and then went on to produce offspring exhibiting transgenerationally lasting disturbed behaviour, depression and giving up early in those notorious forced swimming tests across 5, 6, 7 or more generations.

You are right about recognizing this is a still very blank spot on the map of the therapeutics world. I suggest there is treasure to be found.

Check his medications for neutropenia or agranulocytosis as a listed (rare) side effect and if so have those drugs removed or replaced.

There are some studies on e.g. diabetes where vitamin E prevented or replenished a drop in neutrophilic granulocytes, without changing their functioning.
And other studies on vitamin C improving neutrophil functioning.
Glutathion reductase (B2+B3 dependent) has been found relevant for mobilization and functioning of neutrophils.
Histamine has been found to inhibit neutrophil functioning (phagocytosis and neutrophil extracellular traps) through histamin-2 receptor activation.

In contrast to kvirion's 1g daily dosing idea,
I had started with 2grs of Na-butyrate, 4-5 times a day (i.e. 8-10grs per day in total) on Wednesday. Since Thursday my skin and body has been feeling warmer and better perfused.
Most noticably, on Thursday and Friday, all off a sudden I had functioning GI mucous layers again: Whilst bowel movements were frequent, the stools were the smoothest I've had in years if not ever. So smooth that no Tp was necessary at all.
Then Saturday and Sunday that strongly reverted to the very opposite. I could even smell some butyrate as a cause or a consequence of this disturbance.

I've then decreased the dosage to 1g NaB four times a day.
Now my thoughts are:
Did I overdo the butyrate dosages and by this deplete necessary cofactors,
or did I overdo the butyrate and do its beneficial effects maybe follow a Gaussian distribution curve. I.e. is there an ideal, optimum dosage range for butyrate, with higher amounts reverting much of its benefit?
In other words, is there an inverse dose response past a certain amount?

In a human study with 4-phenylbutyrate 9g/day increased to 21g/day over 24 weeks, Phase 2 study of sodium phenylbutyrate in ALS, 2009,

"The greatest increase in histone acetylation occurred at the lowest dose (9g/day) but did not reach the levels of normal individuals – the authors were unclear why an increase in histone acetylation was highest at the lowest dose".

There were 40 participants but only 26 of them completed the trial through the dosage increments. Because the daily dosage was increased weekly it's also not possible to distinguish the effects between daily dosage and prolonged drug exposure or disease progression.

participants took three tablets t.i.d. from the baseline visit to week 2 (9 g/day), 
four tablets t.i.d. from week 2 to week 4 (12 g/day), 
five tablets t.i.d. from week 4 to week 8 (15 g/day), 
and six tablets t.i.d. week 8 through week 12 (18 g/day). 
At 12 weeks, the subject took seven tablets t.i.d. (21 g/day) through week 20, 
the last day of the treatment phase of the trial (Figure 1).
If participants could not escalate dosage because of
adverse events, they were maintained on their maximum tolerated dosage.

In figure 3 the authors show Histone acetylation levels with NaPB dose taken prior to the blood draw. The peak is clearly highest (but perhaps even post-maximum?) at the lowest trialled dosage of 3g NaPB (=1.4g butyrate = 1.8g Na-B) and significantly declines at higher doses of 4g or 5g, respectively.

4-phenylbutyrate contains 53% butyrate by weight.
Sodium 4-phenylbutyrate (used in the ALS trial above) contains 47% butyrate.
Sodium butyrate contains 79% butyrate by weight.
Calcium butyrate contains 81% butyrate by weight.
Magnesium butyrate contains 88% butyrate by weight.

The 9g Na-PBA used in the ALS trial therefore equals 4.23g butyrate, as in 5.35g Na-butyrate per day.
If aiming at such a maximum amount of butyrate per day, this accordingly equals
• 5.2g calcium butyrate which also provides a practically convenient amount of 992mg calcium,
• 4.8g magnesium butyrate which also provides a very substantial 577mg magnesium.

A 5:1 or 4:2 blend of Ca-B to Mg-B could be good over the long term:
Max. 5g of a 5:1 blend yields c. 790mg calcium, 100mg magnesium, 4.1g butyrate.
Max. 5g of a 4:2 blend yields c. 630mg calcium, 200mg magnesium, 4.2g butyrate.
I like how this can beneficially cover extra Ca and Mg needs in contrast to the equivalent extra sodium, which is probably an unneccessary burden to most people except for those with very speficic kidney issues.

It could be rewarding to find out about the histone demethylation mechanisms for H3K9 specifically.

It looks demethylation of H3K9 is a job of the LSD=KDM class of histone demethylases.
So the aforementioned folate- and FAD-dependent LSD1 is =KDM1A and demethylates H3K4me2/me1.
H3K9me3 demethylination is trough KDM4A, specifically:

This table's right column reveals whether demethylation activates or represses genes.
from Vitamin D and the epigenome, 2014
This paper was a chance find for me when looking for H3K9me3.
-> There are some serious implications on HDAC and epigenetics through ligand-activated VDR by 1,25-OH-D3 (or its ligand-inactivation by 25-OH-D3). The details of it depend a lot on co-conditions. In general, activated-VDR does not directly boost overall HDAC levels, but
it strongly recruits HDAC enzymes to specific histone sites. And it prevents KDM histone demethylation.
It offers necessary DNMT1/3B inhibition on promoter genes of innate immunity.
That HDAC recruitment is really crappy.
E.g. HDAC1 strongly prevents cell differentiation.
It fits in with e.g. a high density of VDR in irritable bowel disease and the general observations of forcing a higher 25-OH-D3/1,25-OH-D3 ratio by exogenous D3-supplementation (also topically) to bring about alleviating, healing, pro-metabolic effects on epithelial cell lines of e.g. skin, GI, airway surfaces.

(Preexisting) HDAC3 induction strongly suppresses 1,25-OH-D3 synthesis and VDR expression and therefore innate immunity.

1,25-D3 inhibited the expression of several histone demethylases (e.g., KDM4A/4C/4D/5A/2B, JMJD5/6, PLA2G4B), 
and induced the expression of others, JARID2 and KDM5B (Pereira et al., 2012).
Members of the KDM4 family catalyze tri-demethylation of H3K9 and/or H3K36 (Cloos et al., 2006; Fodor et al., 2006; Klose et al., 2006; Whetstine et al., 2006; Lin et al., 2008). 
H3K9me3 is a mark for heterochromatin and demethylation of H3K9 is suggested to be linked with chromosomal instability (Cloos et al., 2006). 
Inhibition of expression of KDM4 family members by 1,25-D3 could thus contribute to genome stability.
[...]
The histone deacetylase HDAC3, one of the most frequently upregulated genes in cancer, seems to inhibit VDR expression. 
[...]
As early as 1984, Yoneda et al. (1984) have shown that the histone acetyltransferase inhibitor butyrate augments 1,25-D3 actions. 
Several studies confirmed these findings (e.g., Rashid et al., 2001) and have suggested that the action of butyrate could be through upregulation of VDR or CYP27B1 expression (Gaschott and Stein, 2003). 
Whether this effect is mediated by direct acetylation of the VDR or CYP27B1 promoters, has not been determined.

Here's another paper:
Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP4 pathway activation in human colon organoids, 2024
-> No explicit mentioning of HDAC or DNMT, but pointing towards change of epigenetics expression
-> Limited cell renewal with high VDR-activation -> more stem-cell reserves.
But what's the use of withholding stem cells? Statically, I can't think of a benefit. Situationally, it could be very beneficial i.e. as in maintaining low 25-OH-D3 = high VDR-activation before chemotherapies, then stimulate stem cell differentation to quickly replace damaged tissue after chemotherapy.

In wonder what other substances stimulate (specific) KDM histone demethylases.

@cs3000 said in All things Histone Deacetylase (HDAC) and DNA Methyl Transferase (DNMT) inhibitory - reversing epigenetics from metabolic insults:

(hibernation i think reflects as a darkened hellish depression state for humans, humans dont hibernate so the closest thing is creating a drive towards death. sleep isnt hibernation hibernation is closer to death just on the edge)

That's an oddly-terrifying novel description for a subjective state of being. A metabolic stasis. Hibernation torpor, metabolic depression, apnoic breathing, hypoxia, blurred states of consciousness and bodily functioning all don't sound too well indeed.

Good finds: In this first paper you linked they observed overall CpG-hypomethylation in hibernation. As for histones, they referred to a prior 2006/2009 paper of which you quoted the summary of table 1: Increased HDAC activity (x1.8), decreased H3S10 phosphorylation (x0.61), decreased H3K23 acetylation (x0.75). And, unsurprisingly, much reduced genetic transcription.

What do we take from this? That DNMT inhibition is crucial for innate immunity and anti-cancer genetic expression but the dismal hibernation is mediated mainly through increased HDAC? So HDAC activity really sets the metabolic quality of life.
And maybe, in some circumstances, low DNA methylation (beneficial) could even go hand in hand with high histone/chromatin compaction (dismal)?
Unless there's a smart combination or at least compensation of pathologically deranged factors.

Smart considerations could be to regard year-round continous D3 supplementation as a misuse for it's HDACi + KDM side effect and it to be better to rather choose a HDACi. Or VDR stimulation + butyrate HDACi.

@cs3000

Thanks for this. I've just read the stressed mice study about first decreased, then significantly increased BA levels in the ileum, alongside drastically decreased free amino acids and a microbiotic shift.
So actually increased (ileal) BA levels associated with bad outcomes... ileal bacterial dysbiosis and overgrowth... Free-amino-acid starvation of beneficial ileal bacterial species... Due to lack of digestive functions in the more proximal parts of the GI system? Which more BA in the proximal parts would prevent and heal? Hence indeed the preference for uncoated BA instead of slow-release formulas as you suggest. I'll heed that founded advice.
At first, that study turned me somewhat angry for contradicting the model about lack of BA. But I take it's a cascade of which it is best to start at the top.

Most current studies suggest that the intestinal mucosal barrier damage caused by CUMS
is associated with low BA levels in the intestinal lumen. However, some reports described 
high fecal BA concentrations in CUMS model mice [21]. Some patients with mental disorders
such as depression and autism also exhibit high intestinal BA concentrations. 

That study actually touches on and summarizes so many crucial elements of health. Not least when thinking about sprue or disaccharide intolerances or the vaguely ominous biogenic amines burden. Look at those dwindling goblet cells and exploding serum LPS and villous atrophy:

In the black-and-white bar graph above: Obliterated H3-acetylation by chemical injury (DSS).
Where did you derive or read the <200mg Na-But dose from? In that mice study they used 20mg∙kg−1.

The importance of butyrate supplementation has been demonstrated by the impaired
butyrate metabolism in the inflamed, intestinal mucosa of patients affected by IBD 
(De Preter et al., 2012). In fact, data show that this deficiency in butyrate results 
from a reduction in butyrate uptake by the inflamed mucosa due to the down-regulation 
of the monocarboxylate transporter (MCT)-1 expressed on the apical membrane of
intestinal epithelium (Thibault et al., 2007).

Reduced BA uptake in the chronically inflamed states. So it'd be better to really blast up the dosage? Perhaps even so much as to provide BA through serum circulation and the basal membrane (from within the body) instead of the apical side (from the intestinal lumen)?

From Protective CO2 and aging:
Prolonged lack of CO2, i.e. also hypoxic states -> epigenetic silencing/hibernation. Got it! That seems sensible to apply!

I'm not fan of methionine. E.g. a high methionine, low cysteine ratio in many vegan protein powders feels very unsatisfactory for me. Betaine or trimethylglycine don't feel well either. Accordingly, red beets are a horror. IME, after a 2-3 days' subjective boost, those methyl donors can really worsen things. Yet merely avoiding their overabundance is insufficient in itself to put things back on a right track. The same with the idea of nicotinamide to deplete methyl-groups: That never worked for me. Choline however is really important for liver functions, chylomicrons etc. That thinking about the absolute dietary supply of methyl groups must either be way too simplistic or a mere drop in the ocean of stronger factors.

Speaking methylation: That's an ambiguous mechanism because whilst we don't want excessive methylation of DNA CpG sites which prevent genetic transcription, methylation of the lysine groups on histone bodies either contributes to their unfolding OR to genetic silencing.
On H3K9 tri-methylation (reportedly a stubbornly long-term, transgenerational impact!) acts silencing so directly opposes the effects of acetylation or bOHB. Which makes HDACis like butyrate or beta-hydroxybutyrate direct antagonists to overmethylation. I wish Peat had followed that up.
It could be rewarding to find out about the histone demethylation mechanisms for H3K9 specifically.

Some ponderings on that current H G 7 craze on the RPF. I am wondering whether indeed the central and crucial part about it all is the EGCG. And all other substances merely serve EGCG so that it's well tolerated.
And the EGCG's main function, aside from the removal of the intracellular metallothionine deposits (I'd still want to read up more on this hypothesis), would be that of an DNMT inhibitor: Releasing silenced genes, reenabling and strengthening cellular and tissue level activity and differentiation.

So, the concurrent zinc will be taken up by EGCG and carried into the cells instead of the zinc freely floating around in circulation and giving you headaches etc. Zinc stores would be repleted and spared as in absolute terms EGCG would mainly chelate metals other than zinc, like iron.

Some thoughts: My lazy ChatAI inquiry responds with:
"Studies indicate that under certain conditions (e.g., neutral to slightly basic pH), one molecule of EGCG can bind two zinc atoms (Zn²⁺)"
By this, theoretically, each 350mg of EGCG could bind to 100mg of elemental zinc at the very most.
However, "the protocol" states 100mg zinc for about twice to triple the amount of EGCG (750-1200mg). So fully saturating the EGCG with zinc (if at all possible) is neither desired nor a great thing to do.
If I am not mistaken, the picolinic acid zinc salt already acts somewhat as an ionophere for shuttling zinc into cells. The experimental protocol so far concludes that people aren't responding as well to zinc picolinate as to other forms.
I would therefore speculate that it's not essentially about the zinc getting into the cells per se but instead about saturating some degree of EGCG with zinc.
Either to reduce its reactivity outside the cells or to promote it carrying predominantly zinc rather than other metals into the cells, and carrying other metals rather than zinc outside of the cells. Whilst somewhow shuffling around all the metals.

Maybe someone with more dedicated brain activity to spare can look into that more profoundly. I.e. the specific affinities of EGCG to metals. And the formation and possible routes of degradation of metallothionine stores.
And maybe find out whether EGCG actually degrades MTs absolutely, or whether it changes the MTs' overall metal storage composition towards more zinc and less of other toxic metals.
Or whether EGCG by induction of Nrf2 simply upregulates MTs even more, alongside iron-binding ferritin, so just makes things run more smoothly by getting the free metals out of the way rather than truly excreting them.

@happyhanneke said in Antibiotics for parasites and H pylori:

Any thoughts?
I know nothing about this.

Against H. pylori in regions with endemic resistancies instead of going for a fluoroquinolone-based antibiotic combo (as offered with the package above) afaik a bismuth quatruple therapy would be much safer.
Dunno if available in Nicaragua.
In Argentina it'd be called "Trylori", as seen here under "Equivalencias internacionales": https://www.vademecum.es/espana/equivalencias/39634/pylera-140-mg-125-mg-125-mg-capsulas
The metronidazole it contains is no candy either and will leave an aftermath of damaged cells and mitochondria and works well against amoeba, though.

Also, I don't see the prescribed antibiotic to have any effect against parasites. Amoeba maybe.
Against parasites you'd need to know which.
I recommend against albendazole if possible because that is super brutal.
The much less absorbed mebendazole is the tolerable choice for action within the intestinal lumen, if the parasites in question are susceptible to that and do not require a differenct substance class altogether.

Although I wouldn't decline some vorinostat aka SAHA aka suberoylanilide hydroxamic acid or romidepsin I'll go for the non-pharmaceuticals first:
• I am about to get the whole range of available butyrates; Na-But, Ca-But, Mg-But, K-BHB! And hopefully those will be as effective and pervasive into tissues as phenylbutyrate (without the nitrogen/glutamine/BCAA-depletion of the latter) or even better at an equivalent daily dosing between 10-20grs. The BHBs are and add-on for bOHbutyrylation, of the histone site H3K9, predominantly.
The different HDAC enzymes all preferably target different sites of the lysine chains.
• Choosing between sulforaphan (SFN) or erucin or isothiocyanates I'm going for EGCG to inhibit DNMT activity because the latter, in comparison, has the extra benefit of shuttling zinc across membranes and binding free iron instead of "merely" upregulating ferritin and intracellular metallothionine deposits. That action against free iron should prevent ferroptosis in healthy cells and increase intracellular TET proteins (which oxidize DNA methylation).
• Furthermore, maintain GSH (against hypermethylation) with extra NAC and
• maintain sufficient zinc, but not in excess!? Yet enough to competitively displace an overly abundant ratio of free iron and copper?*.
• As well as sufficient B2 and folate which are necessary for binding to a FAD‐dependent histone demethylase named lysine‐specific demethylase‐1 (LSD1). Folate is a necessary scavenger of formaldehyde which is being created by demethylization and therefore a coenzyme for demethylization enzymes as DMGDH, SDH in the liver.
• I'll avoid niacinamide because of its inhibition of PGC-1α through inhibition of SIRT1 (and also SIRT2) and rather use niacinic acid? And keep B5 at a sane, low amount to not overexpress CoA which is said to speed up the reaction rates of HDAC1 and HDAC2?

Would that be a solid approach?

Other HDACi:
• Btw butein looks good, too, but it also being a very potent tyrosine kinase inhibitor (decreases mitogenesis, cell division and cell proteins) sort of predestinates it for use in cancers with/by overactive TK activity rather than for non-anticancerous use, I guess.

• Puerarin looks interesting as it stimulates AMPK, PGC1α, Nrf2.
Increases autophagy, reduces Apoptose (PI3K/Akt activation = GSK3beta inhibition).
Inhibits mTOR, TNFα, NF-κB, JNK, Cox2, HDAC1 and HDAC3
Regulates PPARy.

• Apigenin ?! Inhibition of DNMT and HDAC.

• Decursin, which is a coumarin-derivative from Angelica plants. Predominantly DNMTi (looks for for synergy with a HDACi).

Orphan drugs or still in pharmaceutical trials:
• Panobinostat (cancelled in US, available in EU for >€4100/6 tablets)
• (Mocetinostat aka MGCD0103, inhibits mainly HDAC1, plus 2/3/11)
• (Entinostat aka MS-275 (patented), inhibits class I HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM, respectively.)
• (Belinostat aka PXD101, only i.v.)
• Vorinostat aka SAHA aka suberoylanilide hydroxamic acid,
• Romidepsin, HDAC1,2 + HDAC4, 6 (weaker)
• Valproic acid

• Biotin: HDACi. Yet IME in a very specialized way because it's exacerbating when not in combination with a broad-range base.
• Vitamin E (which forms exactly?): HDACi. Yet IME in a very specialized way because it's exacerbating when not in combination with a broad-range base.

• Possibly alkanes like:
Terpenes such as Phellandren, α-Terpinen, Limonen, Undecan

• Resveratrol increases SIRT1. It's reported to inhibit DNMT1 and DNMT3b. It's a dirty, double-edged substance, imo, with a wide range of opposing effects. I don't like it much. It's kind of like eating super tasty icecream that has laxatives mixed into it.

Background info bits:

• The traditional DNA hypomethylating agents (HMAs) such as decitabine (DAC) and azacytidine (AZA) are super toxic and destructive.

• "The DNA methyltransferase (DNMT) family is comprised of the catalytically active DNMT1, DNMT3A, and DNMT3B, which methylate cytosines within CpG dinucleotides, as well as DNMT3L, which lacks catalytic activity and serves as a regulatory factor. Using S-adenosyl-l-methionine (SAM) as the methyl donor, DNMT3A and −3B establish the DNA methylation pattern de novo while DNMT1 is primarily responsible for propagation of this methylation pattern to daughter strands following DNA replication. Thus, DNMT1 preferentially binds to and methylates DNA containing a hemi-methylated CpG dinucleotide."

• On DNMT and HDAC interrelations: !
-> DNMT1 is acetylated by TIP60 promoting its degradation. TIP60 regulates DNMT1 acetylation, while histone deacetylase 1 (HDAC1) controls DNMT1 deacetylation.

• GDNF, BDNF etc are all influenced by inhibiting HDAC.

• Here's a bit on the decisive short-term benefits of proper vitamin A; Food for thought for everyone who feels acute benefits from Retinyls:
"retinol/retinoic acid (vitamin A) and ascorbate (vitamin C) synergistically diminish DNA methylation levels and in doing so enhance the generation of naïve pluripotent stem cells.
This is achieved by two complementary mechanisms. Retinol increases cellular levels of TET proteins (which oxidize DNA methylation), whereas ascorbate affords them greater activity by reducing cellular Fe3+ to Fe2+" [10.1073/pnas.1608679113, 2016]

Some papers:
• Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy, 2018
• Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation, 2020
• *: Therein, wrt zinc the HDAC familiy classification:
• And from here the same with descriptions of the respective HDAC enzymes' main targets:

• Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective, 2021
• Function and mechanism of histone beta-hydroxybutyrylation in health and disease, 2022

@CrumblingCookie said in Random, interesting studies:

@cs3000 said:

something interesting,
when thyroid receptors aren't bound by the hormone / agonist they block DNA transcription. using HDAC. HDAC inhibition is 1 way to help the people who have receptor mutation / resistance, (sort of)
https://academic.oup.com/hmg/article/23/10/2651/614693#10263757
https://scholars.mssm.edu/en/publications/histone-deacetylase-inhibition-reduces-hypothyroidism-induced-neu
So basically people can get some of the gene effects from T3 activation if its lacking, without the t3 , by hdac inhibition . not full effects but some

Bam! So the working mechanism of T3 is not directly cellular stimulation, but inhibition of the inhibition of cell metabolism?
Therefore, vice versa, a practically hypothyroid state would be mimicked by overmethylation of the CpG sites on the DNA (blocking the transcription of genes) or by deacetylated/dephosphorylated/demethylated/de-beta-hydroxybutyrylated sites of the lysine chains of the histones (compressing the histones which wrap the DNA strands which prevents DNA access)?

To supplement thyroid hormones would work in such circumstances but be a kind of force-feeding, rawhiding override and circumvention of the actual underlying culprits?
But using other inhibitors of HDAC or DNMT could then be actually better and closer to the original cause and also effectively act like thyroid hormones?

I used to think of HDACis only as some very beneficial class of substances in a vague context of cancer (even though even in that they are very restricted).
Now they appear much more crucial in all kinds of diseases and chronic impairments.
If I were casually being offered some pure quality HDAC inhibitors I would gladly take them and run a treatment course with them.

@alfredoolivas said in Random, interesting studies:

CrumblingCookie HDAC inhibition also increases expression of thyroid receptor itself.

@Mauritio said in Random, interesting studies:

@CrumblingCookie Good point .
Well, sodium butyrate is widely available ...

@cs3000 said:

something interesting,
when thyroid receptors aren't bound by the hormone / agonist they block DNA transcription. using HDAC. HDAC inhibition is 1 way to help the people who have receptor mutation / resistance, (sort of)
https://academic.oup.com/hmg/article/23/10/2651/614693#10263757
https://scholars.mssm.edu/en/publications/histone-deacetylase-inhibition-reduces-hypothyroidism-induced-neu
So basically people can get some of the gene effects from T3 activation if its lacking, without the t3 , by hdac inhibition . not full effects but some

Bam! So the working mechanism of T3 is not directly cellular stimulation, but inhibition of the inhibition of cell metabolism?
Therefore, vice versa, a practically hypothyroid state would be mimicked by overmethylation of the CpG sites on the DNA (blocking the translation of genes) or by deacetylated/dephosphorylated/demethylated/de-beta-hydroxybutyrylated sites of the lysine chains of the histones (compressing the histones which wrap the DNA strands which prevents DNA access)?

To supplement thyroid hormones would work in such circumstances but be a kind of force-feeding, rawhiding override and circumvention of the actual underlying culprits?
But using other inhibitors of HDAC or DNMT could then be actually better and closer to the original cause and also effectively act like thyroid hormones?

I used to think of HDACis only as some very beneficial class of substances in a vague context of cancer (even though even in that they are very restricted).
Now they appear much more crucial in all kinds of diseases and chronic impairments.
If I were casually being offered some pure quality HDAC inhibitors I would gladly take them and run a treatment course with them.