All things Histone Deacetylase (HDAC) and DNA Methyl Transferase (DNMT) inhibitory - reversing epigenetics from metabolic insults
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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 someBam! 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 ... -
@CrumblingCookie
https://raypeat2.com/articles/articles/protective-co2-aging.shtml,
For the butyrate forms i think its better to avoid coated forms for general use, the ones that have fats coating them (small intestine is probably vulnerable to increased amounts released there https://pmc.ncbi.nlm.nih.gov/articles/PMC11641654/#sec2-ijms-25-12998, plus the undiluted sodium when coated, normal form gets absorbed higher)
and only small amounts needed < 200mg as sodium butyrate for h3 acetylation
doi.org/10.1111/bph.13637
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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. -
@CrumblingCookie said in All things Histone Deacetylase (HDAC) and DNA Methyl Transferase (DNMT) inhibitory - reversing epigenetics from metabolic insults:
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?
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.Where did you derive or read the <200mg Na-But dose from? In that mice study they used 20mg∙kg−1.https://pubmed.ncbi.nlm.nih.gov/25240644/ here valproic acid induced autism-like defects when given during pregnancy , but weirdly this or sodium butyrate fixed them when given for 5 weeks a while after birth. (affects folate during pregnancy idk if that applies to butyrate too, but maybe best to avoid HDAC inhibitors during)
np interesting thread & the 20mg/kg dose for HDAC inhibition orally for mice is about 100mg - 150mg for human when u account for metabolism differences. its not exact depends on substance but generally for mice its (3/37) * dose * human weight in kg , or just dose *5 to simplify for 60kg person and add or reduce as needed for weight. for rats 6/37 or dose *10
useful link for different animals conversion https://www.westernu.edu/media/research/iacuc/dose_conversion_between_animals_and_human_-jbcp_2016.pdfFrom Protective CO2 and aging:
Prolonged lack of CO2, i.e. also hypoxic states -> epigenetic silencing/hibernation. Got it! That seems sensible to apply!
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.ah key context there then , here global methylation was actually lower in hibernation https://pubmed.ncbi.nlm.nih.gov/25908059/ with a global transcriptional decrease https://pubmed.ncbi.nlm.nih.gov/19412897/ with increase in HDAC too especially hdac1 and 4.
(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)
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)?
thats what im thinking too the underneath part, gonna try standard butyric acid diluted in water, into circulation and see if helps a small intestine problem at the ileum from the underside. but some will absorb direct too. i think taking it uncoated = you still get it absorbed a lot in small intestine but spread out absorption in duodenum jejenum ileum and diluted with water, instead of overwhelming just the ileum and with the undiluted sodium release too as extra that doesnt release until then otherwise
1g+ looks like high dose used for acute repair boost and general use lower, (for histone acetylation they showed its effective systemically in tissues at low dose <200mg as the sodium, because most of the sodium butyrate wouldnt havent reached that colon tissue sample direct, so if bumping up 50% to make room for absorption issues still <300mg or 2x <500mg generally) -
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 a novel and unnerving description of my subjective state. Ah, the hibernation torpor! Metabolic depression. Apnoic breathing. Hypoxia. Slowly, creeping horror of drifting away in a blurred state of consciousness and bodily functioning.
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.
