All things Histone Deacetylase (HDAC) and DNA Methyl Transferase (DNMT) inhibitory - reversing epigenetics from metabolic insults

[Kvirion]

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

Thank you for sharing. I learned a lot

Here is why he maybe didn't warm up to SCFAs like butyrate, as he connected their synthesis to the many drawbacks associated with the abundance of gastrointestinal bacterial fermentation [...]

Yeah, this explains my negative experiences with butyrate a long time ago...

[CrumblingCookie]

@Kvirion said:

Yeah, this explains my negative experiences with butyrate a long time ago...

What do you remember about them?
I don't see how exogenous butyrate supplementation fits into Peat's objections as this foregoes the whole endogenous synthesis from bacterial fermentation. The But is not the cause for fermentation with all its associated endotoxin production but an isolated result of it.

[CrumblingCookie]

I've started taking 100mg apigenin twice daily.
However, the half-life of apigenin in rodents is reportedly much longer (several days) than in humans (a few hours) so I'm as yet uncertain about the ultimate dosage.

Apigenin, luteolin and chrysin are all congeneric,
with apigenin having 2 hydroxygroups at its B-ring,
luteolin having only one OH-group at its B-ring and
chrysin having none and being the weakest HDACi of those.

• They inhibit HDAC as well as DNMT and also Histone Methyltransferase (HMT), which is distinct from Histone Demethylase LSD1.
• The mechanism for DNMTi is different than the one by EGCG.
• Their DNMTi ist similarly powerful as 5-Aza-dC! Which sounds impressive because Aza is super toxic and irreversebly damaging to DNA.
• They also inhibit in particular the trimethylation of H3K2 through inhibition of EZH2 (Enhancer of zeste homolog 2).

• In our study, DNMT inhibition by plant flavones seems to be due to the binding of flavones at the catalytic binding pocket of DNMTs. These might be different from catechol-containing polyphenols, such as epigallocatechic-3-gallate, in which the noncompetitive inhibition of DNA methylation catalyzed by DNMTs is majorly due to the higher levels of SAM resulting from the catechol-O-methyltransferase-mediated O-methylation of these compounds

• Our results showed that the intercalation of flavones with calf thymus DNA causes major reductions in the intensity of the UV-Vis absorption band characteristics between 260–280 nm, where Apigenin and Luteolin with the 1 and 2 hydroxy groups in the B ring resulted in significant intercalation with DNA. Chrysin (no hydroxyl group in the B ring) resulted in less significant DNA binding.

• Because Apigenin and Luteolin are less water soluble than Chrysin, they are less solvated and consequently susceptible to intercalation within DNA.

Dietary Flavones as Dual Inhibitors of DNA Methyltransferases and Histone Methyltransferases

Overall, apigenin sounds very promising and powerful.
Whilst also being an aromatase inhibitor one one hand the caveat is that it's really exerting estrogenic and progestogenic effects on the other hand. Which seem quite unpredictable.

[Kvirion]

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

What do you remember about them?

It was before peating. I had IBS-D, and butyrate increased my fluctuance and GI discomfort and probably forced me to visit the toilet more often...

Regarding apigenin, I'm interested in your experiences.
BTW, what do you think about some MAO-A inhibition by apigenin?
https://link.springer.com/article/10.1007/BF02977772

[CrumblingCookie]

To underscore this thought:

With Acetyl-CoA and the ACP acyl-carrier-protein being dependent upon B5 and PDH that will also impact my approach to HDAC inhibition as we naturally need to raise acetylation levels for concurrent inhibition of deacetylation to have any meaningful effect on the balance of histone acetylation after all.

Some researchers are actually following up on inhibitors of Histone acetyltransferases (HATs) as anti-cancer strategies. I.e. preventing histone acetylation.
While I don't know how successfully those are going to pan out ...
here's what they found out about their use of HATi:

• Acetyl-CoA biosynthesis drives resistance to histone acetyltransferase inhibition:
• • "we determined that elevated acetyl-CoA concentrations can outcompete drug-target engagement to elicit acquired drug resistance [of HATi]"
• • "Altogether, this work uncovers CoA metabolism as an unexpected liability of anticancer HAT inhibitors"

This means that stimulating synthesis of CoA and CoA-Ac will strongly increase histone acetylation. Which should be a complement (or beginner's alternative) to inhibiting histone deacetylation (HDACi).

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Wrt to cancer there actually seems to be some specific merit to inhibiting CoA availability in lung and breast cancers, where the SMVT appears significantly upregulated, effectively supplying the tumorous cells with increased supplies of biotin (and pantothenic acid), promoting cell survival and proliferation (which we would like to see more of in non-tumorous but of course not in tumorous tissues). That happens through activation of the Wnt/β-catenin pathway.
And Foxd3 appears to be responsible for upregulating SLC5A6.

• "This study explores the role of the SLC5A6 gene, which encodes a sodium-dependent multivitamin transporter critical for mitochondrial function, in LUAD progression. We found that SLC5A6 is significantly upregulated in LUAD tissues and is associated with poor prognosis. Overexpression of SLC5A6 enhanced cell proliferation and migration, while knockout of SLC5A6 impaired these processes and induced apoptosis by disrupting mitochondrial function. Additionally, we identified Foxd3 as a key transcription factor regulating SLC5A6 expression. In vivo experiments demonstrated that SLC5A6 knockout effectively inhibited tumor growth."
  From: Foxd3/SLC5A6 axis regulates apoptosis in LUAD cells by controlling mitochondrial biotin uptake

It would be funny if delving into the origin of increased Foxd3 revealed a causation which could be tackled by DNMTi or HDACi.