Posts made by CrumblingCookie

@Mauritio said:

Why do you think it's less than 5 ? I haven't calculated it but I guess it should be higher . Especially once adding potassium bicarbonate. Why benzoic acid?

It's just a thought for avoiding the degree of scalp skin disinfection from the ethanol or its alternative of 20-30% propylene glycol. Of which I cannot say how much significance that bears wrt to the skin microbiome.
What's the minimum ethanol concentration for enhancement of absorption?

• The efficacy of benzoic acid and benzoate as a preservative is dependent on the pH, i.e. a pH <5 would be a requirement for the use of BzOH.
  At low pH BzOH's antibacterial action works through inhibition phosphofructokinase (PFK) and therefore prevention of (an)aerobic fermentation of glucose. PFK being touted the rate limiting enzyme for glycolysis of course urges to keep its topical concentration sensible so that the pH balances out and there'll be no inhibition of glycolysis in the cytoplasm of skin/HF/DP cells.
  Commonly BzOH is <1% (up to 5%) for preservation of cosmetics (limited to 0.5% in the EU and 0.2% in Japan.
• It's easy to confuse with benzyl alcohol, though, which is usually termed BA and used at <1% for preservation of cosmetics because of it being a skin irritant. It needs to be at least 0.9% however as the MIC. BA oxidizes to BzOH.
• I've thought of boric acid as a preservative, too, but I can't get my hands on that one.

@Mauritio said:

I just recall from one of the studies I read today that they said it was am epigenetic mechanism stabilizing the pro-hair genes .

The linked study showing activation of BMP genes by trichostatin A is likely by HDACi. As yet I know nothing about those bone morphogenetic proteins.
The authors wrote:

• BMPs are important in orchestrating tissue architecture by inducing a group of pivotal morphogenetic signals.

• In stem cells, the presence of BMPs in culture has been shown to be crucial for the maintenance of their primitive states

• BMP signaling in DP cells is required for the maintenance of their hair follicle-inductive properties. In the absence of BMP signals, DPs lose their signature characteristics in vitro and fail to generate hair follicles when engrafted with epithelial stem cells in vivo

• In our previous study, we found that BMP2, BMP 4 or BMP6, with BMP4 in particular, could increase the AP [alkaline phosphatase] activity of culture expanded SKPs [multipotent skin-derived precursor cells], and supplementation of BMP4 to the culture increased the hair induction ability of SKPs

Stem cell senescene is being alleviated and their autocrine functions [regulation of a cell's own behaviour by itself] restored by H3K14Ac and H3K19Ac. This definetly targets the HFSC and DP.

In dermatological practice they really should be checking up such markers in hair biopsies instead of the useless "Ah well yes sir/m'lady, the results of laboratory analysis of your painfully plucked hairs are in: They are telogen and falling out and we advice you take this agent of chemical castration, brain neurotransmitter and collagen degeneration" - "Gee, thank you, doc. I better heed this because, boy, I really wouldn't know what to do without your great sophistication!"

@Mauritio said:

Lol I've been peating too long to voluntarily apply lactic acid to my scalp, I feel safer with giving my scalp the raw material(s) ,mainly dextrose, and then let it figure it out.

That guy linked by @Hearthfire who used potassium bicarbonate (antimycotic + for the ion channels instead of minoxidil) also applied diluted acetic acid (white wine vinegar) before and after to enhance scalp perfusion and to (maybe/wishfully) dissolve skin calcium deposits.
Might as well choose lactic acid for that instead? Its use (5%) against acne, rosacea, for stimulating skin collagen and ceramide synthesis and for retaining skin moisture seems very safe and established.
If it were to only benefit the scalp skin even that would be beneficial for the perfusion and nutrient gradient behind the skin barrier. If the skin cells are more stable they wouldn't need to quarrel with HF, DP and stem cells about who get's the glucose and glutamine. I'd consciously deem it wise if skin cells always were to be prioritized over hair.

@Mauritio said:

But they study cited another one showing that HFSC rely on ANaerobic glycolisis, generating large amounts of lactate (not pyruvate)
So lactate itself might be wanted and needed for hair (stem cells).. something I never thought I'd say.
Or at least less lactate = less hair stem cells

But is their a cost?
Meaning more stem cells = less actively growing hair.

• "To assess the role of anaerobic glycolysis and lactate on 3C-HFSC proliferation in our system, we inhibited lactase dehydrogenase using FX11 (Flores et al., 2017) and observed that inhibiting lactate production attenuated proliferation of both HFSCs and ORS progenitors (Figure S4H), but did not affect the proportions of the two populations (Figure 4D). This indicated that, consistent with Flores et al., anaerobic glycolysis is required for HFSC activation, but it does not influence HFSC to ORS lineage progression."

Oh wow. HFSC do require lactate for their own proliferation. But on average it doesn't seem to hinder their absolute differentiation, it seems.

@Mauritio said:

The study even cited 2 other studies showing beneficial effects of HDACs on hair.

https://pubmed.ncbi.nlm.nih.gov/30814580/
https://pubmed.ncbi.nlm.nih.gov/22506014/

Nice follow up on this! I am unsure, however, whether these effects are mediated through HDACi or whether they are separate effects on Akt activation->GSK3beta inhibition->Wnt activation. It may be a distinct mechanism? But indeed why do they list 4-phenyl-butyrate (HDACi) as having the same effects? And trichostatin A (TSA) in the other study (which increased the acetylation level of histone H3K19 and H3K14).
They say VPA inhibits GSK-3beta "indirectly by an as-yet-unknown pathway" but that's info back from 2002. There seem to have been later studies in which HDAC activity was blocked or irrelevant and yet VPA directly inhibited GSK3β enzymatic activity. TSA on the other hand, as in the linked study, doesn't seem to act through Wnt/β-catenin but through increasing bone morphogenetic proteins (BMPs) which sound odd in the context of skin and hair.
(Topical) lithium will also do the Akt activation->GSK3beta inhibition->Wnt activation, but directly.

Even in conditions of sufficient glycolysis the activation of the Wnt/β-catenin pathway apparently lies at the very beginning at DP activation and HF induction because of the presence of overriding other adverse, inhibitory influences.
Which matches my experiences with topical glucose yielding strenghtened hair roots yet no proliferation.

@Mauritio said:

Here's an interesting review. Under 3.4.3 they talk about lactate and hair loss.

Lactate increases VEGF, leading to new blood vessels and better nutrients supply.

... so, topical lactate? If the topical solution remains at pH <5 we may even use benzoic acid or benzoate at 0.5-0.9% as a preservative instead of the high 35% ethanol. Maybe combined with an equimolar amount of glycine to allow for its enzymatic conversion to hippuric acid once applied and absorbed.

@Mauritio said:

haidut always says NMN is basically niacinamide, which I don't think is true. Not in hair and not in all of the rest of the body .

I've ditched all my NAM. I find its effects outright antimetabolic beyond the very short term yet those of nicotinic acid much more agreeable and I've been wanting to source NMN.

@Mauritio said:

I discussed the hair metabolism in this post
https://bioenergetic.forum/post/41937

Sorry I had missed this post. It's essentially the same study and authors we both dug out there.

@Mauritio said:

On the other hand they show that excessive glutamine or blocking mtorc2, long term depletes the HFSC pool, and I guess over long time frame that would lead to impaired regeneration and thinning hair.

This is also explains why they saw such drastic effects in the study above, but I'm not sure if that would be the same long term.

So, maybe cyclic addition of glutamine would be best. Between 1-10% , maybe 1 month on 2 months off or sth like that ?

The "spatiotemporal" effects really open up a different angle to determine suitable combinations and timings of different topical substrates. We wouldn't want a limited phase of fully engaged "hair growth bloom" followed up by depletion of the underlying stem cells and exacerbated balding.

It's very important that when I think of true hair loss reversal I am thinking of reactivated dermal papilla. Whereas feeding preexisting hair follicles only impacts hair thickness and rate of growth.
Of course outer sheath and hair thickness and follicle formation are crucial for robustness and rootedness of the hair follicle and for distinguishing proper head hair from vellus hair.
So we do need stimulation of both. Maybe in cyclic variation of topical regiments.

I've discovered a metabolic study in which the authors set up a 3D sphere culture to generate hair follicles from dermal papilla (DP) activating skin epithelial stem cells:
Glucose metabolism regulates expression of hair-inductive genes of dermal papilla spheres via histone acetylation

• "Here we show that active DP exhibit robust aerobic glycolysis. We observed decrease of signature genes associated with hair induction by DP in presence of low glucose (2 mM) and glycolysis inhibitors. Moreover, hair shaft elongation was attenuated by glycolysis inhibitors. Interestingly, excessive glucose is able to increase the expression of hair inductive genes and elongation of hair shaft. We also observed glycolysis-mediated histone acetylation is increased and chemical inhibition of acetyltransferase reduces expression of the signature genes associated with hair induction in active DP. "

• "energy metabolism has been shown to be one of the major cues during hair follicle formation. Especially, lactate dehydrogenase (LDHA), an enzyme involved in anaerobic glycolysis is required for hair follicular stem cell activation."

• "To determine whether sDP exhibit anaerobic or aerobic glycolysis, we measured pyruvate and lactate levels. sDP showed higher pyruvate levels but not lactate levels, which indicating aerobic glycolysis is activated by sDP (Fig. 1e,f)."

-->DP also rely on aerobic glycolysis. So no obvious contradictions between HF and DP so far.
Yet I am wondering what happens with all that excess pyruvate in HF and DP:
@Mauritio said:

...Aerobic glycolisis leads to copious amounts of intermediate generation like lactate and pyruvate . Which can be used to build nucleotides and keratin for new hair . In OxPhos the carbon goes towards CO2.

• "In addition to ATP production, SCs utilize glucose-derived carbons for lipid synthesis and for production of hexosamines, ribose, glycerol, serine, and glycine." *

Anyway, (excessive, 10-20mM) glucose concentrations (/extra energy) go hand-in-hand with histone acetylation and epigenetic activation of (dormant) DP under assumed normal circumstances:

• "Expression of DP signature genes including BMP4, LEF1, WNT5A, VCAN and FGF7 were decreased from sDP in presence of low glucose (2 mM) compared with physiological of glucose (5.5 mM) without alteration in cellular viability (Fig. 2a–f)."

• "Interestingly, excessive glucose (10 mM) supplement increased expression of the signature genes associated with hair induction (Fig. 2p-t). [...] We also found that hair shaft elongation was enhanced by increased glucose concentration (Fig. 2w,x).

Which seems to underscore the first and foremost importance of energy substrates but also makes me wonder under what (sick or altered) conditions and toeholds and auxilliary cells non-energy-subtrate HDACi or DNMTi or HMTi or LSD/KDM and coriander and apple phenols etc exert their action in this context.
If the extent of glycolysis directly drives histone acetylation in DP and HFs then more isolated benefits can be expected by reducing histone or DNA methylation back to prior physiologically states. Topical EGCG, decursin, apigenin?
The reducing qualities of plant phenols may be necessary whenever increasing the small proportion of OXPHOS in HF and DP, e.g. by NMN? Or generally for the larger proportions of OXPHOS in the afferent capillaries?

Interestingly, feeding ketones/fatty acids to hair follicles inhibits the PPP synthesis of ribonucleotides (your 1991 HF study. Don't know what the actual effects of this will be):

• "Both palmitate and beta-hydroxybutyrate inhibited glucose flux through the pentose phosphate pathway. "

@Mauritio said:

In wondering what other more benign amino acids do for the hair, like glycine ?

• "The suggestion that glutamine may be an important metabolic substrate in skin is strengthened by one further observation: the concentration of most amino acids in sweat reflect, largely, their concentration in blood; but the concentration of glutamine in sweat is only 3% of that of blood, 18"

which is taken from a 1974 study on healthy subjects during sauna bathing, i.e. an increase of metabolism surely met by increased tissue perfusion yet probably not by sufficiently increased glucose utilization. Are excessive sauna-goers and endurance sportsmen balding more widely and quickly?

Leucine and (sources of) sulfate may be worth a look because of biglycan as a significant messenger to Wnt activation for hair follicle renewal:
Dermal papilla cell-secreted biglycan regulates hair follicle phase transit and regeneration by activating Wnt/β-catenin
Activated VDR is an important factor for Wnt/β-catenin activation. So any of the numerous pathogens which express antagonizing ligands will suppress Wnt/β-catenin, as would excessive D3 and 25-OH-D3.

For dermal papilla functions, activating the Akt pathway and increasing the
level of Bcl-2 as well as VEGF and IGF-1 all seem important. DP also excrete powerful exosomes which induce their own activation via Wnt/β-catenin in neighbouring tissues. Reminds me quorum sensing in bacterial cultures. The more adjacent hair you have, the more hair you keep/get:

• "A growth factor cocktail of keratinocyte-conditioned media such as VEGF and IGF-1 was found to significantly increase the proliferation of DPCs and induce hair follicles in mouse models [13]. The results of experimental studies showed that Wnt1a- and BM-MSC-conditioned media stimulate the conversion of hair follicles from the telogen to anagen phase. This cocktail was also found to significantly increase the number of hair follicles in mice [45]"

Maintaining Hair Inductivity in Human Dermal Papilla Cells: A Review of Effective Methods

@wrl said in Sativa marijuana is peaty:

CBG is an α2A agonist which reduces adrenaline and is pro-GABA.

but CBG is also a 5-HT1A antagonist at 52nM: Not "peaty" at all.
Whereas CBD is a partial 5-HT1A agonist and therefore less objectionable.
THC again is serotonergic and exhibits those detrimental effects on gonadal functions, androgenic hormones and fertility etc. as already mentioned before by the others. So pushing THC and prohibiting or muddling with clean tobacco smoking fits well into the trend of a widely known general agenda.

Those terpenes likes limonene etc. may be much more exciting. But yes then any kind of aromatherapy and vaporisation of other medicinal herbs become just as interesting.

Colostrum. Reduces and prevents upper respiratory tract infections, flu:

Jones et al[21] reported significantly decreased URTI symptoms and episodes in athletes receiving BC compared with the placebo group.

• "COL limits the increased salivary bacterial load in physically active males during the winter months which may provide a novel mechanism of immune-modulation with COL and a relevant marker of in vivo (innate) immunity and risk of URI. "

Cesarone et al[22] reported that BC reduced flu episodes, and suggested that supplementation with BC might be more effective than vaccination against influenza virus.

• "After 3 months of follow-up, the number of days with flu was 3 times higher in the non-colostrum subjects. The colostrum group had 13 episodes versus 14 in the colostrum + vaccination group, 41 in the group without prophylaxis, and 57 in nontreated subjects. Part 2 of the study had a similar protocol with 65 very high-risk cardiovascular subjects, all of whom had prophylaxis. The incidence of complications and hospital admission was higher in the group that received only a vaccination compared with the colostrum groups. Colostrum, both in healthy subjects and high-risk cardiovascular patients, is at least 3 times more effective than vaccination to prevent flu and is very cost-effective."

And a review of studies on Colostrum Therapy for Human Gastrointestinal Health
and Disease

• "In animal models, bovine colostrum benefits NSAID enteropathy, IBD, and intestinal failure. In human trials, there is substantial evidence of efficacy of bovine colostrum in inflammatory bowel disease and in infectious diarrhea."

@Gaston said:

What about ornithine a-ketoglutarate?

Good find. I can't wrap my head around it all atm so maybe someone else may elucidate.
I remember ornithine works for scavenging/converting ammonia to urea and that less ammonia spares a-KG for more energy from the TCA. Then ornithin-aKG could be doubly beneficial.

It would be great if anyone can find the equivalent study to this study Intermediary metabolism of the human hair follicle but done on the dermal papilla.
According to this ex vivo/in vitro study the human hair follicles (and skin) mainly rely on

1. aerobic glycolysis of glucose, i.e. predominantly foregoing mitochondrial oxphos which only accounts to about 10% of all the glucose used up.
2. energy from glutamine by peripheral consumption of circulating amino acids or protein catabolism.

So glutamine and glucose seem to be an equally important energy substrates for hair follicles.
Replacing the 1% glucose with 1% L-glutamine may be an option. Or using both L-Glut and glucose in combination, which in the study above lead to much higher follicle ATP content than only glucose (in case that higher ATP content is a good thing and not sign of a backlog).

Yet I'm thinking that feeding other substrates (like a-KG) directly into the mitochondrial TCA of skin or hair follicles could unleash significant, additional metabolic energy capacities.

@Mauritio said:

Sodium butyrate increases Testosterone in mice on a HFD. It even exceeded the value of the control group. It also helped with sperm health .

Dissolve it into a suspension with MCTs or into your favourite water-based lotion and try it on your lower parts or even as general skin care and observe any pleasant short term effects.

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 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.

@Gaston said:

Possible role of β-hydroxybutyrate in inducing inflammation in alopecia areata

https://onlinelibrary.wiley.com/doi/full/10.1111/exd.15117

• Serum BHB levels were found to be significantly elevated in patients with AA compared with healthy controls, with higher levels correlating with severity of hair loss. BHB treatment increased inflammatory cytokine production in outer root sheath (ORS) cells, mimicking the inflammatory conditions seen in AA.

Hmm. That's a flip side. So the BHB seems to be strongly immunostimulative. Not necessarily merely proinflammatory per se. That leads us down to question the possibilities of what is underlying such (auto)immunological responses in alopecia areata, which may be due to specific or indistinct pathogen infection. And whether tackling such infection is possible rather than feeding or suppressing the immune response against it.

I can't find BHB serum measurements at the standard labs. Knowing those before would of course be nice to figure out which scenario one's in.

@Gaston said:

https://www.bulksupplements.com/products/potassium-bhb

Those are good offers for BHB. Unfortunately they don't sell butyrate or a-KG yet.

@Hearthfire said:

I've seen some stuff about how potassium may be a key to reversing hair loss.

https://www.hairloss-research.org/carnitine-and-hairloss/

Thanks. If I'm grasping it correctly the effects of the potassium only replaces the use of minoxidil: So in all cases where minoxidil proves to be of no benefit there would be no benefits from potassium either.
That and the AA/BHB-connection really points to wanting to first figure out the underlying mechanism of one's hair loss. Or to at least set up a plan of one's own trials as in "if not AA, then...", "if minoxidil, then K" or "if not minoxidil/K, then..."

In Ray Peat's newsletter "Epigenetics, sickness-aging, and changing science" (2014 01), which IMO starts off as a rather tiring albeit not unjustified rant, HDACi emerge as a significant factor against endometriosis and excessive menstruational symptoms (page 5):

• Although every organ seems to be renewed
  (more or less regularly) by the maturation of stem
  cells, the lining of the uterus is interesting because
  it has a monthly cycle, in which stem cells multi-
  ply actively during part of the month, and then
  enter a phase of maturation, with the ability to
  support a pregnancy. In the proliferative phase,
  cells are dominated estrogen, and in the
  maturation phase, by progesterone. During the
  estrogen phase genes are massively silenced by the
  HDAC enzymes, and during the progesterone
  phase, those HDAC enzymes are inhibited.
  Prolonged excessive exposure to estrogen with
  deficient influence of progesterone can lead to the
  development of endometriosis and endometrial
  cancer. The combination of progesterone and
  other HDAC inhibitors is effective in treating
  endometriosis and endometrial cancer, and proba-
  bly in other tumors, such as neuroblastomas (Atif,
  et aI., 2011) and lymphomas. Cyproheptadine,
  known mainly as an antiserotonergic antihista-
  mine, is also an HDAC inhibitor, helpful in
  treating mantle cell lymphoma (Paoluzzi, et al.,
  2009). Aspirin, with an acetylating effect that has
  been considered to be harmful, appears to activate
  a histone, synergizing with a variety of HDAC
  inhibitors to improve the effectiveness of cancer
  treatments.

And for some more Ray Peat blessing fairy dust to the sake of this thread:

• An epigenetic point of view suggests that a
  generalized view of beneficial synergistic effects
  should be considered--things that fundamentally
  support the organism's full development activate
  genes, and are antagonistic to things which funda-
  mentally interfere with that development. Under
  harmful conditions, genes are being silenced in
  the organism's defense, in an organized way, and
  b understanding the nature of that organisation,
  more coherent interventions to protect the organ-
  ism will be possible.
  Radiation, heavy metals, hypoxia, and estro-
  gen excess tend to create excess gene silencing,
  and what they have in common is the creation of
  over-excitable electrons, a reductive and nucleo-
  philic state. The opposing' electronic state,
  electron-withdrawing, typically with one or more
  ketone groups in resonance with one or more
  double bonds as in naphthoquinones (e.g., Inks, et
  aI., 2012) characterizes many of the protective
  substances, for example emodin (found in cascara
  and aloe), curcumin, progesterone, caffeine and
  theophylline.
  Some chemicals known to have protective effects on
  oxidative metabolism, such as short chain
  saturated fatty acids and procaine and procaina-
  mide, are also HDAC inhibitors with a broad
  range of protective effects. Niacinamide (vitamin
  B3) is a powerful HDAC inhibitor; vitamins A
  and D have some synergistic interactions with
  HDAC inhibitors.

• An optimal air pressure, or balance between
  oxygen and carbon dioxide, regular exposure to
  bright light, and foods that supply an appropriate
  balance of amino acids, minerals, vitamins,
  glucose and protective substances, such as HDAC
  inhibitors, would help to support developmental
  plasticity.

There we have Ray Peat endorsement of HDACis.
And the crucial caveat as to why this will remain in the fringes and shadows of "science":

• Many commonly used drugs have unexpected
  harmful epigenetic (degenerative) side-effects.
  Csoka and Szyf have said (2009) "We propose
  that epigenetic side-effects of pharmaceuticals
  may be involved in the etiology of heart disease,
  cancer, neurological and cognitive disorders,
  obesity, diabetes, infertility, and sexual dysfunc-
  tion." Although many researchers are now inter-
  ested in an epigenetic approach, there is no
  assurance that the medical and pharmaceutical
  industry will ever make the adjustment, because
  the most basic assumptions of their science are
  challenged.

Ray Peat's Newsletter "Imprinting and Aging" (2015 07):

• In aging, expression of genes is broadly inhib-
  ited by a general increase in DNA methylation.
  Because of the involvement of similar epigenetic
  modifications of gene expression, aging can be
  thought of as a type of imprinting that involves
  features similar to learned helpless[ness], in which the
  organs and tissues, including the brain, are unable
  to mobilize the energy needed for ordinary
  adaptive processes.

He then mentioned vasopressin, which may be worth a good look on it being influenced by inhibitors of HDAC, DNMT, HMT. He reports that vasopressin also inhibits klotho and increases tissue calfication by increasing phosphate uptake and decreasing klotho-dependent renal phosphate clearance.
He suggested that such vasopressin along with microvesicles or exosomes of stressed cells is being being carried and released systemically [and from human to human, as is actually known], affecting all other cells and tissues of the body, dragging them into the same downturn.

• Stress affects gene methylation to increase production of vasopressin. Antagonists to vasopressin can reverse the learned helplessness produced by stress. Vasopressin is responsible for the intestinal bleeding of stress, causing constriction of the bowel blood vessels, and damages the barrier function of the bowel, and also the blood brain barrier and generally increases vascular leakiness.

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:

• The food industry is promoting the use of
  various gums and starches, which are convenient
  thickeners and stabilizers for increasing shelf-life,
  with the argument that the butyric acid produced
  when they are fermented by intestinal bacteria is
  protective. However, intestinal fermentation
  increases systemic and brain serotonin, and the
  short-chain fatty acids can produce a variety of
  inflammatory and cytotoxic effects.

@cs3000 said:

Looked into the effect of sodium butyrate on causing senescence / stopping cells proliferate. it can do that to normal fibroblasts (even tho showed increased wound healing). but effect is selective

I can't remember which study and which HDACi substance but the other day I also read a paper on wound healing and how, in vitro, almost every single crucial stage of cell line and activity suggested impairments of the different stages of wound closure - which overall however didn't materialize as wound healing was improved and "more structured".
I'm still wondering on what to stack or balance HDACi with to also promote proliferation of progenitor cells, though. Maybe aKG? Which may also induce OCT4, SOX2, KLF2 for reversal to pluripontent stem cells (iPSC)?

@Mauritio said:

"...may be exploited to promote human HF growth, metabolism, pigmentation and/or antimicrobial defences."
https://www.morressier.com/o/event/62d558b38a1a1f00195adc16/article/62fa00a7cf455b001a73dd1e

Did you notice the c. x250 increase in dermcidin? I hadn't known about this antimicrobial peptide before but may now start regularly washing or rubbing my face with butyrate solution. Interesting that the But is a metabolite of S. epidermis and is to both feed the hair follice and to thwart skin and follicle infections. The ex vivo nutrient solution was a mere 11mg But per 100ml (0.01%). I'm going to use 500mg per 100ml (.5%).
The skin surface may be just as out of whack as the intestines after any (early life) antibiotic insults. Will add But + S. epidermis body spray to my imaginary list of product innovations.

I've been wondering whether BHB or butyrate would be better energy substrates to hair follices rather than dextrose. I'm thinking preferrably as potassium or magnesium salts.
But alpha-ketoglutaric acid /glutarate may be the energy substrate to prefer (LeeLemonoil had discovered that paper):

Highlights
 • mTOR and AMPK modulation by rapamycin, metformin, and a-KG induces anagen hair growth
 • Autophagy induction is necessary and sufficient for anagen entry and hair growth
 • Autophagy is increased during anagen phase of the natural hair follicle cycle
 • Aged mice fed the autophagy-inducing metabolite a-KB are protected from hair loss

Stimulation of Hair Growth by Small Molecules that Activate Autophagy

It's widely and cheaply available as arginine aKG. I know there are many shampoos etc. with arginine "to promote skin circulation" but not sure if the arginine is a good part. Calcium aKG is difficult and expensive to get and I reckon the calcium is disadvantageous in the skin.
Pure aKG (free acid) is even more difficult to get thatn Ca-aKG. So perhaps the AAKG is good.
a-KB is alpha-ketobutyrate. Which I can't find listed for sale anywhere but it surely looks great for hair.

I've seen apicidin [cyclo(N-O-methyl-l-tryptophanyl-l-isoleucinyl-d-pipecolinyl-l-2-amino-8-oxodecanoyl)] in a graphic put into the same HDACi group of cyclic peptides along with romidepsin and briefly followed up on that one:

It appears apicidin is orally and parenterally effective in vivo against protozae like plasmodium (malaria) by inducing hyperacetylation of histones in treated parasites. Potentially also active against toxoplasma, cryptosporidia etc.

"Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents."

Apicidin: A novel antiprotozoal agent that inhibits parasite histone deacetylase

"Treatment of P. falciparum cells with 70nM of apicidin at these three developmental stages resulted in ∼90% reduction of growth (IC90)"

Histone Deacetylases Play a Major Role in the Transcriptional Regulation of the Plasmodium falciparum Life Cycle

This in-silico modelling shows butyric acid being also an inhibitor of class IIa (HDAC7). It also reveals that phenylbutyrate does indeed exert stronger action:

From: In Silico and in Vitro Interactions between Short Chain Fatty Acids and Human Histone Deacetylases

Apigenin and the congeneric luteolin are potent class I HDACi, especially strong against HDAC2 and HDAC8.
Much less affinity to HDAC7, which would be targeted by class IIa HDACi (HDAC4/5/7/9).

[The more negative the value of docking score, the higher is the affinity of ligand toward receptor.]

On a simple by-weight calculation this could convert to 100-150mg apigenin/day for a human:

"Moreover, oral intake of defined flavone (20 and 50 μg/mouse/day) for more than 8-week period has revealed a substantial reduction in tumor growth of PC-3 xenografts in athymic nude mice [41]."

From: In silico approaches for investigating the binding propensity of apigenin and luteolin against class I HDAC isoforms

Luteolin, promising a very good safety profile, may alleviate hyperalgesia, chronic inflammatory or neuropathic pain. The authors make no mention of HDAC or epigenetics at all but point to luteolin's strong anti-inflammatory and antioxidant properties. Ultimately it may well be due to inhibitions of HDAC, similar to and in line with the aforementioned baicalin:

Luteolin: A promising natural agent in management of pain in chronic conditions

@LucyJ said in Tianeptine:

I have a major glutamate anxiety issue and want to try this to see if it helps...

Just a thought if glutamate is at the core of your issues you may need to stabilize the excitory signallings by ramping up intracellular glutathione. E.g. with the help of NAC, plus complementary SFN and low dose B2, B3.
IMO tianeptine is another crutch and good for the first couple of weeks, then quickly diminishing and messy wrt to benefits.

@Mauritio said:

baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression https://pubmed.ncbi.nlm.nih.gov/23684218/

Yet it enhances HDAC2 and inhibits histone demethylase (LSD1) at an IC50 of 3.01μM.
The LSD1 inhibition can be either a welcome or unwelcome dual-function.
https://pubmed.ncbi.nlm.nih.gov/22421405/
https://pubmed.ncbi.nlm.nih.gov/27814566/
I wouldn't know when to use baicalin and when not beside the neuropathic pain scenario.
There has actually been research into a series of dual HDAC and LSD1 inhibitors via conjugating the LSD1 inhibitor tranylcypromine to various o-aminoanilide and hydroxamic acid-based HDAC inhibitors, preferably with vorinostat by Duan et al., 2017 and with entinostat by Kalin et al., 2018.
Domatinostat is by itself already an class I HDACi and LDS1i. Those bifunctional HDACi+LDS1i compounds appear to be significantly more effective against cancer.

Specifically against cancer baicalin works through a different pathway: Inhibition of hexokinase II which is located at the outer mitochondrial membranes and provides the cancer cell's excessive glucose needs.

@alfredoolivas Ah, yes. I'll just wait for the raw powder then to spoon-feed on.
@jamezb46 Thanks for your clarification. I hadn't known about his Arginine Ursolic Acetate specialty. So regular ursolic acid would mainly exert only indirect systemic effects via its intraluminal workings in the GIS. Which may be powerful, but a different ball game.
Have you already tried any of these products like the Ur, 11KT or 11OXO?