Up - regulation of androgen receptor by heat shock protein 27 and miR - 1 induces pathogenesis of androgenic alopecia

[Dimitri001]

It would seem that AR activation upregulates the PRLR, which induces HSPs, and those HSPs increase AR transcription, creating a positive feedback loop keeping Twist1 expression high and causing premature catagen through HSP-mediated Twist upregulation.

If the role of PRLR is downstream of AR activation, wouldn't you then expect elimination of AR activity (castratos) to regrow hair the way the monkeys did once PRLR was turned off?

However, you say AR activation UPREGULATES PRLR, so I guess that could be the distinction, maybe returning PRLR to normal activity (again, the castration scenario) is not sufficient and you need to get no PRLR activity at all for regrowth.


So is it possible that Twist overexpression is THE single downstream effect that causes hairloss, perhaps only of the PRLR end of the cascade?

 

[jamesbooker1975]

If the role of PRLR is downstream of AR activation, wouldn't you then expect elimination of AR activity (castratos) to regrow hair the way the monkeys did once PRLR was turned off?

However, you say AR activation UPREGULATES PRLR, so I guess that could be the distinction, maybe returning PRLR to normal activity (again, the castration scenario) is not sufficient and you need to get no PRLR activity at all for regrowth.


So is it possible that Twist overexpression is THE single downstream effect that causes hairloss, perhaps only of the PRLR end of the cascade?

there basically 3 steps
1) We now know why male pattern baldness occurs, we got more androgen receptor in the follicles cause this damns two proteins
2) Then DHT is necessary
3) Then , there is a cascade of reaction , that we know little about it ( specially after the PDG2 fiasco ) .
I think that to avoid side effects, the real treatment should to intervene in the "3" . But all the intent to intervine in the phase 3 ( well, with the exception of Cetirizine, Minoxidil and latanoprost ....in part ) was not succefully . First in the early 2000s , when we thought that Tacrolimus topical will be a game changer, it wasn't . To Dr Lee surprice, it didn't even work . And then, 20 years later, Setipiprant, show that it didn't even work .

 

[Dimitri001]

there basically 3 steps
1) We now know why male pattern baldness occurs, we got more androgen receptor in the follicles cause this damns two proteins
2) Then DHT is necessary
3) Then , there is a cascade of reaction , that we know little about it ( specially after the PDG2 fiasco ) .
I think that to avoid side effects, the real treatment should to intervene in the "3" . But all the intent to intervine in the phase 3 ( well, with the exception of Cetirizine, Minoxidil and latanoprost ....in part ) was not succefully . First in the early 2000s , when we thought that Tacrolimus topical will be a game changer, it wasn't . To Dr Lee surprice, it didn't even work . And then, 20 years later, Setipiprant, show that it didn't even work .

But how do the higher than normal levels of DHT fit into that model?

From the paper:

The levels of DHT and HSP27 in the Androgenetic Alopecia group were (361.4±187.7) pg/mL and (89.4±21.8) ng/mL, respectively, which were higher than those in the control group [(281.8±176.6) pg/mL and (41.2±13.7) ng/mL, both P<0.05].

If the initial pathological change is more ARs, how does that lead to higher levels of DHT? If anything it should be lower due to more places to bind.

Is it possible ARs are somehow involved in creating 5ar, so more ARs->more 5ar->more DHT?

I wonder what the initial pathological change is, in other words what's the element that's different in men with Androgenetic Alopecia relative to those without that then starts the chain reaction which ends up creating all these differences relative to normal scalps that the paper talks about and that we know of from eslewhere.

I agree that ideally treatment should aim at as downstream a point as possible, to avoid sides and affecting things you don't want to affect.

 

[pegasus2]

If the role of PRLR is downstream of AR activation, wouldn't you then expect elimination of AR activity (castratos) to regrow hair the way the monkeys did once PRLR was turned off?

AR gets permanently activated in male pattern baldness like in crpc. Blocking the PRLR may switch it off so to speak. That could be the reason results last so long with HMI-115

So is it possible that Twist overexpression is THE single downstream effect that causes hairloss, perhaps only of the PRLR end of the cascade?

I think it could be. It's a shame it's so difficult to block Twist. It's a target of great interest in cancer, but there hasn't been a drug found for it yet.

 

[Armando Jose]

Is it possible ARs are somehow involved in creating 5ar, so more ARs->more 5ar->more DHT?

AR gets permanently activated in male pattern baldness like in crpc.

Acording to my theory the only way to diminish problems with sebum flow,
The only way for the pilosebaceous follicle to try to resolve the stoppage of sebum flow (clogged and oxidized on the way to the dermal papilla) is to try to produce new, light sebum that can drag the blockage. If you want to produce more sebum, you need more DHT, so it is really a defense mechanism.
The increase in AR receptors is logical from my point of view. I take this opportunity to indicate that people who go to the doctor for oily scalp problems prescribe keto to reduce sebum. You have to distinguish what the problem is, if it is dry fat, dandruff type, it is not good initially to use medicines that reduce the production of natural sebum

 

[jamesbooker1975]

Acording to my theory the only way to diminish problems with sebum flow,
The only way for the pilosebaceous follicle to try to resolve the stoppage of sebum flow (clogged and oxidized on the way to the dermal papilla) is to try to produce new, light sebum that can drag the blockage. If you want to produce more sebum, you need more DHT, so it is really a defense mechanism.
The increase in AR receptors is logical from my point of view. I take this opportunity to indicate that people who go to the doctor for oily scalp problems prescribe keto to reduce sebum. You have to distinguish what the problem is, if it is dry fat, dandruff type, it is not good initially to use medicines that reduce the production of natural sebum

So , according your theory, how hair transplant works ?

 

[Armando Jose]

So , according your theory, how hair transplant works ?

Are you serious?
Hair trasplant works because is trasplanted all pilosebaceous unit without blockade of sebum.

 

[pegasus2]

Are you serious?
Hair trasplant works because is trasplanted all pilosebaceous unit without blockade of sebum.

Why does the transplanted hair not develop the same blockage over time? We know that in most cases transplanted hairs are permanent. Additionally, the prostate doesn't have sebaceous glands so what drives BPH? Whatever is happening in the scalp is nearly the same process that happens concurrently in the prostate.

HSPs help prevent damage from oxidative stress that causes canities. This is at least in-part mediated by increasing transcription of Twist1, which increases AR expression. Twist1 binds with TCF4, which beta catenin also binds with to promote hair growth. Twist1 is proliferative, but it may promote skin and sebaceous gland cell fate instead of hair growth. Twist1 is not required for hair growth in adults, and too much of it may shift the balance from beta-catenin/tcf gene transcription to Twist1/tcf/b-catenin gene transcription. Shitfing that balance would conceivabley cause premature catagen in the scalp, making the DP progressively smaller with each shortened cycle, while causing growth in the prostate and metastasis. We have to look to prostate cancer for the cure.

At the 7p21.1 locus, we found TWIST1, a DP signature gene expressed in both BAB[balding] and BAN[non-balding] (Figure 1e and see Supplementary Table S1a), being up-regulated in BAB[balding] (Table 1). Twist1, a basic helix-loop-helix protein, is crucial for anagen-to-catagen transition during the hair growth cycle with Twist1 protein ablation in adult mice DP resulting in prolonged anagen (Xu et al., 2013 ). Hence, TWIST1 up-regulation in DPCs of balding scalps compared to non-balding scalps may result in accelerated transition from anagen to catagen and thus a shortened period of anagen during the hair cycle, a phenomenon in balding scalps that leads to the formation of short vellus hairs instead of long terminal hairs (Paus and Cotsarelis, 1999 ). Furthermore, basic helix-loop-helix proteins such as Twist1 bind to the consensus 5′-NCANNTGN-3′ E-box motif; suggesting that the down-regulation of genes in BAB compared to BAN with E-box motif in their promoter regions (see Supplementary Table S9a and Supplementary Materials) may be attributed to repression by TWIST1. Interestingly, we identified another TWIST protein gene, TWIST2, as a potential candidate gene at the 2q37 risk locus. TWIST2 has been implicated in mesenchymal cell lineage development, but little is known about its function in the DP. The combinatorial binding and interaction of TWIST1 and/or TWIST2 with other basic helix-loop-helix proteins at the promoters of target genes may result in gene regulation in DPC. TWIST1 also interacts and binds to HDAC4 to regulate gene expression. In addition, binding of TWIST1 at E-boxes in the AR promoter region results in up-regulated AR expression. Our observation of both TWIST1 and AR up-regulation in BAB compared to BAN could be attributed to increased regulation of AR expression by the increased TWIST1 levels in BAB compared to BAN. This potential relationship between AR and TWIST1 in balding DPC, which to our knowledge has not been considered previously, provides support for these two candidate genes to be the causative Androgenetic Alopecia genes at the 7p21.1 and Xq12 susceptibility loci.

Differential Expression between Human Dermal Papilla Cells from Balding and Non-Balding Scalps Reveals New Candidate Genes for Androgenetic Alopecia​

This study found that "Twist1 is required for androgen-induced migration of prostate cancer cells.", and that AR upregulates Twist1 through ETV1. It also found that "Twist1 depletion strongly repressed the migration of prostate cancer cells, comparable in effect to AR knockdown". ETV1 is then a potential target for treating hair loss. When comparing chick hairs that cycle(enter catagen) to those that stay in anagen forever, ETV1 was the second-most upregulated gene in those that enter catagen, and NRF2 was the most downregulated gene. However, ETV1 did not show up in this human DP analysis.

Gene expression differences in quiescent versus regenerating hair cells of avian sensory epithelia: implications for human hearing and balance disorders

Abstract. The sensory receptors for hearing and balance are the hair cells of the cochlea and vestibular organs of the inner ear. Permanent hearing and bal

academic.oup.com

Here they found that in castration resistant prostate cancer Twist1 is upregulated by PKC.

inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction....NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.

High Twist1 expression indicates a very poor prognosis in prostate cancer. Twist1 upregulation is responsible for AR induction at the transcript level even when the AR is blocked. Is this also happening in the hair follicle? This new paper about HSP27 and mir-1 finds that AR remains activated at the transcription level in balding follicles.

This study finds that Twist1 forms a complex with TCF4 and beta catenin in DP cells, upregulating c-myc and survivin. The study is very inconclusive. It found that Twist1 can promote expression of downstream target genes of TCF4, but that knockdown of Twist1 did not affect this. I think that's because in the absence of Twist1, beta-catenin is doing the job, which is what we want. When Twist1 bonds with TCF4 and beta-catenin it must promote an altered gene transcription vs when beta-catenin bonds with TCF4 alone. Twist/Tcf heterodimers upregulate some genes that are positive for hair growth by more than beta catenin, but it's apparently not inducing others. Or, perhaps it's the fact that Twist1 upregulates AR, and that is altering the gene transcription to prevent Wnt activation. Only beta catenin can activate Wnt without also upregulationg AR expression and transcription(even when blocked). Why else would Twist1 induce catagen as we know that it does, and why is it upregulated in balding follicles? If the Twist/TCF gene expression were the same as b-catenin gene expression then those hairs wouldn't be miniaturized. We know that loss of Wnt signaling is the cause of hair loss. Wnt signaling is greatly downregulated in bald scalp and decreases into catagen while Twist1 increases into catagen and is upregulated in bald scalp.

Tcf4 was colocalized with a subset of Twist1 in the nucleus of some Twist1 expressing DPCs in vivo (Figures 6C,D). These results demonstrate that Twist1 may physically interact with Tcf4 and β-catenin in DPCs.

Tcf4 responds to the β-catenin signal and initiates the downstream Wnt signaling pathway, thus promoting cell proliferation and differentiation (Cadigan, 2012). Disruption of Tcf4 or β-catenin can block the Wnt signaling pathway and lead to complete loss of cell proliferation (Ma et al., 2020). Our previous studies have shown that Tcf4 was highly expressed in growing hair follicles and in DPCs cultured in vitro when its morphological features were still in the agglutinative growth mode (Xiong et al., 2014). The Wnt signaling pathway mediated by the Tcf4/β-catenin complex plays an important role in hair follicle morphogenesis. However, it is not clear how Tcf4/β-catenin participates in the process of hair follicle induction and growth. In this study, we found that Twist1 could promote the proliferation of DPCs (Figure 1), and the overexpression of Twist1 could promote the expression of downstream target genes of Tcf4 and the secretion and release of growth factors in DPCs (Figures 2, 3). The function of Twist1 was consistent with that in a previous report (Shen et al., 2019). Therefore, Twist1 may be a positive regulatory partner of Tcf4. However, the knockdown of Twist1 did not affect the target gene expression, growth factors secretion or release of DPCs. One possible explanation for this difference is that the effects of downstream gene activation and transcription may be compensated for or replaced by other molecules.

Because Twist1 is a positive regulator of TCF4, Twist1 may play a key role in regulating the Wnt signaling pathway as it relates to DPC growth and hair follicle induction. However, from our data, we found that only a subset of Twist1 expressing cells expressed Tcf4, and only a sunset of Twist1 expressing foci also expressed Tcf4 in the cell nucleus. All Tcf4 expressing cells or foci expressed Twist1. These expression patterns suggested that Twist1 might have other functions in the cell.

What are those other functions? Could it be this? "basic helix-loop-helix proteins such as Twist1 bind to the consensus 5′-NCANNTGN-3′ E-box motif; suggesting that the down-regulation of genes in BAB compared to BAN with E-box motif in their promoter regions (see Supplementary Table S9a and Supplementary Materials) may be attributed to repression by TWIST1"

 

[jamesbooker1975]

Are you serious?
Hair trasplant works because is trasplanted all pilosebaceous unit without blockade of sebum.

So ? the old one is still present ( which actually means more sebum ) and the new one can be blocked too .

 

[pegasus2]

It seems the best way to inhibit PKC is with Calphostin C. You want a potent PKC inhibitor that has very little effect on PKA. Hexadecylphosphocholine(miltefosine) was the most effective one found in the study in this patent.

Protein kinase inhibitors having both a PKC-inhibiting activity and a PKA-inhibiting activity could not always be
expected to produce satisfactory hair growth-promoting results. H-7 and 3-amino/hydroxy-4-[4-benzoyl-phenyl carbon-
ylamino/oxy]azepanes could not always be expected to produce satisfactory hair growth-promoting results, because
such compounds have both a PKC-inhibiting activity and a PKA-inhibiting activity.
The present inventors have first found that PKC-specific inhibitors produce satisfactory hair growth-promoting results.

https://patentimages.storage.googleapis.com/63/12/01/86418ac298d745/EP0797978A2.pdf

Treatments were topically administered to BALB/c mice infected with Leishmania (Leishmania) amazonensis. The dispersions containing 0.5% Milt eliminated 99% of the parasites and cured the lesions with a complete re-epithelisation, no visible scar and re-growth of hair.

Efficacy of topical Miltefosine formulations in an experimental model of cutaneous leishmaniasis - PubMed

Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in ~ 90 countries, with an increasing incidence. Presently available pharmacotherapy implies the systemic administration of moderately/very toxic drugs. Miltefosine (Milt) is the only FDA-approved drug to treat CL via the oral...

pubmed.ncbi.nlm.nih.gov

This combined with an ETV1 inhibitor seems to be the easiest way to target Twist1.

I might even try harmine. It's so cheap and easy to get, and fairly potent. I never tried because it inhibits Wnt signaling in adipocytes, but that may just be because of its Twist inhibition. Its Wnt inhibition is cell-specific, so maybe it doesn't inhibit Wnt in DPCs since Twist seems to disrupt Wnt there instead of activating it. The plant that harmine comes from is known to cause hair growth when applied to the scalp. A concentrated form might do even better.

Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1​

 

[Dimitri001]

AR gets permanently activated in male pattern baldness like in crpc. Blocking the PRLR may switch it off so to speak. That could be the reason results last so long with HMI-115

But if all blocking the PRLR does is block or restore to normal functioning a perpetually active AR, then you'd expect the same results from blocking the PRLR as you get from castration - stops hairloss, but no regrowth - whereas blocking the PRLR leads to regrowth, this is, of course, assuming HMI turns out to induce regrowth in humans the way it does in monkeys.

High Twist1 expression indicates a very poor prognosis in prostate cancer. Twist1 upregulation is responsible for AR induction at the transcript level even when the AR is blocked. Is this also happening in the hair follicle? This new paper about HSP27 and mir-1 finds that AR remains activated at the transcription level in balding follicles.

In other words, with more than normal level of Twist1, the AR is perpetually active, even if it's not activated by androgens binding to it? But if it were so, wouldn't you then expect finasteride and other drugs that somehow reduce or block the binding of androgens to the AR to have no effect?

 

[pegasus2]

But if all blocking the PRLR does is block or restore to normal functioning a perpetually active AR, then you'd expect the same results from blocking the PRLR as you get from castration - stops hairloss, but no regrowth - whereas blocking the PRLR leads to regrowth, this is, of course, assuming HMI turns out to induce regrowth in humans the way it does in monkeys.

I don't think that's the only way that it works, but it might be. Twist1 keeps the AR activated even after castration. It is androgen-independent. It also likely has AR-independent effects through binding to TCF4 and E-box motifs.

In other words, with more than normal level of Twist1, the AR is perpetually active, even if it's not activated by androgens binding to it? But if it were so, wouldn't you then expect finasteride and other drugs that somehow reduce or block the binding of androgens to the AR to have no effect?

No. I would expect them to still reduce AR signaling, just not to eliminate it. Enzalutamide works in CRPC even though the AR is confirmed to still be activated by Twist1. It just doesn't work forever, or work well enough to stop the cancer. Blocking the AR will still prevent some transcription, and all transcription in cells that don't have higher levels of Twist1.

I also don't think that Twist1 is the only mechanism through which HMI works, just the primary one. It also should increase Shh for example. Direct Twist inhibition could work synergistically with HMI.

 

[EndlessPossibilities]

This study may be relevant here. It's accepted within this field of research that people who do not go bald, in general, go grey early. Prolactin's hsp90-mediated promotion of ATM might have something to do with that. While Prolactin is promoting miniaturization by inducing hsp90 and through other pathways, it may be protecting hair pigment at the same time. A lot of people have a significant amount of grey hair on the sides where they aren't prone to baldness, but little on top. ATM promotes HSP27. ATM promotes ROS protection and DNA repair, and its inhibition causes hair loss, so ATM itself probably doesn't cause miniaturization.

Stress-sensing in the human greying hair follicle: Ataxia Telangiectasia Mutated (ATM) depletion in hair bulb melanocytes in canities-prone scalp - Scientific Reports

Canities (or hair greying) is an age-linked loss of the natural pigment called melanin from hair. While the specific cause(s) underlying the loss of melanogenically-active melanocytes from the anagen hair bulbs of affected human scalp remains unclear, oxidative stress sensing appears to be a key...

www.nature.com

ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair - PubMed

Ataxia telangiectasia (A-T) is a human disease caused by ATM deficiency characterized among other symptoms by radiosensitivity, cancer, sterility, immunodeficiency and neurological defects. ATM controls several aspects of cell cycle and promotes repair of double strand breaks (DSBs). This...

pubmed.ncbi.nlm.nih.gov

Hollyshit. How interesting you say that. i nocited guys who have full heads of hair and lots of white and grey. Even my friend is going white fast and full head of hair. That’s insane u discovered this. Is there not a way to still keep color and keep hair ?

 

[EndlessPossibilities]

Also anyone know of a natural substance that blocks prolactin. Receptors? I think ascorbic acid potentiates dopamine blocking of prolactin receptor

 

[pegasus2]

Also anyone know of a natural substance that blocks prolactin. Receptors? I think ascorbic acid potentiates dopamine blocking of prolactin receptor

Nothing will work. Everyone has looked for something to inhibit prolactin signaling in the follicle. We tried SMI-6 which is potent, but it didn't seem to work that well. We just have to wait for HMI-115.

 

[Janko]

Nothing will work. Everyone has looked for something to inhibit prolactin signaling in the follicle. We tried SMI-6 which is potent, but it didn't seem to work that well. We just have to wait for HMI-115.

How about Del1-9-G129R-hPRL ?

 

[RagnarLothbrok]

Uhm, just stumbled with this, im on a pretty heavy cold/heat exposure regime right now (which is known to upregulate significantly heat shock proteins). Is there any link to either worsening or improvement for doing this in hairloss?

Extracellular Release and Signaling by Heat Shock Protein 27: Role in Modifying Vascular Inflammation - PMC

Heat shock protein 27 (HSP27) is traditionally viewed as an intracellular chaperone protein with anti-apoptotic properties. However, recent data indicate that a number of heat shock proteins, including HSP27, are also found in the extracellular ...

www.ncbi.nlm.nih.gov

 

[EndlessPossibilities]

Only thing I can think of is a stat5 inhibitor and there is no natural efficient stat5 inhibitor. I know believe prolactim is def the angle. And we just may be super lucky. Hmi can’t come soon enough

 

[RagnarLothbrok]

Only thing I can think of is a stat5 inhibitor and there is no natural efficient stat5 inhibitor. I know believe prolactim is def the angle. And we just may be super lucky. Hmi can’t come soon enough

Yeah but we still don't know if it works in humans like in macaques. If it works as suspected we have a very promising roadmap next 5 years focusing on these new pathways instead the old shitty ones... but if it doesnt work... oh boy.

 

[pegasus2]

Only thing I can think of is a stat5 inhibitor and there is no natural efficient stat5 inhibitor. I know believe prolactim is def the angle. And we just may be super lucky. Hmi can’t come soon enough

You'd need to inhibit STAT3 too. Probably won't work any better than JAK inhibitors, especially not a natural one. Then again if you had a potent STAT3/5 inhibitor it might have an advantage over JAK inhibitors if it doesn't inhibit RUNX2. If it does then maybe PGE2 could overcome that.