Boosting AR signaling without affecting expression [Preliminary Work]

HSPs inducers aren’t associated with an oncogenic risk - even potent ones such as Geranylgeranylacetone.

It takes a great deal of HSP induction to maintain AR signaling regardless of androgen deprivation therapy. The cell has to be very stress while having many dysregulated pathways to ship out enough HSP induction to maintain AR signaling independent of circulating androgens. Please refer to:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306198/

HSPs inducers might restore some AR signaling, but I doubt it can fully reverse the muted signaling enough to actually lead to increased tumor risk (further than pre-drug baseline anyway). In a sense, if prostate AR receptors are silenced in PFS, maybe PFS grants a degree of tumor resistance? who knows.

As for Androgen response elements (ARE), they are the basic promoter regions of androgen-sensitive genes that respond to nuclear androgen receptor stimulation.
Androgens --> AR --> ARE (via chaperones) --> DNA

So, as long as the receptor is a nuclear androgen receptor, my hypothesis applies to it whether the receptor is present on the prostate, the brain, or any other area.

You can read more on Androgen Responsive Gene Database (ARGDB):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419166/

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Would be really great of some of the senior members of this forum could share their thoughts on this, also to hear if this was looked into by this community in the past already or not.
@awor @Northern_Star @Dubya_B @axolotl

Also worthwhile to share this topic from the pssdforum. Although still very experimental, it shows there is progress in understanding this better. To be continued …

http://www.pssdforum.com/viewtopic.php?f=20&t=3399&sid=116c9431cf47c0c723a3fdab0bea32fc

Thanks for reading,
Jaxx from pssdforum

I tried Schisandra some time ago and crashed. It worsened my ED, I was taking it only for few days.

Hi @DeRa,

Welcome. I am sure there’s no poor intent so I’d just like to make you aware that while you are free to speculate here, please mark posts as speculation - do not write things such as “theoretically this should work” or other things to encourage confidence in therapeutic ideas. Harm to patients from self experimentation has preceded suicide, and doctors/professors involved in the issue have drawn our attention to their patients having significantly worsened their condition. As such, we ask for users to ideally report what helped them and how, or mark speculative ideas very clearly, without asserting etiological confidence. This is a matter of what are prepared to host as we are shifting to greater involvement within our professional network. Further info is here:

https://forum.propeciahelp.com/faq#theories

Hey @NotJaxx,

Thanks so much for surveying (as everyone - it really is important). We’re very busy with a few things for the next months and will (hopefully january or so) be happy to discuss anything specific further having hopefully finished a thorough literature review.

Yes we’re aware of the heat shock protein family. Theoretically, I think this is a house of cards and do not consider assumptions to be accurate.

Firstly, even assuming this as a pathological cause, there is no suggestion from the published controlled studies or from the current understanding of androgen signaling that an increase in AR nuclear transportation or dimerization would be beneficial in PFS. At least symptomatically, I would speculate the stated aims could exacerbate symptoms, though I have no idea what else these substances are doing. I don’t see there would be a theoretical benefit to increasing nuclear localisation. @awor has personally had translocation assessed against controls by immunohistochemical import assay without a finding in the past many years ago, incidentally.

While an upregulation of HSP27 is often found to be concurrent with AR in CRPC and can be involved in maintaining its signaling in refractory disease (partly due to its conserved role in trafficking https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897588/), this is one of hundreds of deregulated genes (https://www.ncbi.nlm.nih.gov/pubmed/29324665, https://www.ncbi.nlm.nih.gov/pubmed/22158653), many of which strongly contribute to adaptive escape via multiple pathways. Disparate primary molecular events converge upon the maintenance of androgen signaling in the condition - it is highly complex and far, far from a single pathway. This includes all the other families of heat shock protein holdase/foldeases.

The heat shock proteins are important to protein folding and cell homeostasis. Exogenous alteration can disrupt cellular protein control mechanisms (https://www.cell.com/cell/fulltext/S0092-8674(00)80928-9). Substances interacting with the HSPs indiscriminately are not usually well tolerated, such as the hsp90 inhibitor Tanespimycin. With specific regard to the AR, the outcome would be unpredictable as the other HSPs function to maintain AR protein conformation for ligand binding and prevent degradation while in the cytosol (40, 70 and ultimately 90), although hsp70 at least also interacts with the clearance machinery.

In short I don’t think this reasoning is sound and I would personally expect an increase in HSP27 may have the effect of symptom exacerbation. I have no idea what inducing the other HSP chaperones would do, though I agree these will influence AR signaling and could modulate the pathology somehow.

Personally, if I was forced to choose, of all HSP-relevant options I would be most interested in a substance I don’t believe has been discussed (outside forum staff) called Arimoclomol (https://pubmed.ncbi.nlm.nih.gov/28943839, https://pubmed.ncbi.nlm.nih.gov/22591194). It is generally well tolerated (though that isn’t reassuring in PFS), and some studies I’ve read have suggested specificity to sites of endoplasmic reticulum stress, but I can’t find that off hand. As a thorough disclaimer I have no idea what would happen with this either, do not advise anyone to take it, and don’t consider it safe to do so. Just providing it as something potentially interesting given the discussion.

best regards and good luck

axo

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Hi @axolotl,

First, thanks for the elaborate reply. Seeing that you are a moderator here, there are several points I must address and get out of the way.

I have explicitly stated my reason for posting this thread in a perfectly clear manner. I also posted several disclaimers throughout the thread:

Unfortunately, theoretical data doesn’t always translate to practical outcomes. Being pragmatic, it’s essential not to put too much hope on this until HSP27-inducers are experimented with.

Keep in mind that I haven’t looked too much into these substance to know all their other mechanisms of action. For instance, I know that Schisandra is an AChEI and boosts serotonin, and dopamine. I know that Shikonin inhibits estradiol synthesis - which can be a very bad thing.

As such, this is just preliminary work. The reason I’m sharing this in its early stage is to ask you this: Have you ever tried any of the above substances/extracts for at least 3 months at a sufficiently high dose?

Ergo, it’s solely for the data collection purpose. Not for suggesting a trial-and-error of said substances.

Disparate primary molecular events converge upon the maintenance of androgen signaling in the condition - it is highly complex and far, far from a single pathway. This includes all the other families of heat shock protein holdase/foldeases.

You seem to imply that I’ve made confirmatory statements regarding the etiology of PFS. Even worse, you are implying that I’m presenting HSP27 as the sole etiological origin. You are putting words in my mouth sir; never did I once stated that HSPs were involved in the etiology of PFS.

What I have stated, however, is that boosting HSP27 facilitates AR trafficking to the nucleus - which should offer partial symptomatic relief. Thus, it’s a perfectly valid assumption on my part.

As for my opinion on the hypothesis propagated by admins and which forum members follow despite of the several discrepancies present in the paper, I find it a very respectable effort that offers interesting ideas on PFS - but it shouldn’t be treated as a bible. There exist discrepancies in the hypothesis. But let’s keep that to another time as to not get off-topic.

I don’t see there would be a theoretical benefit to increasing nuclear localisation. @awor has personally had translocation assessed against controls by immunohistochemical import assay without a finding in the past many years ago, incidentally.

You haven’t exactly provided a counter-argument. It could offer a disease-modifying effect via androgen-mediated potentiation of genomic activity of nuclear AR, facilitated by HSP27, yes? (unless you assume full methylation). This stress response is also valid under a disease-free condition.

I understand that you guys are looking for a full cure/reversal - but did you know that DMARDs are FDA-approved? looking for a cure shouldn’t hinder effort for finding symptomatic-relief options for the short-term. But I won’t force my ideology on you, and vice-versa.

I would personally expect an increase in HSP27 may have the effect of symptom exacerbation. I have no idea what inducing the other HSP chaperones would do, though I agree these will influence AR signaling and could modulate the pathology somehow.

The other chaperones and co-chaperones are involved in AR expression upregulation and stabilization. If you are going by the theory of AR over-expression and methylation, they would definitely be bad news.

HSP27, on the other hand, modulates (up/down) AR expression (at least in the prostate) while boosting signaling strength.
https://www.ncbi.nlm.nih.gov/pubmed/22362414

Induction of HSP70 upregulates AR. It enhances clearance/solubility of AR as you’ve kindly noted. However, it’s not a modulatory chaperone beyond upregulation.

Exogenous alteration can disrupt cellular protein control mechanisms (https://www.cell.com/cell/fulltext/S0092-8674(00)80928-9).

The study you have linked does not deal with exogenous alteration. You are drawing a baseless conclusion and I don’t think this reasoning is sound. Allow me to enlighten you with an example on practical data regarding HSP inducers:
** Teprenone/Geranylgeranylacetone** (HSP70 & 90 inducer):
http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=34199
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522658/
https://www.ncbi.nlm.nih.gov/pubmed/8690199
https://www.ncbi.nlm.nih.gov/pubmed/16406313
https://www.ncbi.nlm.nih.gov/pubmed/28781154

As expected of a stress-response protein, it’s neuroprotective and has relatively mild side-effects. (Used in Japan as a novel treatment for gastic ulcers). Even DMARDs, which are FDA-approved, have severe side-effects (which are common, btw) but they offer relief that outweighs the risk of having these side-effects.

Substances interacting with the HSPs indiscriminately are not usually well tolerated, such as the hsp90 inhibitor Tanespimycin.

Certainly, an inhibitor would be far less tolerable as it’s inhibiting a stress-response protein. It’s comparing oranges and apples.

Personally, if I was forced to choose, of all HSP-relevant options I would be most interested in a substance I don’t believe has been discussed (outside forum staff) called Arimoclomol (https://pubmed.ncbi.nlm.nih.gov/28943839 , https://pubmed.ncbi.nlm.nih.gov/22591194 ). It is generally well tolerated (though that isn’t reassuring in PFS), and some studies I’ve read have suggested specificity to sites of endoplasmic reticulum stress, but I can’t find that off hand. As a thorough disclaimer I have no idea what would happen with this either, do not advise anyone to take it, and don’t consider it safe to do so. Just providing it as something potentially interesting given the discussion.

I’d like to get to know your ideology better regarding PFS if I’m to fit here. Personally, I’m all for self-experimenting with a trial-and-error approach (that is based on sound hypotheses). That said, I explicitly reaffirm that encouraging trial-and-error was not the point of this thread.

I don’t believe has been discussed (outside forum staff)

I hope that the forum staff are at least sharing most of their discussions with the rest of the forum and this case is just an exception.

Thanks for your patience.

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At the top right, there is a little magnifying glass icon wich will allow you to search our forum. Have you tried that?

As a modern day internet user I am suspecting that you did search our forum and do know the answer to your question, namely that no one has tried any of these substances. So why are you asking this question? Did anyone in the PSSD community ever try any of these substances? If so with what result? If not, why so? Do you have PSSD? If so, why don’t you try any of these yourself?

Yes, what exactly is the point of your thread?

It’s not in the least a valid assumption. While I welcome closer collaboration between PSSD and PFS communities, I feel that being a little more humble, listening a little more before talking, and understanding what is known through published research about PFS, would serve you well and allow you better reception in this community.

We’re not in the bible business. Our focus is to promote research by institutions which have the capacity, credibility and capability to execute relevant studies, with a holistic view. At the end of the day, that’s what we need: True molecular level understanding of our problem and not more theories/beliefs/hypothesis.

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Haha why do the mods respond so defensive to this. What is the use of that?

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that so fawking toxic and narrow minded approach from Axo and Awor. It can take a decade to develop a cure or treatment and DeRa was just hoping to get some constructive discussion here from educated people, but instead he got rude and toxic response. Well done moderators.

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I can’t speak to their intentions but considering that years of speculation and discussion, no matter how educated and informed have not gotten us any therapeutic tools, I think they’re just trying to make sure we don’t go down another rabbit hole that ends up wasting more time, and potentially results in the loss of more lives.

Also there’s a ton of speculation.

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It is important that we keep our eye on the ball and focus on finding out what causes this before trying to treat this. I believe this is infinitely more important for a disease such as PFS/PAS/PSSD, unlike other chronic illnesses, because what other illness is there where you eat the wrong vegetable and you could turn into one?

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I came here to collect data exactly for not finding threads on the substances. As PFS heavily involves the androgen receptor, it was the logical step to do as people may have exacerbated on these and haven’t reported back. I also wanted to share my findings on AR with you in order to have a productive discussion for the sake of the community.

People are desperate for short-term relief and are going to self-experiment anyway. This often involves discussions that lack any sound back-and-forth scientific debates. If you have a scientific background, it’s your duty to at least try providing them an educated guess to minimize potential damage they can inflict on themselves.

It’s not in the least a valid assumption.

That’s hardly a counter-argument. I’ve hoped there could be a productive discussion.

We’re not in the bible business. Our focus is to promote research by institutions which have the capacity, credibility and capability to execute relevant studies, with a holistic view. At the end of the day, that’s what we need: True molecular level understanding of our problem and not more theories/beliefs/hypothesis.

Short-term relief is as important as long-term cure that could take a decade or two (or even more). Especially when people are going to self-experiment either way.

I rest my case. I will neither force my ideology on you nor practice it within your domain. Thus, I will take my leave to a place I’m appreciated.

Good luck with your endeavors!

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While I can’t speak on behalf of the community with complete confidence, I suspect most of us would have preferred this thread to involve discussion, even debate of the merits of what a clearly knowledgeable newcomer is saying. I didn’t interpret his style as particularly rude, but rather very direct.

I don’t see him violating any of the tenets of this forum - he is simply offering his well-reasoned opinion. Instead of patronising him, I and others would prefer the ideas themselves to be teased out and if possible refuted, rather than his manner condemned. It’s too simplistic a reaction and it shuts down meaningful discussion which may have the potential to benefit us.

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Very unprofessional to patronize a newcomer. Yes the likelyhood that anything works with PFS is extremely low and the risks involved with experimentation high, but that shouldnt be an excuse to patronize a newcomer with a snobby tone.

After all, axo and awor have zero clue what PFS is either or what can or can not help. Zero clue.

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keep it up @DeRa
you have proved your PSSD theories multiple times by yourself
a good pharmacist is God

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I believe that’s the exact reason why they refrain from suggesting treatments and discourage others from doing so.

We have learnt from numerous sources that he is the PSSD forum guru and is asking for / accepting money from PSSD members to find a cure. I personally find this suspect and highly unethical. For the past 12 years I have contributed to the PFS cause in numerous ways, including financially, and have never asked for any money in return from anyone.

Given his background, I am questioning the motives of his post. From a simple search it is obvious that we don’t have any experience with any of these substances. So what is the true point of this “data collecting”? If he is looking to establish his guru status here with the goal to further financially benefit, then I do not want that. However, if he is prepared to step down for a moment, start off fresh by simply asking some questions, having a dialog, instead of ramming this place top-down with his (incorrect) assumptions, then I am fine with that. Overall, I am very interested in PSSD-PFS (and other) collaboration. However, I am not interested in guruism.

Those were the motives for my post, though I do admit that I could have handled it better. Sorry for that.

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This is a weird argument. DeRa said he used the search bar and couldn´t find people posting about it. So he wanted to check if maybe other users, used it, who didn´t make a post about it. (many don’t post about their experience)

Here you have it. A guy commenting about his experience. So this alone already proves why this post was usefull, and why the argument you bring up here doesn’t make sense. Because unlike you claim, people here DO have experience with this substance.

Wow, PSSD-PFS wars. Ambitious crossover!

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If we knew what it was we were doing, it would not be called research, would it?

-Albert Einstein