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.
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):
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.