ADORA2B agonist BAY 60-6583

[pey ron]

ADORA2B agonist BAY 60-6583 significantly inhibited myofibroblast transformation:

10.1016@j.jsxm.2018.05.003.pdf - DocDroid

[hope794]

Good find, pey ron. I think that some existing treatments, like Navitoclax, could help to stop myofibroblast proliferation. The aim of the researchers is to find something that REVERSES existing fibrosis. But the encouraging fact is that they are understanding more and more about the mechanisms of fibrosis disorders, and that's great.

[hope794]

This is interesting too:
(Losartan by TEVA)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876242/

[pey ron]

i had got losartan from Mexico. You have to stay out of the sun while taking it, exactly like pirfenidone, since just as pirfenidone does, it lowers TGF-beta1

[Hontas]

Ok one question, is growth using TGF B1 a natural process in our body? If that is the case i actually see no value in lowering TGF B1 since healthy cells get affected from it much more than Peyronies Disease cells while producing myofibroblasts, my intuition tells me that if healthy cells react more to a growth factor this shows that growth factor is not the bad guy causing plaques here is it? I am just brainstorming because i have no information about TGF B1 though. If there is any molecular genetics expert, i would love the input on this.

[Cacogen]

@Hontas

TGF-β1 is involved in multiple processes in the body, so yeah, if it were powerfully inhibited systemically, that could have undesirable side effects. But some compounds can specifically target TGF-β1 at cells responsible for pathological collagen deposition, and not inhibit TGF-β1 signalling everywhere. Here is one such pathway:

2017 - Trihydroxyphenolic compounds target fibroblastic TGF-β1 signaling - Peyronies Society Forums

So one might inhibit TGF-β1-driven fibroblast-to-myofibroblast transition, targeting (hyper)active fibroblasts.

But another approach would be to selectively ablate the myofibroblasts responsible for remodeling the extra-cellular matrix. That is, inhibit anti-apoptotic factors in the myofibroblasts that are preventing them from undergoing apoptosis -- destroy the apopotosis-resistant myofibroblasts and restore local homeostasis. This is what Navitoclax appears to do in a mouse model of scleroderma (which is a fibrosing pathology). As I understand it, (myo)fibroblasts from different parts of the body (and in different mammals, I would think) have different patterns of genetic expression, so possibly Peyronie's myofibroblasts might be avoiding apoptosis in a different way -- someone needs to do this darn research. Even if it's not the exact right drug, Navitoclax could be the right approach; it's particularly exciting that ablating myofibroblasts actually caused some reversal of fibrosis, through some mechanism that's not quite understood (as far as I can tell). I would guess it has something to do with a feedback -- killing the offending cells changes the local ECM environment, which in turn instructs cells to somehow repair the area. There's not-entirely understood communication between ECM and cells -- it's all quite complicated.

Disclaimer: I'm no molecular biologist, not by a long shot -- just a highly motivated reader of relevant journal articles. :-) I'm sure I've misunderstood some things.

[Hontas]

nice finds

[diehardpatriot]

This sus good Dino thank you