Some Evidence For A Positive Feedback Loop Between Pgd2 And Ptgds Gene Expression

[cocona]

If you are unfamiliar with PGD2 start here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982925/

I'm a somewhat technical person so this will be somewhat technical:

Nrf2 is a transcription factor that protects against inflammatory diseases, but the underlying mechanism of this effect remains unclear. Here, we report that Nrf2 uses lipocalin–prostaglandin D synthase (L-PGDS) as a mechanism for suppressing inflammation.

Exogenously added prostaglandin D2 (PGD2) induced L-PGDS expression in bone-marrow-derived macrophages (BMDMs), suggesting a positive feedback loop between L-PGDS expression and PGD2. Unlike lipopolysaccharide (LPS)-induced L-PGDS expression, PGD2-mediated expression was independent of MAPK, PU.1, or TLR4. Sequence analysis located a putative Nrf2 binding site in the murine L-PGDS promoter, to which Nrf2 bound when treated with PGD2. Chemical activation, or overexpression, of Nrf2 was sufficient to induce L-PGDS expression in macrophages, BMDMs, or lungs of Nrf2-knockout (KO) mice, but treatment with PGD2 failed to do so, suggesting a pivotal role for Nrf2 in the expression of L-PGDS. Consistent with this, expression of Nrf2 in the lungs of Nrf2-KO mice was sufficient to induce the expression of L-PGDS and to reduce neutrophilic lung inflammation elicited by LPS. Furthermore, expression of L-PGDS in mouse lungs decreased neutrophilic infiltration, ameliorating lung inflammation in mice. Together, our results show that Nrf2, activated by PGD2, induced L-PGDS expression, resulting in decreased inflammation. We suggest that the positive feedback induction of L-PGDS by PGD2 is part of the mechanism by which Nrf2 regulates inflammation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367156/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367156/

Some information that might help with understanding:

• 1. Basically you have 2 versions of PTGDS(The enzyme that is used to create PGD2 when this gene expression is increased it results in an increase of the enzyme that results in an increase in PGD2 via the Archiadonic Acid chain.)
  
  
• 2. Lipocalin-prostaglandin D synthase = L-PGDS = Lipocalin PTGDS
  
  
• 3. The is also Hematopoietic PTGDS.
  
  
• 4. Lipocalin PTGDS is the type of PTGDS that was observed to have elevated levels in cases of Androgenetic Alopecia back in 2012 by cots.
  
  
• 5. PGD2 serves differrent immune regulating functions in the body depending where it is. In the scalp it likely is what induces inflammation via activation of GPR-44.

The point of this post:

Basically this is evidence for this happening:

Increase in pgd2 -> Increase in L-PGDS expression(This is assuming that macrophages in the scalp behave similiarly) -> increase in PGD2

Assuming this positive feedback loop exists then inhibiting PGD2 results in a decrease of L-PGDS which results in decreased production of PGD2. And by inhibiting PGD2, I mean actually lowering the levels of PGD2 in the scalp not necessarily GPR-44 like seti inhibits. Basically you need to drop the PGD2 levels in the scalp. Either with something that binds to PGD2 or a gene transcription blocker for PTGDS. Legit PTGDS inhibs are too expensive so we need to attack the problem upstream.

But there's more to it you still have production of PGD2 in Mast cells and you also still have the question of H-PGDS as well.

Basically the big open question would be "Is the overexpression of PGD2 in the scalp reversible?"

This also suggest that an alternate way of preventing the transcription of PTGDS using a molecule that binds to Nrf2 would be a therapy approach.

 

[signal]

Interesting. Are you a biologist?

 

[jnestor481]

There was a study done that computer simulated different compounds to determine PGDS blocking ability. I believe our old friend castor oil came out to be one of the best compounds according to their simulations. On my phone now but I'll try to dig up the study later on my pc.

 

[cocona]

Interesting. Are you a biologist?

Software Engineer.

I would like to move into the bioinformatics sector eventually however. I read a lot of biology papers in my free time.

 

[cocona]

You're a real believer in the PGD2 angle right?

Official results of seti will be published this summer if all goes well.

There is a lot of evidence for it. From many different sources. Exogenous application of PGD2 triggers early catagen in explanted hair follicles. Application of PGJ2(A downstream product of PGD2) triggers premature apoptosis of keratinocytes in hair follicles. There is a lot more evidence as well.

Cots paper from 2012
PGJ2 kills Keratinocytes
PGD2 inhibits hair follicle neogenesis via GPR44


Aside that it makes sense from a reasoning standpoint.

• Prostaglandins are poorly understood so this would easily be missed as related to Androgenetic Alopecia until recently.
  
  
• Prostaglandins behave differently based on which part of the body they are in.
  
  
• Other common angles are really likely just bullshit from hucksters. It if was wnt or shh or thyroid or zinc deficiency the phenotype of Androgenetic Alopecia would likely be much broader because these are all systems which have strong influence all over the body.
  
  
• This is why samumeds up-regulating wnt gets such poor results. Sure you can increase the metabolism of hair growth and get some results but that doesn't attack the issue.
  
  
• Prostaglandins are hormonally responsive in other systems so it would be no suprise if Kythera's hypothesis that DHT has a downstream effect of increasing PGD2 in people with Androgenetic Alopecia

So yes I guess you could say that. I wouldn't say that reducing PGD2 levels to normal in the scalp is going to just straight up cure Androgenetic Alopecia however but I do believe is holds just as much promise therapeutically as Dutasteride.

 

[mooreu]

Thanks for the info cocona.

In lieu of applying castor oil with dmso, I dermastamp (0.5mm) my scalp and then apply castor oil. I leave it in for 30 mins and wash it out. I've also begun taking 1 tsp internally every morning.

What do you think about using a topical bimatoprost solution together with the castor oil protocol described above?

 

[cocona]

Thanks for the info cocona.

In lieu of applying castor oil with dmso, I dermastamp (0.5mm) my scalp and then apply castor oil. I leave it in for 30 mins and wash it out. I've also begun taking 1 tsp internally every morning.

What do you think about using a topical bimatoprost solution together with the castor oil protocol described above?

Wouldn't know. Haven't tried it. Not willing to go oral castor since I don't want hypertrichosis.

 

[Ziggyz123]

Wouldn't know. Haven't tried it. Not willing to go oral castor since I don't want hypertrichosis.

You won’t get hypertrichosis to the extent you think, or are worried about. You’d have bowel issues that would make you quit before that anyway lol. I used it orally for 6 months.. had no effect for me and I was on setipiprant at 1000mg a day from the private forum.. seti does seem to help at HIGH doses. My hair loss is odd and doesn’t respond to anything really. Not even 10mg of dutasteride.

But non the less, I am with you on prostaglandins playing a bigger role than previously thought. Good post.