Sertaconazole Nitrate Increases Pge2

[HairCook]

"sertaconazole treatment resulted in the activation of p38 MAP kinase and its downstream substrate, the small heat-shock protein 27 (Hsp27), in a dose- and time-dependent manner. "

I made thread about heatshockproteins potentially helping hair growth here, if someone has a bit more data on it...!

Next, we evaluated the effect of different concentrations of sertaconazole on PGE2 production from HaCaT keratinocytes. Figure 2b shows that sertaconazole treatment results in a twofold increase in PGE2 release. To assess the involvement of COX-2 in sertaconazole-mediated PGE2 release, cells were preincubated with NS398, a specific inhibitor of COX-2 (Gierse et al., 1995) before sertaconazole treatment. Sertaconazole-mediated PGE2 production was inhibited in the presence of the COX-2 inhibitor (Figure 2b), suggesting the involvement of COX-2 in PGE2 production. Next, we evaluated whether sertaconazole regulated the TNF-α-dependent PGE2 production in these cells and interestingly it was observed that in a similar manner sertaconazole upregulated TNF-α-induced PGE2 release (Figure 2c)."

www.sciencedirect.com/science/article/pii/S0022202X15337428

It has been shown in multple studies that tnf-a is actually important in the early phase of the wounding process for hair follicle neogenesis. Maybe this is directliy connected to pge2? Last wounding session I used 4.5 hours before diclofenac as NSAIDs did show to increase TNF-A. If so, this might be even better with wounding than that. (you find everything regarding tnf-a wounding by search function or also linked in my fractional laser wounding thread )

Now, I found setaconazole also mentions in swisstemples ask.fm, he answered that he answered the question already, I cannot find it though... So, I am not sure what is the issue with it as pge2 agonist could be, considering has not been listed as pge2 agonist.

Edit: Seems to increase pgd2 also. I thought about that before, anyways, it is similiar to minoxidil then. Can be tried but should be used at least with an antiandrogen or even better: a pgd2 inhibitor.

The p38 MAP kinase is activated in response to various extracellular stimuli such as UV light, heat, osmotic shock, inflammatory cytokines, and growth factors (Zarubin and Han, 2005).

Thus, from these results, we believe that sertaconazole stimulates superoxide radical formation to induce p38 MAP kinase

Sertaconazole did not increase H2O2 formation in human keratinocytes (data not shown) and treatment with catalase was ineffective in reducing the phosphorylation of p38 by sertaconazole, suggesting that the peroxide formation was not a factor in p38 activation. In contrast to sertaconazole, another antifungal agent, miconazole nitrate, was shown to induce H2O2 formation (Kobayashi et al., 2002); however, miconazole does not inhibit cytokine release or elicit anti-inflammatory activity comparable with sertaconazole (Agut et al., 1996; Liebel et al., 2006) and therefore does not probably activate the same signal transduction cascade. Thus, from these results, we believe that sertaconazole stimulates superoxide radical formation to induce p38 MAP kinase

Miconazole was shown to be PGE1. Someone here actually had some success with it (inspired by Brotzu), and swiss was/is also using it.

PGE1 and PGE2 are both known to be positively for our hair, nonetheless they have an antagonistic character to each other. For minoxidil it is for example argued that it increases pge1 and pge2 (if you are responder), however because of this effect you apparently end up with more pge1. Im not part of that private forum, so I am not 100% yet what makes them believe that pge1 wins the battle here.
Anyways, you see here two exact oppositve mechanisms, pge2 is considered to be stronger as it turns into pgf2a and its four recepter seem to have different kind of benefits. Ep3 for example turns into fgf9 for example, which was shown to be missing on the wounding process of humans, multiple productlines seem to be incoming in future based on this finding. ( 1 , 2 ) It makes perfectly sense, one being PGE1 and PGE2 or at least it would not be surprising at all...

I wrote already more than I wanted. I think it is worth trying, especially with wounding due to increased tnf-a-pge2 induction. If someone tries it, pls do a picture protocoll (you dont need to show your face ofc! No need to feel unconfortable).

Thanks for the read. I hope this gets some attention.

 

[HairCook]

Now another thing about the nitrate part. It seems that wounding keeps hair anagen of existing hair for 5-7 days. This wounding state also suppresses CD200 activaton by Lgr5. Lgr5 can be activated also by ROS. ROS are generally bad for hair, however in small dosis they can be beneficial for our hair as they stimutlate Lgr5. Means 5-7 days in our wounding cycle, playing around with nitrates (which are not supposed to be taken lightly by any means) might help leading us to terminals. (again thanks to Ante on hlh, his thread which died out within 2 pages for no reason, made me learn and re-realize the importancy of certain research finding a lot)

 

[HairCook]

In hindsight I was just remembered my VDR (vitamin D receptor) readings. VIT D Analogue stimulates CD200. VDR was also shown to mediate other hair growth related factors such as PGE2 and wnt in other tissues like lungs. CD200 regulates TNF-A. Stimulating CD200 unnecessarily, right on the wounding process seems not to do too well, because it will most likely adress TNF-A and downregulate the following chain of growth factors and prostaglandins. In other words, I guess it might even be smart to wait a bit with CD200 stimulation after the complete wounding process ticked in. Then cd200 tickling might lead to stronger positive effects. In fact, before wounding, is where we could exploit Selenium Disulphide. It has been shown to increase PGE2, decrease PDG2 and sadly lower Cd200 by 15d-PGJ2 agonism.

So to summarize my theory based on this:

1) On Wounding: we want a TNF-A spike (nsaids, sunburns, uv-b ... whatever), Cd200 expression lowered (selenium sulfide)
2) Wounding process is induced: Exact opposite of 1), TNF-A can probably be ignored, focus lays on Cd200 stimulation which should take care of TNF-A by itself then. (Tickling Lgr5 with Ros = nitrate = Sertaconazole should be preferred as pge2 leads through ep3 to the needed FGF9 + other direct cd200 stimulants like the vit D analogue; licl,...)

This is just to add to current theory behind stem cell reactivation. There is ofc more (licl fixes also gsk-b and wnt stimulation, tretinoin ptgds/tcf3) more importantly , and in this case I added a lot based on my reading (my first thread was about the vdr youll find most sources there, I did ofc some other reading since then, my vdr model is here). I might be wrong, but thats also the reason I post here. There is also still the timing to figure out (when is the tnf-a woundhealing process completely induced?), if I am correcty.

 

[InBeforeTheCure]

Edit: Seems to increase pgd2 also. I thought about that before, anyways, it is similiar to minoxidil then. Can be tried but should be used at least with an antiandrogen or even better: a pgd2 inhibitor.

There's still a problem: Highly overexpressed PTGDS in keratinocytes of balding hair follicls will outcompete PTGES for PGH2 and probably make much more PGD2 than PGE2. Even if you block the PGD2 receptor, cells will still make much less PGE2 because of this. Here's a drawing:

(Additional reference for CREB/ATF1 activation by p38)

Ep3 for example turns into fgf9 for example, which was shown to be missing on the wounding process of humans, multiple productlines seem to be incoming in future based on this finding. ( 1 , 2 )

That's in gamma-delta T cells, and this is the pathway (source):

But tough luck for us - Humans have very few gamma-delta T cells in our skin, so we don't get that same benefit. (source)

Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding.

And one other thing: Lgr5 is a target gene of Lhx2 in hair follicle stem cells and outer root sheath cells (source - see Fig. 4 and Supplementary Material - mmc2)

 

[HairCook]

Wow, that's some great insight.Thanks man, helps having people like you around

There's still a problem: Highly overexpressed PTGDS in keratinocytes of balding hair follicls will outcompete PTGES for PGH2 and probably make much more PGD2 than PGE2. Even if you block the PGD2 receptor, cells will still make much less PGE2 because of this. Here's a drawing:

Damn that sucks. I wonder how much we can control PTGDS right now in combination with retinoids, castor and selenium sulfide (guess not even remotely enough) :/
I guess this also explains why a lot of people did not have any results with seti alone (low dose topically in german forums), you need actually exogenous PGE or a PTGDS Inhibitor to restore PGE-Levels.

But tough luck for us - Humans have very few gamma-delta T cells in our skin, so we don't get that same benefit. (source)

Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding.

Wow, that's seriously taking some wind out of castor oil then for me. Heck, we probably need even some exogenous FGF-9 if there no other way of building it. At least there seem to be a few things in the pipeline that consider these findings.


What is your opinion about HSP27? I am still doing readings on it, but there seems to be something about them:

https://www.ncbi.nlm.nih.gov/pubmed/16635662 (hsp27 strongest expression in anagen.)

That it's also being found in the sebaceous glands makes me worry a bit though, as I am under the impression that it is what we dont want in Androgenetic Alopecia.

https://www.researchgate.net/profil...y_Stimulus/links/551009ae0cf2ac2905afaeca.pdf
(HSP27 anti-inflammatory)

Guess its part of the TNF-A response during wounding.

https://www.ncbi.nlm.nih.gov/pubmed/9066782
Seems like it correlates with prostaglandins all over. As it goes with pgd2 as well as pge2, I guess it might be indifferent either way? :/


https://www.sciencedirect.com/science/article/pii/S0022202X15338458

Downregulation of Hsp27 using Hsp27-specific small interfering RNA increased prostaglandin E2 (PGE2) production in both unstimulated and tumor necrosis factor-α (TNF-α)-stimulated keratinocytes. Moreover, downregulation of Hsp27 increased the release of the pro-inflammatory cytokine IL-8 from TNF-α-stimulated and UV-irradiated keratinocytes, and this increase was inhibited by pretreatment with the NF-κB inhibitor BAY11-7082.

Wow, I found papers that showed pge2 and pgd2 increasing stress-induced hsp27. That inhibiting hsp27 can lead to increased pge2 is interesting.

https://www.ncbi.nlm.nih.gov/pubmed/28902366
https://www.nature.com/articles/s41536-017-0013-4

Seems like HSP27 also suppresses PDGF-BB which apparently is needed for stem cell proliferation...

This gives me somewhat the impression that HSP27 works like the wounding process, keeping stem cells low and existing terminals in anagen...

 

[InBeforeTheCure]

Well, all kinds of stressors can activate Hsp27 through p38. For example, TGF-beta can activate p38 through generation of reactive oxygen species in keratinocytes (source), and p38 induces both transcription of Hsp27 in keratinocytes (source) and activates it by phosphorylation. I would expect the p38 pathway to be more active in balding HFs than non-balding due to oxidative stress (induced by TGF-beta, perhaps? - known to be highly produced in M.P.B).

Anyway, here's some random stuff I have on Hsp27 (aka Hspb1):

- According to Michael Rendl's Hair-GEL site, Hsp27 mRNA is highest in hair follicle stem cells and the outer root sheath, which is consistent with the study you posted where Hsp27 protein was highest in the outer root sheath.

The other p38 target gene we discussed, Cox2 (Ptgs2), is also highest in HFSCs/ORSCs.

- When beta-catenin is knocked out in the bulge, Hsp27 mRNA rises slightly (microarray data from Lien et al.). So beta-catenin might slightly repress Hsp27 transcription.
Ensembl_ID gene_symbol coordinates Bcat_cKO_FPKM Bcat_Het_FPKM Log2 fold change(cKO/Het)
ENSMUSG00000004951 Hspb1 chr5:136363788-136365433 472.438 323.546 0.546153
- I also discovered that there's such a thing as "Longdong cashmere goats" LOL.

Not sure if any of that helps you. I don't know of any studies on Hsp27's role in hair biology. Its downstream enhancement of NF-kB activity would have its effects, but I'm more familiar with NF-kB's role in early hair follicle development and in the hair matrix, and not so much on its role in the outer root sheath.

 

[bridgeburn]

so basically,
androgens-->tgfb-->p38-->hsp27--> reduced pge2 and PDGF-BB?


so maybe this is one of the ways minoxidil works?

we know minoxidil affects tgfb:
inhibits of TGF beta induced apoptosis of hair matrix cells by opening the Kir 6.0 channel pore coupled with SUR on the mitochondrial inner membrane,

and pge2 too:

Minoxidil stimulated the activity of purified ovine PGHS-1 in vitro and increased production of PGE2 in cultured human dermal papilla cells and mouse fibroblasts"

so maybe minoxidil inhibits tgfb affect and increases pge2 some by activating b catenin which may slightly inhibit hsp27?

 

[HairCook]

Well, all kinds of stressors can activate Hsp27 through p38. For example, TGF-beta can activate p38 through generation of reactive oxygen species in keratinocytes (source), and p38 induces both transcription of Hsp27 in keratinocytes (source) and activates it by phosphorylation. I would expect the p38 pathway to be more active in balding HFs than non-balding due to oxidative stress (induced by TGF-beta, perhaps? - known to be highly produced in M.P.B).

Anyway, here's some random stuff I have on Hsp27 (aka Hspb1):

- According to Michael Rendl's Hair-GEL site, Hsp27 mRNA is highest in hair follicle stem cells and the outer root sheath, which is consistent with the study you posted where Hsp27 protein was highest in the outer root sheath.
View attachment 73851
The other p38 target gene we discussed, Cox2 (Ptgs2), is also highest in HFSCs/ORSCs.
View attachment 73852

- When beta-catenin is knocked out in the bulge, Hsp27 mRNA rises slightly (microarray data from Lien et al.). So beta-catenin might slightly repress Hsp27 transcription.
Ensembl_ID gene_symbol coordinates Bcat_cKO_FPKM Bcat_Het_FPKM Log2 fold change(cKO/Het)
ENSMUSG00000004951 Hspb1 chr5:136363788-136365433 472.438 323.546 0.546153
- I also discovered that there's such a thing as "Longdong cashmere goats" LOL.

Not sure if any of that helps you. I don't know of any studies on Hsp27's role in hair biology. Its downstream enhancement of NF-kB activity would have its effects, but I'm more familiar with NF-kB's role in early hair follicle development and in the hair matrix, and not so much on its role in the outer root sheath.

Thanks man, guess gonna do some more readings on that, though it seems I might be too focused on something small here considering it is connected to nf-kb in the end. The ß-catenin relation is for sure interesting though.

Also, dem longdong cashmere goats xD
Reading that in the morning made my day

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so basically,
androgens-->tgfb-->p38-->hsp27--> reduced pge2 and PDGF-BB?


so maybe this is one of the ways minoxidil works?

we know minoxidil affects tgfb:
inhibits of TGF beta induced apoptosis of hair matrix cells by opening the Kir 6.0 channel pore coupled with SUR on the mitochondrial inner membrane,

and pge2 too:

Minoxidil stimulated the activity of purified ovine PGHS-1 in vitro and increased production of PGE2 in cultured human dermal papilla cells and mouse fibroblasts"

so maybe minoxidil inhibits tgfb affect and increases pge2 some by activating b catenin which may slightly inhibit hsp27?

Yeah, got the same understanding. Minoxidil seems to be a PGH1 agonist giving us more Prostaglandins including PGD2. With minoxidil we enhance Androgenetic Alopecia a bit, but thanks to the postive effects overweigthing we usually win more land than we lose. Also used with finasteride and crth2 inhibitor might be still the best. Though ptgds might be still a worry. I still wonder if serta would not do actually the same considering the success of miconazole and minoxidil. Guess I will put on my list on somewhat worth to be tested. If the old Ante theory regarding Lgr5 stimulation by ROS is worth it, it might still be something worth to consider post-wounding, as we still probably wanna focus more on PGE2 post-wounding rather than inducing PGE1 with miconazol.

 

[bridgeburn]

Minoxidil seems to be a PGH1 agonist giving us more Prostaglandins including PGD2

oh sh*t, was not aware of this.

but thanks to the postive effects overweigthing we usually win more land than we lose.

It has a few other mechanisms of action affecting hair like allowing andenosine into cells which stimulates Fgf-7. I think minoxidil is great in combinations but not when used alone.

Also used with finasteride and crth2 inhibitor might be still the best.

before I have tried castor oil with dmso, dermarolling, lithium chloride, stemoxydine, sulfasalizine, sunlight exposure, miconazle.

Im not sure if it really did anything.
Swiss was using dutasteride as well, but i believe he probably lost ground again since he dissapeared and never showed his regrowth from a distance. Westonli at least got maintenance with seti.. But what I've never seen anybody try yet is the prostaglandin protocol combined with dutasteride and minoxidil.
of course the ghetto version isn't ideal long term because of the Uv burns and that sulfasalizine is an immunosuppressant.

 

[HairCook]

Regarding microneedling (lets get rid of dermaroller as term, a pen/stamp does way more clean wounds and we dont want unnecessary collagen to clump up) I put up some ideas here: https://imgur.com/a/ATqS6 .

It is basically a just thought of mine, why swiss had success and many others not. I read some stuff on forums from an ex-mod on the private forum, seems like it was not the cure for anyone really. However I still believe that there is something in Swiss his history thats being the key. Maybe it is just our poor luck, but throwing him away as scam or being wrong is just not right. He is probably the closest we got since the campfire man as anecdotal evidence for hf neogenesis in humans.

 

[bridgeburn]

Regarding microneedling (lets get rid of dermaroller as term, a pen/stamp does way more clean wounds and we dont want unnecessary collagen to clump up) I put up some ideas here: https://imgur.com/a/ATqS6 .

wait, so youre thinking about trying a 3mm needle??

 

[HairCook]

Yup. Just on a small spot. I guess this time I gotta get a local pain killer for that.

I am kinda short on cash right now, so pumping another 30bucks into something experimental is kinda meh.
However I want to see the potential, if it fails I know at least the whole fibrosis thing is humbug.

 

[bridgeburn]

I am kinda short on cash right now, so pumping another 30bucks into something experimental is kinda meh.

I wanted to get the Derminator but I was short on cash when I was experimenting with that stuff. I didnt actually roll with a dermaroller though, I tried to push it in the skin straight down and then straight out.

 

[bridgeburn]

It is basically a just thought of mine, why swiss had success and many others not. I read some stuff on forums from an ex-mod on the private forum, seems like it was not the cure for anyone really. However I still believe that there is something in Swiss his history thats being the key. Maybe it is just our poor luck, but throwing him away as scam or being wrong is just not right. He is probably the closest we got since the campfire man as anecdotal evidence for hf neogenesis in humans.

so youre saying that he had success because he used a dermapen over a demaroller and cause he used skin eating chemicals before he switched to the PG protocol.

 

[HairCook]

I wanted to get the Derminator but I was short on cash when I was experimenting with that stuff. I didnt actually roll with a dermaroller though, I tried to push it in the skin straight down and then straight out.

Well, I 1.5mm a mechanical stamp version as well. The derminators are expensive and they seem to have differering qualites. Most of them offer only limited length. On amazon the max I can find is a 3mm as mechanical pen. Surely nothing for a Norwood 4+, the torture would be real. Hell, even some professional studios I found seem to offer nothing beyond 3mm xD

 

[HairCook]

so youre saying that he had success because he used a dermapen over a demaroller and cause he used skin eating chemicals before he switched to the PG protocol.

It is just an idea. The fibrosis theory is around for ages. However many, including me, never took it really serious as it is very incomplete. Nonetheless there should be a reason why this guy had real temple regrowth after years.

I am also going to do some more reading. I need also to look into safety measurements on this depth for me and potentially needed post-treatments. Also, some sweet feedback from the smart people would be great.

 

[bridgeburn]

It is just an idea. The fibrosis theory is around for ages. However many, including me, never took it really serious as it is very incomplete. Nonetheless there should be a reason why this guy had real temple regrowth after years.

but there is fibrosis in bald scalp. 4x as much as non balding scalp. some also get success in using skin thinning agents like corticosteriods.

 

[HairCook]

but there is fibrosis in bald scalp. 4x as much as non balding scalp. some also get success in using skin thinning agents like corticosteriods.

Yes, I am also using DMSO at 33%. I saw some people using pure DMSO on their scalps. Pretty ridiculous if you ask me. But I also applied last time two hours after wounding session my castor dmso+ mix; and yes, I felt it

It is more a question of how relevant the fibrosis is.

 

[bridgeburn]

Yes, I am also using DMSO at 33%. I saw some people using pure DMSO on their scalps. Pretty ridiculous if you ask me. But I also applied last time two hours after wounding session my castor dmso+ mix; and yes, I felt it

It is more a question of how relevant the fibrosis is.

Dmso stings like a b**ch

 

[HairCook]

Dmso stings like a b**ch

And nothing to handle carelessly for sure. I did my readings, but am still afraid that I mess up at some point, get it on my fingers and rub my eyes, or something along the lines...