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ledhead
01-23-2016, 09:30 AM
Is there a certain egcg I should look for on Amazon or will any do?

Thanks

Sogeking
01-23-2016, 09:43 AM
I've stupidly mixed some evening Primrose oil with the remainder of my minox and then found out GLA enhances the skins barrier function. So I might not see any more regrowth for the next two weeks. My mid scalp is shedding and I've been skipping applications the last few days. Luckily the hairs that I regrew arent thinning and are getting longer so its not too bad. Ultimately I want to find a set of treatments that I can put in a cream and just use that for the rest of my life. This liquid vehicle formulation is very difficult to be consistent with and I have to keep my head tilted back until it dries, which sucks because I dont always have time/feel bothered to do.
I know about polysorbate 80 and DMI that can be used to create creams (courtesy of Seuxin), but I wonder if gels might be better suited for drugs that dissolve better in ethanol vehicles.
Chemical what Evening primrose oil? I finally got all the components and am also trying to add rosemary and apple polyphenols from the start. I also intended to add Evening primrose oil, should I add it independently from the ECGC/OL solution? Or do you think its not worth using it at all?

BRIANBOY
01-23-2016, 02:34 PM
Chemical - I am using about 4-6 ml EtOH 70% in the distilled water solution of 74ml. Also, I am using the Green Tea / EGCG 40% blend, which I find better than just pure EGCG. I feel the compliment of green tea polyphenols as well as EGCG have a positive effect.

Seuxin
01-23-2016, 02:57 PM
* Procyanidin B-2, extracted from apples, promotes hair growth: a laboratory study :
http://www.ncbi.nlm.nih.gov/pubmed/11841365


* Procyanidin B-3, isolated from barley and identified as a hair-growth stimulant, has the potential to counteract inhibitory regulation by TGF-beta1 :
http://www.ncbi.nlm.nih.gov/pubmed/12473061



* Procyanidin oligomers counteract TGF-beta1- and TGF-beta2-induced apoptosis in hair epithelial cells: an insight into their mechanisms :
http://www.ncbi.nlm.nih.gov/pubmed/16778458


* Investigation of the topical application of procyanidin oligomers from apples to identify their potential use as ahair-growing agent :
http://www.ncbi.nlm.nih.gov/pubmed/17168871

Chemical
01-24-2016, 05:01 AM
seriously need the article with all info contained in a single post :-)

For EU residents, which products do you recommend we buy? It'd be nice to have an easy table from which US/EU residents can easily buy the ingredients. Same for the new ones you seem to have added (apple polyphenols, rosemary extract, etc) - dosage, etc..

I'm writing everything up as we speak. I'll put it all in a separate thread so its easier to find. I think we should have this thread for disussion and progress logs and the new thread just for research and treatment info.


Is there a certain egcg I should look for on Amazon or will any do?

I'm using swansons Teavigo which has EGCG standardized to 90% (150mg actual per capsule). You can use a different brand but if the EGCG is low you might end up saturating the solution with other ingredients reducing the amount of EGCG penetrating the skin.


Chemical what Evening primrose oil? I finally got all the components and am also trying to add rosemary and apple polyphenols from the start. I also intended to add Evening primrose oil, should I add it independently from the ECGC/OL solution? Or do you think its not worth using it at all?

I would recommend not mixing any oils with minox, I've learnt my lesson now. The EPO might absorb better after using an ethanol solution which will weaken the stratum corneum's barrier function. I think using the EPO by itself or mixed with Emu Oil would be ideal. Any subsequent treatment after EPO may not absorb properly until its completely gone or cut down by ethanol again. The EPO may not be convenient but if you want to use it, then using it at night after everything else has absorbed should be fine. I'm still testing it but I'm not sure if it'll work as good as EGCG or rosemary (I dont know how well it absorbs). I bought the capsules and dumped the contents of one cap into my minox. I noticed it leaves my scalp very smooth and soft.


Chemical - I am using about 4-6 ml EtOH 70% in the distilled water solution of 74ml. Also, I am using the Green Tea / EGCG 40% blend, which I find better than just pure EGCG. I feel the compliment of green tea polyphenols as well as EGCG have a positive effect.

Yes I do remember you saying that but wouldnt a 70/30 Ethanol/water solution be more optimal? And I did read that the other catechins present in green tea possess 5ar suppressing effects - I'm looking for the study.



Procyanidin B-2, extracted from apples, promotes hair growth: a laboratory study (http://www.ncbi.nlm.nih.gov/pubmed/11841365)

Procyanidin B-3, isolated from barley and identified as a hair-growth stimulant, has the potential to counteract inhibitory regulation by TGF-beta1 (http://www.ncbi.nlm.nih.gov/pubmed/12473061)

Procyanidin oligomers counteract TGF-beta1- and TGF-beta2-induced apoptosis in hair epithelial cells: an insight into their mechanisms. (http://www.ncbi.nlm.nih.gov/pubmed/16778458)

Investigation of the topical application of procyanidin oligomers from apples to identify their potential use as ahair-growing agent. (http://www.ncbi.nlm.nih.gov/pubmed/17168871)

Excellent finds Seuxin! I will be adding these to the post on Apple polyphenols in the new thread (with credit to you).

Sogeking
01-24-2016, 05:19 AM
Hey Chemical thank you for the effort mate. This may or may not work for me but at least I am trying something instead of sitting on my ass and complaining.

bluesuedeshoes
01-24-2016, 11:55 AM
I followed BrianBoy's protocol, with slightly less EGCG. Around 700mg EGCG and 300mg OL in 60ml (40ml distilled water, 20ml Eth (95%)). With some drops of Jojoba, Rosemary extract, tea tree and bergamot oil.

Does not seem to fully dissolve though. Solution is cloudy and sediment is floating around. Guess at least a lot of it is dissolving and will still be effective?!

Maybe less water and more eth is needed? Think it's the OL that is tougher to dissolve.

potato1987
01-24-2016, 03:23 PM
Hi Chemical, Swiss seems to think that Oleuropein is Decreases PGD2 (COX ?) a WNT agonist, do you think we should limit its use on some days?

BRIANBOY
01-24-2016, 11:10 PM
I followed BrianBoy's protocol, with slightly less EGCG. Around 700mg EGCG and 300mg OL in 60ml (40ml distilled water, 20ml Eth (95%)). With some drops of Jojoba, Rosemary extract, tea tree and bergamot oil.

Does not seem to fully dissolve though. Solution is cloudy and sediment is floating around. Guess at least a lot of it is dissolving and will still be effective?!

Maybe less water and more eth is needed? Think it's the OL that is tougher to dissolve.

Yes, you will have some residual sediment which does not dissolve. Just shake it each time you are ready to apply. You are probably right about the OL. It is partially soluble only in fat / oil. Not to worry. The sebum in the skin will most likely break the residual down further. The more alcohol you use, the more possibility of irritation, but, you can alter the mixture as you go and respond.

bluesuedeshoes
01-25-2016, 09:52 AM
Yes, you will have some residual sediment which does not dissolve. Just shake it each time you are ready to apply. You are probably right about the OL. It is partially soluble only in fat / oil. Not to worry. The sebum in the skin will most likely break the residual down further. The more alcohol you use, the more possibility of irritation, but, you can alter the mixture as you go and respond.


Thanks. If I notice anything I'll report back. Your input has been greatly appreciated.

justbreezy
01-25-2016, 03:27 PM
Revita shampoo contains Procyanidin B-2 and Ketoconozale in it's ingredients. I was purely using that for a few months after my really bad shed in the summer. I think it helped decrease the shedding and added a touch of regrowth, but i was using it almost daily and after getting dermatitis you should regrow hair a little. I would say it helped, but without stopping the minituarization of the follicles its pointless.

My shedding started after a festival, seems i had developed a case of sebhorreic dermititis. I had been dandruff free since my teenage years, so to have an onset of dermatitis was even quite shocking. I feel like the severe shed was triggered from after a severe case of the flu, overly sweating too much at a festival and having to shower with water which was pumped and filtered from the sea. For the first month or two, i would get a really severe burning on the back left side of my scalp, then it shifted to the top then the sides and currently the front. My hair went from brown and thick to now black and thinning, my hair had always been receeding but slow enough for me not to notice, now it's receeding at the temples and pretty bad at the front where the hair used to be really strong and thick.

Post Dermititis: https://www.dropbox.com/sc/vbsrmuis7milqzk/AAB2pPNtNOitOVmG5AFY13jha
November: https://www.dropbox.com/sc/o9bgv54757o3r3p/AADZJhiqwbFk67KI_9sTtRE7a
Last week: https://www.dropbox.com/sc/mc7zqqt8n07fqi3/AACs2HHvyk2d727nCjgFsWN1a

Hadn't used fin, minoxidil.. just Revita and Stemyoxidine. Now, i'm using regenpure. I can see my hair is thinning out, compared to how it used to be. Having said that, up untill this month from August i had no waves in my hair which is exactly how it used to be before the shed. I have naturally curly hair when i was young, i have to say somewhat it's straighter and less thick, but as you can see it's not a terrible recovery. But the hair quality is pretty crappy, i can't use styling product and combing the hair upwards/tightness can feel a tight pulling at times. I'm 26 just for an age reference.

Anyway, i wish guys all the luck in your efforts but personally for me all this time and money invested just isn't worth it. Until something more permanent comes out CRISPR, Replicel or Histogen then i might just entertain shaving it.

Sogeking
01-25-2016, 04:25 PM
Revita shampoo contains Procyanidin B-2 and Ketoconozale in it's ingredients. I was purely using that for a few months after my really bad shed in the summer. I think it helped decrease the shedding and added a touch of regrowth, but i was using it almost daily and after getting dermatitis you should regrow hair a little. I would say it helped, but without stopping the minituarization of the follicles its pointless.

My shedding started after a festival, seems i had developed a case of sebhorreic dermititis. I had been dandruff free since my teenage years, so to have an onset of dermatitis was even quite shocking. I feel like the severe shed was triggered from after a severe case of the flu, overly sweating too much at a festival and having to shower with water which was pumped and filtered from the sea. For the first month or two, i would get a really severe burning on the back left side of my scalp, then it shifted to the top then the sides and currently the front. My hair went from brown and thick to now black and thinning, my hair had always been receeding but slow enough for me not to notice, now it's receeding at the temples and pretty bad at the front where the hair used to be really strong and thick.

Post Dermititis: https://www.dropbox.com/sc/vbsrmuis7milqzk/AAB2pPNtNOitOVmG5AFY13jha
November: https://www.dropbox.com/sc/o9bgv54757o3r3p/AADZJhiqwbFk67KI_9sTtRE7a
Last week: https://www.dropbox.com/sc/mc7zqqt8n07fqi3/AACs2HHvyk2d727nCjgFsWN1a

Hadn't used fin, minoxidil.. just Revita and Stemyoxidine. Now, i'm using regenpure. I can see my hair is thinning out, compared to how it used to be. Having said that, up untill this month from August i had no waves in my hair which is exactly how it used to be before the shed. I have naturally curly hair when i was young, i have to say somewhat it's straighter and less thick, but as you can see it's not a terrible recovery. But the hair quality is pretty crappy, i can't use styling product and combing the hair upwards/tightness can feel a tight pulling at times. I'm 26 just for an age reference.

Anyway, i wish guys all the luck in your efforts but personally for me all this time and money invested just isn't worth it. Until something more permanent comes out CRISPR, Replicel or Histogen then i might just entertain shaving it.
I too started losing hair slowly thinning and a few months after I got a fierce onset of sebhorreic dermititis. Sebhorreic dermititis might expedite the hair loss. The treatment for it is ketocotonazole(Nizoral).

Swooping
01-25-2016, 04:53 PM
Thank you for your extensive response Chemical.

potato1987
01-25-2016, 04:55 PM
Any help ?

http://www.ncbi.nlm.nih.gov/pubmed/18283040
and
https://www.baldtruthtalk.com/threads/22104-Updated-Research-and-Knowledge-Cutting-Edge?p=229032#post229032

justbreezy
01-25-2016, 05:49 PM
I too started losing hair slowly thinning and a few months after I got a fierce onset of sebhorreic dermititis. Sebhorreic dermititis might expedite the hair loss. The treatment for it is ketocotonazole(Nizoral).

Totally, definitely can see it speeding up the process. I felt my hair was itchy, but never thought much about it. I went to the barbers for a haircut, he started brushing my hair and there was chunks of hair coming out attached to yellow-ish flakes. Not only embarassing but quite shocking, initially i did a search and thought maybe i have TE, but it didn't take me long to work out it was my families history of AGA.

Bobbylobbyhobbythrobby
01-26-2016, 10:57 PM
I'm very new here, but find this all extremely fascinating. I had no former signs of balding until roughly 2.5 months ago. For the last 8 months I have been trying to tackle a Giardia infection, I believe I may have gotten rid of it (although I am still having problems digesting fat and particularly lactose.) But what I found most strange is that 3.5 months ago I started taking this (http://www.amazon.co.uk/dp/B002ZS6E8C/ref=pd_lpo_sbs_dp_ss_1?pf_rd_p=569136327&pf_rd_s=lpo-top-stripe&pf_rd_t=201&pf_rd_i=B006YR9T7I&pf_rd_m=A3P5ROKL5A1OLE&pf_rd_r=15N3VPHR6BHBZD4JB9QY) orally to rid myself of the Giardia bug. I took it for about a month, having a teaspoon with each meal 3 times a day.

After a month of stopping this supplement, I started heavily shedding and have not stopped since. I now wonder after reading your in depth knowledge Chemical, specifically about olive leaf extract whether this would have been a major contributor to my rapid balding?

UNBEAT
01-27-2016, 06:26 AM
CHemical
what do you think about fgf11 approach with AR receptors? might he has found out something interesting??

UNBEAT
01-27-2016, 06:39 AM
JUSTBREEZY
Hey man some thing happen to me with seborreah(severe dundruff with patches) and not only terrible thinning but also very poor quality of hair.
Seems like a mouse hair. I have been 2 years with this and i havent find out something that work.
My doctors said that you can not cure this.

BigSean
01-27-2016, 11:24 PM
Chemical,

Do you think human growth horomone (hgh) can inhibit the production DHT? I read about studies which shows intermittent fasting to increase hgh levels by up to 2000%.

BigSean
01-27-2016, 11:28 PM
UNBEAT, have you tried apple cider vinegar as a treatment?

UNBEAT
01-28-2016, 06:02 AM
BIGSEAN
NO i havent tried. Do you think it can work?

Chemical
01-28-2016, 01:18 PM
Hi Chemical, Swiss seems to think that Oleuropein is Decreases PGD2 (COX ?) a WNT agonist, do you think we should limit its use on some days?

A reduction in PGD2 is what we want so if OL does decrease it - even better!

On the topic of Swiss, I think his methodology is off. His belief that DHT/AR is irrelevent and PGD2 is the only factor we need to address is inaccurate. Theres insurmountable evidence that Androgens significantly blunt hair growth by inhibiting β-Catenin accumulation. Sure he's seen some progress, but with the amount of β-Catenin he's increasing by inhibiting GSK3β (with VA + LiCl) and wounding (PGE2) I'm not surprised he believes he's on the right track. Alot of people can achieve regrowth with aggressive growth agonists. If he incorporates some form of AR/5ar suppressor then he'd be nw0 already. Hes trying to make his car go faster while having his foot still on the brakes (logic?).

You can get away with not targeting PGD2 itself by attacking its downstream cascades: GSK3β and PKC (references in new thread soon) with EGCG, Valproic Acid, OL, Anything that activates PKA (GSK3β inhibitors) + Apple polyphenols (procyanidin mediated PKC inhibition). Or if you suppress 5ar/AR you can prevent the PTGDS rise from the top.


Anyway, i wish guys all the luck in your efforts but personally for me all this time and money invested just isn't worth it. Until something more permanent comes out CRISPR, Replicel or Histogen then i might just entertain shaving it.

Your hair doesnt look too bad. Unfortuneately alot of us including myself dont look good with a shaved head. I'm getting tired of seeing treatments that are always 2-5 years away. People on forums have been saying this for years, I remember when I first started receding at 17 there were cures supposedly 2-3 years away and it's still the same. The only cure I can think of is transplanting sideburn hair along the nw0 hairline evenly spaced out. The sideburn hairs are the first to respond to androgens so they have greater potential to secrete IGF-1 to nearby follicles which should slow down the effects of T/DHT. Then you can just get away with the occasional topical 5ar suppressor like GLA (more on this later) or keto or some other mild maintenance treatment. Thats the best cure I can realistically think of atm. A hair transplant is out of the question, the density and natural direction of growth is never the same. All these cell replication treatments dont look too promising either - how are they going to create a functioning ORS to form the hair canal itself? The DPC is useless without a canal/surrounding epithelial cells.


Any help ?
http://www.ncbi.nlm.nih.gov/pubmed/18283040

It would be useful if it worked topically without going systemic. I've known about tomatoes being bad for men, but I hadnt thought about its applications in AGA. Will do more research on this.


But what I found most strange is that 3.5 months ago I started taking this (http://www.amazon.co.uk/dp/B002ZS6E8C/ref=pd_lpo_sbs_dp_ss_1?pf_rd_p=569136327&pf_rd_s=lpo-top-stripe&pf_rd_t=201&pf_rd_i=B006YR9T7I&pf_rd_m=A3P5ROKL5A1OLE&pf_rd_r=15N3VPHR6BHBZD4JB9QY) orally to rid myself of the Giardia bug. I took it for about a month, having a teaspoon with each meal 3 times a day.

After a month of stopping this supplement, I started heavily shedding and have not stopped since. I now wonder after reading your in depth knowledge Chemical, specifically about olive leaf extract whether this would have been a major contributor to my rapid balding?

Taken orally Oleuropein can increase systemic WNT10b levels and reduce adipogenesis/increase osteogenesis. In the case of skin, this translates to enhanced keratinocyte proliferation and hair growth. It has the potential to work to increase hair if taken systemically - especially seeing as you were spacing it out throughout the day. (high doses have been shown not to have any effect so your single teaspoon might have been perfect). If it did prolong anagen then you're seeing the catch-up shed which happens when the anagen cycle is artificially extended. I dont fully understand how the feedback cycle works but the BMP signals try to reset the cycle to telogen as the hair progresses into late anagen. This is all speculation, it could all be coincidence.


what do you think about fgf11 approach with AR receptors? might he has found out something interesting??

I share his view that AR is root cause. His idea of viral gene transfection is not new but the application is the interesting part. The cost is a concern too. If he has figured out what he claims he has then I think it'll be revolutionary. A few injections to permanently turn off the AR gene is a cure imo. Executing it is easier said then done. Alternatively if we can permanently downregulate an AR coactivator to blunt the effects of AR by 50%+ thats kind of a semi cure too. There might even be a supplement out there that does this already but we havent found it yet.


JUSTBREEZY
Hey man some thing happen to me with seborreah(severe dundruff with patches) and not only terrible thinning but also very poor quality of hair. My doctors said that you can not cure this.

Have you tried zinc pyrithione shampoos (H&S classic) or selenium sulfide (selsun blue) shampoos to at least manage the symptoms?


Chemical, Do you think human growth horomone (hgh) can inhibit the production DHT?

I've done a fair bit of research on HGH and its conflicting as to whether HGH modulates the HPTA axis. I've not read anything that mentions HGH physically interfering with 5ar or AR, but the possibility of it effecting the LH/HPTA loop is there (testosterone production).

Anyways. I'm sorry I havent been posting lately, I've been busy gathering all the research into one big easy to read pile which I'll be posting in a separate read-only thread.

As for my progress update. I'm going through a shed which I'm not happy about. It could mean new hairs? But then I'd have to wait 2 months for the density to come back so whats the frickin point of new hairs. I've bought a 6 months supply of minox because I keep forgetting to but more. I've also bought some Valproic acid which'll be here next week. I plan to use 5% mixed with minox, that should definitely speed up growth. I've been using the following solution for the past 10 days:

Minox
OL 1mg/ml
EGCG ~8mg/ml
GLA 2.6mg/ml

I'm seeing more terminal hairs pop up along my nw1 hairline, not visible on camera but I can feel/see them (will post pics soon). The hairs I regrew on my left side are seem to be getting thicker but I cant tell for sure. The GLA might actually be doing something... I've come across some new research regarding safflower oil and theres a genetically modified version (Sonova 400 (http://www.ncbi.nlm.nih.gov/pubmed/21853296)) that has 400mg of GLA per 1000mg. Normal safflower doesnt contain GLA at all lol. The EPO I'm using only has a measly 80mg so I think a higher dose is what I need to really inhibit 5ar. I'm going to get my hands on this GLA, and also because safflower (what sonova uses) also has the ability to grow hair independent of GLA. I'll be posting an analysis soon.

I was going over the research on EGCG and it seems it might not be as strong as I'd anticipated so I'm going to get some Rosemary too. Chuck in apple polyphenols for good measure. I'm going all out because I really dont want to have to wait 2 months just to get my density back.

TubZy
01-28-2016, 01:24 PM
Thoughts on thymosin beta 4?

paleocapa89
01-28-2016, 01:56 PM
Hi, thanks for your work, I'm vary fascinated by your and swisstemle's work. I just wanted to add two things that I noticed:

1: Swiss posted this on reddit, and ask.fm: "Oleuporin is a dud I discussed this with a very helpful guy on my ask.fm. Beta catenin is not the only way in which pge2 works, not at all", and "Oleic acid is a precursor to PGE2/PGF2a. It doesn't however really boost the snythesis itself from what I see." Maybe you can do something with this information, I certainly can't :)

2: Swiss is on dutasteride to my best knowledge, so he does have the AR/DHT pathway covered.

Chemical
01-28-2016, 02:41 PM
I couldnt find where he discussed oluropein. It would be nice if he referenced his comments. However he does have Oleuropein listed in his protocols table.

Sadly he hasnt stated "the other mechanisms" by which PGE2 works. But regardless, whatever other mechanism PGE2 uses, all pathways that grow hair converge on β-Catenin. Every single treatment that grows hair stops working in the presence of a β-Catenin inhibitor. Be it DKK-1 which inhibits WNT induced β-Catenin, or PGD2 which inhibits β-Catenin via GSK3β/PKC, to grow hair you need β-Catenin. If people are going to deny this fact then at least clarify how you think this whole thing works.

You are right, he is on DUT for 3 years (https://ask.fm/swisstemples/answers/133412853100). Not sure if he still is. But if he is then it sure as hell is helping his results. This is dutasteride we're talking about.



Dut won't inhibit PGD2. Even with zero DHT you will still have PGD2 in your scalp which keeps you from regrowing hair.
Do you understand what I mean? Here's a diagram. http://i.imgur.com/ujqSDHS.png

I think with zero DHT you will have alot less PGD2 - judging from that diagram. No DHT doesnt mean no Testosterone so its AR that needs to be blocked. And plus not everyone is sensitive to PGD2 anyway.

iaskdumbquestions
01-28-2016, 04:41 PM
Chemical, thank you for all of your hard work and for sharing it with everyone here. Not only that, but you take the time to respond to everyone's questions without any arrogance.

It seems that your regiment has evolved since you began this thread and that it continues to change. Do you think you're near a point where you will have finalized the regiment or do see it being a work in progress indefinitely?

Also, what is your opinion on the current pipeline of treatments? Which do you think will have the greatest chance of success if any? (Replicel, histogen, SM, CB, etc.)

Thanks again. I wish I were half as knowledgable as you on this.

Bobbylobbyhobbythrobby
01-28-2016, 06:09 PM
Thanks Chemical, much appreciate the in depth response. Really is fascinating stuff.

gchr
01-28-2016, 10:48 PM
Hi Chemical,

You have a lot of information posted on here. I haven't been able to read all of it, a bit overwhelmed reading all of fgf11. It seems like a lot of interesting assumptions but as others pointed out in his post, they are skeptical if he is really correct. Then again I don't know why someone would put that much time to type something fake.

I was curious how can you for sure that your assumptions are working? For example hair loss may be a factor of many complex things so how do you go about it? Also I somewhat agree with you regarding how companies indicate they are only a few years away but do you really think Replicel / Histogen / other treatments aren't going to work or be available soon? (They mentioned in 2018)

Also im curious about some of your pics, do you have any better pics to share? I try to stay away from forums because a lot of times people can manipulate their pics etc.

Can you make a post on the exact supplements you are taking and dosages? I know one of them was Oleuropein.

BTW what is your take on biotin, saw palmetto with Beta-Sitosterol, pumpkin seed oil extract? Some have calimed saw palmetto did nothing but i wonder if they took it with the beta sitosterol

gchr
01-28-2016, 11:13 PM
Chemical apologize for previous post, my edit didn't go through and some remarks don't make sense.

I was curious how can you be sure that your mixtures / suggestions are working and it isn't because of the Minoxidil only?

I have read some people have bad experience with keta shampoo / nizoral and experience massive hair falling out. I don't want to risk having clumps of my hairs gone

Also there was a lot of users that got on the RU wagon but later on people experienced side effects with RU too and now CB is suppose to be the miracle...

Keeper
01-29-2016, 02:45 AM
Any Update Chemical?

Seuxin
01-29-2016, 04:09 PM
To Seek : Modulation of Androgen Receptor Activity by P160

https://www.google.fr/search?tbm=bks&hl=fr&q=Modulation+of+Androgen+Receptor+Activity+by+P160 #q=Modulation+of+Androgen+Receptor+Activity+by+P16 0&hl=fr

Chemical
01-30-2016, 06:55 AM
Thoughts on thymosin beta 4?

Thoughts? More than thoughts. Thymosin beta 4 is an absolute goldmine. (Thanks for sharing this)

Thymosin beta 4 induces hair growth via stem cell migration and differentiation. (http://www.ncbi.nlm.nih.gov/pubmed/17947589)

Without looking too hard I found this. TB4 acts directly on the stem cells to induce hair follicle growth. Sadly the abstract doesnt go over the mechanism of TB4 that they discovered.


Thymosin beta4 upregulates the expression of hepatocyte growth factor and downregulates the expression of PDGF-beta receptor in human hepatic stellate cells. (http://www.ncbi.nlm.nih.gov/pubmed/17584975)

HGF is a known stem cell pluripotency maintainer providing further evidence of TB4's stem cell effects.

Thymosin β4 induces the expression of vascular endothelial growth factor (VEGF) in a hypoxia-inducible factor (HIF)-1α-dependent manner.

We know that VEGF expression leads to increased hair follicle size and growth rate.

Regulation of glycogen synthase kinase-3 by thymosin beta-4 is associated with gastric cancer cell migration. (http://www.ncbi.nlm.nih.gov/pubmed/20691219)

And it also inhibits GSK3β which leads to more β-Catenin. However the study mentioned they noticed a decrease in β-Catenin in response to TB4.

Over-expression of thymosin beta4 promotes abnormal tooth development and stimulation of hair growth (http://www.ijdb.ehu.es/web/descarga/paper/082735hc)



Accelerated hair growth in thymosin β4 transgenic mice The effect of thymosin β4 on hair growth was analyzed in the transgenic mice. We watched the hair growth pattern of transgenic mice after birth but could not detect any differences in the onset of hair growth when compared with the wild type mice. However, we found significant difference in the speed of hair re-growth after shaving. Shaved mice were observed and the speed of hair re-growth was compared by measuring the hair area on the shaved spot at 2 weeks using an image analysis program. The speed of hair growth on the skin of the transgenic mice was accelerated as shown in Fig. 3. These data suggest that the increased expression of thymosin β4 in the hair follicles (Fig. 1B) promoted hair re-growth in the transgenic mice. To analyze the expression pattern of thymosin β4 on the hair follicle, we stained for thymosin β4 in the skin of transgenic mice. As shown in Fig. 3B, thymosin β4 was expressed on surface of the hair follicles especially in the external root sheath.

Induced expression of laminin-5 in thymosin β4 transgenic mice

We examined the expression of laminin-5 in the thymosin β4 over-expressing mice since laminin-5 was one of the candidate genes associated with hair growth among the proteins upregulated by thymosin β4. Western blot analysis and immunohistochemistry were used with the skin of wild type and transgenic mice to characterize the expression of laminin-5. As shown in Fig. 4A, Western blot shows that the expression of laminin-5 was increased approximately 5-fold in the transgenic mice relative to the wild type mice. Immunohistochemistry showed that the expression of laminin-5 was specifically increased in the root of the hair follicles and this staining pattern is different from that of thymosin β4 (Fig. 4B). The expression of laminin-5 around the root of the hair follicle suggests that laminin-5 is induced by the over-expression of thymosin β4 and that this induced laminin-5 expression may stimulate hair follicle stem cells and play a role in the thymosin β4- stimulated hair growth.

Looking at the deeper mechanisms of TB4 we see that it interacts with laminin 5. I've never heard of laminin 5 so I did some research:

Laminin-10 is crucial for hair morphogenesis (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC155997/)



Our results, as well as the results of a number previous studies, suggest that laminin-10 supports hair follicle development through a mechanism other than the maintenance of dermal–epithelial cohesion. A comparison between inhibition of laminin-5 and laminin-10 in the skin illustrates this point. In human skin xenografts, laminin-5 antibodies induced extensive epidermal detachment within 24 h of application, while in our studies, skin treated with laminin-10 antibodies did not show blisters or epidermal detachment even after 3 weeks. Similarly, extensive blistering is seen in patients with HJEB, who lack laminin-5. Absence of laminin-5 in Lama3 –/– mice produced extensive epidermal detachment as well as detachment-associated cell death (anoikis). In contrast, in our studies, we were unable to demonstrate significant epidermal detachment or anoikis in Lama5 –/– mouse skin. On the other hand, while inhibition of laminin-10 in both human and murine skin produced marked effects on hair follicle development, no hair follicle defects were demonstrated in laminin-5/6 null mouse skin, and hair follicle development is typically normal in HJEB patients. In conclusion, laminin-5 and laminin-10 appear to have non-overlapping functions in the skin, with laminin-5 promoting epidermal adhesion and laminin-10 promoting epithelial development.

So it seems laminin 5 is crucial for cellular adhesion. But what does cellular adhesion do?

http://www.nature.com/nrm/journal/v4/n9/images/nrm1199-i2.gif

Cellular adhesion is necessary for epithelial mesenchymal transition to take place and it also increases intracellular β-Catenin. You can read more about E-cadherins role in hair growth here:

E-cadherin controls adherens junctions in the epidermis and the renewal of hair follicles (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC275417/)

It looks like TB4 is designed for the sole purpose of growing hair, nearly everything it does is directly promotes the development of hair follicles. I will doing more research on ways of increasing TB4 (endogenously or exogenously).

While I was researching laminin 5 I came across this excerpt which talks about DPC regeneration by "growth of papilla cells in 3D spheroid cultures" implanted into skin:



Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth (http://www.pnas.org/content/110/49/19679.full)

The observation of hair follicles within grafts, as described above, suggests that the 22% restoration of papilla signature is sufficient for follicle neogenesis. However, as complete hair-follicle morphogenesis involves epithelial:mesenchymal interactions, it is likely that external paracrine signals will be required for full signature restoration and development of external hairs. Importantly, in this study, we have demonstrated that dermal spheroids are, by themselves, capable of initiating the hair induction process in non-hair-bearing human skin, where there are no previous epidermal “hair-follicle” signals.

I dont know what to say. Just let that sink in.




It seems that your regiment has evolved since you began this thread and that it continues to change. Do you think you're near a point where you will have finalized the regiment or do see it being a work in progress indefinitely?

Also, what is your opinion on the current pipeline of treatments? Which do you think will have the greatest chance of success if any? (Replicel, histogen, SM, CB, etc.)

Thanks again. I wish I were half as knowledgable as you on this.

You are very welcome.

I started off using minox, emu oil, oleuropein, Saw palmetto and ketoconazole. Now I'm using Minox, EGCG, OL, GLA, ketoconazole and miconazole. I'm going to add Valproic acid, apple polyphenols, Rosemary and a different brand of GLA in the form of safflower oil. I think this is as far as I will go and this should be more than enough to see steady regrowth. The problem is I'm being impatient and thats a bad trait to have when watching hair to grow (or a tree to grow). If I were to choose a few core treatments to stick to I'd say minox, egcg, ol, keto, rosemary and gla. We keep discovering new studies and pathways that enhance or inhibit hair growth so its inevitable that in a few months time this protocol will change. This is still an experiment in progress so nothing is fixed yet until I've become nw0. Moreover, treating AGA is an optimisation problem where we have to find the treatments that have the best cost to effectiveness ratio and ease of acquisition/application - which takes trial and error. And even after complete regrowth, we have to find a maintenance protocol that doesnt require aggressive planning or time. I firmly believe in never settling for less. There is always room for improvement.

Looking at histogens preliminary results and theory (http://www.histogen.com/applications/hsc.htm) I would say their treatment has potential to grow hair in less aggressive AGA. This idea of using cultured stem cell/growth factors (?) injected only once into scalps is definitely more convenient than daily topical use. The only problem is AR.

Replicels methodology is better that histogens on paper:

https://youtu.be/cCe5mg7X6zg?t=122

I previously stated that these implanted DPC cells might fail to create a functional hair canal with outer root sheath cells but that was ignorant of me to say without fully understand how follicular neogenesis works.



Human DP cells isolated from temporal scalp dermis (Promocell, Heidelberg, Germany) from six donors were propagated in vitro according to manufacturer's recommendations. Alkaline phosphatase activity, a DP marker which correlates with hair-inducing capacity, was measured in vitro using the BCIP/NBT substrate on passage 5 DP cells. Alkaline phosphatase activity was variable between samples, with cells from 3 of the donors showing alkaline phosphatase activity in more than 50% of the cells (Table 1). DECs were constructed by combining DP cells with rat tail collagen type 1, adding NFKs on top and bringing the constructs to the air-liquid interface for 2 days before grafting onto female nude mice. Eight weeks after grafting, HFs were observed in mice grafted with the 3 human DP cells with higher alkaline phosphatase activity (Table 1, Figure 1a). HFs had a bulb, dermal sheath, hair matrix and cortex (Figure 1b). Epithelial compartments of the HFs were intact with concentric layers of inner and outer root sheaths, sebaceous glands and hair shaft (Figure 1c-e).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947143/


Instead of occipital hair cells I think replicel might have more success with beard DPC since they actually thrive in the presence of DHT and release IGF-1 to nearby follicles. I realise that culturing these cells is not an easy task so atm its all looking really good on paper. But just because it seems to work on paper and mice doesnt mean it'll translate the same in human balding scalp.


Also I somewhat agree with you regarding how companies indicate they are only a few years away but do you really think Replicel / Histogen / other treatments aren't going to work or be available soon? (They mentioned in 2018)

Can you make a post on the exact supplements you are taking and dosages? I know one of them was Oleuropein.

I was curious how can you be sure that your mixtures / suggestions are working and it isn't because of the Minoxidil only?

I have read some people have bad experience with keta shampoo / nizoral and experience massive hair falling out. I don't want to risk having clumps of my hairs gone. Also there was a lot of users that got on the RU wagon but later on people experienced side effects with RU too and now CB is suppose to be the miracle...

For now all we can do guess when they will be ready to release their treatments. I think the main problem is the researchers like hyping their work before they can actually execute it properly. I think we should stop holding our breath for these companies and look for alternative treatments that we can use immediately, and when these do finally come out, it'll be a win-win. Otherwise you'll just be setting yourself up for disappointment.

Yes I'm nearly finished writing up the material for the new thread which will all the treatments with the relevant dosing and science, plus all the research in this thread formatted nicely so it's easy to find. Its proving to harder than I thought gathering all the research scattered all over this thread but I'm nearly done.

I've stated before that I fully believe my results were attributed to minox with the other treatments merely potentiating the rate of regrowth. When I tried minox, fin and keto back in april 2015 it took 2 months before I saw visible improvement and it wasnt anything spectacular. With OL + Minox and keto/mico I saw very fast terminal differentiation of vellus hairs when I was applying 3x a day for 2 weeks. (I will make a proper progress log too). I will talk more about testing methodology and gauging effectiveness of treatments in the new thread so I dont keep repeating myself however the point you raise about which treatment is actually working - is important.

I cant comment on keto and RU since their side effects are subjective and varying but personally I havent experienced anything bad with Keto (I use the cream form). This shedding that people experience could be a good sign of new anagen entry but it could also be coincidence - you will see more bad experiences because people dont post unless they see a change for the worst. Thats something to keep in mind when reading anecdotes.


To Seek : Modulation of Androgen Receptor Activity by P160

https://www.google.fr/search?tbm=bks&hl=fr&q=Modulation+of+Androgen+Receptor+Activity+by+P160 #q=Modulation+of+Androgen+Receptor+Activity+by+P16 0&hl=fr

Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen-dependent and castration-resistant AR-expressing prostate cancer cells. (http://www.ncbi.nlm.nih.gov/pubmed/23270728)

Good find as always Seuxin.

Nearly forgot:

http://imgur.com/a/g6TdQ

http://imgur.com/a/aV65d - taken today.

Seuxin
01-30-2016, 12:50 PM
The problem with TB500 (Thymosin beta 4) is it needsto be injected, and it's expensive ! In addition, i think some peoples already tried it :(

TubZy
01-30-2016, 01:17 PM
Thoughts? More than thoughts. Thymosin beta 4 is an absolute goldmine. (Thanks for sharing this)

Thymosin beta 4 induces hair growth via stem cell migration and differentiation. (http://www.ncbi.nlm.nih.gov/pubmed/17947589)

Without looking too hard I found this. TB4 acts directly on the stem cells to induce hair follicle growth. Sadly the abstract doesnt go over the mechanism of TB4 that they discovered.


Thymosin beta4 upregulates the expression of hepatocyte growth factor and downregulates the expression of PDGF-beta receptor in human hepatic stellate cells. (http://www.ncbi.nlm.nih.gov/pubmed/17584975)

HGF is a known stem cell pluripotency maintainer providing further evidence of TB4's stem cell effects.

Thymosin β4 induces the expression of vascular endothelial growth factor (VEGF) in a hypoxia-inducible factor (HIF)-1α-dependent manner.

We know that VEGF expression leads to increased hair follicle size and growth rate.

Regulation of glycogen synthase kinase-3 by thymosin beta-4 is associated with gastric cancer cell migration. (http://www.ncbi.nlm.nih.gov/pubmed/20691219)

And it also inhibits GSK3β which leads to more β-Catenin. However the study mentioned they noticed a decrease in β-Catenin in response to TB4.

Over-expression of thymosin beta4 promotes abnormal tooth development and stimulation of hair growth (http://www.ijdb.ehu.es/web/descarga/paper/082735hc)



Looking at the deeper mechanisms of TB4 we see that it interacts with laminin 5. I've never heard of laminin 5 so I did some research:

Laminin-10 is crucial for hair morphogenesis (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC155997/)



So it seems laminin 5 is crucial for cellular adhesion. But what does cellular adhesion do?

http://www.nature.com/nrm/journal/v4/n9/images/nrm1199-i2.gif

Cellular adhesion is necessary for epithelial mesenchymal transition to take place and it also increases intracellular β-Catenin. You can read more about E-cadherins role in hair growth here:

E-cadherin controls adherens junctions in the epidermis and the renewal of hair follicles (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC275417/)

It looks like TB4 is designed for the sole purpose of growing hair, nearly everything it does is directly promotes the development of hair follicles. I will doing more research on ways of increasing TB4 (endogenously or exogenously).

While I was researching laminin 5 I came across this excerpt which talks about DPC regeneration by "growth of papilla cells in 3D spheroid cultures" implanted into skin:



I dont know what to say. Just let that sink in.




You are very welcome.

I started off using minox, emu oil, oleuropein, Saw palmetto and ketoconazole. Now I'm using Minox, EGCG, OL, GLA, ketoconazole and miconazole. I'm going to add Valproic acid, apple polyphenols, Rosemary and a different brand of GLA in the form of safflower oil. I think this is as far as I will go and this should be more than enough to see steady regrowth. The problem is I'm being impatient and thats a bad trait to have when watching hair to grow (or a tree to grow). If I were to choose a few core treatments to stick to I'd say minox, egcg, ol, keto, rosemary and gla. We keep discovering new studies and pathways that enhance or inhibit hair growth so its inevitable that in a few months time this protocol will change. This is still an experiment in progress so nothing is fixed yet until I've become nw0. Moreover, treating AGA is an optimisation problem where we have to find the treatments that have the best cost to effectiveness ratio and ease of acquisition/application - which takes trial and error. And even after complete regrowth, we have to find a maintenance protocol that doesnt require aggressive planning or time. I firmly believe in never settling for less. There is always room for improvement.

Looking at histogens preliminary results and theory (http://www.histogen.com/applications/hsc.htm) I would say their treatment has potential to grow hair in less aggressive AGA. This idea of using cultured stem cell/growth factors (?) injected only once into scalps is definitely more convenient than daily topical use. The only problem is AR.

Replicels methodology is better that histogens on paper:

https://youtu.be/cCe5mg7X6zg?t=122

I previously stated that these implanted DPC cells might fail to create a functional hair canal with outer root sheath cells but that was ignorant of me to say without fully understand how follicular neogenesis works.



Instead of occipital hair cells I think replicel might have more success with beard DPC since they actually thrive in the presence of DHT and release IGF-1 to nearby follicles. I realise that culturing these cells is not an easy task so atm its all looking really good on paper. But just because it seems to work on paper and mice doesnt mean it'll translate the same in human balding scalp.



For now all we can do guess when they will be ready to release their treatments. I think the main problem is the researchers like hyping their work before they can actually execute it properly. I think we should stop holding our breath for these companies and look for alternative treatments that we can use immediately, and when these do finally come out, it'll be a win-win. Otherwise you'll just be setting yourself up for disappointment.

Yes I'm nearly finished writing up the material for the new thread which will all the treatments with the relevant dosing and science, plus all the research in this thread formatted nicely so it's easy to find. Its proving to harder than I thought gathering all the research scattered all over this thread but I'm nearly done.

I've stated before that I fully believe my results were attributed to minox with the other treatments merely potentiating the rate of regrowth. When I tried minox, fin and keto back in april 2015 it took 2 months before I saw visible improvement and it wasnt anything spectacular. With OL + Minox and keto/mico I saw very fast terminal differentiation of vellus hairs when I was applying 3x a day for 2 weeks. (I will make a proper progress log too). I will talk more about testing methodology and gauging effectiveness of treatments in the new thread so I dont keep repeating myself however the point you raise about which treatment is actually working - is important.

I cant comment on keto and RU since their side effects are subjective and varying but personally I havent experienced anything bad with Keto (I use the cream form). This shedding that people experience could be a good sign of new anagen entry but it could also be coincidence - you will see more bad experiences because people dont post unless they see a change for the worst. Thats something to keep in mind when reading anecdotes.



Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen-dependent and castration-resistant AR-expressing prostate cancer cells. (http://www.ncbi.nlm.nih.gov/pubmed/23270728)

Good find as always Seuxin.

Nearly forgot:

http://imgur.com/a/g6TdQ

http://imgur.com/a/aV65d - taken today.

I actually have been using tb500 for the past few weeks on and off. I have taken a few weeks off and now back on 8mg injected one a week. I bought enough this time to run it for at least 6 weeks at 8mg a week. It definitely has an impact on hair color and growth because my hair did look way healthier and darker when I only used it for a 3 weeks in the past . The only downside is the price as it's costing me $31 for 2mg vial but the stuff I have it 100% legit. I heal way quicker too from weight lifting. I just did my first shot again this past Wednesday and plan to keep going for another 5 weeks or more if I have the money.

lukey
01-30-2016, 02:24 PM
Chemical, could you please confirm how much OL and EGCG we should be using per ml? Thanks.

jamesst11
01-30-2016, 02:36 PM
it's hard to tell what's going on this pics? can you take a couple more with your hair combed the same way and at the same angle?

burtandernie
01-30-2016, 09:34 PM
Could you take this stuff orally and how much of each thing to get any result? There still is a pretty large number of people looking for that magic fin alternative. I guess I should really try fin before trying all this other random stuff.

Unsure1
01-31-2016, 12:49 AM
Where You scalp or sub q injecting tb 500?
Injecting 2-4mg into the scalp weekly I saw minor quality improvement though nothing too significant

champpy
01-31-2016, 03:22 AM
Hey Tubzy, can you tell us the source you got the TB4 from?

Seuxin
01-31-2016, 04:21 AM
I actually have been using tb500 for the past few weeks on and off. I have taken a few weeks off and now back on 8mg injected one a week. I bought enough this time to run it for at least 6 weeks at 8mg a week. It definitely has an impact on hair color and growth because my hair did look way healthier and darker when I only used it for a 3 weeks in the past . The only downside is the price as it's costing me $31 for 2mg vial but the stuff I have it 100% legit. I heal way quicker too from weight lifting. I just did my first shot again this past Wednesday and plan to keep going for another 5 weeks or more if I have the money.

SO....you're paying 124$ / week for TB500 ???????

Forestry
01-31-2016, 11:09 PM
i have been following (this forum is great, special thanks to Chemical for elaborating your findings) and researching and wanted to add this.

when reading wikipedia on keratinocyte (https://en.wikipedia.org/wiki/Keratinocyte) differentiation and the associated expression of specific keratins at each stage, i came to the section on the Role in Wound Healing, and the associated reference:

...Wounds to the skin will be repaired in part by the migration of keratinocytes to fill in the gap created by the wound. The first set of keratinocytes to participate in that repair come from the bulge region of the hair follicle and will only survive transiently... At the opposite, epidermal keratinocytes, can contribute to de novo hair follicle formation during the healing of large wounds (https://www.ncbi.nlm.nih.gov/pubmed/17507982).

https://www.ncbi.nlm.nih.gov/pubmed/17507982

"the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits, mice and even humans fifty years ago. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles."

I wonder if this (WnT signalling) study has been conducted in the presence of DHT and receptor diminishing regimen for such.

Forestry
01-31-2016, 11:18 PM
Hair regrowth following a Wnt- and follistatin containing treatment: safety and efficacy in a first-in-man phase 1 clinical trial. (http://europepmc.org/abstract/med/22052313)
...
These results demonstrate that a single intradermal administration of HSC improved hair growth in subjects with androgenetic alopecia and is a clinical substantiation of previous preclinical research with Wnts, follistatin, and other growth factors associated with wound healing and regeneration.

Seuxin
02-01-2016, 04:38 AM
WNT agonist is very important.

TheKaneShop is selling a WNT agonist named "6BIo", as 99$ for 500mg. Nevertheless i don't know the amount to use per day. I think it's a little amount because WNT agonist at high dose can be dangerous.

It can be a good addition...

In addition, Follistatin is VERY IMPORTANT for hair, it's used in the famous Histogen ( HSC) protocol ( KGF, VEGF, and Follistatin), nevertheless AFAIK, there is different type of follistatin....Maybe it could be good to find a simple an cheap way to increase production of follistatin.

-> Increasing VEGF is simple ( With hypoxia like Stemoxydine, or with Minoxidil )
-> Increasing KGF is simple ( With Minoxidil, or buying directky KGF for cheap on the skinactive website )

So we need to find a way to increase Follistatin !

And we have to find the amount to use for 6-BIO.

SriHanuman
02-01-2016, 06:02 AM
rice bran:

http://www.ncbi.nlm.nih.gov/pubmed/24389480
http://www.ncbi.nlm.nih.gov/pubmed/26632177 full article: https://www.jstage.jst.go.jp/article/bpb/38/12/38_b15-00387/_pdf

TubZy
02-01-2016, 09:27 AM
SO....you're paying 124$ / week for TB500 ???????

Ballin lol. Yeah I just want to see if it works well or not. Not really planning to stay on it long term unless I get pretty decent results, just need some thickening, hairline is still pretty decent (NW1).

Higher dose topical OC has seemed to cut my shedding down a lot.

I do it SubQ or IM. I think you should you at least 8mg or even 10mg if you could afford it. I have clopro coming in soon so that should be a decent growth stim combo (clopro & TB500).

Forestry
02-01-2016, 06:49 PM
I've only ready the first link SriHanuman , that is a good read and shows RB-SCE a decent alternative to minoxidil.

In terms of the stack, Linoleic Acid (LA) is there (here I'm lumping together GLA and LA) with Evening Primrose*.

The new item appears to be Gamma Oryzanol (www.amazon.com/gp/product/B00MXYPH9A/)(OZ).

I wish the study went out past 4 weeks. The OZ really kicked in at week 4.

*per Wikipedia, natural sources of LA (https://en.wikipedia.org/wiki/Linoleic_acid):
Name % LA
...
Safflower oil 74.62%
Evening Primrose oil 73%
...
Grape seed oil 69.6%
Sunflower oil 65.7%
...
Walnut oil 51%
Sesame oil 45%
Rice bran oil 39%

burtandernie
02-01-2016, 08:17 PM
One issue I always have is some things that are natural SOUND good, but do they actually work as the small studies might seem to indicate? Tons of natural products have many of these ingredients like revivogen listed below comes to mind. It never really had much success from user stories back then, and I tried it as well back when it was the latest fad. Why would it not work if it was formulated with many of these natural ingredients your mentioning? Right off the bat it has linolenic acid, beta-sis, saw palmetto among many others.

revivogen
SD Alcohol 40 (Denat. Alcohol), Purified Water (Aqua), Linolenic Acid (Gamma & Alpha), Linoleic Acid, Oleic Acid, Saw Palmetto Extract (Serenoa Serrulata), Ethyl Laurate, Beta-Sitosterol, Caffeine, Octyl (Ethylhexyl) Gallate, Dodecyl Gallate, Pyridoxal 5-Phosphate, Tocopherol (Vitamin E), Procyanidin B2 (Vitis Vinifera Extract), Azelaic Acid , Zinc Sulfate, Menthol, EDTA, Perfume (Parfum).

SriHanuman
02-02-2016, 01:25 AM
I've only ready the first link SriHanuman , that is a good read and shows RB-SCE a decent alternative to minoxidil.



Too bad, the second link is "16-week double-blind randomized controlled single-center trial to evaluate the safety and efficacy of dermal rice bran supercritical CO2 extract (RB-SCE) in the treatment of androgenic alopecia."

ryan82
02-02-2016, 02:18 AM
WNT agonist is very important.

TheKaneShop is selling a WNT agonist named "6BIo", as 99$ for 500mg. Nevertheless i don't know the amount to use per day. I think it's a little amount because WNT agonist at high dose can be dangerous.

It can be a good addition...

In addition, Follistatin is VERY IMPORTANT for hair, it's used in the famous Histogen ( HSC) protocol ( KGF, VEGF, and Follistatin), nevertheless AFAIK, there is different type of follistatin....Maybe it could be good to find a simple an cheap way to increase production of follistatin.

-> Increasing VEGF is simple ( With hypoxia like Stemoxydine, or with Minoxidil )
-> Increasing KGF is simple ( With Minoxidil, or buying directky KGF for cheap on the skinactive website )

So we need to find a way to increase Follistatin !

And we have to find the amount to use for 6-BIO.
Bio-6 is a better VPA. Why is it dangerous with high dose? Do you have experience with bio-6?

pepmorg79
02-02-2016, 04:32 AM
Hi Chemical,

I am a fan of your studies, I am fighting against hairloss since 6 years at least and I have tried a lot of treatments: FIN, MINOX, RU, KETO, CB, LATANOPROST, SETIPIPRANT, and someone more that now I don't remember it.

Last mont I have started to read you and follow your instructions and my hair are better, I have a nice regrowth that I hope continue next months. My actual treatment is:

- CB 1% (70% ethano 30% propilenglicol) at morning
- OL 1mg/ml (70% ethanol 30 %distilled water) at midday
- 1,15 mg of FIN at midday
- MINOX with OL (minox 5%, OL 1mg/ml (60mg of OL in bottle of 60ml of Minox) at night.

I think the regeneration hair is for the increase of betacatenin which produced Oleuropein, but I have some questions about OLEUROPEIN in my head wich last days I am a little worried, and I am very happy if you can answer me:

1.- betacatenin can increase the risk about the proliferation cancer cells? because I have read something in internet and I am quite worried about it.

2.- betacatenin influence in the sleeping time? because last weeks I sleep worse and a little of insomnia

3.- betacatenin can increase the oxidation of body, increase the wrinkles in the front or in the eyes, produce bones calcification? because I have my skin in nice conditions and I don¡t want destroy it

4.- other question about it is if the antioxidants can reduce the quantity of betacatenin? because I read that some antioxidants like magnesium or vit.d can reduce betacatenin

5.- if are true, what are the antioxidants who affect betacatenin in major percentage? do you know about vit c or vit e effects?
Because the objective global is can regrowth hair without generate radical free or maintaining the skin in good conditions.

6.- the last question is about diet: what can I do with our diet relationed with betacatenin? If I eat a lot of verdures (brocoli, salmon, fishes, calabacin, etc..) which have antioxidant propierties are we reducing the results of OL? Or it is independent and doesn't have relationed?
Because I consume some brocoli for example, the antioxidant propierties, furthermore inhibitor aromatasa action could reduce the benefits of OL?

Sorry for a lot of questions, but I admire your studies about regrwoth hair, you have helped to start regrowth my hair and I am happy for this, now I do this questions because I am apasionate like you about find solutions of hair and I hope this solutions don't damage other things.
However, I am quite worried with the relation about betacatenin and cancer and the oxidation of body and damages skin.

I hope your answer when you can,

SriHanuman
02-02-2016, 05:44 AM
3.- betacatenin can increase the oxidation of body, increase the wrinkles in the front or in the eyes, produce bones calcification? because I have my skin in nice conditions and I don¡t want destroy it



http://www.ncbi.nlm.nih.gov/pubmed/21707762

Bobbylobbyhobbythrobby
02-02-2016, 05:46 PM
Has anyone tried this method (below), or does anyone think that these supplements would help?

http://forum.bodybuilding.com/showthread.php?t=160444941

Bobbylobbyhobbythrobby
02-02-2016, 05:47 PM
Has anyone tried this method (below), or does anyone think that these supplements would help?

http://forum.bodybuilding.com/showthread.php?t=160444941

Forestry
02-02-2016, 08:04 PM
Too bad, the second link is "16-week double-blind randomized controlled single-center trial to evaluate the safety and efficacy of dermal rice bran supercritical CO2 extract (RB-SCE) in the treatment of androgenic alopecia."

I read the second study, which confirms RB-SCE as inhibiting the 5-AR enzyme in androgen-responsive organs (the skin organ in this case). the results were "similar to slightly lower than those reported for 2% minoxidil after 48 weeks or 1% pro
-cyanidin B-2 after 16 weeks."

I was also interested in this study in that they published their stack:1

INCI % (as w/w)
----------------------------
Water (aqua), demineralized as 100%
Glycerin 1.0
Hydroxyethyl cellulose 0.5
Tetrasodium EDTA 0.03
C12–14 Pareth-12 2.0
Hyaluronic acid 0.5
Alcohol 15.0
RB-SCE 0.5
PEG-40 castor oil 2.0
Triethanolamine 0.3

INCI = International Nomenclature of Cosmetic Ingredients;
RB-SCE = rice bran supercritical CO2 extract.

Forestry
02-02-2016, 08:21 PM
Too bad, the second link is "16-week double-blind randomized controlled single-center trial to evaluate the safety and efficacy of dermal rice bran supercritical CO2 extract (RB-SCE) in the treatment of androgenic alopecia."

I read the second study, which confirms RB-SCE as inhibiting the 5-AR enzyme in androgen-responsive organs (the skin organ in this case). the results were "similar to slightly lower than those reported for 2% minoxidil after 48 weeks or 1% pro-cyanidin B-2 after 16 weeks."

I was also interested in this study in that they published their stack:

INCI................................... % (as w/w)
----------------------------- -----------
Water (aqua), demineralized . as 100%
Glycerin................................ 1.0
Hydroxyethyl cellulose............ 0.5
Tetrasodium EDTA................. 0.03
C12–14 Pareth-12................. 2.0
Hyaluronic acid...................... 0.5
Alcohol................................ 15.0
RB-SCE................................ 0.5
PEG-40 castor oil................... 2.0
Triethanolamine..................... 0.3

INCI = International Nomenclature of Cosmetic Ingredients;
RB-SCE = rice bran supercritical CO2 extract.

I did not look at all of these, but i did look at Hyaluronic Acid (https://en.wikipedia.org/wiki/Hyaluronic_acid).

It appears (total guess on my part) that HA may be added due to it's value in cell proliferation and migration, and possible reduction of normally occuring local HA synthesis due to the lowering of TGF-Beta1 by RB-SCE (as noted in the first rice bran study in SriHanuman's post).

http://www.jbc.org/content/290/52/30910.long

This study does mention high molecular weight HA (might be the type used in the RB-SCE study (?)).

"The turnover of HA in most tissues is extraordinarily rapid; the half-life of HA in the skin, which contains about half of all HA in the body, is 1–1.5 days. Thus, the tight control of HA synthesis and degradation is necessary for this turnover and seems to finely balance the amounts of high molecular mass HA (1,000–10,000 kDa) within tissues. On the other hand, an imbalance of synthesis and degradation causes the accumulation of HA with different molecular weights, which is commonly observed in diseases such as arthritis and cancers."

"TGF-β1 conferred the most potent effect on production of high molecular weight HA by up-regulation of HAS expression and down-regulation of HYBID (HYaluronan-Binding protein Involvedin hyaluronan Depolymerization), aka KIAA1199, expression via distinct signaling pathways."

joshuk
02-03-2016, 05:37 AM
chemical do you think adding OL to lipogaine would work, only reason im asking is becasue its a diffrent type of vehicle

Seuxin
02-03-2016, 01:19 PM
joshuk, you can whitout problems ;

@Chemical : These studies about rice bran supercritical CO2 extract are very awesome !

It could be a great and cheap addition to our regimen !

Here is a link..if we used at 1%...it could last very long time :)

http://www.aromantic.co.uk/home/products/botanical-co2-extracts/organic-rice-bran-oil-co2-extract.aspx

Need investigations !

bananana
02-03-2016, 05:24 PM
Here is the full resolution BEFORE/AFTER pic.

When you zoom in you can see some progress, but it's too early to say for sure, in my opinion.
http://postimg.org/image/o3vhp8lij/full/

Lemme know what do you think.

Seuxin
02-04-2016, 01:51 AM
Can really be improve with an AA ( Duta, Fin, RU, CB)

Forestry
02-05-2016, 12:05 AM
Review of dkk1:

http://www.jidonline.org/article/S0022-202X%2815%2933732-5/pdf
Dihydrotestosterone-Inducible Dickkopf 1 from Balding Dermal Papilla Cells Causes Apoptosis in Follicular Keratinocytes


http://www.freepatentsonline.com/y2010/0040619.html
"Dickkopf-1 (Dkk-1) is a member of the dickkopf family of proteins that have been shown to be negative regulators of the canonical Wnt-signaling pathway, which has a central role in bone development and formation (see, for example, Glinka et al., Nature 391:357-62 (1998); Fedi et al., J Biol Chem 274(27):19465-72 (1999); Zorn, Curr Biol 11:R592-95 (2001); and Krupnik et al., Gene 238: 301-13 (1999)). Dkk-1 inhibits Wnt signaling through its interaction with the Wnt co-receptors LRP5 or LRP6 and the kremen proteins (see, for example, Bafico et al., Nature Cell Biol 3:683 (2001); Mao et al., Nature 411(17):321 (2001); Mao et al., Nature 417:664 (2002); and Semënov et al., Curr Biol 11:951-61 (2001). By binding LRP5 (LRP6) and kremen proteins, Dkk-1 prevents LRP5 or LRP6 from associating with members of the Wnt pathway and thus prevents Wnt-mediated signal transduction, which in turn results in the inhibition of bone formation.

LRP5 is a key protein in regulating bone mass (see, for example, Gong et al., Cell 107:513-23 (2001); Patel, N Eng J Med 346(20):1572 (2002)). An autosomal recessive disorder characterized by low bone mass (osteoporosis-pseudoglioma syndrome, or “OPPG”) has been identified as being caused by loss-of-function mutations in LRP5 (Gong et al., 2001). In addition, gain-of-function mutations in LRP5 have been shown to result in autosomal dominant high bone mass in humans (Little et al., Am J Human Genetics. 70(1):11-19, 2002). The same mutations in LRP5 that result in high bone mass can interfere with the ability of Dkk-1 to inhibit LRP5 signaling (see, for example, Boyden et al., N Eng J Med. 346(20):1513-1521, 2002). Thus, Dkk-1 is appropriately characterized as being a negative regulator of bone deposition.

In view of the involvement of Dkk-1 in the regulation of bone formation and its role in various other diseases that are associated with bone loss (e.g., cancer and diabetes), there is a need for improved anti-Dkk-1 antibodies for therapeutic use and for other purposes."

http://www.ncbi.nlm.nih.gov/gene/22943

other dkk1 blockers:

Horny Goat Weed: "Flavonoids of Herba Epimedii regulate osteogenesis of human mesenchymal stem cells through BMP and Wnt/beta-catenin signaling pathway." http://www.ncbi.nlm.nih.gov/pubmed/19703516

L-ascorbic acid 2-phosphate (https://www.caymanchem.com/app/template/Product.vm/catalog/16457) represses the dihydrotestosterone-induced dickkopf-1 expression in human balding dermal papilla cells. http://www.ncbi.nlm.nih.gov/pubmed/20701628

Preventable effect of L-threonate (http://www.swansonvitamins.com/swanson-ultra-calcium-l-threonate-100-mg-90-veg-caps), an ascorbate metabolite, on androgen-driven balding via repression of dihydrotestosterone-induced dickkopf-1 expression in human hair dermal papilla cells. http://www.ncbi.nlm.nih.gov/pubmed/21034532

Keeper
02-05-2016, 01:22 AM
L-ascorbic acid 2-phosphate is possible too buy around 40 dollars

Seuxin
02-05-2016, 04:37 AM
I have 100g of MAP ( magnesium ascorbyl phosphate), i can inhib DKK-1 too but a member here in a few weeks spoke that Vitamine C was no good hair hairs...

UNBEAT
02-05-2016, 05:50 AM
ALL this info is good ,but makes us a bit confuse.Can someone make a summary of what to use ,how to use ect.

bananana
02-05-2016, 07:22 AM
ALL this info is good ,but makes us a bit confuse.Can someone make a summary of what to use ,how to use ect.

+1

Hicks
02-06-2016, 05:36 AM
Would be interesting to have different protocols listed for others to try. That's a lot of work. This stuff is over my head.

UNBEAT
02-06-2016, 06:08 AM
these protocols should be categorized like:
name protocol
how does it work
what to use
how to make ,find stuff
how to use
ALL THESE WOULD MAKE VERY EASY TO FIND A SOMETHING THAT WORKS FOR EACH OF US DEPENDING ON THE TYPE OF HAIRLOSS WHICH WE HAVE

iaskdumbquestions
02-06-2016, 07:05 AM
these protocols should be categorized like:
name protocol
how does it work
what to use
how to make ,find stuff
how to use
ALL THESE WOULD MAKE VERY EASY TO FIND A SOMETHING THAT WORKS FOR EACH OF US DEPENDING ON THE TYPE OF HAIRLOSS WHICH WE HAVE

Stop complaining. Chemical has been generous enough to share his research with us. If you're too lazy to comb through and this thread and find his regiment then that's your fault.

Hicks
02-06-2016, 07:48 AM
Stop complaining. Chemical has been generous enough to share his research with us. If you're too lazy to comb through and this thread and find his regiment then that's your fault.

It's called being to busy to comb through the thread.
Hats off to chemical and others but the majority of people that viewed this thread don't have a clue. Myself included. If there's us a simple protocol to follow others might try and report results.

allTheGoodNamesAreTaken
02-06-2016, 01:26 PM
A separate thread where no discussion is allowed would be good, ingredients and instructions only.

joshuk
02-07-2016, 05:02 AM
chemical im going to be buying some Sodium Valproate when kane gets back from holidays, what vehicle would you use 70/30 eth/pg or is their a better one. was thinking about using 70mg a day

machi
02-07-2016, 05:53 AM
Hi guys. I would like to try the new treatment but I do not know how. I have not enough knowledge to understand what explains chemist.
I'm thinking about buying CB but is very expensive , and I could only use 1% once a day , and I 'm not sure I would have good results. I need to strengthen my crown and my temples .
Has anyone tried the new treatment ??? someone can explain step by step how to follow this treatment ??? I'm not lazy but I have no knowledge and I do not speak English well .

Phoenix7
02-08-2016, 11:02 AM
Thanks for the topic, Chemical, any further updates?

Started Minox/Olueropein last week, seemed to have a allergic reaction at first... rashes on body. Herxheimer reaction from clearing up of toxins?

Other than that scalp feels good, too early to tell anything though, will update if/when results are had.

Forestry
02-08-2016, 12:04 PM
i have been following (this forum is great, special thanks to Chemical for elaborating your findings) and researching and wanted to add this.

when reading wikipedia on keratinocyte (https://en.wikipedia.org/wiki/Keratinocyte) differentiation and the associated expression of specific keratins at each stage, i came to the section on the Role in Wound Healing, and the associated reference:

...Wounds to the skin will be repaired in part by the migration of keratinocytes to fill in the gap created by the wound. The first set of keratinocytes to participate in that repair come from the bulge region of the hair follicle and will only survive transiently... At the opposite, epidermal keratinocytes, can contribute to de novo hair follicle formation during the healing of large wounds (https://www.ncbi.nlm.nih.gov/pubmed/17507982).

https://www.ncbi.nlm.nih.gov/pubmed/17507982

"the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits, mice and even humans fifty years ago. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles."

I wonder if this (WnT signalling) study has been conducted in the presence of DHT and receptor diminishing regimen for such.

Response to Microneedling Treatment in Men with Androgenetic Alopecia Who Failed to Respond to Conventional Therapy (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458936/http://)

"
What was known?


Efficacy of conventional therapies (viz. finasteride and minoxidil) in the treatment of androgenetic alopecia with respect to new hair growth is moderate.
Microneedling has recently been reported to be promising and safe treatment modality in the treatment of AGA.

...
Microneedling is a novel and safe tool in the treatment of androgenetic alopecia which induces hair regrowth by the following.


Release of platelet-derived growth factor and epidermal growth factors are increased through platelet activation and skin wound regeneration mechanism
Activation of stem cells in the hair bulge area under wound healing conditions which is caused by a dermaroller
Overexpression of hair growth-related genes, vascular endothelial growth factor, B catenin, Wnt3a, and Wnt10 b as documented in animal studies.

...
What is new?


Modification of microneedling protocol to reduce frequent visits of the patients to the clinic.
It is the first case series to report the boosting effect of microneedling with respect to new hair follicle stimulation in patients with androgenetic alopecia who were poor responders to conventional therapy.

...
the total number and frequency of sessions and long-term sustainability of response of microneedling need to be evaluated within a larger population.
"

machi
02-08-2016, 01:00 PM
Chemical, thank you so much for your investigation. I have 2 questions for you.

1) What do you think about CB-03-01??? I had tought use it but it is very expensive (150$/gr) and I am not sure CB have good results.


2) ¿Can I use oleuropeina with emu oil for example? I would not want to use minoxidil. it's possible? I just need to stop my hair loss and thicken my hair weak , I do not need regrowth .


Thank you.

machi
02-09-2016, 04:22 AM
Chemical forgive me for making you so many questions , I do not want to bother you .
you say that you use every day cream Keto. Do not cause irritation ??? shampoo Keto causes irritation and can not be used daily . not the case using the cream topically Keto ??? may your hair is improved because Keto cream and not because of oleuropein ???
I have read your investigation many times but I am not sure how to use your treatment. You said that you used it four weeks and you rest 2 weeks. Is that so? or you have to use it every day?
you have to use morning and evening ?? when I wash my head , before or after using oleuropein .
you said using oleuropein to 0.5 % ? I'll buy oleuropein in amazon and I also want to buy ECGC . I do a lotion of ethanol and Propylene Glycol with oleuropeina and ECGC , you see it right ?? Can you say what quantities to use ?? I'm just going to use on my crown and temples.

Seuxin
02-09-2016, 07:05 AM
CB-03-01 is the god but we need a big price decrease...without group buy....just a shop with CB at low price...We need to find a lab !

potato1987
02-10-2016, 01:00 PM
Top work chemical! thank you for the read only post summary! :) https://www.baldtruthtalk.com/threads/22991-Treatments-and-Science-Read-Only

FeelsBad
02-10-2016, 09:09 PM
I'm currently using rosemary leaf extract, teavigo (ECGC), and olive leaf extract (oleuropein) in an ethanol/water vehicle. I have started shedding heavily after a few weeks, and a lot of the hairs have a white bulb at the end. What does this mean? Anyone have thoughts? Should I continue?

FADI
02-11-2016, 07:18 AM
hi chemical what about keto cream you did not indicate it in the treatment protocol?

FADI
02-11-2016, 07:22 AM
i read that sheding hairs with a white bulb is due to induction of hair growth cycle, thats mean that the treatment is effective and forcing the hair follicles to start a new growth cycle.

Phoenix7
02-11-2016, 06:03 PM
This is making my scalp, and area below the hairline shinier... That can't be a good sign, no?

FADI
02-12-2016, 01:09 AM
This is making my scalp, and area below the hairline shinier... That can't be a good sign, no?

What do you mean by this ? what is making this shedding?

Phoenix7
02-15-2016, 05:53 AM
What do you mean by this ? what is making this shedding?

I'm undecided. The reflectiveness could have just been the solution. I think I'm getting hairs on hairline that weren't there before, definitely am on the sides of the head. However, the front midsection has gone very thin. Hopefully its a big shed before regrowth.

Anyone shed quite badly on the minox/oleuropein?

Phoenix7
02-15-2016, 07:15 AM
Oleuropein is a cox-2 inhibitor and inhibits PGE2....

Sketchy as **** that this has been left out of chemical's analysis.

Sogeking
02-15-2016, 07:35 AM
Cox-2 inhibition promotes hair growth. Oleuropein is cox-2 inhibitor. In turn by inhibiting cox-2 we are implicitly inhibiting pgd2.
As for shedding. I've been using my mix for a week now. Shedding is the same as pre-use.

Minox is infamous for shedding. Google it. My mix has no minox.

Is it working for me? Not sure yet.

Phoenix7
02-15-2016, 08:28 AM
But why obfuscate the fact it inhibits PGE2 in such a detailed analysis? I can't think of a reason. And haven't cox 2 inhibitors been tried and failed already potentially for this very reason?

Been on the minox approaching 2 months so don't think its causing the shed (although can't be sure).

Sogeking
02-15-2016, 10:57 AM
But why obfuscate the fact it inhibits PGE2 in such a detailed analysis? I can't think of a reason. And haven't cox 2 inhibitors been tried and failed already potentially for this very reason?

Been on the minox approaching 2 months so don't think its causing the shed (although can't be sure).

WEll so far I found that oleuropein is COX-2 inhibitor. By inhibiting COX-2 you can promote hair growth as noted here:
http://cancerres.aacrjournals.org/content/62/9/2516.full.pdf
Also the study that propmted this thread says that it induces anagen hair growth:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462586/
The only place I found that mentions pge2 down regulation is this article (well found another study):
http://download.springer.com/static/pdf/79/art%253A10.1186%252Fs12967-014-0219-9.pdf?originUrl=http%3A%2F%2Ftranslational-medicine.biomedcentral.com%2Farticle%2F10.1186%2Fs 12967-014-0219-9&token2=exp=1455557573~acl=%2Fstatic%2Fpdf%2F79%2Fa rt%25253A10.1186%25252Fs12967-014-0219-9.pdf*~hmac=f21e3868ea4491fbcab02bbb095a16c5ed517e a364f1fc707b8e876be2541258

It has a table with PGE2 and an arrow going down. The reference points to an article:
http://www.sciencedirect.com/science/article/pii/S0955286313001782
IT says that hydroxytyrosol reduced PGE2 after:

The increase in prostaglandin E2 and interleukin 1β after reoxygenation were inhibited after incubation of brain slices with HT and after oral administration
So yeah if it were to reduce PGE2 why did oleuropein show induced anagen hair growth? Maybe the incubation of brain slices had some effect on PGE2 down regulation. Or maybe it was administering it orally?
Too many questions. The article is behind paywall. I'm gonna go with the the newest study about anagen hair growth.
As for results. So far there aren't any for me. But I started on 6th Feb.
Of course if you fear this is not helping you then stop using it. Not trying to be glib here. We actually can't say for sure if this will work. Most of the studies were done in mice so basically we are all live guinea pigs for this. Best of luck mate.

Also I am thinking about adding tea tree oil to my concoction (Eth/PG vehicle with OL, ECGC, Rosemary extract, Apple polyphenols) since it helps with seborrheic dermatitis.

SriHanuman
02-16-2016, 02:07 AM
Here is what I am using. Vehicle is Eth/Pg/Water and I made 2 concoctions.

First:
- Oleuropein ~0.6mg/ml
- Baicalin ~1mg/ml
- Apple polyphenols ~17mg/ml
- EGCG ~10mg/ml
- Rosemary extract ~1mg/ml
- Rice bran ~0.02mg/ml

I use this in the morning, started a week ago.

Second:
- Oleuropein ~0.6mg/ml
- Baicalin ~1mg/ml
- Fo-Ti ~17mg/ml
- EGCG ~10mg/ml
- Rosemary extract ~1mg/ml

I use this in the evening, started a month ago. There is no minox in any of the concoctions.

Nothing extraordinary to report yet, I maybe seeing more velus hairs and scalp feels great and that's about it for now. I will report back with the experiment if there is any positive results to report about.

UNBEAT
02-19-2016, 05:25 AM
anything new??any result using this

musky
02-21-2016, 09:59 AM
+1

Sogeking
02-21-2016, 12:08 PM
I'm at 2 weeks now. So far nothing to report. I might be having some decrease is shedding but it might be my wishful thinking. I'll be going with this for 3 months then I'll evaluate my results.

joshuk
02-21-2016, 01:16 PM
will be starting again next week with an eth/PG mix of OLE/EGCG/APPLE POLY

also recently bought 10g of CB-03-01 which i will be using again as i stopped all hairloss treatments for 2 weeks as i was in hospital. cant really take stuff like that in their haha.

noisette
02-26-2016, 02:04 PM
Topical Treatment of Hair Loss with Formononetin by Modulating Apoptosis.

Kim MH1,*Choi YY1,*Lee JE1,*Kim K2,*Yang WM1.

Author information

1College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, Seoul, Korea.2Department of Ophthalmology, Otorhinolaryngology and Dermatology of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.

Abstract

Formononetin is one of the main components of red clover plants and its role on hair regrowth against hair loss has not been established yet. In the present study, we assessed the potential effects of formononetin on alopecia, along with impaired hair cycles by induction of apoptosis-regression.Depilated C57BL/6 mice were used for monitoring the hair cycles. Formononetin (1 and 100 µM) was topically treated to the dorsal skin for 14 days. Topical formononetin treatment induced miniaturized hair follicles to recover to normal sizes. Tapering hair shaft began to grow newly, emerging from the hair follicles by formononetin. In addition, formononetin inhibited the activation of caspase-8 and decreased the procaspase-9 expression. As a result of formononetin treatment, anti-apoptotic Bcl-2 was up-regulated, whereas pro-apoptotic Bax and p53 were down-regulated, resulting in a decrease of caspase-3 activation. Formononetin showed the obvious inhibition of apoptosis under terminal deoxynucleotidyl transferase dUTP nick end labeling staining thereafter.Taken together, our findings demonstrate that formononetin exerted the hair regrowth effect on hair loss, in which the underlying mechanisms were associated with Fas/Fas L-induced caspase activation, thus inhibiting apoptosis.

Georg Thieme Verlag KG Stuttgart · New York

Seuxin
02-27-2016, 03:43 PM
Thanks Noisette !

Sadlly, it's only on mices...
Formononetin appear to be expansive...

Maybe have to find a natural component who contain it (red clover plants powder ?)

http://www.starwest-botanicals.com/category/red-clover-blossoms/

musky
03-07-2016, 06:36 AM
Yo McChemical dog you have misinterpreted this study

http://www.ncbi.nlm.nih.gov/pubmed/1632630


5 alpha-Dihydrotestosterone, the principal androgen mediating prostate growth and function in the rat, is formed from testosterone by steroid 5 alpha-reductase. The inactivation of 5 alpha-dihydrotestosterone involves reversible reduction to 5 alpha-androstane-3 beta,17 beta-diol by 3 beta-hydroxysteroid oxidoreductase followed by 6 alpha-, 7 alpha-, or 7 beta-hydroxylation. 5 alpha-Androstane-3 beta,17 beta-diol hydroxylation represents the ultimate inactivation step of dihydrotestosterone in rat prostate and is apparently catalyzed by a single, high-affinity (Km approximately 0.5 microM) microsomal cytochrome P450 enzyme. The present studies were designed to determine if 5 alpha-androstane-3 beta,17 beta-diol hydroxylation by rat prostate microsomes is inhibited by agents that are known inhibitors of androgen-metabolizing enzymes. Inhibitors of steroid 5 alpha-reductase (4-azasteroid analogs; 10 microM) or inhibitors of 3 beta-hydroxysteroid oxidoreductase (trilostane, azastene, and cyanoketone; 10 microM) had no appreciable effect on the 6 alpha-, 7 alpha-, or 7 beta-hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol (10 microM) by rat prostate microsomes. Imidazole-type antimycotic drugs (ketoconazole, clotrimazole, and miconazole; 0.1-10 microM) all markedly inhibited 5 alpha-androstane-3 beta,17 beta-diol hydroxylation in a concentration-dependent manner, whereas triazole-type antimycotic drugs (fluconazole and itraconazole; 0.1-10 microM) had no inhibitory effect. The rank order of inhibitory potency of the imidazole-type antimycotic drugs was miconazole greater than clotrimazole greater than ketoconazole. In the case of clotrimazole, the inhibition was shown to be competitive in nature, with a Ki of 0.03 microM. The imidazole-type antimycotic drugs inhibited all three pathways of 5 alpha-androstane-3 beta,17 beta-diol hydroxylation to the same extent, which provides further evidence that, in rat prostate microsomes, a single cytochrome P450 enzyme catalyzes the 6 alpha-, 7 alpha-, and 7 beta-hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol. These studies demonstrate that certain imidazole-type compounds are potent, competitive inhibitors of 5 alpha-androstane-3 beta,17 beta-diol hydroxylation by rat prostate microsomes, which is consistent with the effect of these antimycotic drugs on cytochrome P450 enzymes involved in the metabolism of other androgens and steroids.

Ketocanzole and miconazole inhibited the HYDROXYLATION of beta-diol, this means less beta-diol will be converted into it's hydroxy metabolites, which means if you use Keto there will be MORE beta-diol lying around. Food for thought dog.

bej
03-09-2016, 03:46 PM
There was discussion of using gamma linolenic acid and also linoleic acid (both omega-6) topically to help hair. I guess the premise is that they are precursors to eventually be turned into, among other things, PGE2.

I was looking at the pathway diagrams, and arachidonic acid is like 3 or 4 steps closer to PGE2 than those other fatty acids. Wouldn't arachidonic be superior to GLA and LA? Arachidonic acid should be easy to obtain, there are supplements for it.

tiktok
03-10-2016, 03:19 PM
There was discussion of using gamma linolenic acid and also linoleic acid (both omega-6) topically to help hair. I guess the premise is that they are precursors to eventually be turned into, among other things, PGE2.

I was looking at the pathway diagrams, and arachidonic acid is like 3 or 4 steps closer to PGE2 than those other fatty acids. Wouldn't arachidonic be superior to GLA and LA? Arachidonic acid should be easy to obtain, there are supplements for it.


Might be on to something there http://www.ncbi.nlm.nih.gov/pubmed/26848219 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737836/. Can buy here: http://www.bulknutrients.com.au/products/arachidonic-acid-40.html

bej
03-11-2016, 04:06 AM
Might be on to something there http://www.ncbi.nlm.nih.gov/pubmed/26848219 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737836/. Can buy here: http://www.bulknutrients.com.au/products/arachidonic-acid-40.html

The GLA and LA may have other functions, like inhibiting 5AR, but those activities are probably weak, and trumped by including something like RU in the regimen.

One caveat to all of these oils is whether they will dissolve in a vehicle. In my own experiments at home, I haven't found any oils that mix into a vehicle. One possible exception to that is Castor oil, which I read is miscible with ethanol. I don't have the patience to put several different things on my head every day.

bej
03-11-2016, 04:06 AM
deleted double post

bej
03-12-2016, 11:34 AM
Has anyone actually obtained some 20% oleuropein / olive leaf extract and tried dissolving it in a vehicle? It could be one of those things that just floats around in chunks, never dissolving. The oleuropein paper looked pretty good though. Too bad it wasn't a human study, but the mouse data, plus the human DP cell culture data showed a lot of good gene expression going in the desired direction.

InBeforeTheCure
03-12-2016, 11:42 AM
Has anyone actually obtained some 20% oleuropein / olive leaf extract and tried dissolving it in a vehicle? It could be one of those things that just floats around in chunks, never dissolving. The oleuropein paper looked pretty good though. Too bad it wasn't a human study, but the mouse data, plus the human DP cell culture data showed a lot of good gene expression going in the desired direction.

In a 50% ethanol/30% polysorbate 80/20% dimethyl isosorbide vehicle, it dissolves easily at .75%, the concentration he was using. It won't dissolve at 5% say in that vehicle, but if you first mix it around in a bit of DMSO and then add the other stuff, it works.

FeelsBad
03-12-2016, 05:56 PM
Has anyone actually obtained some 20% oleuropein / olive leaf extract and tried dissolving it in a vehicle? It could be one of those things that just floats around in chunks, never dissolving. The oleuropein paper looked pretty good though. Too bad it wasn't a human study, but the mouse data, plus the human DP cell culture data showed a lot of good gene expression going in the desired direction.

I bought some olive leaf extract that was already extracted in a water/glycerin base. It mixes easily with ethanol. Not sure if this is more or less effective though

Sogeking
03-12-2016, 08:07 PM
I got mine in 70% Eth / 20 % PG and it dissolved well enough. Same goes for apple olyphenols, ECGC and rosemary...

potato1987
03-14-2016, 01:36 PM
Chemical where are you mate?

ryan82
03-15-2016, 03:16 AM
Somebody already results or it that too early to ask? :confused:

lucky1987
03-16-2016, 05:01 AM
got the olive, egcg, gla and rosemary today.
only need to order the alcohol, but the ones being linked to are out.
i wonder if this will be good as wel:
http://www.drank.nl/winkel/pure-alcohol/

its 96% pure alcohol, if i understand it correctly this should work, if anyone can verify this.

also i want to make progression pictures, but i am a diffuse thinner, tried to take pictures, but you just dont see it on in the pictures.
if anyone has some advice on this.

Sogeking
03-16-2016, 01:57 PM
got the olive, egcg, gla and rosemary today.
only need to order the alcohol, but the ones being linked to are out.
i wonder if this will be good as wel:
http://www.drank.nl/winkel/pure-alcohol/

its 96% pure alcohol, if i understand it correctly this should work, if anyone can verify this.

also i want to make progression pictures, but i am a diffuse thinner, tried to take pictures, but you just dont see it on in the pictures.
if anyone has some advice on this.

That alcohol should be good enough. I actually use a mixture of 70% Eth and water mixed with PG as vehicle itself.
I too took pictures with my shitty smartphone 2 weeks ago. However those pictures will be only good enough if there are cosmetic improvements. So far I only have some velus hair on left temple that was bare. I am waiting to see if those hair go terminal or will they stay that way. Can't say for the rest of the scalp because I'm a diffuse thinner and so far only the left temple is totally bare and easily discernible with the naked eye.
Then again it could be placebo. Gonna have to wait for 3 month mark.

There were plenty of different treatments where people reported velus hair, however with the exception of minox and propecia none of them turned velus to terminal hair.

ryan82
03-17-2016, 05:17 AM
That alcohol should be good enough. I actually use a mixture of 70% Eth and water mixed with PG as vehicle itself.
I too took pictures with my shitty smartphone 2 weeks ago. However those pictures will be only good enough if there are cosmetic improvements. So far I only have some velus hair on left temple that was bare. I am waiting to see if those hair go terminal or will they stay that way. Can't say for the rest of the scalp because I'm a diffuse thinner and so far only the left temple is totally bare and easily discernible with the naked eye.
Then again it could be placebo. Gonna have to wait for 3 month mark.

There were plenty of different treatments where people reported velus hair, however with the exception of minox and propecia none of them turned velus to terminal hair.

if you never had velus hair there, then this is a improvement ?

lucky1987
03-17-2016, 05:25 AM
Thanks for the answer Sogeking!
Bought it, and mixed it together, 80% ethanol 20% pg.
used it as follow in a 60 ml mixture:
ol 1 mg/ml (bit more then a third of a capsule)
egcg 5 mg/ml (2 caps)
Rosemary 3 mg/ml (little over a third, i got 500 mg capsules)
GLA 5 mg/ml (just emptied 1 cap in the mixture)

Got a little residue left over, but only a very small amount, when i left it it sank to the bottom and used a syringe to put it into the bottle ( this made sure i did not get the pieces).
i also use finasteride, stemoxydine and 2 ml caster orally, hoping this all together will make the difference :)

bej
03-17-2016, 02:48 PM
In the pubmed abstracts I looked up on EGCG, it inhibits both PGD2 and PGE2. I'm not sure why people would speculate that that is going to come out as a net-positive. Are there any hair growth studies of topically applied EGCG that I missed? Those kind of results trump speculation. But if I had to just speculate, EGCG doesn't look like it would be helpful.

lucky1987
03-17-2016, 03:39 PM
In the pubmed abstracts I looked up on EGCG, it inhibits both PGD2 and PGE2. I'm not sure why people would speculate that that is going to come out as a net-positive. Are there any hair growth studies of topically applied EGCG that I missed? Those kind of results trump speculation. But if I had to just speculate, EGCG doesn't look like it would be helpful.

I believe you mean the ol, if not go ahead and link the study please :)

FADI
03-18-2016, 04:32 AM
Epigallocatechin-3-gallate (EGCG) from Green Tea

EGCG (usually derived from the dried leaves of green tea) has attained a stellar reputation worldwide for its purported health benefits and weight reduction properties. There is not enough proof of many of these benefits, but green tea in general has become synonymous with good health. So it is no surprise that there are several studies that have concluded EGCG to have a favorable impact on mouse hair as well as on human hair.



Oleuropein (Olive Drupe)

We keep reading about the miracle of olive oil and a Greek/ Mediterranean diet’s positive impact on human lifespan. Now there is yet one more reason to buy olives: a study from earlier this year from South Korea found that topical application of oleuropein induces anagen hair growth in mice. The study is quite technical and it seems like oleuropein stimulates the critical Wnt10b/β-catenin signaling pathway (which is also crucial when it comes to human hair). Oleuropein also upregulates IGF-1, KGF, HGF, and VEGF gene expression in mice. Hopefully they will do a human study on this soon.

FADI
03-18-2016, 04:57 AM
Epigallocatechin-3-gallate (EGCG) from Green Tea

EGCG (usually derived from the dried leaves of green tea) has attained a stellar reputation worldwide for its purported health benefits and weight reduction properties. There is not enough proof of many of these benefits, but green tea in general has become synonymous with good health. So it is no surprise that there are several studies that have concluded EGCG to have a favorable impact on mouse hair as well as on human hair.



Oleuropein (Olive Drupe)

We keep reading about the miracle of olive oil and a Greek/ Mediterranean diet’s positive impact on human lifespan. Now there is yet one more reason to buy olives: a study from earlier this year from South Korea found that topical application of oleuropein induces anagen hair growth in mice. The study is quite technical and it seems like oleuropein stimulates the critical Wnt10b/β-catenin signaling pathway (which is also crucial when it comes to human hair). Oleuropein also upregulates IGF-1, KGF, HGF, and VEGF gene expression in mice. Hopefully they will do a human study on this soon.

bej
03-18-2016, 10:32 AM
I believe you mean the ol, if not go ahead and link the study please :)

OK, I just did a pubmed search, and pulled up every paper that mentions both EGCG and PGE2. In just about every instance, EGCG causes a reduction in PGE2.

This first paper below is the most important one, it's topically applied EGCG to human skin. The second paper below shows that EGCG reduced beta-catenin activity, which is very bad if you want to grow hair. The remaining abstracts just reiterate the point that every time EGCG is put on something, PGE2 goes down, across a wide variety of animals and cell types. I highlighted the relevant parts in bold for easy skimming. In the second to last abstract listed, EGCG even downregulated the PGE2 receptors.


Photochem Photobiol. 1999 Feb;69(2):148-53.

Polyphenolic antioxidant (-)-epigallocatechin-3-gallate from green tea reduces UVB-induced inflammatory responses and infiltration of leukocytes in human skin.

Katiyar SK1, Matsui MS, Elmets CA, Mukhtar H.

Identification of natural products capable of affording protection against UVB radiation-induced inflammatory responses and generation of oxidative stress may have important human health implications. The UVB exposure-induced skin injury and oxidative stress has been associated with a variety of skin disease conditions including photoaging, inflammation and cancer. Tea is a popular beverage consumed worldwide. In several mouse skin models, topical application as well as oral consumption of green tea has been shown to afford protection against chemical and UVB-induced carcinogenesis and inflammatory responses. In the present study, we investigated in human skin, whether topical application of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent in green tea, inhibits UVB-induced infiltration of leukocytes (macrophage/neutrophils), a potential source of generation of reactive oxygen species (ROS), and generation of prostaglandin (PG) metabolites. Human subjects were UVB irradiated on sun-protected skin to four times their minimal erythema dosage (MED) and skin biopsies or keratomes were obtained either 24 h or 48 h later. We found that topical application of EGCG (3 mg/2.5 cm2) before UVB (4 MED) exposure to human skin significantly blocked UVB-induced infiltration of leukocytes and reduced myeloperoxidase activity. These infiltrating leukocytes are considered to be the major source of generation of ROS. In the same set of experiments we found that topical application of EGCG before UVB exposure decreased UVB-induced erythema. In additional experiments, we found that microsomes from EGCG pretreated human skin and exposed to UVB, compared to UVB exposure alone, produced significantly reduced PG metabolites, particularly PGE2. The PG metabolites play a critical role in free radical generation and skin tumor promotion in multistage skin carcinogenesis. Careful microscopic examination of skin sections, stained with hematoxylin and eosin, under higher magnification (x400) also revealed that EGCG pretreated and UVB-exposed human skin contained fewer dead cells in the epidermis with comparison to nonpretreated UVB-exposed skin. Taken together, our data demonstrate that EGCG has the potential to block the UVB-induced infiltration of leukocytes and the subsequent generation of ROS in human skin. This may explain the possible mechanism involved in anti-inflammatory effects of green tea. We suggest that EGCG may be useful as a topical agent for protection against UVB-induced ROS-associated inflammatory dermatoses, photoaging and photocarcinogenesis. Further studies are warranted in this direction.

PMID: 10048310



Toxicol Appl Pharmacol. 2013 Dec 1;273(2):418-24.

Green tea polyphenol, (-)-epigallocatechin-3-gallate, induces toxicity in human skin cancer cells by targeting β-catenin signaling.

Singh T1, Katiyar SK.

The green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), has been shown to have anti-carcinogenic effects in several skin tumor models, and efforts are continued to investigate the molecular targets responsible for its cytotoxic effects to cancer cells. Our recent observation that β-catenin is upregulated in skin tumors suggested the possibility that the anti-skin carcinogenic effects of EGCG are mediated, at least in part, through its effects on β-catenin signaling. We have found that treatment of the A431 and SCC13 human skin cancer cell lines with EGCG resulted in reduced cell viability and increased cell death and that these cytotoxic effects were associated with inactivation of β-catenin signaling. Evidence of EGCG-induced inactivation of β-catenin included: (i) reduced accumulation of nuclear β-catenin; (ii) enhanced levels of casein kinase1α, reduced phosphorylation of glycogen synthase kinase-3β, and increased phosphorylation of β-catenin on critical serine(45,33/37) residues; and (iii) reduced levels of matrix metalloproteinase (MMP)-2 and MMP-9, which are down-stream targets of β-catenin. Treatment of cells with prostaglandin E2 (PGE2) enhanced the accumulation of β-catenin and enhanced β-catenin signaling. Treatment with either EGCG or an EP2 antagonist (AH6809) reduced the PGE2-enhanced levels of cAMP, an upstream regulator of β-catenin. Inactivation of β-catenin by EGCG resulted in suppression of cell survival signaling proteins. siRNA knockdown of β-catenin in A431 and SCC13 cells reduced cell viability. Collectively, these data suggest that induction of cytotoxicity in skin cancer cells by EGCG is mediated by targeting of β-catenin signaling and that the β-catenin signaling is upregulated by inflammatory mediators.

PMID: 24096034


Int J Oncol. 2002 Dec;21(6):1275-83.

Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats.

Li ZG1, Shimada Y, Sato F, Maeda M, Itami A, Kaganoi J, Komoto I, Kawabe A, Imamura M.

The present study was conducted to assess the inhibitory effects of EGCG (epigallocatechin-3-gallate) on NMBA-induced rat esophageal tumorigenesis and to seek the potential mechanisms. In experiment I, 81 F344 rats were randomly divided into seven experimental groups according to the different regiments of NMBA 1 mg/kg subcutaneously (s.c.) and EGCG 4 mg/kg or 10 mg/kg orally or intraperitoneally (i.p.). The experiment was terminated at 24 weeks. In experiment II, 48 rats were allocated into two groups, each group contained 24 rats, in which the rats were injected with NMBA 1 mg/kg only or a combination of NMBA 1 mg/kg and EGCG 4 mg/kg i.p. Six rats from each group were sacrificed at the 12th, 16th, 20th and 24th week, respectively. The expression of cyclin D1 and cyclooxygenases (COX-2 and COX-1) was detected using semi-quantitative RT-PCR, and the production of prostaglandin E2 (PGE2) was measured by ELISA. In the groups which were treated with EGCG at a dose of 4 mg/kg i.p., or 10 mg/kg both orally and i.p., the mean number of tumors per rat was significantly reduced to 48, 56 and 61%, respectively (p<0.05). The incidence rate of esophageal carcinomas in the rats that were treated with EGCG 4 mg/kg i.p., was significantly lower than that in the rats which only received NMBA 1 mg/kg (p<0.05). The expression of cyclin D1 and COX-2, and the levels of PGE2 were also decreased by EGCG treatment. These results indicated that EGCG significantly inhibits the NMBA-induced rat esophageal carcinogenesis and it inhibitory effects may partly target cyclin D1 and COX-2 expression, and PGE2 production.

PMID: 12429978


Oncol Rep. 2003 Mar-Apr;10(2):421-6.

Promotion effects of hot water on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats.

Li ZG1, Shimada Y, Sato F, Maeda M, Itami A, Kaganoi J, Komoto I, Kawabe A, Imamura M.

This study is to determine the effects of hot water on N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis model. F344 rats received one treatment of hot water 1 ml/kg and NMBA 1 mg/kg, or a combination treatment of NMBA 1 mg/kg pus hot water 1 ml/kg, or/and EGCG (epigallocatechin-3-gallate) 10 mg/kg. The experiment was concluded at the 20th week. Our results showed that the number of tumors and incidence of carcinomas were significantly increased by hot water (65 degrees C) (p<0.05, p<0.03, respectively), as compared with the group which received NMBA injections only. EGCG treatment did not significantly reduce the number or the size of tumours as the temperature of added hot water increased. In addition, PGE2 production was induced by NMBA, and further significantly increased by added hot water (p<0.05). On the other hand, EGCG slightly decreased the elevated PGE2 production, however, this effect of EGCG was offset by hot water. Our study further confirmed that the drinking of hot beverages increased the risk of esophageal carcinogenesis, and the drinking hot tea will abolish the inhibitory effects of EGCG on this disease.

PMID: 12579283


J Pharmacol Exp Ther. 2005 Dec;315(3):1172-80.

Epigallocatechin-3-gallate impairs chemokine production in human colon epithelial cell lines.

Porath D1, Riegger C, Drewe J, Schwager J.

A major component in green tea, epigallocatechin-3-gallate (EGCG), is reported to interfere with different steps of a number of inflammatory pathways. After oral administration, EGCG is retained in the gastrointestinal tract, where it is thought to exert preventive functions against inflammatory bowel disease and colon cancer. In this study, the human colon adenocarcinoma cell lines HT29 and T84 were used to investigate the effect of EGCG on intestinal inflammation. HT29 and T84 cells were stimulated with tumor necrosis factor (TNF)-alpha to induce the inflammatory condition and to trigger the inflammatory cascade in vitro and treated with EGCG to study its effect on inflammatory processes. The secretion of the chemokines interleukin (IL)-8, macrophage inflammatory protein (MIP)-3alpha, and prostaglandin E2 (PGE2) was determined by enzyme-linked immunosorbent assay. The gene expression level was measured by quantitative real-time polymerase chain reaction. Treatment of TNF-alpha-stimulated HT29 cells with EGCG dose-dependently inhibited the synthesis of IL-8, MIP-3alpha, and PGE2. Treatment with EGCG also inhibited the production of IL-8 and MIP-3alpha in TNF-alpha-stimulated T84 cells. Gene expression analysis in both HT29 and T84 cells revealed that EGCG down-regulates genes involved in inflammatory pathways. This study shows that EGCG acts broadly on the production of chemokines and PGE2 in the chemokine and eicosanoid pathways of colon epithelial cells. Therefore, EGCG might prove useful for the prevention and/or attenuation of colonic disorders.

PMID: 16123309


J Exp Ther Oncol. 2005;5(1):69-78.

EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells.

Shimizu M1, Deguchi A, Joe AK, Mckoy JF, Moriwaki H, Weinstein IB.

Increased expression of COX-2 appears to play an important role in the development of colorectal cancer. The level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of RTKs. We previously reported that in HT29 human colon cancer cells EGCG, the major biologically active component of green tea, inhibits activation of two members of this family, EGFR and HER2, and multiple downstream signaling pathways. In this study we examined the effects of EGCG on the HER3 RTK and on COX-2 expression in the SW837 human colon cancer cell line that expresses a high level and constitutive activation of HER3 and also expresses a high level of COX-2. Treatment of these cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused, within 6 hours, a decrease in the phosphorylated (i.e. activated) forms of not only EGFR and HER2, but also HER3. At 6 to 12 hours there was a decrease in the phosphorylated forms of the downstream signaling proteins ERK and Akt. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activities of the COX-2, AP-1, and NF-kappaB promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 microg/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of EGFR, HER2, and HER3, a decrease in the levels of COX-2 and Bcl-xL proteins, and apoptosis. These results provide the first evidence that a low concentration of EGCG can inhibit activation of, at least, three members of the EGFR family of RTKs, and also inhibit COX-2 expression in colon cancer cells. These findings extend our previous evidence that EGCG may be useful in the chemoprevention and/or treatment of colorectal cancer.

PMID: 16416603


Exp Biol Med (Maywood). 2006 Jun;231(6):1123-7.

Antitumor effect of green tea polyphenol epigallocatechin-3-gallate in ovarian carcinoma cells: evidence for the endothelin-1 as a potential target.

Spinella F1, Rosanò L, Decandia S, Di Castro V, Albini A, Elia G, Natali PG, Bagnato A.

The green tea polyphenol, epigallocatechin-3-gallate (EGCG), has been shown to prevent cancer; however, a precise mechanism responsible for tumor growth inhibition has not yet been clearly described. The endothelin (ET) A receptor (ET(A)R)/ET-1 autocrine pathway is overexpressed in ovarian carcinoma and triggers tumor growth, neoangiogenesis, and invasion. These latter tumor-promoting effects are mediated through the activation of cyclooxygenase (COX)-1- and COX-2-dependent pathways by ET-1. In the present study, pretreatment of HEY and OVCA 433 ovarian carcinoma cell lines with green tea and EGCG inhibited ET-1/ET(A)R expression, ET(A)R-mediated COX-1/2 mRNA expression, and COX-2 promoter activity. These effects were associated with a significant reduction in the COX-1/2-derived prostaglandin E2 (PGE2) production. These results provide a novel insight into the mechanism by which EGCG, by affecting ET(A)R-dependent COX-1/2 pathways may inhibit ovarian tumors suggesting that EGCG may be useful in preventing and treating ovarian carcinoma in which activation of ET(A)R by ET-1 plays a critical role in tumor growth and progression.

PMID: 16741061


Biol Pharm Bull. 2008 Mar;31(3):527-30.

Identification of hop polyphenolic components which inhibit prostaglandin E2 production by gingival epithelial cells stimulated with periodontal pathogen.

Inaba H1, Tagashira M, Honma D, Kanda T, Kou Y, Ohtake Y, Amano A.

Chronic marginal periodontitis is a destructive inflammatory disease caused by an imbalance between bacterial virulence and host defense ability, resulting in eventual tooth exfoliation. Porphyromonas gingivalis, a major periodontal pathogen, triggers a series of cellular inflammatory responses including the production of prostaglandin E2 (PGE2), which causes periodontal destruction; thus, anti-inflammatory reagents are considered beneficial for periodontal therapy. In the present study, we examined whether hop- and apple-derived polyphenols (HBP and ACT, respectively) inhibit PGE2 production by human gingival epithelial (HGE) cells stimulated with P. gingivalis components. HGE cells were stimulated with P. gingivalis membrane vesicles, and the effects of HBP, ACT and epigallocatechin gallate (EGCg) on PGE2 production by HGE cells were evaluated using an enzyme-linked immunosorbent assay. HBP and EGCg significantly inhibited PGE2 production, whereas ACT did not. By further fractionation steps of HBP to identify the effective components, 3 components of HBP, 2-[(2-methylpropanoyl)-phloroglucinol]1-O-beta-D-glucopyranoside (MPPG), quercetin 3-O-beta-D-glucopyranoside (isoquercitrin), and kaempferol 3-O-beta-glucopyranoside (astragalin), were found to be elements which significantly inhibited cellular PGE2 production. These results suggest that HBP is a potent inhibitor of cellular PGE2 production induced by P. gingivalis, and HBP may be useful for the prevention and attenuation of periodontitis.

PMID: 18310924


PLoS One. 2011;6(10):e25224.

Green tea catechins reduce invasive potential of human melanoma cells by targeting COX-2, PGE2 receptors and epithelial-to-mesenchymal transition.

Singh T1, Katiyar SK.

Melanoma is the most serious type of skin disease and a leading cause of death from skin disease due to its highly metastatic ability. To develop more effective chemopreventive agents for the prevention of melanoma, we have determined the effect of green tea catechins on the invasive potential of human melanoma cells and the molecular mechanisms underlying these effects using A375 (BRAF-mutated) and Hs294t (Non-BRAF-mutated) melanoma cell lines as an in vitro model. Employing cell invasion assays, we found that the inhibitory effects of green tea catechins on the cell migration were in the order of (-)-epigallocatechin-3-gallate (EGCG)>(-)-epigallocatechin>(-)-epicatechin-3-gallate>(-)-gallocatechin>(-)-epicatechin. Treatment of A375 and Hs294t cells with EGCG resulted in a dose-dependent inhibition of cell migration or invasion of these cells, which was associated with a reduction in the levels of cyclooxygenase (COX)-2, prostaglandin (PG) E(2) and PGE(2) receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, also inhibited melanoma cell migration. EGCG inhibits 12-O-tetradecanoylphorbol-13-acetate-, an inducer of COX-2, and PGE(2)-induced cell migration of cells. EGCG decreased EP2 agonist (butaprost)- and EP4 agonist (Cay10580)-induced cell migration ability. Moreover, EGCG inhibited the activation of NF-κB/p65, an upstream regulator of COX-2, in A375 melanoma cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited cell migration. Inhibition of melanoma cell migration by EGCG was associated with transition of mesenchymal stage to epithelial stage, which resulted in an increase in the levels of epithelial biomarkers (E-cadherin, cytokeratin and desmoglein 2) and a reduction in the levels of mesenchymal biomarkers (vimentin, fibronectin and N-cadherin) in A375 melanoma cells. Together, these results indicate that EGCG, a major green tea catechin, has the ability to inhibit melanoma cell invasion/migration, an essential step of metastasis, by targeting the endogenous expression of COX-2, PGE(2) receptors and epithelial-to-mesenchymal transition.

PMID: 22022384


J Inflamm (Lond). 2014 Mar 28;11(1):8

Expression of pro-inflammatory mediators is inhibited by an avocado/soybean unsaponifiables and epigallocatechin gallate combination.

Ownby SL1, Fortuno LV, Au AY, Grzanna MW, Rashmir-Raven AM, Frondoza CG.

BACKGROUND:
Osteoarthritis (OA) is characterized by inflammation, joint immobility, and pain. Non-pharmacologic agents modulating pro-inflammatory mediator expression offer considerable promise as safe and effective treatments for OA. We previously determined the anti-inflammatory effect of an avocado/soybean unsaponifiables (ASU) and epigallocatechin gallate (EGCG) combination on prostaglandin E2 (PGE2) production and nuclear factor-kappa B (NF-κB) translocation. The aim of this study was to evaluate the effects of ASU + EGCG on pro-inflammatory gene expression.

FINDINGS:
Articular chondrocytes from carpal joints of mature horses were pre-incubated for 24 hours with control media alone or ASU (8.3 μg/mL) + EGCG (40 ng/mL), followed by one hour activation with interleukin-1 beta (IL-1β, 10 ng/mL) and tumor necrosis factor-alpha (TNF-α, 1 ng/mL). Total cellular RNA was isolated and real-time PCR performed to measure IL-1β, TNF-α, interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and interleukin-8 (IL-8) gene expression. Intracellular localization of NF-κB was analyzed by immunohistochemistry and Western blot. Pre-treatment with ASU + EGCG significantly (P < 0.001) decreased gene expression of IL-1β, TNF-α, IL-6, COX-2, and IL-8 in cytokine-activated chondrocytes. Western blot and immunostaining confirmed NF-κB translocation inhibition.

CONCLUSIONS:
We demonstrate that ASU + EGCG inhibits cytokine-induced gene expression of IL-1β, TNF-α, IL-6, COX-2, and IL-8 through modulation of NF-κB. Our results indicate that the activity of ASU + EGCG affects a wide array of inflammatory molecules in addition to decreasing PGE2 synthesis in activated chondrocytes. The responsiveness of chondrocytes to this combination supports its potential utility for the inhibition of joint inflammation.

PMID: 24678847

Seuxin
03-18-2016, 12:32 PM
Yeah, ECGC is just antioxydants, it's shitty for hair, useless, and bad since it inhibe pge2 ! No news about chemical...maybe he's totally bald...

ledhead
03-18-2016, 03:20 PM
Bej what are your thoughts on Oleuropein?

ledhead
03-18-2016, 04:11 PM
Nvm saw your post on the other page. I am using about 5-7 drops in a 3ml application of adenogen mixed with RU

SriHanuman
03-19-2016, 12:23 AM
In the pubmed abstracts I looked up on EGCG, it inhibits both PGD2 and PGE2. I'm not sure why people would speculate that that is going to come out as a net-positive. Are there any hair growth studies of topically applied EGCG that I missed? Those kind of results trump speculation. But if I had to just speculate, EGCG doesn't look like it would be helpful.

http://www.bettinamoritz.com.br/alunos/artigos/cha_verde_cabelo.pdf

Sogeking
03-19-2016, 12:38 AM
if you never had velus hair there, then this is a improvement ?

I mean that is an improvement, however those velus hair aren't doing me much good.
I guess I'll have to wait and see how this turns out.
About two weeks ago I also added some small amount of castor and rice bran oil to the mix.

bej
03-30-2016, 05:54 AM
Bej what are your thoughts on Oleuropein?

The data available look good, for mouse studies and human hair cell culture. The alterations in gene expressions look very desirable. It would be nice to see this tested in humans.

I ordered some Olive Leaf Extract with 20% Oleuropein. Unfortunately, it would be very crude for a topical. I put some extract in pure ethanol, and it had almost no solubility. The powder in the capsules appeared to be a fine olive-green. But it doesn't look so fine when you try to dissolve it. The solution turns green, so something dissolves a little bit. But it largely settles out with a fine greenish-brown powder, a heftier white powder, and a whole bunch of gnarly green chunks. If pure Oleuropein was available, I'd revisit this, but until then, I'm not pursuing it.

bej
03-30-2016, 05:55 AM
Bej what are your thoughts on Oleuropein?

The data available look good, for mouse studies and human hair cell culture. The alterations in gene expressions look very desirable. It would be nice to see this tested in humans.

I ordered some Olive Leaf Extract with 20% Oleuropein. Unfortunately, it would be very crude for a topical. I put some extract in pure ethanol, and it had almost no solubility. The powder in the capsules appeared to be a fine olive-green. But it doesn't look so fine when you try to dissolve it. The solution turns green, so something dissolves a little bit. But it largely settles out with a fine greenish-brown powder, a heftier white powder, and a whole bunch of gnarly green chunks. If pure Oleuropein was available, I'd revisit this, but until then, I'm not pursuing it.

Seuxin
03-30-2016, 07:06 AM
A first solution will be to made a tincture of oleuropein....or to buy directly a high dosed tincture.
Second solution, if you have oleuropein as powder is to try to coumpound a cream, maybe with an HRT Cream. But i think a tincture will be better...

Diffuse Danny
04-05-2016, 06:32 AM
I add a heaped teaspoon of Oleuropein powder into an 84ml bottle of Garnier fructis stemox, it dissolves quickly and perfectly

79BirdofPrey
04-06-2016, 02:21 AM
Can anyone share where one can purchase some quality Oleuropein here in the states? Thanks.

ryan82
04-07-2016, 01:11 AM
The key is the oleuropein for the velus hair and not EEGC ?

bej
04-08-2016, 06:15 AM
I add a heaped teaspoon of Oleuropein powder into an 84ml bottle of Garnier fructis stemox, it dissolves quickly and perfectly

Thanks. I might have bailed out too early. I also heard from someone else that it dissolves in water. I made the assumption that alcohol would be best, but looks like that was a wrong assumption.

bej
04-08-2016, 06:17 AM
deleted double post

bej
04-08-2016, 06:19 AM
Does applying the dissolved olive leaf extract leave a green residue on the skin? Or too faint to notice?

FeelsBad
04-08-2016, 07:11 PM
Slightly green but it's not noticeable

Chemical
04-12-2016, 02:09 PM
Hey guys, sorry about disappearing all of a sudden. I took a holiday but I'm back now and I'll be continuing where I left off. Theres alot to talk about, and I'll get around to it once I've caught up with this thread. Anyways just thought I'd let you know I'm back to do some real research and answer some of your questions.

monoid
04-12-2016, 06:36 PM
Hey guys, sorry about disappearing all of a sudden. I took a holiday but I'm back now and I'll be continuing where I left off. Theres alot to talk about, and I'll get around to it once I've caught up with this thread. Anyways just thought I'd let you know I'm back to do some real research and answer some of your questions.

Glad you are back!

Thanks for your new post! I've learned a lot. However, I strongly advise against trying this stuff:


Polygonum Multiflorum (Fo-Ti)


This plant is called 何首乌 (He-shou-wu) in Traditional Chinese medicine and is known to be highly hepatotoxic (toxic to liver). The root of this plant is very black, hence ancient Chinese people related it to black, healthy hair (common alternative medicine reasoning, which is of course BS). There has been numerous cases of liver damage caused by this substance.

InBeforeTheCure
04-12-2016, 10:46 PM
Nice to see you're still among the living, Chemical. ;)

A while back you posted this study:


Androgen treatment revealed a significant decrease in the cytoplasmic/total β-catenin protein ratio and upregulation of the activity of glycogen synthase kinase-3β in DPC, indicative of canonical Wnt pathway inhibition.

http://www.ncbi.nlm.nih.gov/pubmed/22283397

When they say there is a "significant decrease in the cytoplasmic/total beta-catenin protein ratio", where is the beta-catenin now? In the nucleus bound to AR, dragged there by DHT-induced AR translocation to the nucleus?

In A Mouse Model of Androgenetic Alopecia (http://sci-hub.io/10.1210/en.2009-1474), the authors find that AR binds beta-catenin in a DHT-dependent manner.

Co-immunoprecipitation of AR and beta-catenin:

http://s21.postimg.org/9n50im5xz/ct1.png

Another study: Keratinocyte Growth Inhibition through the Modification of Wnt Signaling by Androgen in Balding Dermal Papilla Cells (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682470/)


To examine whether the differences in HaCaT cell proliferation in coculture with AGA and non-AGA male DP cells were mediated by the action of AR and β-catenin, we investigated the subcellular distribution of AR and β-catenin in the cultured DP cells after treatment with DHT and/or Wnt3a. In DP cells of AGA40M (Fig. 2B​2B),), AR was diffusely distributed in cytoplasm, and β-catenin was present in pericellular cytoplasm in the absence of DHT and Wnt3a. In the presence of DHT, AR was significantly translocated to the nucleus, whereas cytoplasmic distribution of β-catenin was not so changed. When the DP cells were treated with Wnt3a, AR was present in the cytoplasm. In contrast, β-catenin was strongly enhanced and exhibited filamentous appearance. With the addition both of DHT and Wnt3a, AR and β-catenin were distributed in the nucleus in which they were colocalized. Similar distribution patterns of AR and β-catenin were observed in DP cells from other AGA males (Fig. 2C​2C).

Next we show that there is intracellular localization of AR and β-catenin in a ligand-free condition in DP cells of non-AGA males (Fig. 2D​2D).). Addition of either DHT or Wnt3a yielded this same intracellular localization in AGA40M or other male AGA cells. When DHT and Wnt3a were added together, colocalization of AR and β-catenin in the nucleus was sparse.

In AGA40M, after Wnt is added, beta-catenin remains locked down in the cytoplasm even in the absence of DHT:

http://s15.postimg.org/vit365dx7/kit1.png
Localization of AR and β-catenin in DP cells. A, DP cells of AGA40M and non-AGA male were treated with DHT (10−9 m) for various times (10 min, 1 h, 2 h). The cells were fixed and labeled with anti-AR and anti-β-catenin antibodies, followed by fluorescent second antibodies. All images were captured using confocal laser-scanning microscopy. DP cells of AGA40M (B) and from other AGA males (C) and non-AGA male (D) were cultured in the absence of both DHT and Wnt3a (−), presence of DHT, presence of Wnt3a (20 ng/μl) (W), or presence of both DHT and Wnt3a (WD) for 2 h. The cells were visualized as in A. Fluorescent images shown in green are AR, whereas the images in red are β-catenin. Merged images are shown in the right panels. Bar, 10 μm.


By using image analysis software, we examined the degree of nuclear colocalization of AR and β-catenin semiquantitatively using the ratio of merged dots in the nucleus/AR dots in cells treated with both Wnt3a and DHT (Fig. 3A​3A).). The ratios in DP cells from AGA males was higher by 2.5-fold than in DP cells of non-AGA males. These results indicate that AR and β-catenin in the nucleus was more highly colocalized in DP cells of AGA40M and other AGA males than in that of non-AGA males.

Co-localization of AR and beta-catenin:

http://s28.postimg.org/ujdtd80t9/kit2.png
C, AGA40M cells and non-AGA DP cells were treated with either DHT and/or Wnt3a for 2 h. Immunoprecipitation (IP) with anti-AR antibody was carried out using each cell lysate. Precipitates were analyzed by immunoblotting with each antibody. The upper panel shows the detection of β-catenin after immunoprecipitation with anti-AR antibody and the lower panel shows the detection of AR on the same membrane. D, Presence of DHT; W, presence of Wnt3a; WD, presence of both DHT and Wnt3a; WB, western blot.

This shows that in AGA40M, AR/beta-catenin binding is androgen-independent. This is different from the "mouse model" study where AR/beta-catenin binding was androgen-dependent. I guess this goes back to the FGF11 hypothesis that AGA becomes androgen-independent given enough time and androgen exposure, but virtually no work has been done to investigate this in any depth, so for now we don't really know.

If there is ligand-independent binding of AR/beta-catenin, AR antagonists that compete with androgens by binding to the AR LBD would have limited effectiveness because they can only counteract androgen-dependent AR activation. Something like MDV3100 would be more effective because it actually degrades the AR. There is a guy claiming to use MDV3100 who had dramatic results that he was unable to get with RU alone: https://www.baldtruthtalk.com/threads/23023-My-treatment-works-only-RU58841-5-10-and-MDV3100-2

EGCG may be helpful for that as well -- it potently inhibits AR transcription in vitro. However, it has a short half-life, so you would have to apply it several times a day, and even then I'm not sure how potent 2-3% EGCG (it's not soluble beyond that amount) is in vivo.

Anyway...Of course, as you know, dermal beta-catenin is critical for inducing epithelial hair follicle gowth.

β-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893731/)


The activity of keratinocytes in the hair follicle is regulated by signals from a specialized mesenchymal niche, the dermal papilla. Here, mice expressing cre recombinase in the dermal papilla were developed to probe the interaction between follicular keratinocyte populations and the dermal papilla in vivo. Inactivation of the β-catenin gene within the dermal papilla of fully developed hair follicles results in dramatically reduced proliferation of the progenitors and their immediate progeny that generate the hair shaft and, subsequently, premature induction of the destructive phase of the hair cycle (catagen). It also prevents regeneration of the cycling follicle from stem cells resident in the permanent portion of the follicle. Gene expression analysis reveals that β-catenin activity in the dermal papilla regulates at least two signaling pathways, FGF and IGF, that can mediate the inductive effects of the DP on keratinocytes. This study reveals a reciprocal signaling loop that employs Wnt/β-catenin signaling in both epithelial progenitor cells and their mesenchymal niche to govern and coordinate the interactions that are essential for the function of these two compartments.

Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621486/)


Although the hair shaft is derived from the progeny of keratinocyte stem cells in the follicular epithelium, the growth and differentiation of follicular keratinocytes is guided by a specialized mesenchymal population, the dermal papilla (DP), that is embedded in the hair bulb. Here we show that the number of DP cells in the follicle correlates with the size and shape of the hair produced in the mouse pelage. The same stem cell pool gives rise to hairs of different sizes or types in successive hair cycles, and this shift is accompanied by a corresponding change in DP cell number. Using a mouse model that allows selective ablation of DP cells in vivo, we show that DP cell number dictates the size and shape of the hair. Furthermore, we confirm the hypothesis that the DP plays a crucial role in activating stem cells to initiate the formation of a new hair shaft. When DP cell number falls below a critical threshold, hair follicles with a normal keratinocyte compartment fail to generate new hairs. However, neighbouring follicles with a few more DP cells can re-enter the growth phase, and those that do exploit an intrinsic mechanism to restore both DP cell number and normal hair growth. These results demonstrate that the mesenchymal niche directs stem and progenitor cell behaviour to initiate regeneration and specify hair morphology. Degeneration of the DP population in mice leads to the types of hair thinning and loss observed during human aging, and the results reported here suggest novel approaches to reversing hair loss.

A combination of cellular senescence and apoptosis in DP cells as well as maybe "effective" loss of DP cells due to AR binding of beta-catenin -> progressively lower actual/effective DP cell count -> hair follicle miniaturization

Krajcik et al (http://sci-hub.io/10.1067/mjd.2003.95) showed that vellus hairs from bald scalp progressively recover and grow thick terminal hair again after transplanted onto SCID mice. Why?

There was another study (http://sci-hub.io/10.1046/j.1523-1747.2000.00063.x) done a few years before Krajcik where they transplanted (healthy) human hair onto SCID mice. They found that the follicles soon went into something called dystrophic catagen -- large-scale apoptosis of the hair follicle -- followed by regeneration. Perhaps this process "resets" the follicle by removing senescent cells and other cells with screwy gene expression.

Interestingly enough, topical estrogen accelerates hair regrowth in mice after chemotherapy-induced alopecia by favoring the dystrophic catagen response pathway to damage. (http://www.ncbi.nlm.nih.gov/pubmed/14962083) Maybe this is one reason (among others) why estrogen is so effective at regrowing hair in even advanced cases of AGA.

Seuxin
04-13-2016, 01:03 AM
Hello Chemical,

What about your progress ( Oleuropein, etc....)

Thanks

InBeforeTheCure
04-13-2016, 04:21 AM
Another study: Keratinocyte Growth Inhibition through the Modification of Wnt Signaling by Androgen in Balding Dermal Papilla Cells (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682470/)



In AGA40M, after Wnt is added, beta-catenin remains locked down in the cytoplasm even in the absence of DHT:

http://s15.postimg.org/vit365dx7/kit1.png
Localization of AR and β-catenin in DP cells. A, DP cells of AGA40M and non-AGA male were treated with DHT (10−9 m) for various times (10 min, 1 h, 2 h). The cells were fixed and labeled with anti-AR and anti-β-catenin antibodies, followed by fluorescent second antibodies. All images were captured using confocal laser-scanning microscopy. DP cells of AGA40M (B) and from other AGA males (C) and non-AGA male (D) were cultured in the absence of both DHT and Wnt3a (−), presence of DHT, presence of Wnt3a (20 ng/μl) (W), or presence of both DHT and Wnt3a (WD) for 2 h. The cells were visualized as in A. Fluorescent images shown in green are AR, whereas the images in red are β-catenin. Merged images are shown in the right panels. Bar, 10 μm.



Co-localization of AR and beta-catenin:

http://s28.postimg.org/ujdtd80t9/kit2.png
C, AGA40M cells and non-AGA DP cells were treated with either DHT and/or Wnt3a for 2 h. Immunoprecipitation (IP) with anti-AR antibody was carried out using each cell lysate. Precipitates were analyzed by immunoblotting with each antibody. The upper panel shows the detection of β-catenin after immunoprecipitation with anti-AR antibody and the lower panel shows the detection of AR on the same membrane. D, Presence of DHT; W, presence of Wnt3a; WD, presence of both DHT and Wnt3a; WB, western blot.


The weird thing is looking at Figure 4, it seems like Tcf/Lef are still activating their target genes (higher luciferase activity w/ Tcf/Lef responsive promoter). Also in non-AGA males, DHT looks to be about as good as Wnt signaling for activating Tcf/Lef target genes??? :confused:

Chemical
04-13-2016, 12:48 PM
Glad you are back!

This plant is called 何首乌 (He-shou-wu) in Traditional Chinese medicine and is known to be highly hepatotoxic (toxic to liver). The root of this plant is very black, hence ancient Chinese people related it to black, healthy hair (common alternative medicine reasoning, which is of course BS). There has been numerous cases of liver damage caused by this substance.

I was under the impression topical application wouldnt cause much systemic absorption. I havent taken it but the studies demonstrated that it had alot of potential to stimulate the proliferation of DPC/Keratinocytes, not the traditional beliefs of the Chinese. We dont pass hearsay as scientific proof around here. Thank you for the welcome!

@InBeforeTheCure

A study as a welcome present, what more could I ask for. Excellent analysis as always.


Keratinocyte Growth Inhibition through the Modification of Wnt Signaling by Androgen in Balding Dermal Papilla Cells (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682470/)

When HaCaT cells were cocultured with an AGA patient-derived DP cell line, AGA40M, the number of HaCaT cells was not influenced by the addition of DHT. But the number of HaCaT cells was significantly increased in the presence of Wnt-3a, and this growth was significantly suppressed by the addition of DHT (Fig. 1B​1B).). A similar effect of DHT was detected in the coculture of the HaCaT cells with DP cells from other AGA patients (data not shown). In the coculture with DP cells of non-AGA males, the number of HaCaT cells was also increased by the addition of Wnt3a, but significant growth suppression due to DHT was not detected (Fig. 1C​1C).

Wnt3a treatment significantly accelerated the growth of HaCaT cells in the single cell culture, but the addition of DHT did not affect growth (Fig 1D​1D).). On the other hand, the growth of DP cells was not affected by Wnt3a in single cell culture conditions (data not shown). It has been reported that androgen does not influence growth of DP cells in a single cell culture condition (26,27). These results indicate that Wnt3a-dependent keratinocyte proliferation is reduced by DHT in the coculture with AGA DP cells. This suggests that this DHT effect is not a direct action on keratinocytes but is mediated through DP cells.

There is a very strong genetic component here with the AGA DPC. The cells respond to the DHT by further antagonizing the growth of the adjacent cells in addition to the DHT mediated TCF/LEF suppression:


DP cells were transfected with a reporter plasmid in which the luciferase gene was connected downstream to the Lef/Tcf-binding promoter. Lef/Tcf-mediated transcriptional activity was induced by treatment with Wnt3a in AGA40M cells, but this induction was significantly suppressed by the addition of DHT (Fig. 4A​4A).). The same result was observed in DP cells of other AGA male. In contrast, in DP cells of non-AGA males, the transcriptional activity was not suppressed by DHT. These results indicate that the Wnt-β-catenin signaling pathway is negatively influenced by ligand-activated AR in DP cells of AGA but not DP cells of non-AGA males.


Regarding this:


The weird thing is looking at Figure 4, it seems like Tcf/Lef are still activating their target genes (higher luciferase activity w/ Tcf/Lef responsive promoter). Also in non-AGA males, DHT looks to be about as good as Wnt signaling for activating Tcf/Lef target genes??? :confused:

This should answer your question:



It has been reported that Tcf-4 is a downstream target of AR in skeletal muscle (28); therefore, we investigated expression of Tcf-4 protein in the DP cells by immunoblotting. Both AGA and non-AGA DP cells expressed Tcf-4 protein (Fig. 4C​4C).


AR can and does use Beta Catenin to exert some of its anabolic effects so it makes sense that it interacts with TCF.




When they say there is a "significant decrease in the cytoplasmic/total beta-catenin protein ratio", where is the beta-catenin now? In the nucleus bound to AR, dragged there by DHT-induced AR translocation to the nucleus?

Exactly like you've said:



Thus, we assumed that AGA-derived DP cells specifically inhibited the growth of keratinocyte and the potential of Lef/Tcf mediated transcription might be due to differences in translocation of AR and β-catenin to the nucleus. As expected, in the presence of DHT and Wnt3a, a significantly higher ratio of AR to β-catenin was cotranslocated to the nucleus in DP cells of AGA than in DP cells of non-AGA males. Considering this result together with analysis of Lef/Tcf mediated transcription, it is conceivable that nuclear interaction of liganded AR with β-catenin inhibits transcriptional activity in DP cells of AGA. In fact, direct binding of AR and β-catenin was more frequent in AGA DP cells than non-AGA DP cells as determined by the present immunoprecipitation analysis.





In AGA40M, after Wnt is added, beta-catenin remains locked down in the cytoplasm even in the absence of DHT:

This shows that in AGA40M, AR/beta-catenin binding is androgen-independent. This is different from the "mouse model" study where AR/beta-catenin binding was androgen-dependent. I guess this goes back to the FGF11 hypothesis that AGA becomes androgen-independent given enough time and androgen exposure, but virtually no work has been done to investigate this in any depth, so for now we don't really know.

This is something I had a hard time accepting. Its not so obvious in the pictures but I can see what you're talking about, however I am still reluctant to jump to this conclusion. If AR does indeed permanently change the response of DPC to T/DHT then it means the sensitivity of AGA to androgens increases as time goes on making regrowth even harder for individuals.



If there is ligand-independent binding of AR/beta-catenin, AR antagonists that compete with androgens by binding to the AR LBD would have limited effectiveness because they can only counteract androgen-dependent AR activation. Something like MDV3100 would be more effective because it actually degrades the AR. There is a guy claiming to use MDV3100 who had dramatic results that he was unable to get with RU alone: https://www.baldtruthtalk.com/threads/23023-My-treatment-works-only-RU58841-5-10-and-MDV3100-2

Absolutely. If AR is upregulated then preventing the binding of AR to LBD or translocating to the nucleus will do jack sh!t if the AR is taking up beta-catenin. We would need something that can interact with the stability of AR. Even EGCG would have little effect seeings as its already a very mild AR antagonist (post coming soon).



Anyway...Of course, as you know, dermal beta-catenin is critical for inducing epithelial hair follicle gowth.

A combination of cellular senescence and apoptosis in DP cells as well as maybe "effective" loss of DP cells due to AR binding of beta-catenin -> progressively lower actual/effective DP cell count -> hair follicle miniaturization

Krajcik et al (http://sci-hub.io/10.1067/mjd.2003.95) showed that vellus hairs from bald scalp progressively recover and grow thick terminal hair again after transplanted onto SCID mice. Why?

There was another study (http://sci-hub.io/10.1046/j.1523-1747.2000.00063.x) done a few years before Krajcik where they transplanted (healthy) human hair onto SCID mice. They found that the follicles soon went into something called dystrophic catagen -- large-scale apoptosis of the hair follicle -- followed by regeneration. Perhaps this process "resets" the follicle by removing senescent cells and other cells with screwy gene expression.


Like you say, the AGA DPC are preprogrammed to respond to DHT in a self-destructive manner so long as they contain the genetic code specific to the frontal scalp. If you remove Androgens from the equation they will function as normal but theres absolutely no way we can completely abolish T/DHT. I've said before about the DPC having direct access to the blood supply's androgens, so it looks like a hopeless battle trying to use the existing DPC to maintain hair. And since prenatal DPC dont exactly disappear and only become senescent, the code is still present, so even if you manage to achieve regrowth and the cells go into anagen, the DPC will still be susceptible. The only solution I see is hijacking the keratinocytes ability to form HF when over-expressed with beta-catenin. That way the DPC that are formed might not have the sensitivity to DHT. The guys at histogen (or was it replicel) claimed to have seen progressive regrowth and maintenance with infrequent injections of powerful mitogenic growth factors like HGF.

My current progress

I stopped everything around 2 months ago. Before I stopped I was using the following for two weeks:

Minox by itself - morning
Minox + EGCG - night
Minox + OL - night
Water + VPA - night
Keto + Mico - morning & night
Evening primrose - night

After stopping, a week later I saw a ridiculous amount of vellus hairs all along my nw0 hairline, so much that it looked like I'd cured my recession. I strongly suspect this a residual effect of all the treatments finally showing results - or it could be because I stopped. I really really regret not taking pictures which means we're going to have to write it off as not happening but I have hope that I'll be able to recreate the results again and this time will take pictures. I didnt have my treatments with me so I couldnt continue but I had good density and I was quite happy. 6 weeks later I started receding again and lost all the vellus hairs but surprisingly I didnt lose the hairs on the side I was concentrating all my treatments (pics soon). I've got more density than I've had in the past year and I'm back on minox, keto, mico, EPO and borage oil. The EGCG is quite irritating so I've dropped it and I've ordered some more OL. I've managed to regrow hair using only minox and OL in the past - without an AR blocker, so the EPO and Borage oil should definitely help. I might use the VPA again and I'm considering creating a topical out of my fin tablets.

monoid
04-13-2016, 11:42 PM
I was under the impression topical application wouldnt cause much systemic absorption. I havent taken it but the studies demonstrated that it had alot of potential to stimulate the proliferation of DPC/Keratinocytes, not the traditional beliefs of the Chinese. We dont pass hearsay as scientific proof around here. Thank you for the welcome!

Well if it has solid scientific proof then OK. Be careful with it since its hepatotoxicity is confirmed.

burtandernie
04-14-2016, 03:55 PM
I think some people on here like chemical should be researching an actual treatment for MPB. Some of the guys here know as much as the researchers almost. Can you use those supplements orally instead of having to mix a topical vehicle? how do you know using that stuff causes any hair growth verses it being from the minox which is obviously one of the best regrowth agents.
What is the best and safest way to stop the most androgens?

InBeforeTheCure
04-14-2016, 11:35 PM
AR can and does use Beta Catenin to exert some of its anabolic effects so it makes sense that it interacts with TCF.

But in the stains, it looks like very little AR or beta-catenin is in the nucleus after Wnt is added in AGA40M?

Anyway, I'm wondering if AR binding to beta-catenin could maybe alter the way in which beta-catenin interacts with Wnt response elements -- for instance by recruiting HATs and HDACs to remodel chromatin structure, or by other interactions with certain transcription factors -- and thereby downregulate some Wnt target genes and upregulate others. DKK1 for example is actually a Wnt target gene -- and indeed DKK1 is upregulated over 2x in response to Wnt in DPCs (http://sci-hub.io/10.1016/j.jdermsci.2010.02.011) -- and as you've pointed out DKK1 is (further) upregulated in balding DP cells in response to DHT. The new gene transcription "profile" of DPCs in response to Wnt could then fail to induce epithelial stem cell activation. Highly speculative, but could it be possible?


This is something I had a hard time accepting. Its not so obvious in the pictures but I can see what you're talking about, however I am still reluctant to jump to this conclusion. If AR does indeed permanently change the response of DPC to T/DHT then it means the sensitivity of AGA to androgens increases as time goes on making regrowth even harder for individuals.

Increased sensitivity to androgens could happen by

- Upregulation of AR
- An increase in androgen-independent activation of AR. Let's say z is the threshold in AR activation that causes hair loss, x is the androgen-independent level of activation, and y is activation caused by androgens. And let's say androgen-independent activation is very low in early stages of balding, but rises somehow over time as a result of DHT-bound AR transcribing its target genes. Left untreated, x rises over time and it takes less y to push x + y over the threshold (z). Eventually x > z and no anti-androgen or even castration could push AR activation below z -- the DPC's inductive ability is lost.

In this model castration > dut > fin. A prediction of this model is that someone who is maintaining on fin who goes on dut, regrows some on dut, but then switches back to fin would lose the hair he gained on dut (is this how it is in reality?). This would be expected based on a model where AR is upregulated or androgen-independent activation of AR increases over time with exposure to DHT, or both. At least, I think it would fit such a model better than a model where DP cells in recently lost hair are "repaired" in response to androgen removal.

I'm just speculating here, of course.


Absolutely. If AR is upregulated then preventing the binding of AR to LBD or translocating to the nucleus will do jack sh!t if the AR is taking up beta-catenin. We would need something that can interact with the stability of AR. Even EGCG would have little effect seeings as its already a very mild AR antagonist (post coming soon).

Sulforaphane? (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757849/) Don't know how good it would be in practice though. Seems to have a half-life of only a couple hours too, so even if it did work you might have to use it 20 times a day or so, including at night. ;)


Like you say, the AGA DPC are preprogrammed to respond to DHT in a self-destructive manner so long as they contain the genetic code specific to the frontal scalp. If you remove Androgens from the equation they will function as normal but theres absolutely no way we can completely abolish T/DHT. I've said before about the DPC having direct access to the blood supply's androgens, so it looks like a hopeless battle trying to use the existing DPC to maintain hair. And since prenatal DPC dont exactly disappear and only become senescent, the code is still present, so even if you manage to achieve regrowth and the cells go into anagen, the DPC will still be susceptible. The only solution I see is hijacking the keratinocytes ability to form HF when over-expressed with beta-catenin. That way the DPC that are formed might not have the sensitivity to DHT. The guys at histogen (or was it replicel) claimed to have seen progressive regrowth and maintenance with infrequent injections of powerful mitogenic growth factors like HGF.

Yes, but dystrophic catagen could remove senescent cells and other malfunctioning cells from the cell cycle. Then dermal stem cells regenerate the dermal papilla. Sure, over time it will malfunction again, but you would just need maintenance treatments then to stop that from happening. And then eventually, once the technology is available, you could get the AR gene knocked down permanently in your scalp and never have to worry about AGA again. :cool:

UNBEAT
04-15-2016, 02:29 AM
so CHIMICAL , INBEFORETHECURE : fgf 11 with his theory about AR genes and what he is trying to do is right , or not??? It can be like a cure?

InBeforeTheCure
04-15-2016, 10:26 AM
Anyway, I'm wondering if AR binding to beta-catenin could maybe alter the way in which beta-catenin interacts with Wnt response elements -- for instance by recruiting HATs and HDACs to remodel chromatin structure, or by other interactions with certain transcription factors -- and thereby downregulate some Wnt target genes and upregulate others. DKK1 for example is actually a Wnt target gene -- and indeed DKK1 is upregulated over 2x in response to Wnt in DPCs (http://sci-hub.io/10.1016/j.jdermsci.2010.02.011) -- and as you've pointed out DKK1 is (further) upregulated in balding DP cells in response to DHT. The new gene transcription "profile" of DPCs in response to Wnt could then fail to induce epithelial stem cell activation. Highly speculative, but could it be possible?


The more I look into it, the more I think this is probably correct. It's probably not so much that AR binds beta-catenin and prevents it from acting (as FGF11 thought). I think it's more likely that AR hijacks the Wnt pathway for its own nefarious purposes by binding to beta-catenin and altering the way that beta-catenin/TCF4 interacts with Wnt response elements, either enhancing them or (relatively) repressing them. From this model you can actually derive, for example, why PGD2 is upregulated in AGA with reference to both theory and experimental results. You can also imagine how a similar mechanism could actually account for why androgens stimulate facial hair growth while causing hair loss on your head. However, I'd like to develop this idea further before really getting into that (maybe I'll create a new thread sometime).

This is not exactly a novel idea, as something similar is known to happen in prostate cells (http://sci-hub.io/10.1002/pros.22828), for example.


so CHIMICAL , INBEFORETHECURE : fgf 11 with his theory about AR genes and what he is trying to do is right , or not??? It can be like a cure?

I think the answer is "I don't know". :p

tylerbose
04-15-2016, 11:04 AM
Minox + OL - night

hi everyone, sorry for the off topic question.

did you put the OL caps inside the minox jar ? or are t they separated ?
if so, would it be possible to use something other than ethanol as vehicle ?
thank you

Chemical
04-15-2016, 12:26 PM
"the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits, mice and even humans fifty years ago. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles."

I wonder if this (WnT signalling) study has been conducted in the presence of DHT and receptor diminishing regimen for such.

Hope you're still around, some excellent research you've got here.

I've read alot of studies on Wound Induced Hair regeneration in humans and most of them point towards pge2 mediated anagen induction instead of actual HF formation. The platelet derived growth factors seem like another potential candidate in increasing the probability of anagen induction. I'm more interested in new HF formation with wounding, in the hope that it might create HF's that arent susceptible to DHT.


Hair regrowth following a Wnt- and follistatin containing treatment: safety and efficacy in a first-in-man phase 1 clinical trial. (http://europepmc.org/abstract/med/22052313)
...
These results demonstrate that a single intradermal administration of HSC improved hair growth in subjects with androgenetic alopecia and is a clinical substantiation of previous preclinical research with Wnts, follistatin, and other growth factors associated with wound healing and regeneration.

Histopathological evaluation of the treatment site biopsies taken at 22 and 52 weeks post-treatment revealed no abnormal morphology, hamartomas, or other pathological responses. Trichoscan image analysis of HSC-treated sites at 12 and 52 weeks showed significant improvements in hair growth over the placebo. At the initial 12-week evaluation period, HSC-treated sites demonstrated an increase in hair shaft thickness (6.3%±2.5% vs. -0.63%±2.1%; P=0.046), thickness density (12.8%±4.5% vs. -0.2%±2.9%; P=0.028), and terminal hair density (20.6±4.9% vs. 4.4±4.9%; P=0.029). At one year, a statistically significant increase in total hair count (P=0.032) continued to be seen. These results demonstrate that a single intradermal administration of HSC improved hair growth in subjects with androgenetic alopecia and is a clinical substantiation of previous preclinical research with Wnts, follistatin, and other growth factors associated with wound healing and regeneration.

This is histogen (GK Naughton)

How is it that just one injection continues to work even after 1 year? Either this is complete bs or its a scientific breakthrough. I'm tempted to say that these growth factors created new follicles that weren't affected by DHT and since non AGA DPC secrete growth factors to nearby cells it could very well be that this started a chain reaction. Follistatin can be purchased and this has my curiosity.


I've only ready the first link SriHanuman , that is a good read and shows RB-SCE a decent alternative to minoxidil.

In terms of the stack, Linoleic Acid (LA) is there (here I'm lumping together GLA and LA) with Evening Primrose*.

The new item appears to be Gamma Oryzanol (www.amazon.com/gp/product/B00MXYPH9A/)(OZ).

I wish the study went out past 4 weeks. The OZ really kicked in at week 4.


I forgot to say thanks for posting this, pointed me in the direction to discover GLA is a fairly powerful 5ar inhibitor.


chemical im going to be buying some Sodium Valproate when kane gets back from holidays, what vehicle would you use 70/30 eth/pg or is their a better one. was thinking about using 70mg a day

Water! 50mg/ml vs 30mg/ml ethanol. Distilled water preferably.


But why obfuscate the fact it inhibits PGE2 in such a detailed analysis? I can't think of a reason. And haven't cox 2 inhibitors been tried and failed already potentially for this very reason?

Been on the minox approaching 2 months so don't think its causing the shed (although can't be sure).

I couldnt find any obvious research indicating that OL directly inhibited PGE2 but as with anything that inhibits COX-2 there is bound to be a decrease in PGE2 synthesis. COX-2 is an inflammatory response so I wouldnt be surprised if an anti-inflammatory reduces COX-2.


Yo McChemical dog you have misinterpreted this study

http://www.ncbi.nlm.nih.gov/pubmed/1632630

Ketocanzole and miconazole inhibited the HYDROXYLATION of beta-diol, this means less beta-diol will be converted into it's hydroxy metabolites, which means if you use Keto there will be MORE beta-diol lying around. Food for thought dog.


The inactivation of 5 alpha-dihydrotestosterone involves reversible reduction to 5 alpha-androstane-3 beta,17 beta-diol by 3 beta-hydroxysteroid oxidoreductase followed by 6 alpha-, 7 alpha-, or 7 beta-hydroxylation. 5 alpha-Androstane-3 beta,17 beta-diol hydroxylation represents the ultimate inactivation step of dihydrotestosterone in rat prostate and is apparently catalyzed by a single, high-affinity (Km approximately 0.5 microM) microsomal cytochrome P450 enzyme. The present studies were designed to determine if 5 alpha-androstane-3 beta,17 beta-diol hydroxylation by rat prostate microsomes is inhibited by agents that are known inhibitors of androgen-metabolizing enzymes. Imidazole-type antimycotic drugs (ketoconazole, clotrimazole, and miconazole; 0.1-10 microM) all markedly inhibited 5 alpha-androstane-3 beta,17 beta-diol hydroxylation in a concentration-dependent manner, whereas triazole-type antimycotic drugs (fluconazole and itraconazole; 0.1-10 microM) had no inhibitory effect.

Hydroxylation is the process by which 5ar gets converted to 3beta-diol. Keto and mico inhibit this step thus preventing the conversion of DHT to 3Beta-diol.


The GLA and LA may have other functions, like inhibiting 5AR, but those activities are probably weak, and trumped by including something like RU in the regimen.

One caveat to all of these oils is whether they will dissolve in a vehicle. In my own experiments at home, I haven't found any oils that mix into a vehicle. One possible exception to that is Castor oil, which I read is miscible with ethanol. I don't have the patience to put several different things on my head every day.

GLA and LA's predominant function in AGA would be 5ar suppression imo. Studies show GLA to be far better than any other nutraceutical at inhibiting 5ar. There havent direct comparisons with Serenoa Repens (saw palmetto) but on paper it seems far superior. The whole point of these outlandish treatments to block 5ar is to avoid the systemic effects of HPTA overcompensation increasing T production and subsequently offsetting the effects of fin or dut. Oils are tricky in terms of absorption but I guess the whole point of oils is that they'll eventually get absorbed.


OK, I just did a pubmed search, and pulled up every paper that mentions both EGCG and PGE2. In just about every instance, EGCG causes a reduction in PGE2.

This first paper below is the most important one, it's topically applied EGCG to human skin. The second paper below shows that EGCG reduced beta-catenin activity, which is very bad if you want to grow hair. The remaining abstracts just reiterate the point that every time EGCG is put on something, PGE2 goes down, across a wide variety of animals and cell types. I highlighted the relevant parts in bold for easy skimming. In the second to last abstract listed, EGCG even downregulated the PGE2 receptors.

What you've posted are studies done on carcinogenic cell lines demonstrating the wonderful paradoxical effects of EGCG on different tissues. Its something that I was puzzled by but apparently thats how EGCG works, its a powerful anti-tumor agent in cancerous cells but acts as a mitogenic agent in normal cells.

Chemical
04-15-2016, 02:00 PM
There was another study (http://sci-hub.io/10.1046/j.1523-1747.2000.00063.x) done a few years before Krajcik where they transplanted (healthy) human hair onto SCID mice. They found that the follicles soon went into something called dystrophic catagen -- large-scale apoptosis of the hair follicle -- followed by regeneration. Perhaps this process "resets" the follicle by removing senescent cells and other cells with screwy gene expression.

I missed this sorry. (whats up with the sci-hub.io links? I never get to see the damn article, it shows me some russian page and I feel left out of your scientific research)

I wonder why the cells go into catagen only to regenerate? I was doing some in depth reading on the DPC and how even in AGA telogen the DPC remains intact - although senescent. Which means you'll always have the dysfunction no matter how many times you go through anagen and its only the DPC that are the faulty cells. If you permanently destroy the DPC however, the dermal sheath can regenerate a new DPC! (would recommend reading whole article, very interesting)

Review of hair follicle dermal cells (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818774/)



DS has been considered as a cellular reservoir of DP cells during the hair follicle cycle[9], and it was hypothesized that stem cells might reside in the DS similar to its epithelial counterpart, the outer root sheath [10]. DS cells share similar characteristics with the DP and can regenerate a new DP after loss of the DP [11–13]. In classic transection studies of rat vibrissae, Oliver and colleagues demonstrated that removal of the lower follicle resulted in regeneration of the DP, apparently from the DS, while removal of the follicle at the level of the bulge did not allow for DP regeneration [14].

My question is do the DS cells contain the AGA code? Doing some more digging around I found out that the DS cells are continually renewed from the stem cell bulge, they move all around the HF from the bulge so my hope is that stem cells do not contain the code.

Also Androgens cause senescence of stem cells via WNT inhibition/GSK3b upregulation (study (http://www.ncbi.nlm.nih.gov/pubmed/22283397)), I suspect this is due to insufficient WNT feedback from DPC which keeps the stem cell pool pluripotent.



But in the stains, it looks like very little AR or beta-catenin is in the nucleus after Wnt is added in AGA40M?

Yeah I noticed that too but I wasn't sure if that was just a staining thing. your explanation below is probably my best bet, something to do with epigenetics.



Anyway, I'm wondering if AR binding to beta-catenin could maybe alter the way in which beta-catenin interacts with Wnt response elements -- for instance by recruiting HATs and HDACs to remodel chromatin structure, or by other interactions with certain transcription factors -- and thereby downregulate some Wnt target genes and upregulate others. DKK1 for example is actually a Wnt target gene -- and indeed DKK1 is upregulated over 2x in response to Wnt in DPCs (http://sci-hub.io/10.1016/j.jdermsci.2010.02.011) -- and as you've pointed out DKK1 is (further) upregulated in balding DP cells in response to DHT. The new gene transcription "profile" of DPCs in response to Wnt could then fail to induce epithelial stem cell activation. Highly speculative, but could it be possible?




Increased sensitivity to androgens could happen by

- Upregulation of AR
- An increase in androgen-independent activation of AR. Let's say z is the threshold in AR activation that causes hair loss, x is the androgen-independent level of activation, and y is activation caused by androgens. And let's say androgen-independent activation is very low in early stages of balding, but rises somehow over time as a result of DHT-bound AR transcribing its target genes. Left untreated, x rises over time and it takes less y to push x + y over the threshold (z). Eventually x > z and no anti-androgen or even castration could push AR activation below z -- the DPC's inductive ability is lost.

In this model castration > dut > fin. A prediction of this model is that someone who is maintaining on fin who goes on dut, regrows some on dut, but then switches back to fin would lose the hair he gained on dut (is this how it is in reality?). This would be expected based on a model where AR is upregulated or androgen-independent activation of AR increases over time with exposure to DHT, or both. At least, I think it would fit such a model better than a model where DP cells in recently lost hair are "repaired" in response to androgen removal.

I'm just speculating here, of course.

What you're describing reminds me of prostate cancer how it starts off as androgen dependent then becomes independent during Androgen depletion. The model is eerily similar to PC and the reality of it further points me to believe this is true. Even when people start RU they dont see complete regrowth after being on it for a long time, which completely goes against intuition. The DPC arent cancerous so its not mutation based adaption, so it has to be something subtle like you described above.



Sulforaphane? (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757849/) Don't know how good it would be in practice though. Seems to have a half-life of only a couple hours too, so even if it did work you might have to use it 20 times a day or so, including at night. ;)

I'm a bit reluctant about messing with HSP90 because it's used by quite a few pathways notably PI3K/AKT.

Here's a cool diagram I found:

https://media.bcm.edu/images/2014/34/prostate-cancer-illustration.jpg

MDV-3100 would've answered our problems but its not exactly a viable solution.



Yes, but dystrophic catagen could remove senescent cells and other malfunctioning cells from the cell cycle. Then dermal stem cells regenerate the dermal papilla. Sure, over time it will malfunction again, but you would just need maintenance treatments then to stop that from happening. And then eventually, once the technology is available, you could get the AR gene knocked down permanently in your scalp and never have to worry about AGA again. :cool:

I dont think the malfunction would happen at all if the cells were renewed. The problem is only the DPC, they control the stem cell pool pluripotency and the whole cycle is orchestrated by the DPC themselves so if they're replaced it could very well be the cure.


The more I look into it, the more I think this is probably correct. It's probably not so much that AR binds beta-catenin and prevents it from acting (as FGF11 thought). I think it's more likely that AR hijacks the Wnt pathway for its own nefarious purposes by binding to beta-catenin and altering the way that beta-catenin/TCF4 interacts with Wnt response elements, either enhancing them or (relatively) repressing them. From this model you can actually derive, for example, why PGD2 is upregulated in AGA with reference to both theory and experimental results. You can also imagine how a similar mechanism could actually account for why androgens stimulate facial hair growth while causing hair loss on your head. However, I'd like to develop this idea further before really getting into that (maybe I'll create a new thread sometime).

This is not exactly a novel idea, as something similar is known to happen in prostate cells (http://sci-hub.io/10.1002/pros.22828), for example.


The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens (http://bmccellbiol.biomedcentral.com/articles/10.1186/1471-2121-9-4)


Transient transfections of several human prostate cancer cell lines with the AR and multiple components of the Wnt signaling pathway demonstrate that the AR overexpression can potentiate the transcriptional activities of Wnt/β-Catenin signaling. In addition, the simultaneous activation of the Wnt signaling pathway and overexpression of the AR promote prostate cancer cell growth and transformation at castration levels of androgens. Interestingly, the presence of physiological levels of androgen or other AR agonists inhibits these effects. These observations are consistent with the nuclear co-localization of the AR and β-Catenin shown by immunohistochemistry in human prostate cancer samples. Furthermore, chromatin immunoprecipitation assays showed that Wnt3A can recruit the AR to the promoter regions of Myc and Cyclin D1, which are well-characterized downstream targets of the Wnt signalling pathway. The same assays demonstrated that the AR and β-Catenin can be recruited to the promoter and enhancer regions of a known AR target gene PSA upon Wnt signaling. These results suggest that the AR is promoting Wnt signaling at the chromatin level.

You are correct, the immediate effect of AR isnt to inhibit WNT, but merely a side effect of AGA mediated AR gene expression in DPC.

Its important not to forget this crucial bit of information;


Wnt3a-dependent keratinocyte growth was suppressed by the addition of dihydrotestosterone in coculture with DP cells that were derived from AGA patients, but growth was not suppressed in coculture with DP cells from non-AGA males. Whereas DP cells from both scalp regions expressed AR protein, the expression levels of AR and cotranslocation with β-catenin, a downstream Wnt signaling molecule, were higher in DP cells of AGA patients than in DP cells from non-AGA males. In addition, significant suppression of Wnt signal-mediated transcription in response to dihydrotestosterone treatment was observed only in DP cells from AGA patients.

DPC do not respond anabolically in single cell cultures to WNT or DHT which tells us its all paracrine/autocrine signalling. The Keratinocytes (HaCaT) do respond directly to WNTs by hypertrophying/growing. But we know its the DPC that are in charge of the entire cycle.


Wnt3a treatment significantly accelerated the growth of HaCaT cells in the single cell culture, but the addition of DHT did not affect growth (Fig 1D​1D).). On the other hand, the growth of DP cells was not affected by Wnt3a in single cell culture conditions (data not shown). It has been reported that androgen does not influence growth of DP cells in a single cell culture condition (26,27).

The DPC transform their internal response to WNTs/Androgens into a positive or negative extracellular response that the adjacent DPC can respond to physiologically. A successful canonical response to WNT/β-catenin pathway leads to enhanced VEGF, IGF-1R, PDGF which kicks off and maintains anagen but the AGA response is DKK1, TGF-Beta, and none of the pro-cytokines.

AGA changes the way androgen interacts with β-catenin like you've pointed out, and the response becomes a destructive one.


By using image analysis software, we examined the degree of nuclear colocalization of AR and β-catenin semiquantitatively using the ratio of merged dots in the nucleus/AR dots in cells treated with both Wnt3a and DHT (Fig. 3A​3A).). The ratios in DP cells from AGA males was higher by 2.5-fold than in DP cells of non-AGA males. These results indicate that AR and β-catenin in the nucleus was more highly colocalized in DP cells of AGA40M and other AGA males than in that of non-AGA males.

AR and β-catenin bind regardless of AGA/non-AGA but the binding is enhanced in AGA!? wtf


A direct interaction of AR and β-catenin was detected even in both untreated AGA and non-AGA DP cells. In addition, the amount of AR-β-catenin complex was increased by the treatment with Wnt3a in AGA40M cells but not the non-AGA male cells. This result is consistent with the result of the subcellular localization analysis.

The more β-catenin you have, the worse it becomes...


Lef/Tcf-mediated transcriptional activity was induced by treatment with Wnt3a in AGA40M cells, but this induction was significantly suppressed by the addition of DHT (Fig. 4A​4A).). The same result was observed in DP cells of other AGA male. In contrast, in DP cells of non-AGA males, the transcriptional activity was not suppressed by DHT. These results indicate that the Wnt-β-catenin signaling pathway is negatively influenced by ligand-activated AR in DP cells of AGA but not DP cells of non-AGA males.

And here the LEF/TCF response is fine in non-AGA (typical IGF-1, IGF-1R, VEGF, PDGF upregulation) but in AGA, you get none of that but instead we get the awesome (!) destructive DKK1 + TGFBeta.

I am convinced the polymerization of AR and β-catenin causes a different gene expression in complete contrast to the canonical TCF/LEF. In non-AGA there is some binding but not nearly as much as AGA, and the canonical pathway is still functional. WHY the frick is the AR/β-catenin binding enhanced - is it AGA itself or an indirect effect we can fix? I can't believe I didnt read this properly all this time, the answer is right here.

You should definitely make a new thread specifically for this topic. I'd like to investigate further.



What about your progress ( Oleuropein, etc....)

Thanks

Give me some time to post pictures. And please dont post in the read only thread.

Chemical
04-15-2016, 02:28 PM
I think some people on here like chemical should be researching an actual treatment for MPB. Some of the guys here know as much as the researchers almost. Can you use those supplements orally instead of having to mix a topical vehicle? how do you know using that stuff causes any hair growth verses it being from the minox which is obviously one of the best regrowth agents.
What is the best and safest way to stop the most androgens?

Unfortunately I dont have a degree in biochem and hate chemistry with a passion (not biology) so I wouldn't be appropriate to work on an actual cure. I'm just trying to understand how this works and if we're lucky someone will be able to use this info to come up with a cure.

As for whether my results were all minox, I dont know. Frankly theres no way to find out since the treatments wont have any effect when used by themselves and so my best guess is they have small additive effect when stacked. If I could do some lab experiments with biopsies and stuff I'd know for sure but right now its all calculated guesswork based on theoretical models. Orally? I'd say oleuropein but it would be very hard to notice any results using oral growth promoters and even if they did work systemically you'd see growth everywhere. To stop most androgens safely (only on your scalp) I'd say... GLA, Rosemary, Serenoa Repens, EGCG, RU, CB. This is all still in experimental stages and dont feel you should jump the gun and try them all.


hi everyone, sorry for the off topic question.

did you put the OL caps inside the minox jar ? or are t they separated ?
if so, would it be possible to use something other than ethanol as vehicle ?
thank you

Yes, in the minox bottle. I personally havent tried any other vehicle since the study used Ethanol + water (I recommend PG because it keeps ethanol from drying up too fast).

machi
04-15-2016, 02:32 PM
chemical , I have no knowledge of alopecia. I suffer aga for 16 years . I was deceived by a surgeon in Spain twice and had to go to Dr. Hasson to solve the problem .
I took finasteride for 7 years with very good results but I gave it up because of side effects . 8 years ago I left finasteride.
currently I do not take drugs for hair loss and I 'm sentenced because I have several capillaries operations.
I read your posts but I do not understand anything . I'm depressed , bitter. please chemical , you seem to have much knowledge. I think we are many users who believe in you. Do you think you come to any conclusion on your research and get a possible future treatment ?

Benis23
04-15-2016, 04:20 PM
My current progress

I stopped everything around 2 months ago. Before I stopped I was using the following for two weeks:

Minox by itself - morning
Minox + EGCG - night
Minox + OL - night
Water + VPA - night
Keto + Mico - morning & night
Evening primrose - night

After stopping, a week later I saw a ridiculous amount of vellus hairs all along my nw0 hairline, so much that it looked like I'd cured my recession. I strongly suspect this a residual effect of all the treatments finally showing results - or it could be because I stopped. I really really regret not taking pictures which means we're going to have to write it off as not happening but I have hope that I'll be able to recreate the results again and this time will take pictures. I didnt have my treatments with me so I couldnt continue but I had good density and I was quite happy. 6 weeks later I started receding again and lost all the vellus hairs but surprisingly I didnt lose the hairs on the side I was concentrating all my treatments (pics soon). I've got more density than I've had in the past year and I'm back on minox, keto, mico, EPO and borage oil. The EGCG is quite irritating so I've dropped it and I've ordered some more OL. I've managed to regrow hair using only minox and OL in the past - without an AR blocker, so the EPO and Borage oil should definitely help. I might use the VPA again and I'm considering creating a topical out of my fin tablets.

Chemical,

I've followed this thread with interest and appreciate all your hard work and research. I'd like to replicate your treatment on myself, but I don't have a chemistry background and want to make sure I'm using the right products and dosages. Is it possible to go into the details of your current regimen so that the followers of this thread can easily replicate what you're doing? If you can provide exact dosages and even brand names you've been using to buy some of these products, that would be really helpful. Thanks again!

InBeforeTheCure
04-16-2016, 02:12 PM
I missed this sorry. (whats up with the sci-hub.io links? I never get to see the damn article, it shows me some russian page and I feel left out of your scientific research)

https://en.wikipedia.org/wiki/Sci-Hub

I post the Sci-Hub links when the full articles are behind a paywall. It should link to a PDF. Sometimes it makes you copy a word into the textbox to proceed to the PDF (to make sure you're human and not a bot).


I wonder why the cells go into catagen only to regenerate? I was doing some in depth reading on the DPC and how even in AGA telogen the DPC remains intact - although senescent. Which means you'll always have the dysfunction no matter how many times you go through anagen and its only the DPC that are the faulty cells. If you permanently destroy the DPC however, the dermal sheath can regenerate a new DPC! (would recommend reading whole article, very interesting)

Review of hair follicle dermal cells (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818774/)


Yeah, I've read that. That and the Krajcik study gives one confidence that the DP can regenerate under the right circumstances. It's just a question of how to do it.


My question is do the DS cells contain the AGA code? Doing some more digging around I found out that the DS cells are continually renewed from the stem cell bulge, they move all around the HF from the bulge so my hope is that stem cells do not contain the code.

I think they probably do actually, and over time after becoming DP cells will develop the AGA phenotype without treatment. I don't see why they wouldn't, since they come from the same source as the other DPCs.


Also Androgens cause senescence of stem cells via WNT inhibition/GSK3b upregulation (study (http://www.ncbi.nlm.nih.gov/pubmed/22283397)), I suspect this is due to insufficient WNT feedback from DPC which keeps the stem cell pool pluripotent.

I think you mean quiescent, not senescent?


What you're describing reminds me of prostate cancer how it starts off as androgen dependent then becomes independent during Androgen depletion. The model is eerily similar to PC and the reality of it further points me to believe this is true. Even when people start RU they dont see complete regrowth after being on it for a long time, which completely goes against intuition. The DPC arent cancerous so its not mutation based adaption, so it has to be something subtle like you described above.

Yeah, I doubt AGA is actually a selected phenotype. I suspect it's probably either random or an off-target effect of some other adaptation(s), and the selection pressure against it was very low, so it wasn't weeded out.


I'm a bit reluctant about messing with HSP90 because it's used by quite a few pathways notably PI3K/AKT.

Here's a cool diagram I found:

https://media.bcm.edu/images/2014/34/prostate-cancer-illustration.jpg

MDV-3100 would've answered our problems but its not exactly a viable solution.

Ideally, you would want to knock out AR. Gene therapy would obviously be the best option for this, but sadly that won't be available to us for who knows how many years. Maybe something will come out of prostate cancer research, since they have basically the same goal. I think that's much more likely than anything miraculous coming from the small and pitiful hair loss field. Besides cell-based treatments, that is.


I dont think the malfunction would happen at all if the cells were renewed. The problem is only the DPC, they control the stem cell pool pluripotency and the whole cycle is orchestrated by the DPC themselves so if they're replaced it could very well be the cure.

I think replacing them would be a temporary, but not permanent, cure. They would eventually malfunction just like their cousins did after they became DP cells. I don't see why they wouldn't?


The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens (http://bmccellbiol.biomedcentral.com/articles/10.1186/1471-2121-9-4)

Thank you. Very interesting study.

http://s24.postimg.org/eptyqm75x/lncap1.png

Hmm...Very interesting shape to that graph. Have we seen anything like that before?

http://s9.postimg.org/606kubcfz/dkk1.png

Ayyy. Add DHT and you enhance the nuclear localization of AR/beta-catenin. Keep adding more and more DHT and AR/beta-catenin is ever more inclined to go transcribe AR target genes rather than Wnt target genes -- Wnt target genes like DKK1. That's probably the main reason why DHT inhibited Lef/Tcf luciferase activity in AGA DPCs in the Japanese study also.

So either beta-catenin is over at AR target genes, or it's at Wnt target genes but transcribing them differentially because it's bound to AR. Either way, when AR is bound to beta-catenin, you're screwed.


You are correct, the immediate effect of AR isnt to inhibit WNT, but merely a side effect of AGA mediated AR gene expression in DPC.

Its important not to forget this crucial bit of information;



DPC do not respond anabolically in single cell cultures to WNT or DHT which tells us its all paracrine/autocrine signalling. The Keratinocytes (HaCaT) do respond directly to WNTs by hypertrophying/growing. But we know its the DPC that are in charge of the entire cycle.

Yes, you can also manipulate the growth factors yourself to achieve regrowth as well (as many have done), but totally mimicking the paracrine growth factors is very hard to do manually. It's true what they say about the "MPB hydra". The argument then comes down to which factors are most important to address.


The DPC transform their internal response to WNTs/Androgens into a positive or negative extracellular response that the adjacent DPC can respond to physiologically. A successful canonical response to WNT/β-catenin pathway leads to enhanced VEGF, IGF-1R, PDGF which kicks off and maintains anagen but the AGA response is DKK1, TGF-Beta, and none of the pro-cytokines.

AGA changes the way androgen interacts with β-catenin like you've pointed out, and the response becomes a destructive one.

Yeah, I honestly think we may have stumbled upon the core etiology of AGA here. I think the theory works and can explain the details of AGA in a coherent way, but of course it would have to be tested experimentally to really know. As Richard Feynman said, "If it disagrees with experiment, it’s wrong. In that simple statement is the key to science. It doesn’t make any difference how beautiful your guess is, it doesn’t matter how smart you are or who made the guess, or what his name is… If it disagrees with experiment, it’s wrong. That’s all there is to it."


AR and β-catenin bind regardless of AGA/non-AGA but the binding is enhanced in AGA!? wtf



The more β-catenin you have, the worse it becomes...



And here the LEF/TCF response is fine in non-AGA (typical IGF-1, IGF-1R, VEGF, PDGF upregulation) but in AGA, you get none of that but instead we get the awesome (!) destructive DKK1 + TGFBeta.

True, true. I think TGFbeta is probably an AR target gene though and not a Wnt target gene like DKK1.


I am convinced the polymerization of AR and β-catenin causes a different gene expression in complete contrast to the canonical TCF/LEF. In non-AGA there is some binding but not nearly as much as AGA, and the canonical pathway is still functional. WHY the frick is the AR/β-catenin binding enhanced - is it AGA itself or an indirect effect we can fix? I can't believe I didnt read this properly all this time, the answer is right here.

There's probably some post-translational modification to AR in AGA, but I'm not sure what that would be exactly.


You should definitely make a new thread specifically for this topic. I'd like to investigate further.

I'll post a thread on this...in 5-10 years. :p

Seriously though, I want to really develop some of the details as I've only scratched the stuface, and then I'll post a thread. That could be as much as a few weeks from now, but we'll see.

InBeforeTheCure
04-16-2016, 03:10 PM
True, true. I think TGFbeta is probably an AR target gene though and not a Wnt target gene like DKK1.


I should rephrase that and say: TGFbeta is probably a downstream effect of AR transcription of AR target genes, possibly as a response to oxidative stress.

burtandernie
04-16-2016, 03:32 PM
Could it be for people using fin/dut that when MPB resumes after years of use that its because the AR use the wnt pathway instead of the lower levels of androgens? So maybe they dont upregulate just use a different pathway

InBeforeTheCure
04-16-2016, 04:38 PM
Could it be for people using fin/dut that when MPB resumes after years of use that its because the AR use the wnt pathway instead of the lower levels of androgens? So maybe they dont upregulate just use a different pathway

There are still some androgens present -- ~30% of original DHT with fin and ~10% with dut, or something like that, plus testosterone. And AFAIK castration stops progression of AGA permanently in 100% of cases, so I would say that progression of AGA is androgen-dependent (but maintenance of AGA is androgen-independent except for recent loss). In those cases the remaining low levels of androgens probably (slowly) drive progression of AGA.

Chemical
04-18-2016, 01:26 PM
https://en.wikipedia.org/wiki/Sci-Hub

I post the Sci-Hub links when the full articles are behind a paywall. It should link to a PDF. Sometimes it makes you copy a word into the textbox to proceed to the PDF (to make sure you're human and not a bot).


I noticed I could access the pdfs on my phone then realised sci-hub was like a piratebay but for research papers lol. This is better than frickin christmas! Thanks to you I've made some discoveries on some potential treatments.



Yeah, I've read that. That and the Krajcik study gives one confidence that the DP can regenerate under the right circumstances. It's just a question of how to do it.


It might be unfeasible to try and destroy the DPC without surgical means and right now it might not even be possible. But if the DPC is dead due to AGA and the DS is intact, then I dont see why it shouldnt be possible without forced intervention. Perhaps in the distant future this will be commercially viable, its a possibility.



I think they probably do actually, and over time after becoming DP cells will develop the AGA phenotype without treatment. I don't see why they wouldn't, since they come from the same source as the other DPCs.


I'm trying to stay ignorantly optimistic. Please dont hit me with a dose a reality.



I think you mean quiescent, not senescent?


Quiescent yes, the stem cells do not lose their proliferative capacity or reach their telomerase limit, thanks for correcting me. Its the DPC that become scenescent (study (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828374/)) (study (http://www.ncbi.nlm.nih.gov/pubmed/17989730)).



Yeah, I doubt AGA is actually a selected phenotype. I suspect it's probably either random or an off-target effect of some other adaptation(s), and the selection pressure against it was very low, so it wasn't weeded out.


My theory is that the frontal DPC's sensitivity to sex steroids has been unintentionally conserved by men when selecting women with thick hairlines, perceiving them to be more youthful and attractive. And this regional difference in DPC response becomes the complete opposite in males, but since women might have given less preference to looks and more on dominance, the genes ended up being conserved.



Ideally, you would want to knock out AR. Gene therapy would obviously be the best option for this, but sadly that won't be available to us for who knows how many years. Maybe something will come out of prostate cancer research, since they have basically the same goal. I think that's much more likely than anything miraculous coming from the small and pitiful hair loss field. Besides cell-based treatments, that is.

Even if we did have gene therapy, to me it seems like it would be very difficult to localise it to just the epidermis of the frontal scalp. And the cost might not justify not getting a transplant instead either from healthy regions or cultured DPC if they get that far in the future.



I think replacing them would be a temporary, but not permanent, cure. They would eventually malfunction just like their cousins did after they became DP cells. I don't see why they wouldn't?

My belief is that the DPC become conditioned during embryogenesis or at some point in the womb and that this is only specific to the DPC. It could very well be that the entire frontal scalp contains the AGA code, but that just seems unintuitive. The stem cells should have the same code regardless of the location (I tell myself). I'm just trying to be optimistic with my delusions.

One thing I find strange is how it takes quite a while for the initial recession to become noticeable but happens quite fast when stopping treatments. I remember reading a study on Hic5/ara55 (Androgen co-activator) and how it starts to get upregulated after puberty. And also reports of Testosterone/DHT being able to upregulate the expression of AR. Perhaps continued activation of AR causes permanent upregulation or enhanced stability of AR. Its also peculiar that RU users stop responding after a while - I mean its not like theres a negative feedback loop here? What do you think?

Looking at CB and RU they seem like the realistic and most ideal AR antagonists currently on the market, they have virtually no systemic effects on the HPTA or GnRH release and only work peripherally. Its just the price and lack of reputable sources (I'm a little cautious of chinese manufacturers) that put me off.



Hmm...Very interesting shape to that graph. Have we seen anything like that before?

Ayyy. Add DHT and you enhance the nuclear localization of AR/β-catenin. Keep adding more and more DHT and AR/β-catenin is ever more inclined to go transcribe AR target genes rather than Wnt target genes -- Wnt target genes like DKK1. That's probably the main reason why DHT inhibited Lef/Tcf luciferase activity in AGA DPCs in the Japanese study also.

So either β-catenin is over at AR target genes, or it's at Wnt target genes but transcribing them differentially because it's bound to AR. Either way, when AR is bound to β-catenin, you're screwed.

http://www.nature.com/onc/journal/v22/n36/images/1206802f8.jpg

Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis (http://www.nature.com/onc/journal/v22/n36/full/1206802a.html)

Also AR is upregulated significantly so that might play a part in increasing the receptor saturation ceiling. It also doesnt make the conclusion robust given that non-AGA DPC have less AR. I want to know what would happen if AR was boosted to AGA levels in non AGA DPC.

We know that DHT/T that causes the binding of β-catenin to AR, and the study showed that without DHT, WNT3a did activate the TCF/LEF genes. Something that worries me is that maybe even an antagonist that binds to AR can recruit β-catenin. I'm thinking if we can prevent the binding of β-catenin to AR, we might not have to worry about Androgens at all. Something that fits into the pocket in place of β-catenin! What about SARMS and steroids? I know there are steroids that have significantly higher AR binding affinities that could easily saturate the receptors, and most of them have altered anabolic:androgenic ratios. Perhaps its the androgenic part that causes this negative response of AGA? Edit: looks like R1881 elicits the same response as T/DHT (http://www.fasebj.org/content/early/2002/12/02/fj.02-0043fje.full.pdf)



Yes, you can also manipulate the growth factors yourself to achieve regrowth as well (as many have done), but totally mimicking the paracrine growth factors is very hard to do manually. It's true what they say about the "MPB hydra". The argument then comes down to which factors are most important to address.


Most treatments themselves do not contain the growth factors, they merely stimulate the release indirectly and I'm wondering if all epidermal cells have the ability to release paracrine growth factors. Furthermore, there is only so much you can proliferate the HF shaft with exogenous growth factors, which explains why people only see vellus hairs getting longer. A functioning anagen DPC with an adequate blood supply thickens the diameter of the hair shaft significantly and continually releases growth factors in comparison the infrequent applications of treatments that may or may not reach target tissues. I'm thinking if theres another way to activate TCF/LEF genes without β-catenin, that would be even better than using indirect growth factors.



Yeah, I honestly think we may have stumbled upon the core etiology of AGA here. I think the theory works and can explain the details of AGA in a coherent way, but of course it would have to be tested experimentally to really know. As Richard Feynman said, "If it disagrees with experiment, it’s wrong. In that simple statement is the key to science. It doesn’t make any difference how beautiful your guess is, it doesn’t matter how smart you are or who made the guess, or what his name is… If it disagrees with experiment, it’s wrong. That’s all there is to it."


All the research points to this theory, the AGA DPC inhibiting growth of keratinocytes but normal DPC promoting growth of HaCat. We already know its androgens, and we kind of knew that AR inhibited β-catenin somehow. I think this is the definitive answer, its the binding of AR to our precious β-catenin that causes AGA.


I should rephrase that and say: TGFbeta is probably a downstream effect of AR transcription of AR target genes, possibly as a response to oxidative stress.

I remember making a post about tgf-beta and dug this up:



The involuntary tonic contraction of occipitofrontalis muscle is related to psychological stress conditions,[23] facial expression,[24] the maintenance of visual field,[19] and an aponeurotic tension model of human craniofacial growth,[25] so the galea aponeurotica supports a continuous stress which is transmitted to ECM and cells of each tissue, dermal papilla, and dermal sheath cells included. The deformation energy does not cause apparent damage to scalp skin, but its interplay with androgens could be fatal in organ remodeling of hair follicles. This androgen-mediated molecular response to mechanical stimulation can play the anabolic role instead of biological virilization role, as it has been extensively studied in tissues whose function is closely linked to the physical force support.[26] Furthermore, it has been reported that TGFβ-1 increases the expression of Hic-5 in hypertrophic scars fibroblasts[27] and it potentiates AR transactivity in balding dermal papilla cells[28] by autocrine loop [Figure 3]. Hence, the long-lasting cyclic strain would cause a slow, chronic, and progressive environmental adaptation process in balding hair follicles since puberty.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639964/

original post (https://www.baldtruthtalk.com/threads/22187-I-think-I-ve-hacked-it?p=226167&viewfull=1#post226167)

So TGF-beta can potentiate AR via autocrine loop? the f***, it just keeps getting worse

Androgen receptor transactivity is potentiated by TGF-b1 through Smad3 but checked by its coactivator Hic-5/ARA55 in balding dermal papilla cells (https://sci-hub.io/10.1016/j.jdermsci.2011.08.010)

(was behind paywall but thats not going to stop me now)


Our data presented here suggest that TGF-b1 can enhance androgen sensitivity through Smad3 in the dermal papilla of AGA in an autocrine manner. Because TGF-b1 from bald DPCs inhibits hair follicle epithelial cell growth in a paracrine manner [1], TGFb1 exerts its pathogenic roles with dual secretion, autocrine and paracrine, between epithelium and dermal papilla in AGA. On the other hand, although Hic-5/ARA55 upregulates androgen sensitivity via coactivation for AR in DPCs [6], the data obtained in our current study indicated that this molecule impedes the AR stimulation by TGF-b1. This may be due to crosstalk between Hic-5/ARA55 and Smad3 [8] or possibly the attenuated effect of TGF-b1 on the high expression of Hic-5/ARA55, which is reportedly increased by TGF-b1 [9]. Given that Hic-5/ARA55 is highly expressed in the androgen-sensitive DPCs from AGA [6], a complex compensatory mechanism through reciprocal interaction must be in place between TGF-b-Smad and androgen-AR signaling pathways in the hair follicles of AGA.

So hic5/ARA55 is already upregulated in AGA when it starts and that is known to enhance AR. Then AR -> ROS -> TGF-beta -> more hic5/ARA55 ¬ (TGF-beta -> smad3 -> AR)

So it looks like hic5/ARA55 is bad, but is keeping check on the additional AR effect of TGF-beta. A powerful or mild anti-oxidant is probably all we need to fix this part but I think we should both look into hic5/ara55 and other co-activators that could be making AGA worse over time.

Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133876/)

Another thing I just noticed is that rat DPC overexpressing AR has the same phenotype as AGA:


During sub-cultivation of DPCs, sensitivity to androgens may be low because of the reduced expression level of AR (11). AR has been detected in the DPCs of human skin (5), and the DPCs of bald frontal scalps express higher levels of AR than those of non-balding occipital scalps (4). Therefore, to confirm our hypothesis, we used rat DPCs that over-express AR.

And they only used DHT which leads me to believe AR will increase ROS regardless of β-catenin being present (or maybe there is some β-catenin being released intracellularly). Maybe in AGA the binding of β-catenin to AR doesnt affect the transcription of AR genes but binds - just because it can and by the time it reaches the nucleus it cant activate TCF/LEF. I was incorrect about β-catenin making the DPC response worse, it just cant target its canonical genes, thats all.

We also know that DKK-1 is induced by reactive species, specifically JNK mediated. And looking back over the research it looks like the DPC themselves produce DKK-1:


DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT.
http://www.ncbi.nlm.nih.gov/pubmed/17657240

But I dont understand why ROS is induced in AGA DPC when in PC it represses it. The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. (http://www.ncbi.nlm.nih.gov/pubmed/11707452)

So although there are quite a few similarities its not quite apples to apples which irritates me.

My current understanding:

Increasing β-catenin will saturate the AR in the presence of DHT/T and will not successfully activate TCF/LEF

However without DHT/T, β-catenin will be able to activate TCF/LEF which is good because we can just try to reduce AR. I'm unsure if AR antagonists will still bind β-catenin.

Increasing β-catenin to suraphysical levels could in theory bypass the AR recruitment

AR will increase ROS and subsequent TGF-β1 + DKK-1 via DPC regardless of β-catenin being present. This can be counteracted with an anti-oxidant

AR can increase GSK3β thereby reducing available β-catenin

Next post will be new treatments and an approach plan along with my current progress.

Chemical
04-18-2016, 02:07 PM
Did some more reading on prostate cancer and AR beta-catenin interaction.

Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis (http://www.nature.com/onc/journal/v22/n36/full/1206802a.html)


Reports have shown a role for the beta-catenin/Tcf pathway in prostate cancer including nuclear localization and beta-catenin mutations in primary prostate tumor samples (Chesire and Isaacs, 2002; Chesire et al., 2002). beta-Catenin has also been described as a ligand-dependent coactivator of the AR (Truica et al., 2000; Mulholland et al., 2002; Pawlowski et al., 2002; Yang et al., 2002). Previously, we have shown that translocating AR can provide a means of nuclear entry and accumulation of beta-catenin (Mulholland et al., 2002). This mode of beta-catenin trafficking has also been shown to hold true in neuronal cells (Pawlowski et al., 2002). Cotrafficking of AR and beta-catenin to the nucleus likely has important implications both for AR and Wnt signaling. While nuclear accumulation of beta-catenin has been shown to correlate with increased AR transcriptional activity, the effects on Tcf signaling have only begun to be explored. Recently, it has been shown that the AR has the ability to inhibit the beta-catenin/Tcf signaling pathway, ligand-dependently (Chesire and Isaacs, 2002). By way of transcriptional reporter assay, this report showed reduced luciferase activity for the Tcf reporter in a ligand-dependent manner in several prostate and colon cancer cell lines. This study also observed reduced transcriptional activity with the use of an AR deletion mutant (for beta-catenin binding), suggesting the possibility of a reciprocal balance of nuclear beta-catenin between the AR and Tcf. In the present study, we corroborate these results but provide mechanistic data to support the hypothesis that repression of the beta-catenin/Tcf signaling is mediated by ligand-occupied AR that is in competition with Tcf for nuclear beta-catenin. Specifically, using transcriptional reporter assays, we show that overexpression of WT Tcf reduced the activity of an AR (ARR3-Luc)-responsive reporter, while overexpression of a DeltaNt Tcf mutant did not have this effect.

Results

TOPFLASH activity = beta-catenin TCF/LEF activity


To evaluate the repressive effect that AR and its physiological ligand had on Tcf signaling, several titrations were performed in PC3 cells. Specifically, we observed decreased TOPFLASH activity with increased amounts of transfected AR (mug/three wells) with no detectable changes observed in either beta-catenin or Tcf4 protein levels (Figure 1a). Basal levels of BCT (TOPFLASH) in untreated PC3 cells were low, while in SW480 cells luciferase counts were 6–8-fold higher. In either cell line, control FOPFLASH values were about 10% of basal TOPFLASH levels. To confirm the ligand dependency of Tcf inhibition, we used AR deletion mutants (Figure 1b), including those coding the amino- and DNA-binding domain regions (Nt/DBD), as well as the DNA-binding region plus ligand-binding region (DBD/LBD). While the Nt/DBD mutant showed little ability to repress TOPFLASH, the DBD/LBD mutant was capable of a 3.5–4-fold repression in the presence of DHT. This suggests that in an AR overexpressed state, the ARNt is dispensable for Tcf repression. Further verification that the LBD is vital for repression is shown by increased relief of AR-mediated repression in cells treated with the pure AR antagonist Casodex (1 and 10 mum), which was able to efficiently relieve AR (DBD/LBD)-mediated repression of TOPFLASH. Having shown that repression is both AR and ligand dependent, we next evaluated the effect of increasing the concentration of DHT.


So bicalutamide reduced beta-catenin recruitment! Woohoo!


As a prerequisite, we verified that we could, in fact, detect an AR/beta-catenin complex upon transfection with AR (Figure 6b, arrow). Consistent with our previous studies (Mulholland et al., 2002), we detected more AR/beta-catenin complex from cells treated with DHT, suggesting a ligand-sensitive interaction. We also detected an association with beta-catenin and Tcf-HIS, but did not detect this association in the DeltaNt Tcf-myc deletion mutant. Importantly, using this assay, interactions between AR and Tcf were very weak as compared to our detected AR/beta-catenin and beta-catenin/Tcf complexes both in prostate and colon cancer cells. Nonimmune, control precipitations were only slightly less than those of the AR/Tcf complex, suggesting that only a small fraction of AR associates with Tcf. We wanted to know whether Casodex, which abrogated both HcRed-Tcf focal accumulation (data not shown) and TOPFLASH activity, could alter the binding of AR and beta-catenin. By treating cells with 5 mum Casodex (dissolved in EtOH) with and without 5 nm DHT, we observed reduced physical interaction between AR and beta-catenin (arrowhead), while also relieving AR-mediated repression of the beta-catenin/Tcf-HIS complex (Figure 6b, star and open arrow heads). To evaluate whether a decreased beta-catenin/TcfHIS complex could be directly affected by the AR TcfHIS and ARS35, in vitro translated products were used in series of binding assays with HIS-tagged recombinant beta-catenin (Figure 6c). Using Ni-NTA beads to precipitate in vitro binding reactions, we observed that upon increased levels of ARS35 (a–d) there was a corresponding decrease in TcfS35 (a–e) precipitated with the HIS-tagged recombinant beta-catenin. Although ARS35 levels up to 10 mul were added per binding reaction, we observed no further increase in detectable AR/beta-catenin-HIS binding greater than 6 mul (point d) or 60% of input by volume.

There is a saturation limit which we can exploit to get beta-catenin to activate TCF/LEF.

Some closing analysis:


The reduction of AR transcription (in the presence of DHT) upon overexpression of Tcf provides evidence of competition. These data are consistent with the notion that modulation of the beta-catenin-Tcf/Lef assembly may be the mechanism by which AR exerts its repression on Tcf/Lef signaling. To test this further, we evaluated the amount of beta-catenin associated with the Tcf/Lef complex with and without AR+androgen, both in vivo and in vitro. Data achieved with these data corroborate morphological data and our overall hypothesis.

Could it be that AR requires beta-catenin to exert its effects?


Other nuclear receptors and Tcf/Lef signaling

It is interesting how two stimulators of cell proliferation (AR/DHT and Wnt) can interact in a repressive manner. One possible interpretation is that androgens may not increase proliferation by, rather, promoting growth and differentiation in prostate epithelia. Prostate cancer cells have cell cycle deregulation compounded by a cell survival response to androgens. The contributions of Wnt signaling in prostate cancer are likely complex, although it is clear that nuclear beta-catenin can serve as a potent AR coactivator. We suggest a scenario whereby beta-catenin could be shuttling between Tcf/Lef-binding sites and AR elements. In the absence of androgen, AR resides mainly in the cytosol, while nuclear beta-catenin associates with Tcf (Figure 8a). In the presence of androgen, beta-catenin could be shuttled by translocating nuclear receptors to both Tcf- and AR-associated response elements to promote coactivation (Figure 8b). Consequently, less beta-catenin would be associated with Tcf and more with AR. This would simultaneously lower Tcf activity and augment AR transactivation.

Very very interesting stuff.

Seuxin
04-19-2016, 12:46 AM
Hmm, so you think using bicalutamide could be good ?

Chemical
04-19-2016, 04:14 AM
For those of you that havent been following the science, our current understanding is that for as long as Testosterone and DHT is around, any treatment that tries to increase beta-catenin will be significantly blunted. The AR will just suck up the beta-catenin and prevent it from working. So we need to reduce AR and 5ar using suppressors and increase aromatase within hair follicles to further divert Testosterone to convert to Estrogen which can enhance the growth of frontal hair follicles. Also since there will be some DHT/T floating around you will need to boost beta-catenin so that even after AR has bound beta-catenin until saturation, there will still be enough left to activate the good TCF/LEF genes that induce and maintain anagen.

Existing Androgen Receptor inhibitors

Ketoconazole


Ketoconazole binds to the human androgen receptor. (http://www.ncbi.nlm.nih.gov/pubmed/1526623)

Ketoconazole competition with [3H]methyltrienolone (R1881) for androgen binding sites in dispersed, intact cultured human skin fibroblasts was determined at 22 degrees C. Fifty percent displacement of [3H]R1881 binding to AR was achieved by 6.4 +/- 1.8 (SE) x 10(-5) M ketoconazole. Additional binding studies performed with ketoconazole in the presence of increasing amounts of [3H]R1881 showed that the interaction of ketoconazole with AR was competitive when the data were analyzed by the Scatchard method. It should be noted, however, that the dose of ketoconazole required for 50% occupancy of the androgen receptor is not likely to be achieved in vivo, at least in plasma. Finally, androgen binding studies performed with other imidazoles, such as clotrimazole, miconazole, and fluconozole, revealed that in this class of compounds only ketoconazole appears to interact with the androgen receptor. Ketoconazole appears to be the first example of a non-steroidal compound which binds competitively to both SSBG and multiple steroid hormone receptors, suggesting that the ligand binding sites of these proteins share some features in common.


Ketoconazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men. (http://www.ncbi.nlm.nih.gov/pubmed/14729013)

Dihydrotestosterone (DHT) binding to androgen receptors (AR) in hair follicles is commonly accepted as the first step leading to the miniaturizing of follicles associated with androgenetic alopecia (AGA). Testosterone is converted to DHT by the enzyme 5alpha-reductase. Finasateride a 5alpha-reducase inhibitor blocks the production of DHT and is currently used to treat AGA. The inhibition is not complete but a reduction of DHT systemically and in the scalp is accomplished. Ketoconazole has been clinically shown to be effective in the treatment of AGA. In this paper, evidence is presented to support the hypothesis that ketoconazole 2% shampoo has a local disruption of the DHT pathway. It is proposed that using ketoconazole 2% shampoo as an adjunct to finasteride treatment could lead to a more complete inhibition of DHT and thus better treat AGA.

Ketoconazole has a plasma half life of 8 hours and I'm not too sure if that relates to skin retention too. The current recommended dosing is 3x a week using the shampoo but I personally encourage the use of the cream 2-3x a day. Its easier to apply, more convenient and you dont need to worry about the shampoo causing irritation from excessive use. Even though keto is a mild AR blocker people still see results using it so its not entirely useless - remember that this is using it 3x a week so imagine if you used it 2-3x a day.

Minoxidil


Minoxidil may suppress androgen receptor-related functions (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039155/)

Minoxidil concentrations were chosen based on most common reports in the literature: 0.1 to 10 μM for oral intake and about 1 mM for topical application of 5% minoxidil (100 mM) in skin tissue (Regaine 5% minoxidil topical solution; monograph, February 2013), assuming 1.7% absorption. In in vitro organ culture or animal studies, high concentrations, ranging from 1-100 mM, have been reported in skin tissue [31, 32]. After treating with different concentrations of minoxidil (1 to 100 μM), cells were harvested and cellular extracts were assayed for luciferase activity. As shown in Fig. Fig.1A,1A, minoxidil suppressed AR reporter activity at the concentrations tested.


To further test minoxidil suppression of AR-related function, we tested the effects of minoxidil on the growth of LNCaP cells, an androgen-sensitive prostate cancer cell line that, as noted above, endogenously expresses AR. As shown in Fig. Fig.1D,1D, minoxidil suppressed DHT-dependent LNCaP cell growth in concentration-dependent manner. Notably, at the highest concentration, cell growth was suppressed to a level comparable to that observed in the absence of DHT. These data provide the first demonstration that minoxidil can suppress AR-related functions, including AR transcription and AR-related cell growth.

To assess possible nonspecific effects of minoxidil at high concentrations, we performed control studies, testing different concentrations of minoxidil (1-100 μM) on glucocorticoid receptor (GR) transcriptional activity. As shown in Fig. Fig.1E,1E, the highest concentration minoxidil (100 μM) did affect GR transcriptional activity in reporter assays in PC-3 cells, whereas lower concentrations (1-10 μM) did not. These data suggest that minoxidil, a small hydrophobic molecule, may have multiple targets in the cell when used at high concentrations.

You can see that minoxidil can suppress AR activity in a dose dependent and time dependent manner providing more evidence that minoxidil works on two levels necessary to treat AGA. This explains why alot of people can achieve regrowth solely using minox seen both in studies and anecdotal reports.

Its important to note that minoxidil does not work if the follicles do not contain adequate sulfotransferase enzymes necessary to convert minoxidil to minoxidil sulphate which is reported to be 14 times more potent.


Minoxidil sulfate is the active metabolite that stimulates hair follicles. (http://www.ncbi.nlm.nih.gov/pubmed/2230218)

An important step in understanding minoxidil's mechanism of action on hair follicles was to determine the drug's active form. We used organ-cultured vibrissa follicles to test whether it is minoxidil or its sulfated metabolite, minoxidil sulfate, that stimulates hair growth. Follicles from neonatal mice were cultured with or without drugs and effects were assessed by measuring incorporation of radiolabeled cysteine in hair shafts of the treated follicles. Assays of minoxidil sulfotransferase activity indicated that vibrissae follicles metabolize minoxidil to minoxidil sulfate. Dose-response studies showed that minoxidil sulfate is 14 times more potent than minoxidil in stimulating cysteine incorporation in cultured follicles. Three drugs that block production of intrafollicular minoxidil sulfate were tested for their effects on drug-induced hair growth. Diethylcarbamazine proved to be a noncompetitive inhibitor of sulfotransferase and prevented hair growth stimulation by minoxidil but not by minoxidil sulfate. Inhibiting the formation of intracellular PAPS with chlorate also blocked the action of minoxidil but not of minoxidil sulfate. Acetaminophen, a potent sulfate scavenger blocked cysteine incorporation by minoxidil. It also blocked follicular stimulation by minoxidil sulfate apparently by directly removing the sulfate from the drug. Experiments with U-51,607, a potent minoxidil analog that also forms a sulfated metabolite, showed that its activity was inhibited by both chlorate and diethylcarbamazine. These studies show that sulfation is a critical step for hair-growth effects of minoxidil and that it is the sulfated metabolite that directly affects hair follicles.

Sulfotransferase levels in scalp vary alot between individuals and that can account for the lack of response in some individuals


Biochemical evidence for minoxidil sulphation by two phenol sulphotransferases has been found in human scalp skin[22] and Dooley[21] reported finding mRNA expression for four sulphotransferases in human epidermal keratinocytes. There are interindividual variations in scalp sulphotransferase activity and this correlates with the level in platelets.[22] In a clinical setting, scalp sulphotransferase activity was higher in men who responded to minoxidil compared with those who did not respond.[23]

http://www.medscape.com/viewarticle/470297_3

I'm currently looking into ways of boosting scalp sulfotransferase levels to improve the efficacy of minoxidil.

Valproic Acid - Sodium Valproate

I was quite surprised when I found out VA was a serious Androgen Receptor suppressor. Before we look at that I'd like to show you the study they did on men with AGA with a 8.3% Sodium Valproate spray in a 27% EtOH solution over 6 months, twice a day applications of 1ml.

Topical valproic acid increases the hair count in male patients with androgenetic alopecia: a randomized, comparative, clinical feasibility study using phototrichogram analysis. (http://www.ncbi.nlm.nih.gov/pubmed/24533507)

Full Study (http://sci-hub.io/10.1111/1346-8138.12422)


The representative clinical photographs and macrophotographs are presented at baseline and after 24 weeks of treatment (Fig. 2). The total hair count increased after 24 weeks of treatment in the VPA group; the median hair counts were 181/cm2 (range, 125–241) at baseline and 192/cm2 (range, 153–271) at 24 weeks. However, the total hair count did not change in the placebo group; the median hair counts were 194/cm2 (range, 155–244) at baseline and 197/cm2 (range, 132–253) at 24 weeks (Fig. 3a). The median change in total hair count from the baseline was 23/cm2 (range, 17 to 39) in the VPA group and 1/cm2 (range, 68 to 70) in the placebo group, and the difference between groups was statistically significant (P = 0.047; Fig. 3b).

In the full study you can see a photo of the results, and I can definitely see an increase in hair count both in the closeup and wide angle. You have to understand that there is a very high probability the subjects might not have been too diligent with the treatment and the ages ranged from 27-45. The AGA has probably become alot worse and its very unlikely that 6 months of monotherapy will completely regrow hair. For those of you that expect complete regrowth from one treatment please reevalute your expectations, we do not live in the world of movies and fiction where scientists come up single drugs that cure diseases completely. A small but consistent positive effect of a treatment on a reasonable sample size is a good predictor that a treatment has potential to have additive or even synergistic effect when combined with other treatments. Most of the placebo individuals saw a decline in hair count but a vast majority of VA subjects saw no reduction in hair count or an increase - which means it definitely did something.

The serum levels achieved by topical VA dont seem too bad but its something to keep in mind


The serum VPA concentration was measured in 20 subjects in the VPA group and 19 subjects in the placebo group. The serum VPA level was detectable in only seven subjects in the VPA group (range, 0.4–2.3 lg/mL), whereas it was too low (<0.4 lg/mL) to be detected in the other 13 subjects in the VPA group and all of the subjects in the placebo group.


Valproic acid and its derivatives enhanced estrogenic activity but not androgenic activity in a structure dependent manner. (http://www.ncbi.nlm.nih.gov/pubmed/23892311)

Full Study (https://sci-hub.io/10.1016/j.reprotox.2013.07.019)



Steroid hormones affect metabolic pathways and cellular functions. Valproic acid (VPA), used as antiepileptic drug, inhibits histone deacetylases and interacts with intracellular receptors. We analyzed the impact of VPA and VPA derivatives on activation of estrogen and androgen receptors (ER and AR) using reporter gene assays. VPA and its long-chain derivatives (long name 1), (long name 2) and (long name 3) enhanced 17β-estradiol-induced ERα and ERβ activation partly synergistically with a structure-activity correlation. The extent of this effect regarding to ERα activation increased with prolongation of the aliphatic side chain. Regarding AR activation, VPA, S-pentyl-4-yn- and heptyl-4-yn-VPA slightly induced AR activity when tested alone. In combination with the AR agonist 5α-dihydrotestosterone, VPA, S-pentyl-4-yn- and heptyl-4-yn-VPA showed anti-androgenic effects without an apparent structural relation. Our results indicate that VPA and its derivatives affect estrogen signaling with a structural specificity, while the (anti-)androgenic effects of these compounds are not structurally correlated.

So here we have our first indication that VPA can indeed suppress AR. No mention of how much so lets delve into the study


For VPA, concentrations between 0.001 and 3 mM and for its derivatives between 0.01 and 1 mM were investigated. The therapeutic range of VPA comprises 0.35–0.7 mM in serum [42], whereas concentrations of 3 mM can be attained in the serum of patients after an acute VPA ingestion [43].

In combination with 10−9 M E2, VPA enhanced the E2-induced ER activation synergistically in a concentration-dependent manner with a first significant effect at 0.001 mM. For instance, 2 mM VPA caused a 3.5-fold increase of ER activity compared to 10−9 M E2 alone (E2: 100% vs VPA plus E2: 348% of maximum E2- activation; Fig. 4A). Similarly for ER activation, the co-incubation of VPA (0.001–3 mM) with 10−9 M E2 caused synergistic effects (e.g. E2: 100% vs. 1 mM VPA plus E2: 408% of maximum E2-activation; Fig. 4B). Thus, VPA enhanced the E2-induced activation of both ER types in a dose-dependent manner with a slightly greater effect on ER activation.



VPA is quite powerful at potentiating the ER pathways which is exactly what we want for frontal DPC.


Co-administration of VPA (0.01–4 mM) with 10−9 M DHT reduced AR activity in a dose-dependent manner with a first significant effect at 1 mM (Fig. 7). Butyl-4-yn-VPA did not alter DHT-induced AR activation. S-pentyl-4-yn- and heptyl-4-yn-VPA (≥0.2 mM) also decreased DHT-mediated AR activation. At the highest concentration, VPA and heptyl-4-yn-VPA inhibited the AR activity induced by DHT to control values of untreated cells (Fig. 7).

http://i.imgur.com/7zEFFvlm.png

Just look at what 1mM could do to DHT's ability to bind to AR. Just look at it! And look at what 2mM could do, its identical to frickin flutamide.


The anti-androgenic effects of VPA are also characterized through a reduced AR expression and cell growth inhibition revealed in cell cultures of prostate cancer cells [64,65]. For example, Iacopino et al. [66] have shown that 0.45 mM VPA suppressed DHT-stimulated proliferation of human androgen-sensitive LNCaP prostate cancer cells. Epigenetic regulations byVPA might be involved in the modulation ofAR activity. HDAC inhibition leads to AR acetylation [67] causing reduced cell growth, apoptosis induction and differentiation [64,68]. However in our study, VPA seems to have both anti-androgenic and marginal androgenic effects dependent on the VPA concentration and the presence or absence of DHT. A structural dependency of the VPA derivatives could not be attributed to the AR activity in the presence of DHT.

That was Valproic Acid, what about Sodium Valproate?

Valproate is an anti-androgen and anti-progestin. (https://opus.lib.uts.edu.au/bitstream/10453/16875/1/2010000997.pdf)


We examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a yeast-based steroid receptor-beta-galactosidase reporter assay for the androgen receptor (AR), progesterone receptor (PR) or estrogen receptor (ER). Bioassays were performed (a) to detect agonist activity by exposing yeast to 100 microM CBZ or VPA or (b) to detect antagonist activity by exposing yeast stimulated with testosterone (5 x 10(-9) M, AR), progesterone (1.6 x 10(-9) M, PR) or estradiol (2.6 x 10(-11) M, ER) together with either VPA or CBZ for 4 (PR) or 16 (AR, ER) hours. VPA showed dose-dependent (1-800 microM) inhibition of progesterone-induced PR- and testosterone-induced AR activity but had no ER antagonist bioactivity and no significant PR, AR or ER agonist bioactivity. VPA also showed a dose-dependent (1-200 microM) blockade of DHT's suppression of AR-mediated NF-kappaB activation in human mammalian cells. By contrast, CBZ had no significant PR, AR or ER agonist or AR and ER antagonist bioactivity but at the highest concentration tested (800 microM) it did antagonize PR activity. We conclude that VPA is a non-steroidal antagonist for human AR and PR but not ER. VPA's androgen and progesterone antagonism at concentrations within therapeutic blood levels (350-700 microM) seems likely to contribute to the frequency of reproductive endocrine disturbances among patients treated with VPA.

Since Sodium Valproate is the more readily available form and has excellent water solubility at 50mg/ml, in comparison to 1.3mg/ml for Valproic Acid (source (http://www.acutetox.eu/pdf_human_short/16-Sodium%20valproate%20revised.pdf)) it looks like Sodium Valproate is a strong candidate to be used in our protocols. I use distilled water to dissolve the tablet after crushing them and removing the orange coating but I'm looking for capsules which should make my life easier. I would suggest starting at 5mg/ml then increasing until you get irritation or notice side effects. You can just dilute to bring the concentration down again.

This post is quite lengthy so I'll continue with the other treatments in the next post.

Rog
04-19-2016, 06:09 AM
Chemical, have you seen:

http://www.dannyroddy.com/weblog/antihistaminebaldnessstress

which if correct indicates that Estrogen plays a negative role (causes terminal hair - vellus, is involved in fibrosis of scalp around follicles, etc) rather than a positive role?

bej
04-19-2016, 08:32 AM
Both sodium valproate and VPA are very soluble in vehicles with 30% (or more) ethanol. The human AGA study I think used 27% ethanol with sodium valproate. To have the concentration you want (around 7% or 8%) you probably need the ethanol there or it might separate. I've made a lot of mixtures with VPA and various other components, and the ethanol seems necessary to have useful concentrations.

Seuxin
04-19-2016, 10:31 AM
Bej,

I have a very very importante question ( It's Seuxin...form HairLossHelp too ;) ).

About VPA, what is important....the amount of VPA per day, or the % ?

By example :

If i use VPA at 7% in stemoxydine, and if i use 6ml per day of stemox...it represent more VPA ( as mg) than if i use 1-2ml of solution, right ?

For RU, CB, or Minox for example the important is the amount of solution...but i don't know if for acidic solution it's the same.

Do you understand my question ? What do you think ?

Thanks

Chemical
04-19-2016, 01:03 PM
Hmm, so you think using bicalutamide could be good ?

If you're okay with castration then yes. It will go systemic even if you use it as topical. You want a special AR blocker that doesnt function in the blood stream. Like CB or RU, or a combination of the experimental ones in this thread.


Chemical,

I've followed this thread with interest and appreciate all your hard work and research. I'd like to replicate your treatment on myself, but I don't have a chemistry background and want to make sure I'm using the right products and dosages. Is it possible to go into the details of your current regimen so that the followers of this thread can easily replicate what you're doing? If you can provide exact dosages and even brand names you've been using to buy some of these products, that would be really helpful. Thanks again!

Here's a good place to start:

https://www.baldtruthtalk.com/threads/22991-Treatments-and-Science-Read-Only

My protocol is always changing so you're better off sticking to the main components:

Ketoconazole cream 2% - Daktarin - 2x day
Kirkland minox 5% - 2x day
Borage oil - Solgar (capsules poured into dispenser) - night
Evening primrose oil - Natures Aid capsules (same dispenser) - night
Oleuropein - Swanson (1mg/ml in minox) - night (stopped for now)
Sodium Valproate tablets crushed - 10mg/ml in distilled water and equal amount of minox solution (stopped for now)
Teavigo EGCG - Swanson - 8-10/mg/ml in separate minox solution - night (stopped)


chemical , I have no knowledge of alopecia. I suffer aga for 16 years . I was deceived by a surgeon in Spain twice and had to go to Dr. Hasson to solve the problem .
I took finasteride for 7 years with very good results but I gave it up because of side effects . 8 years ago I left finasteride.
currently I do not take drugs for hair loss and I 'm sentenced because I have several capillaries operations.
I read your posts but I do not understand anything . I'm depressed , bitter. please chemical , you seem to have much knowledge. I think we are many users who believe in you. Do you think you come to any conclusion on your research and get a possible future treatment ?

Hey machi, I want to tell you that I know what it feels like but I havent had it for that long so I can only imagine how hard it is for guys like you. Growing hair is a difficult process and it takes alot time, for some people nothing seems to work and it can be frustrating so I'd encourage you try and stay hopeful. We're in the 21st century and there are alot of promising treatments on the horizon. I'm not going to give you false hope by saying the research we're doing here is going to lead to a cure but we've made some huge leaps in understanding AGA better which will increase the chances of coming across something that helps. You can try the treatments listed in this thread but it will take time and perseverance to see results especially given that you've had AGA for a while. Stay strong.


Chemical, have you seen:

http://www.dannyroddy.com/weblog/antihistaminebaldnessstress

which if correct indicates that Estrogen plays a negative role (causes terminal hair - vellus, is involved in fibrosis of scalp around follicles, etc) rather than a positive role?

I like the authors scientific approach but he seems to use alot of associative reasoning. It pains me to see scientific minds become a victim of confirmational bias, they end up looking for literature that reaffirms their hypothesis and form conclusions based on loose inductive logic.


The heavy focus on androgens and “the genes” as causes of baldness have led people to believe that pattern hair loss is a compartmentalized problem rooted in vanity that has nothing to do with their metabolism or lifestyle. Confusion about the role of androgens probably relates to testosterone’s conversion into estrogen during metabolic stress and that dihydrotestosterone (DHT), like DHEA, can increase to buffer the effects of metabolic stress, for example, as an anti-estrogen.

He believes AGA is more a lifestyle/endocrinology related pathogenesis. Oxidative stress, Immune system, prostaglandins, glucose metabolism, diet, exercise - yeah they all play a part just like breathing provides oxygen to all mitochondria in all the cells. Side effects and symptoms of AGA do not mean that they are causative factors. Alot of people are in the PGD2 bandwagon and with good reason, but InBeforeTheCure has demonstrated that this whole PGD2 thing is caused by Androgens. How are you going to deny that Androgens arent the main factor driving the progression of baldness?


Estrogen, free fatty acids, prostaglandins, mast cells, and histamine are involved in the development of fibrosis, or the abnormal progression of the normal formation of fibrous material between cells due to inflammation. In 1992, Jaworsky et al. found that a prominent feature of baldness was mast cell degranulation and the activation of fibroblasts resulting in fibrotic thickening of the hair follicle.[28] In another experiment, 412 people with pattern baldness (193 men and 219 women) confirmed the presence of a significant degree of perifollicular fibrosis in at least 37% of cases. Moreover, balding men with higher levels of inflammation and fibrosis led to worse outcomes using the traditional hair loss remedy minoxidil compared to those with lower levels.[29]

There is fibrosis in AGA. Estrogens, prostaglandins and histamine are involved in the development of fibrosis. Therefore, Estrogen is bad. Also AGA has three letters. A triangle has three sides. The illuminati created AGA.

I've had this debate about fibrosis and AGA in the past, feel free to read the exchange with youngin from this post (https://www.baldtruthtalk.com/threads/22187-I-think-I-ve-hacked-it?p=226167&viewfull=1#post226167) onwards. In short, the Reactive oxygen species generated by the DPC as a result of Androgen overexpression leads to excessive TGF-beta production. TGF-beta has been shown to kick off the chain that causes fibroblasts to deposit fibrotic tissue.

Estrogens are actually beneficial to frontal hair follicles, being able to stimulate the elongation of hair shafts - I made an in-depth post here here (https://www.baldtruthtalk.com/threads/22991-Treatments-and-Science-Read-Only?p=234547&viewfull=1#post234547).


Both sodium valproate and VPA are very soluble in vehicles with 30% (or more) ethanol. The human AGA study I think used 27% ethanol with sodium valproate. To have the concentration you want (around 7% or 8%) you probably need the ethanol there or it might separate. I've made a lot of mixtures with VPA and various other components, and the ethanol seems necessary to have useful concentrations.

Correct, both VPA and SV are soluble in most solvents and I highly doubt you've want to go beyond 30mg/ml anyway. The only reason I suggested water is because its easier for people to make a solution without too much effort. I have a strong suspicion the study used ethanol to enhance the skin penetration seeing as ethanol strips the lipid barrier and weakens the stratum corneum. I personally encourage the use of ethanol + PG as a primary vehicle for nearly everything. Ideally a you'd want a water based solution with any amount of ethanol (maybe PG too) to enhance skin permeation but I dont see why a water based solution wouldn't work in this case for people who cant get hold of 190 proof alcohol.

Regarding separation? - I've never seen a dissolved molecule separate from a solution before its reached saturation. But I'm not a molecular biologist :rolleyes: and only have experience mixing water and sugar so correct me if I'm wrong lol.

BaldingEagle
04-19-2016, 02:12 PM
@Chemical

Putting aside the negative effects and looking purely at the effects on hair, would Propecia and Nizoral 1% plus Minoxidil be enough to cover the Androgen angle to this or should I just use dut?

joshuk
04-20-2016, 11:42 AM
I have just ordered VPA from inhouse, if i crush a 500mg tablet into 60ml of solution this gives me 8.3mg per ML. can i use a 70/30 eth/pg mixture or is it better to use 60ml of distilled water instead??? want to try this as i cannot use minoxdil.

FeelsBad
04-20-2016, 09:39 PM
Chemical, why did you stop using oleuropein?

Chemical
04-21-2016, 04:20 AM
@Chemical

Putting aside the negative effects and looking purely at the effects on hair, would Propecia and Nizoral 1% plus Minoxidil be enough to cover the Androgen angle to this or should I just use dut?

ketoconazole cream 2% twice a day + finasteride + minox will cover the Androgen side if you've got good density or less aggressive AGA.

The problem with 5ar inhibitors, especially oral ones, is that they have a tendency to increase LH production and subsequently raise blood T levels and a local reduction in T's conversion to DHT leading to even more more T within cells. Suraphysical levels of T can activate the AR just as potently as DHT so it just offsets the potential gain from DHT inhibition. It's a tricky decision, yes Dut will kill more DHT, but you'll have even more T in comparison to Fin. I would stick to Fin.


I have just ordered VPA from inhouse, if i crush a 500mg tablet into 60ml of solution this gives me 8.3mg per ML. can i use a 70/30 eth/pg mixture or is it better to use 60ml of distilled water instead??? want to try this as i cannot use minoxdil.

Did you get the depakote ones or the epilium? It looks like the tablets have some coating, I want tablets without a coating, preferably capsules.

I think I'll scrap the whole mg/ml crap, so long as we know what doses work and there is okayish solubility we can just control the dose with the application. Go with 50/30/20 Ethanol/Water/PG and use as much mg as you want. You dont want the ethanol to dry up quickly. Given that the study used 8mg per application and some individuals probably used less or more, with some cases of slight systemic absorption I think it's pretty safe to bump the dose higher than 8mg. The plasma therapeutic range is 50-125 µg/mL according to google and the topical absorption didnt get anywhere near those numbers. The cases of hairloss associated with oral VA require chronic high doses and even then it only affects a small minority:


http://www.bioline.org.br/pdf?pt05030

Among 211 patients who received sodium valproate (enteric coated tablet), 51% were male and 49% were female (no significant difference). Patients’ mean age of epilepsy onset was 11 years old and mean age starting to receive sodium valproate was 18 years old. More than 78% of patients had experienced tonic–clonic seizures (primary or secondary). All patients received monotherapy (single drug treatment). Overall, there were 6 cases (3.5%) of hair loss and curling of hair. Among them 3 cases were female and 3 were male. This side effect could be observed 3 months after first dose of therapy It took 1-2 years before appearance of hair loss and curly hair in other cases.

I believe the AR inhibitory properties are due to it's ER potentiating effects and I'm seeing more studies showing various ER agonists have the ability to downregulate AR in a dose dependent manner. The hairloss effects of VA could be more noticeable in women than men since female follicles require certain levels of ER to grow and maintain anagen. The study I posted before showed the AR suppressive effects were maximal at 2mM+ so I'm going to try and figure how that translates to topical use. I'm tempted to try alfatradiol (17-alpha Estradiol - available from Amazon.de as Ell Cranell) which supposedly increases the levels of Aromatase - more E2 should help VA work at a lower concentration. 17alpha Estradiol doesnt have the feminizing effects of 17beta Estradiol so you dont need to worry about gyno as long as the dose is low.


Chemical, why did you stop using oleuropein?

The powder dried up in the capsules and I need to buy more. I'm experimenting without it for now to see if I can get regrowth using other stuff.

joshuk
04-21-2016, 04:39 AM
i got the epilium ones 500mg tablets. so can i just crush these up and put them into the solution, or do i need to filter the coating after.

bej
04-21-2016, 11:12 AM
Correct, both VPA and SV are soluble in most solvents and I highly doubt you've want to go beyond 30mg/ml anyway. The only reason I suggested water is because its easier for people to make a solution without too much effort. I have a strong suspicion the study used ethanol to enhance the skin penetration seeing as ethanol strips the lipid barrier and weakens the stratum corneum. I personally encourage the use of ethanol + PG as a primary vehicle for nearly everything. Ideally a you'd want a water based solution with any amount of ethanol (maybe PG too) to enhance skin permeation but I dont see why a water based solution wouldn't work in this case for people who cant get hold of 190 proof alcohol.

Regarding separation? - I've never seen a dissolved molecule separate from a solution before its reached saturation. But I'm not a molecular biologist :rolleyes: and only have experience mixing water and sugar so correct me if I'm wrong lol.

30 mg/mL (a.k.a. 3%) VPA or SV probably isn't going to be strong enough, considering that even at it's best, VPA/SV isn't a super robust hair grower. There was a mouse study that I think the human study used as a preliminary research. In mice, they tried several different concentrations of SV. 3% was not very effective as compared to around 7%.

I believe the SV studies had to use ethanol simply for solubility reasons. Take a look at the molecule, it is, for the most part, a very fatty-like molecule. I've been making different formulations, and one batch I made had too much water & glycerin, and not enough ethanol & butylene glycol. The VPA completely separated. Then I remade this formula, but tweaked it to have less water/glycerin and more ethanol/BG, and the VPA was totally soluble. I took notes on all the amounts used, but I'm going from memory at the moment. If you look at the molecule though, it's obvious it can't dissolve in pure water.

Aha, here it is: a pubchem (good site to look up molecules) reference for VPA (it didn't have much to say about SV solubility). VPA in pure water will only go to about 1 mg/mL, or 0.1%. Although, you can't always trust these solubility numbers, sometimes it's less or more. But that sounds about right to me, because it's a mostly fat-like molecule.

https://pubchem.ncbi.nlm.nih.gov/compound/3121#section=Solubility

Ethanol isn't hard to get. You don't even need 95% Everclear. Most states that make it tough to get the 95% will offer 75.5% ethanol at the liquor store. And from 75.5%, you can easily add water to get down to ~30% ethanol.

I wouldn't recommend PG as a solvent, but rather BG instead. Butylene glycol has similar solvent properties to PG, but BG is typically a lot less irritating. For those buying all kinds of ingredients to use, it would be a shame to go cheap and have skin irritation with PG. I have to avoid PG or my scalp will break out, and a surprising number of people have PG sensitivity. I got BG from lotioncrafters online.

Another good solvent that is under-utilized by the hair loss community is glycerin. Glycerin also looks chemically a lot like PG, but that one extra -OH group makes a big difference. Rather than being an irritant, glycerin is a nutrient that moisturizes the skin, adds some viscosity to the formula (think of hand sanitizers), and the glycerin is actually a 3-carbon sugar that can be used as fuel by the skin cells, or other aspects of cell metabolism. Glycerin is good for skin at up to 20% in a formula.

Chemical
04-21-2016, 02:01 PM
i got the epilium ones 500mg tablets. so can i just crush these up and put them into the solution, or do i need to filter the coating after.

I couldn't find any images of the EC500 and was hoping to get them myself. If theres a coloured coating you might be able to dissolve it until you see the actual powder idk. You could try scraping it off too. I get mine from 4nrx (dirt cheap) and the orange coating just chips off with a little effort. If you cant get it off then it shouldn't cause too much of an issue, probably just sugar and colouring.


30 mg/mL (a.k.a. 3%) VPA or SV probably isn't going to be strong enough, considering that even at it's best, VPA/SV isn't a super robust hair grower. There was a mouse study that I think the human study used as a preliminary research. In mice, they tried several different concentrations of SV. 3% was not very effective as compared to around 7%.


You're right I dont know why I keep thinking 1mg/ml = 1%. The study used 80mg/ml to get 8%. Also can you post the mouse study, I prefer not to go assumptions and random numbers. As for the dose, I've come to realise it's a bit useless working with the solubility if you can control how much of the actual drug you apply. If you went with ethanol and saturated completely to get 30mg/ml, you'd want 2ml to get 60mg and so forth. The human study advised subjects to use around 0.8ml/64mg:


The subjects were instructed to use either the VPA (sodium valproate, 8.3%) or placebo spray twice daily, with seven or eight pumps (~0.8 mL) for each dose.


I've been making different formulations, and one batch I made had too much water & glycerin, and not enough ethanol & butylene glycol. The VPA completely separated. Then I remade this formula, but tweaked it to have less water/glycerin and more ethanol/BG, and the VPA was totally soluble. I took notes on all the amounts used, but I'm going from memory at the moment. If you look at the molecule though, it's obvious it can't dissolve in pure water.

Aha, here it is: a pubchem (good site to look up molecules) reference for VPA (it didn't have much to say about SV solubility). VPA in pure water will only go to about 1 mg/mL, or 0.1%. Although, you can't always trust these solubility numbers, sometimes it's less or more. But that sounds about right to me, because it's a mostly fat-like molecule.

https://pubchem.ncbi.nlm.nih.gov/compound/3121#section=Solubility


You might have missed this comment I made along with the source for the solubility numbers



Since Sodium Valproate is the more readily available form and has excellent water solubility at 50mg/ml, in comparison to 1.3mg/ml for Valproic Acid (source (http://www.acutetox.eu/pdf_human_short/16-Sodium%20valproate%20revised.pdf)) it looks like Sodium Valproate is a strong candidate to be used in our protocols.

Also pubchem didnt have anything on sodium valproate and the human study used sodium valproate. I dont think its fair to compare VPA and SV hence I looked deeper

http://www.scbt.com/datasheet-202378.html

I trust scbt if pubchem doesnt list the exact molecule and both the pdf and scbt show the Sodium Valproate has 50mg/ml solubility in water. Whereas Valproic Acid specifically has very low water solubility corroborated by multiple sources and the trustworthy pubchem. You've also come to realise this with your own experiments that Valproic Acid isn't very poorly soluble in water. But the real question is did you try Sodium Valproate? I'm sure you acknowledge that the two are chemically different.



Ethanol isn't hard to get. You don't even need 95% Everclear. Most states that make it tough to get the 95% will offer 75.5% ethanol at the liquor store. And from 75.5%, you can easily add water to get down to ~30% ethanol.


Good point but water is still an option. Not everyone is in the states remember!



I wouldn't recommend PG as a solvent, but rather BG instead. Butylene glycol has similar solvent properties to PG, but BG is typically a lot less irritating. For those buying all kinds of ingredients to use, it would be a shame to go cheap and have skin irritation with PG. I have to avoid PG or my scalp will break out, and a surprising number of people have PG sensitivity. I got BG from lotioncrafters online.

Another good solvent that is under-utilized by the hair loss community is glycerin. Glycerin also looks chemically a lot like PG, but that one extra -OH group makes a big difference. Rather than being an irritant, glycerin is a nutrient that moisturizes the skin, adds some viscosity to the formula (think of hand sanitizers), and the glycerin is actually a 3-carbon sugar that can be used as fuel by the skin cells, or other aspects of cell metabolism. Glycerin is good for skin at up to 20% in a formula.

The PG is mainly to prevent the ethanol from drying up too quick and give the molecules enough time to soak in after the barrier is weakened. As you can tell I dont know jack about chemistry so couldn't recommend anything other than PG even though many people are sensitive to it. Looks you are right about BG and glycerols being equally effective substitutes to PG - according to these guys (http://chemistscorner.com/cosmeticsciencetalk/discussion/1205/natural-replacement-for-butylene-glycol-propylene-glycol). Glad we've finally got someone with a chemistry background to correct my mistakes!

jjo
04-21-2016, 06:58 PM
ketoconazole cream 2% twice a day + finasteride + minox will cover the Androgen side if you've got good density or less aggressive AGA.

The problem with 5ar inhibitors, especially oral ones, is that they have a tendency to increase LH production and subsequently raise blood T levels and a local reduction in T's conversion to DHT leading to even more more T within cells. Suraphysical levels of T can activate the AR just as potently as DHT so it just offsets the potential gain from DHT inhibition. It's a tricky decision, yes Dut will kill more DHT, but you'll have even more T in comparison to Fin. I would stick to Fin.



Hi Chemical, thanks so much for all your time and effort. Can you go more into what you are saying about oral 5ar inhibitors please?

When fin stopped working for me after years I switched to dut and got a couple years more. Now i'm loosing ground on 1 mg / day dut and have even added 8% ru daily.

This has been really hard on me and I don't know what to do anymore... these drugs worked super good for me and now they don't.. what can I do Chemical? Please any advice would be so much appreciated.

thanks

InBeforeTheCure
04-22-2016, 02:56 AM
I'm trying to stay ignorantly optimistic. Please dont hit me with a dose a reality.

Well, I could be wrong, I guess. I've been wrong about many things before, and I'll be wrong about many things in the future. ;)


My theory is that the frontal DPC's sensitivity to sex steroids has been unintentionally conserved by men when selecting women with thick hairlines, perceiving them to be more youthful and attractive. And this regional difference in DPC response becomes the complete opposite in males, but since women might have given less preference to looks and more on dominance, the genes ended up being conserved.

Speaking of genetics, I've been playing around with something called RegulomeDB (http://regulome.stanford.edu) today. You put in a SNP or list of SNPs, and it combs through high-throughput experimental data and shows you epigenetic factors that those SNPs could be affecting. I threw in all the SNPs in Table S4 from this study (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127852), but focused mostly on the X-chromosome location (EDA2R/AR, with a bunch of SNPs in linkage disequilibrium) and the Chr20 location (around a long non-coding RNA segment called LINC01432 between PAX1 and FOXA2, again with a bunch of SNPs in linkage disequilibrium). The interesting thing about these two is that having the risk alleles for both can act synergistically to give you a 7x risk rather than the 2.8x or whatever it is you would get if you multiplied the odd ratios.

So...The strongest hit in the EDA2R/AR region is from rs6152 on AR, which is just under 1.7kb downstream of the AR promoter: http://regulome.stanford.edu/snp/chrX/66765626

You can see that EZH2 (https://en.wikipedia.org/wiki/EZH2) is there, so maybe the SNP affects EZH2 binding affinity. Since EZH2 is a methyltransferase, maybe rs6152 = A is more highly methylated (and therefore transcription of AR repressed). It's in a good spot for that too. See Fig1a: Negative correlation between methylation and expression is enriched in extensive regions downstream of promoters. (http://www.nature.com/nature/journal/v510/n7506/fig_tab/nature13268_F1.html)

For the Chr20 locus, the highest score was with rs6137444 (position chr20:21785638), the most upstream of the Chr20 SNPs associated with AGA: http://regulome.stanford.edu/snp/chr20/21785638

As you can see, it's around an AR binding site. It probably has nothing to do with FOXA2, since FOXA2 isn't expressed at all in hair follicles. It may affect PAX1, which is expressed in DP cells and which plays a role in pattern formation. Or maybe the culprit is the long non-coding RNA -- long non-coding RNA can have epigenetic roles (http://genesdev.cshlp.org/content/23/13/1494.full.html). Of note:


Noncoding transcription has even been shown to induce the formation of heterochromatin at the p15 tumor suppressor gene locus that persisted after noncoding transcription was turned off, suggesting that the transient expression of ncRNAs can have long-lasting heritable effects on gene expression (Yu et al. 2008).

So maybe androgen-dependent AR binding to this site slowly and permanently changes the epigenetic program of DPCs, which could be irreversible even with AR knockdown. Who the hell knows? It's fun to speculate. :cool:

It would be an interesting experiment if some researcher could see what happens when LINC01432 is overexpressed vs. underexpressed, what roles it may have, whether AR increases or decreases its expression in the presence or absence of DHT, and so on. And then maybe do the same with PAX1.

Of course, these may not actually be the functional variants, but it's fun to play around with this stuff even with limited data.


Even if we did have gene therapy, to me it seems like it would be very difficult to localise it to just the epidermis of the frontal scalp. And the cost might not justify not getting a transplant instead either from healthy regions or cultured DPC if they get that far in the future.

I just Googled "site-specific gene therapy", and it seems to be a topic of ongoing research.


My belief is that the DPC become conditioned during embryogenesis or at some point in the womb and that this is only specific to the DPC. It could very well be that the entire frontal scalp contains the AGA code, but that just seems unintuitive. The stem cells should have the same code regardless of the location (I tell myself). I'm just trying to be optimistic with my delusions.

But these are specialized adult stem cells, so they'll be programmed a particular way, right?


One thing I find strange is how it takes quite a while for the initial recession to become noticeable but happens quite fast when stopping treatments. I remember reading a study on Hic5/ara55 (Androgen co-activator) and how it starts to get upregulated after puberty. And also reports of Testosterone/DHT being able to upregulate the expression of AR. Perhaps continued activation of AR causes permanent upregulation or enhanced stability of AR. Its also peculiar that RU users stop responding after a while - I mean its not like theres a negative feedback loop here? What do you think?

Can you give some examples of people who stopped responding to RU? I can't explain it (if they're using real RU and it hasn't degraded).


Looking at CB and RU they seem like the realistic and most ideal AR antagonists currently on the market, they have virtually no systemic effects on the HPTA or GnRH release and only work peripherally. Its just the price and lack of reputable sources (I'm a little cautious of chinese manufacturers) that put me off.

Yes, I will say that I trust some sources more than others, but I won't get into that here. ;)


http://www.nature.com/onc/journal/v22/n36/images/1206802f8.jpg

Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis (http://www.nature.com/onc/journal/v22/n36/full/1206802a.html)

Also AR is upregulated significantly so that might play a part in increasing the receptor saturation ceiling. It also doesnt make the conclusion robust given that non-AGA DPC have less AR. I want to know what would happen if AR was boosted to AGA levels in non AGA DPC.

We know that DHT/T that causes the binding of β-catenin to AR, and the study showed that without DHT, WNT3a did activate the TCF/LEF genes. Something that worries me is that maybe even an antagonist that binds to AR can recruit β-catenin. I'm thinking if we can prevent the binding of β-catenin to AR, we might not have to worry about Androgens at all. Something that fits into the pocket in place of β-catenin! What about SARMS and steroids? I know there are steroids that have significantly higher AR binding affinities that could easily saturate the receptors, and most of them have altered anabolic:androgenic ratios. Perhaps its the androgenic part that causes this negative response of AGA? Edit: looks like R1881 elicits the same response as T/DHT (http://www.fasebj.org/content/early/2002/12/02/fj.02-0043fje.full.pdf)

The interesting thing is that in AGA males, beta-catenin binding to AR is more enriched with Wnt signaling alone than with DHT alone. They do use a small DHT concentration though, so I imagine that could change with higher concentrations. Nevertheless, it seems like beta-catenin is still able to bind TCF/LEF even when bound to AR (the luciferase activity is high in AGA40M after Wnt despite the AR/beta-catenin binding stain being pretty dark). However, AR could still maybe act as a co-transcription factor at Wnt target genes and screw things up.

By the way:
Acetylation of β-Catenin by p300 Regulates β-Catenin-Tcf4 Interaction (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC381622/)


Lysine acetylation modulates the activities of nonhistone regulatory proteins and plays a critical role in the regulation of cellular gene transcription. In this study, we showed that the transcriptional coactivator p300 acetylated β-catenin at lysine 345, located in arm repeat 6, in vitro and in vivo. Acetylation of this residue increased the affinity of β-catenin for Tcf4, and the cellular Tcf4-bound pool of β-catenin was significantly enriched in acetylated form. We demonstrated that the acetyltransferase activity of p300 was required for efficient activation of transcription mediated by β-catenin/Tcf4 and that the cooperation between p300 and β-catenin was severely reduced by the K345R mutation, implying that acetylation of β-catenin plays a part in the coactivation of β-catenin by p300. Interestingly, acetylation of β-catenin had opposite, negative effects on the binding of β-catenin to the androgen receptor. Our data suggest that acetylation of β-catenin in the arm 6 domain regulates β-catenin transcriptional activity by differentially modulating its affinity for Tcf4 and the androgen receptor. Thus, our results describe a new mechanism by which p300 might regulate β-catenin transcriptional activity.


Most treatments themselves do not contain the growth factors, they merely stimulate the release indirectly and I'm wondering if all epidermal cells have the ability to release paracrine growth factors. Furthermore, there is only so much you can proliferate the HF shaft with exogenous growth factors, which explains why people only see vellus hairs getting longer. A functioning anagen DPC with an adequate blood supply thickens the diameter of the hair shaft significantly and continually releases growth factors in comparison the infrequent applications of treatments that may or may not reach target tissues. I'm thinking if theres another way to activate TCF/LEF genes without β-catenin, that would be even better than using indirect growth factors.

The better we understand it, the better chance we have of being able to do that, I guess. We'll be better able to predict the outcome of manipulating certain things.



I remember making a post about tgf-beta and dug this up:



So TGF-beta can potentiate AR via autocrine loop? the f***, it just keeps getting worse

Androgen receptor transactivity is potentiated by TGF-b1 through Smad3 but checked by its coactivator Hic-5/ARA55 in balding dermal papilla cells (https://sci-hub.io/10.1016/j.jdermsci.2011.08.010)

(was behind paywall but thats not going to stop me now)



So hic5/ARA55 is already upregulated in AGA when it starts and that is known to enhance AR. Then AR -> ROS -> TGF-beta -> more hic5/ARA55 ¬ (TGF-beta -> smad3 -> AR)

So it looks like hic5/ARA55 is bad, but is keeping check on the additional AR effect of TGF-beta. A powerful or mild anti-oxidant is probably all we need to fix this part but I think we should both look into hic5/ara55 and other co-activators that could be making AGA worse over time.

Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133876/)

An interesting note about TGF-beta from the Tasseff paper I posted a few months ago (http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003914):


We investigated the possibility that inhibitory signaling genes may be in the DP enriched group identified as LFO cluster 2, but not well described by the static intracellular expression model. We expect such signaling genes to display an increased expression 14 to 16 days after morphogenesis, near the on-set of catagen and before the sharp decline in the expanding population (Figure 4). Using this criterion, we identified 88 expression signals (relating to 74 unique genes; see Supplementary File S4). We observed that these expression signals, on average, are consistent with population driven changes until near catagen on-set, where they begin to increase more than what was explained by static intracellular expression assumed in the 2-population model (Supplementary Figure S10). Of these genes, 50 were annotated as extracellular genes which yields and enrichment p-value of 7.46E-18, improved enrichment over cluster 2 with a p-value of 3.63E-8. For a full list of significant enrichment categories see Supplementary File S5. Interestingly, this relatively short list includes Tgfβ2, which is currently thought to be one of the signaling molecules produced in DP cells to initiate apoptosis in hair epithelial cells at catagen on-set [7].

Given the observed expression signal, membership in DP enriched cluster 2, high enrichment for extracellular genes and inclusion of Tgfβ2, this list may contain potential targets for molecules that communicate an inhibitory signal from the DP to proliferating hair epithelial cells, closing a negative feedback loop. Obviously further experiments will be required to test this hypothesis; however, it does provide a starting point for future validation of the conclusions drawn above and, perhaps, even those identified in the model of Al-Nuaimi et al. [10].


And they only used DHT which leads me to believe AR will increase ROS regardless of β-catenin being present (or maybe there is some β-catenin being released intracellularly). Maybe in AGA the binding of β-catenin to AR doesnt affect the transcription of AR genes but binds - just because it can and by the time it reaches the nucleus it cant activate TCF/LEF. I was incorrect about β-catenin making the DPC response worse, it just cant target its canonical genes, thats all.

We also know that DKK-1 is induced by reactive species, specifically JNK mediated. And looking back over the research it looks like the DPC themselves produce DKK-1:



But I dont understand why ROS is induced in AGA DPC when in PC it represses it. The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. (http://www.ncbi.nlm.nih.gov/pubmed/11707452)

So although there are quite a few similarities its not quite apples to apples which irritates me.


Probably some of the DKK1 is by the ROS -> p53 -> DKK1 pathway you pointed out (there's a p53 binding site on the DKK1 promoter), but also that tail-off effect is really similar to prostate cancer graphs/stain patterns of Wnt target genes with increasing concentrations of DHT, and DKK1 is a direct Wnt target gene. (http://www.nature.com/onc/journal/v23/n52/full/1207892a.html) Adding DHT could possibly translocate beta-catenin to the nucleus if it's bound to AR and can ride AR into the nucleus.

bej
04-22-2016, 07:10 AM
Also pubchem didnt have anything on sodium valproate and the human study used sodium valproate. I dont think its fair to compare VPA and SV hence I looked deeper

http://www.scbt.com/datasheet-202378.html

I trust scbt if pubchem doesnt list the exact molecule and both the pdf and scbt show the Sodium Valproate has 50mg/ml solubility in water. Whereas Valproic Acid specifically has very low water solubility corroborated by multiple sources and the trustworthy pubchem. You've also come to realise this with your own experiments that Valproic Acid isn't very poorly soluble in water. But the real question is did you try Sodium Valproate? I'm sure you acknowledge that the two are chemically different.


I am mainly working with VPA since that was what I first obtained, and I've got this bottle of it and don't want to waste it. I got the VPA before thinking through VPA vs. SV issues. Maybe I'll someday replace the VPA with SV, but the formulas I'm working on are complicated, and once I get the bugs worked out with VPA, I'll probably stick with that.

Take those product sheets with a grain of salt. The pharmaceutical lab I work in happened to have a small amount of SV, which I discreetly used for a couple solubility tests. The product sheet you link to says SV goes to 3% in ethanol, but I put SV in ethanol at 8%, and it was very easily soluble. Another example, Lithium Chloride that I dissolved in ethanol was only half as soluble as the numbers reported.

In solution, VPA and SV will be chemically identical. Take a look at the two structures side-by-side. You'll see that the only difference is in one single spot where VPA has a hydrogen (H) and SV has sodium (Na). In solution, that H, and that Na, float away (dissociate). All the other bonds in the molecule are permanent (covalent) bonds, and so those atoms continue to stick together. The sodium weighs more than the hydrogen though, so when you take that into account, that's why 8.3% SV will be equivalent to 7.2% VPA, the same number of molecules of valproate per volume of liquid. Also, the H that dissociates from VPA is what makes it an acid. I had concerns about the acidity, but those theoretical concerns turned out to be a non-issue.

ryan82
04-22-2016, 07:36 AM
I am mainly working with VPA since that was what I first obtained, and I've got this bottle of it and don't want to waste it. I got the VPA before thinking through VPA vs. SV issues. Maybe I'll someday replace the VPA with SV, but the formulas I'm working on are complicated, and once I get the bugs worked out with VPA, I'll probably stick with that.

Take those product sheets with a grain of salt. The pharmaceutical lab I work in happened to have a small amount of SV, which I discreetly used for a couple solubility tests. The product sheet you link to says SV goes to 3% in ethanol, but I put SV in ethanol at 8%, and it was very easily soluble. Another example, Lithium Chloride that I dissolved in ethanol was only half as soluble as the numbers reported.

In solution, VPA and SV will be chemically identical. Take a look at the two structures side-by-side. You'll see that the only difference is in one single spot where VPA has a hydrogen (H) and SV has sodium (Na). In solution, that H, and that Na, float away (dissociate). All the other bonds in the molecule are permanent (covalent) bonds, and so those atoms continue to stick together. The sodium weighs more than the hydrogen though, so when you take that into account, that's why 8.3% SV will be equivalent to 7.2% VPA, the same number of molecules of valproate per volume of liquid. Also, the H that dissociates from VPA is what makes it an acid. I had concerns about the acidity, but those theoretical concerns turned out to be a non-issue.

I have used VPA. I had a major shed. Do you experience the same?

potato1987
04-22-2016, 09:26 AM
Thanks for the great write up first off!

Secondly is there anything I can do without fin/minox? wanting kids soon and had a very bad reaction to minox (not itching but skin ageing).

Many thanks,

InBeforeTheCure
04-22-2016, 07:53 PM
For the Chr20 locus, the highest score was with rs6137444 (position chr20:21785638), the most upstream of the Chr20 SNPs associated with AGA: http://regulome.stanford.edu/snp/chr20/21785638

As you can see, it's around an AR binding site. It probably has nothing to do with FOXA2, since FOXA2 isn't expressed at all in hair follicles. It may affect PAX1, which is expressed in DP cells and which plays a role in pattern formation. Or maybe the culprit is the long non-coding RNA -- long non-coding RNA can have epigenetic roles (http://genesdev.cshlp.org/content/23/13/1494.full.html). Of note:



So maybe androgen-dependent AR binding to this site slowly and permanently changes the epigenetic program of DPCs, which could be irreversible even with AR knockdown. Who the hell knows? It's fun to speculate. :cool:

It would be an interesting experiment if some researcher could see what happens when LINC01432 is overexpressed vs. underexpressed, what roles it may have, whether AR increases or decreases its expression in the presence or absence of DHT, and so on. And then maybe do the same with PAX1.


After looking around further, I think it's most likely PAX1. There are PAX1 enhancer regions downstream of PAX1.

A ​PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females (http://www.nature.com/ncomms/2015/150318/ncomms7452/full/ncomms7452.html)


Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10−9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10−10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to ​PAX1, which encodes ​paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.


IS is a sexually dimorphic disease10. Girls and boys exhibit a striking difference in the prevalence of progressive IS, with girls having approximately tenfold greater risk of progressive curves that require operative treatment11. This dichotomy in female/male disease expression, and its correlation with the adolescent growth spurt have prompted investigations of hormonal influences in the development and progression of female IS6.


To discover new genetic risk factors for IS, we performed a two-stage GWAS in 3,102 individuals. Our results define a new susceptibility locus encoding associated SNPs that, surprisingly, are also associated with androgenic alopecia (AGA), or male pattern baldness. We find that the locus is specifically associated with female IS, suggesting that it contributes to the sexually dimorphic expression of the disease. By functional fine-mapping assays in zebrafish, we further define a sequence in the associated locus with enhancer activity that is abolished by IS-associated SNPs. Altogether, our results identify the first functionally characterized candidate mutations for IS susceptibility and expand our understanding of the role of non-coding regulatory elements in the disease. Our findings also suggest hypotheses to explain disease pathogenesis and provide the first insights into its puzzling sexual dimorphism.


Comparing our results to the National Human Genome Research Institute (NHGRI) GWAS catalogue22, we found that the chromosome 20 IS locus was previously associated with early-onset male pattern baldness (AGA). Similar to IS, AGA displays sexual dimorphism, that is, it is biologically unequal in males and females. However, unlike IS, disease progression in AGA (extent of hair loss) is generally more severe in males than in females36. We identified chromosome 20p11.22 SNPs that were previously associated with AGA and that were genotyped in our GWAS37, 38, 39. In this comparison, SNPs that were associated with IS and AGA displayed the opposite direction of effect for the two disorders (Supplementary Table 1). This observation suggested that sequences in the region conferring susceptibility to IS have a protective effect in AGA. To test whether the association we observed was sex-specific, we re-evaluated association with SNPs in the 20p11.22 locus after stratification by sex, that is, separating males and females. This analysis yielded evidence for association with IS in females but not males, with a combined Fisher’s P=6.88 × 10−9 in the former data set (Table 1 and Supplementary Tables 2 and 3).


Our investigation of the chromosome 20p11 locus provides the first genetic evidence to explain the puzzling sexual dimorphism that is a hallmark of IS. Besides susceptibility to progression, the pattern, onset and flexibility of deformity also differ between boys and girls10. Various hypotheses have been proposed to explain male/female differences in IS, including the existence of X-linked genetic risk factors and effects on circulating hormones. Neither mechanism has been clearly supported, although investigations have been limited6, 58. Our identification of a female-specific IS susceptibility locus suggests an underlying mechanism that is sensitive to the female milieu at the time of adolescence. Although we did not find evidence for oestrogen receptor-binding sites within the PEC7 enhancer locus itself, it is interesting to postulate that this locus increases risk of IS via downstream hormonal interactions. We note in this regard that the next-nearest gene, ​FOXA2, is implicated in sexually dimorphic gene expression via cooperation with androgen and oestrogen receptor59. It is possible that PEC7 regulates ​FOXA2. However, we did not detect ​Foxa2 expression in embryonic or postnatal mouse spine (data not shown) and consider it an unlikely candidate for IS susceptibility. ​PAX1 is also expressed in the adult scalp37. Whether variants in PEC7 affect this expression and drive association with early-onset male pattern baldness requires further study, but the overlapping genetic association suggests a possible correlation between the two sexually dimorphic conditions.

burtandernie
04-23-2016, 12:43 PM
How important is it that we get some kind of AR antagonist like RU or CB that can compete with both T and DHT? It just seems like we desperately need another angle to fight androgens because raising T just seems stupid, and propecia has always felt like shooting a fly with a cannon by blowing up your endocrine system for a local problem

"ketoconazole cream 2% twice a day + finasteride + minox will cover the Androgen side if you've got good density or less aggressive AGA.

The problem with 5ar inhibitors, especially oral ones, is that they have a tendency to increase LH production and subsequently raise blood T levels and a local reduction in T's conversion to DHT leading to even more more T within cells. Suraphysical levels of T can activate the AR just as potently as DHT so it just offsets the potential gain from DHT inhibition. It's a tricky decision, yes Dut will kill more DHT, but you'll have even more T in comparison to Fin. I would stick to Fin."

tiktok
04-28-2016, 01:36 PM
The problem with 5ar inhibitors, especially oral ones, is that they have a tendency to increase LH production and subsequently raise blood T levels and a local reduction in T's conversion to DHT leading to even more more T within cells.

That's not correct. (http://www.ncbi.nlm.nih.gov/pubmed/9589555)

joshuk
04-29-2016, 01:13 AM
can i mix oleuropein and VPA together in one vehicle or is it best to keep them seperate. Chemical the epi vpa had a light purple coating which i just peeled off and dissolved the powder into eth/pg

musky
05-03-2016, 08:17 AM
Hydroxylation is the process by which 5ar gets converted to 3beta-diol. Keto and mico inhibit this step thus preventing the conversion of DHT to 3Beta-diol.


that's not what hydroxylation is and 5ar doesn't convert to 3beta-diol. 5ar converts testosterone to dht, dht is then converted by 3beta-hsd into 3beta-diol. 3beta-diol is then hydroxylated by some CP450 enzyme which i can't be bothered to research. it says that clearly in the abstract we keep posting back and forth to eachother.

TheKingofFighters
05-31-2016, 10:27 AM
After looking around further, I think it's most likely PAX1. There are PAX1 enhancer regions downstream of PAX1.

A ​PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females (http://www.nature.com/ncomms/2015/150318/ncomms7452/full/ncomms7452.html)

So tell me, because this is a critical question that i could not answer myself- whether do we need to INCREASE OR DECREASE PAX1's expression in the balding scalp(in order to regrow hair)?

Compounds that decrease PAX1:

Cacitriol(inhibits b-catenin)
Copper
Acetominophen(Panadol)
Bisphenol A(an estrogenic chemical)
Testosterone(androgenic hormone)

Compounds that increase PAX1:

Tretinoin(retinoic acid)
Valeric acid(present in anal cells of skunks)
Valproic acid(synthetic variant of Valeric acid)
Butyric acid(present in vomit)
Proprionic acid(present in sebum)
Ethinyl Estradiol(synthetic form of E2)
Curcumin
Resveratrol

karxxx
05-31-2016, 10:45 AM
http://www.hairloss-research.org/LinkUpdateSawPalmettoandHairGrowthEffects1-14.html
https://www.google.si/patents/US7887694
http://www.hairloss-research.org/LinkUpdateAstaxantinDHT4-12.html

TheKingofFighters
05-31-2016, 11:26 AM
So tell me, because this is a critical question that i could not answer myself- whether do we need to INCREASE OR DECREASE PAX1's expression in the balding scalp(in order to regrow hair)?

Compounds that decrease PAX1:

Cacitriol(inhibits b-catenin)
Copper
Acetominophen(Panadol)
Bisphenol A(an estrogenic chemical)
Testosterone(androgenic hormone)

Compounds that increase PAX1:

Tretinoin(retinoic acid)
Valeric acid(present in anal cells of skunks)
Valproic acid(synthetic variant of Valeric acid)
Butyric acid(present in vomit)
Proprionic acid(present in sebum)
Ethinyl Estradiol(synthetic form of E2)
Curcumin
Resveratrol

We present evidence of a new IS susceptibility locus in an ~100-kb region of chromosome 20p11.22 downstream of ​PAX1. Using a functional fine-mapping approach, we potentially narrow the locus to an ~1.5-kb domain with enhancer activity that is disrupted by disease-associated variants.(the IS-susceptible SNPs disrupts enhancer activity- presumably 'normal' activity for normal spinal development. We know from this study that these very same IS variants offers 'protection' from early onset baldness.) The ​PAX1-encoding region was originally associated with spinal development through studies of the naturally occurring undulated mouse strains. The original undulated (un) strain, first described in 1947, carries a missense mutation in ​Pax1 (ref. 41). Un/un mice display a curved spine with malformations of individual vertebrae including the vertebral bodies and intervertebral discs. Three additional strains, scoliosis (sco) or undulated intermediate (un-i), undulated-extensive (unex), undulated short-tail (uns), harbour partial or complete deletions of ​PAX1, with the latter including all of the gene and displaying the most severe phenotype41, 42.(A decrease/ablation in PAX1's expression confers malformations in the spine of rodents and amongst them- Scoliosis.) In early mouse development, ​Pax1 displays expression restricted to specific structures including the sclerotome that will give rise to the axial spine (vertebrae, ribs, connective tissues and skin). Genomic studies have delineated intervals downstream of ​Pax1 harbouring cis-regulatory activity consistent with this pattern43. In particular, transposon-based deletion mapping and reporter gene assays defined the ~148-kb region 3′ of ​Pax1 as necessary to drive somitic gene expression (that is, in the dorsal sclerotome) during early mouse development. Furthermore, the mouse Xe1 enhancer encoded in this region was shown to be sufficient to drive a similar expression pattern43. Our data using zebrafish transgene assays confirmed the enhancer activity of the human Xe1 orthologue and revealed another element in the region, PEC7, with potential somitic enhancer activity that was disrupted by IS-associated sequence variants.(The 'normal' variants in the affected region posseses potential somitic enhancer activity for proper spinal development, and is disrupted in those carrying the IS-associated variants.This observation strongly suggests that PEC7 itself functions in IS susceptibility, a hypothesis that may be tested in model systems by targeted mutagenesis.

All these implies that PAX1 needs to be DECREASED in order to regrow hair- because a decrease of PAX1 is what gives females a curved spine, but protection from hair loss.

But, im confused because PAX1 is involved with the profileration of stem cells

http://dev.biologists.org/content/141/4/737

So is it an INCREASE or DECREASE of PAX1(which is expressed in the adult scalp) to regrow hair?

Any1 who can answer this question accurately has basically- found the cure to AGA because in those who have carry no other AGA-susceptibility genes(e.g AR/EDAR, HDAC9, etc locus) other than the PAX1 variant- needs only to address this gene in order to regrow hair.

Seuxin
05-31-2016, 12:22 PM
Hmmm Calcitriol is pretty cheap t get no ?
We just need to know an amount to test....

0.1%
1%

?

mlamber5
05-31-2016, 01:30 PM
We present evidence of a new IS susceptibility locus in an ~100-kb region of chromosome 20p11.22 downstream of ​PAX1. Using a functional fine-mapping approach, we potentially narrow the locus to an ~1.5-kb domain with enhancer activity that is disrupted by disease-associated variants.(the IS-susceptible SNPs disrupts enhancer activity- presumably 'normal' activity for normal spinal development. We know from this study that these very same IS variants offers 'protection' from early onset baldness.) The ​PAX1-encoding region was originally associated with spinal development through studies of the naturally occurring undulated mouse strains. The original undulated (un) strain, first described in 1947, carries a missense mutation in ​Pax1 (ref. 41). Un/un mice display a curved spine with malformations of individual vertebrae including the vertebral bodies and intervertebral discs. Three additional strains, scoliosis (sco) or undulated intermediate (un-i), undulated-extensive (unex), undulated short-tail (uns), harbour partial or complete deletions of ​PAX1, with the latter including all of the gene and displaying the most severe phenotype41, 42.(A decrease/ablation in PAX1's expression confers malformations in the spine of rodents and amongst them- Scoliosis.) In early mouse development, ​Pax1 displays expression restricted to specific structures including the sclerotome that will give rise to the axial spine (vertebrae, ribs, connective tissues and skin). Genomic studies have delineated intervals downstream of ​Pax1 harbouring cis-regulatory activity consistent with this pattern43. In particular, transposon-based deletion mapping and reporter gene assays defined the ~148-kb region 3′ of ​Pax1 as necessary to drive somitic gene expression (that is, in the dorsal sclerotome) during early mouse development. Furthermore, the mouse Xe1 enhancer encoded in this region was shown to be sufficient to drive a similar expression pattern43. Our data using zebrafish transgene assays confirmed the enhancer activity of the human Xe1 orthologue and revealed another element in the region, PEC7, with potential somitic enhancer activity that was disrupted by IS-associated sequence variants.(The 'normal' variants in the affected region posseses potential somitic enhancer activity for proper spinal development, and is disrupted in those carrying the IS-associated variants.This observation strongly suggests that PEC7 itself functions in IS susceptibility, a hypothesis that may be tested in model systems by targeted mutagenesis.

All these implies that PAX1 needs to be DECREASED in order to regrow hair- because a decrease of PAX1 is what gives females a curved spine, but protection from hair loss.

But, im confused because PAX1 is involved with the profileration of stem cells

http://dev.biologists.org/content/141/4/737

So is it an INCREASE or DECREASE of PAX1(which is expressed in the adult scalp) to regrow hair?

Any1 who can answer this question accurately has basically- found the cure to AGA because in those who have carry no other AGA-susceptibility genes(e.g AR/EDAR, HDAC9, etc locus) other than the PAX1 variant- needs only to address this gene in order to regrow hair.

In my opinion this is the critical issue in AGA. What in the heck is going on at 20p11? Ar variants only confer greater risk to those of European heritage, it is monomorphic in Asians (existing in roughly only 1 type). 20p11 is by far the greatest at risk spot in asians, and is by a wide margin the second biggest risk point in Europeans. So it is the commonality between the two (along with androgenic hormones themselves... NOT androgen receptor.... only in europeans does this somehow accelerate the process).

http://www.hair-gel.net/

Although this is in mice, this is a highly useful website. In postnatal mouse skin, PAX1 is primarily expressed in the dermal papilla and in a smaller amount in the dermal fibroblasts. But I think we must be careful here on this. The set of SNP's at 20p11 are between PAX1 and FOXA2. The SNP's do lie closer to PAX1... But i'm not sure in which direction the DNA is being read on this strand... aka from PAX1 to FOXA2 or from FOXA2 to PAX1. That can make a big difference. Although FOXA2 is not expressed in postnatal mouse hair follicle environment, a quick look up of the functions of FOXA2 shows that IT HAS TO BE INVOLVED SOMEHOW IN AGA. FOXA2 is involved in ANDROGEN METABOLISM and response to IL-6... you can google these if you like for proof. IL-6 has been shown to be induced by DHT in AGA dermal papilla and it increases expression through p-STAT3 in the ORS and the bulge to induce premature Catagen. Stat3 is also present in dermal papilla and in other tissues has been known to up-regulates Ar gene expression and sensitivity to Androgenic hormones. So in my mind, even though FOXA2 isn't explicitly expressed in mouse postnatal hair follicle.... FOXA2 must be involved in some way in the parthenogenesis of AGA... There is still a lot we do not know about genetics especially when it comes to "junk" DNA (The DNA not directly involved in gene expression or protein coding.... It has a function science just isn't entirely sure how to read it yet). And that is exactly what we are dealing with at 20p11 and AR/EDA2R ( At risk SNP's are between genetic coding on "junk" DNA ).

mlamber5
05-31-2016, 02:00 PM
And secondly the only way to really attack this in the near term (before CRISPR and like-systems) is to find out what proteins/pathways are being activated and silencing them or up-regulate them. I could fill the next 30 posts with articles and information to explain... the information is free for all to research and draw their own conclusions on the internet but in my mind AGA comes down to 4 main factors in people of European ancestry. The first is Androgenic hormones themselves. The second is the Androgen receptor. The third is overexpressed STAT3/PStat3, especially as it relates to the bulge and dermal papilla. And finally the fourth is the cytokine Interleukin-6, which is pro-inflammatory and works mainly through the JAK/STAT3 pathway. It is the interplay of these four which I think is causing the entire phenotype we see in AGA, and the correlation/association between other at risk factors in those that have AGA such as BPH, Diabetes, Prostate Cancer, Parkinson's Disease, and much greater risk of idiopathic scoliosis in females (another 20p11 major at risk spot). Stoping Ar itself will merely slow down the progression of AGA. The only way we know of so far to stop it dead in its tracks is castration, and that obviously isn't an option. I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype.

TheKingofFighters
05-31-2016, 05:51 PM
I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype.

On the Contrary- i do not think so.

InBeforeTheCure
05-31-2016, 06:47 PM
So tell me, because this is a critical question that i could not answer myself- whether do we need to INCREASE OR DECREASE PAX1's expression in the balding scalp(in order to regrow hair)?

Compounds that decrease PAX1:

Cacitriol(inhibits b-catenin)
Copper
Acetominophen(Panadol)
Bisphenol A(an estrogenic chemical)
Testosterone(androgenic hormone)



That's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):

http://s33.postimg.org/m78srozzj/bolton_supp.png

(Bolton et. al, 2007 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1948856/), supplementary material)

Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).

By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/160519/ncomms11616/full/ncomms11616.html


Strongest association in 20p11 with the ordinal assessment of nose wing breadth was observed for SNP rs927833 located in LOC100270679, a long intergenic non-protein coding RNA (LINC01432). There is substantial LD around this SNP and suggestive evidence of association (that is, P values <10−5), for SNPs over a region of ~400 kb extending to the Paired-box gene 1 (PAX1; Fig. 3f), a strong candidate gene in this region. PAX1 is a key developmental transcription factor which has been shown experimentally to affect chondrocyte differentiation through its participation in a regulatory pathway that also includes RUNX2 and SOX9 (ref. 46). More broadly, a Pax-Six-Eya-Dach (Dachshund) network, involving protein–protein and protein–DNA interactions impacting on a range of basic developmental processes has been described47. As indicated above, another PAX gene (PAX3) has been twice reported to impact on nasion position9, 11, and we replicate that association here. A missense mutation in PAX1 has been shown to cause autosomal recessive oto-facio-cervical syndrome, a disorder characterized by various skeletal and facial abnormalities48. It has also been reported that mouse embryos with Gli3-null mutations display drastically reduced Pax1 expression, possibly mediated through Gli3’s involvement in the sonic hedgehog signalling pathway49. Consistent with these experimental findings, we observe a significant statistical interaction of the GLI3 and PAX1 index SNPs on nose wing breadth (P value=0.005, Supplementary Table 17).

So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this. :p

Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.



All these implies that PAX1 needs to be DECREASED in order to regrow hair- because a decrease of PAX1 is what gives females a curved spine, but protection from hair loss.

But, im confused because PAX1 is involved with the profileration of stem cells

http://dev.biologists.org/content/141/4/737

It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).


So is it an INCREASE or DECREASE of PAX1(which is expressed in the adult scalp) to regrow hair?

Any1 who can answer this question accurately has basically- found the cure to AGA because in those who have carry no other AGA-susceptibility genes(e.g AR/EDAR, HDAC9, etc locus) other than the PAX1 variant- needs only to address this gene in order to regrow hair.

Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.


In my opinion this is the critical issue in AGA. What in the heck is going on at 20p11? Ar variants only confer greater risk to those of European heritage, it is monomorphic in Asians (existing in roughly only 1 type). 20p11 is by far the greatest at risk spot in asians, and is by a wide margin the second biggest risk point in Europeans. So it is the commonality between the two (along with androgenic hormones themselves... NOT androgen receptor.... only in europeans does this somehow accelerate the process).

http://www.hair-gel.net/

Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/


Although this is in mice, this is a highly useful website. In postnatal mouse skin, PAX1 is primarily expressed in the dermal papilla and in a smaller amount in the dermal fibroblasts. But I think we must be careful here on this. The set of SNP's at 20p11 are between PAX1 and FOXA2. The SNP's do lie closer to PAX1... But i'm not sure in which direction the DNA is being read on this strand... aka from PAX1 to FOXA2 or from FOXA2 to PAX1. That can make a big difference. Although FOXA2 is not expressed in postnatal mouse hair follicle environment, a quick look up of the functions of FOXA2 shows that IT HAS TO BE INVOLVED SOMEHOW IN AGA. FOXA2 is involved in ANDROGEN METABOLISM and response to IL-6... you can google these if you like for proof. IL-6 has been shown to be induced by DHT in AGA dermal papilla and it increases expression through p-STAT3 in the ORS and the bulge to induce premature Catagen. Stat3 is also present in dermal papilla and in other tissues has been known to up-regulates Ar gene expression and sensitivity to Androgenic hormones. So in my mind, even though FOXA2 isn't explicitly expressed in mouse postnatal hair follicle.... FOXA2 must be involved in some way in the parthenogenesis of AGA... There is still a lot we do not know about genetics especially when it comes to "junk" DNA (The DNA not directly involved in gene expression or protein coding.... It has a function science just isn't entirely sure how to read it yet). And that is exactly what we are dealing with at 20p11 and AR/EDA2R ( At risk SNP's are between genetic coding on "junk" DNA ).

I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html

However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.


And secondly the only way to really attack this in the near term (before CRISPR and like-systems) is to find out what proteins/pathways are being activated and silencing them or up-regulate them.

I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.

mlamber5
05-31-2016, 07:08 PM
I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype.

On the Contrary- i do not think so.

Thanks for your contribution

mlamber5
05-31-2016, 07:11 PM
Looking forward to it. I can see we both have started from the same point, the genes it looks like. If indeed JAK/STAT inhibition does end up reversing AGA it would only make sense that the team that discovered the key pieces of information and cure to hair loss ( Christiano's team ) is a team that focuses on the genetics behind all types of hair loss.

TheKingofFighters
05-31-2016, 07:47 PM
Atually, the possible cure- is in our vomit

TheKingofFighters
05-31-2016, 07:53 PM
That's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):

http://s33.postimg.org/m78srozzj/bolton_supp.png

(Bolton et. al, 2007 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1948856/), supplementary material)

Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).

By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/160519/ncomms11616/full/ncomms11616.html



So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this. :p

Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.



It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).



Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.



Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/



I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html

However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.



I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.

Atually im trying to look from an angle with the viewpoint that the AR is not the culprit of AGA- but rather, it's either an underexpressed, overexpressed or no expression of PAX1 binding to it that is causing AGA. It is also the likely explanation why blocking the AR only halts AGA at best- but does'nt regrowth any hair

BTW, i greatly appreciate yours and mlamber5's valuable input into this topic(PAX1).

TheKingofFighters
05-31-2016, 08:08 PM
Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.

BTW, its:

SHH => Noggin <=> Pax1

Sonic hedgehog induces Noggin, which then induces Pax1's expression. But there was a study that stated Pax1 was upstream of Noggin.

So you are right in that Pax1 is a gene target of Hedgehog signalling

TheKingofFighters
05-31-2016, 08:15 PM
Atually im trying to look from an angle with the viewpoint that the AR is not the culprit of AGA- but rather, it's either an underexpressed, overexpressed or no expression of PAX1 binding to it that is causing AGA. It is also the likely explanation why blocking the AR only halts AGA at best- but does'nt regrowth any hair

BTW, i greatly appreciate yours and mlamber5's valuable input into this topic(PAX1).

In other words, Dut/Fin can only merely be slowing down the inevitable(by staying as the less potent androgen receptor-binding Testosterone instead of converting to DHT)- they can never reverse anything.

TheKingofFighters
06-01-2016, 03:26 AM
That's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):

http://s33.postimg.org/m78srozzj/bolton_supp.png

(Bolton et. al, 2007 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1948856/), supplementary material)

Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).

By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/160519/ncomms11616/full/ncomms11616.html



So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this. :p

Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.



It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).



Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.



Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/



I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html

However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.



I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.

part of the solution to the puzzle lies in the Gluccocorticoid receptor too.

TheKingofFighters
06-01-2016, 04:02 AM
part of the solution to the puzzle lies in the Gluccocorticoid receptor too.

Inbeforethecure- Give me your valuable input on this:

http://www.wikipathways.org/index.php/Pathway:WP2840

Look at 'NR3C1'(centre/south of the diagram)- that's the Gluccocorticoid receptor and it's in a direct relationship with FOS(aka c-FOS) and FOSB

Then look at this http://www.google.com/patents/US20110021599 - Dr Cotsareli's patent on the most downregulated genes in non-balding scalp when compared to balding scalp. FOS and FOSB are the 3rd and 4th most downregulated genes in non-balding scalp, respectively.

What do you think? Gluccocorticoid underexpression or overexpression in AGA? Gluccocorticoid resistance?

Bear in mind that Calcium channel blockers directly inhibits FOS because:

L-type Ca(2+) channel activation regulates induction of c-fos transcription by hypoxia.
Premkumar DR1, Mishra RR, Overholt JL, Simonson MS, Cherniack NS, Prabhakar NR.
Author information
Abstract
In the present study we examined the intracellular pathways that link hypoxia to activation of c-fos gene expression. Experiments were performed on rat pheocromocytoma-12 (PC-12) cells. c-fos mRNA and promoter activities were analyzed by RT-PCR and reporter gene assays, respectively. BAPTA, a Ca(2+) chelator, inhibited c-fos mRNA and promoter activation by hypoxia. Nitrendipine, an L-type Ca(2+)-channel blocker, abolished, whereas BAY K 8644, an L-type channel agonist, enhanced c-fos activation by hypoxia. Ca(2+) currents were augmented reversibly by hypoxia, suggesting that Ca(2+) influx mediated by L-type Ca(2+) channels is essential for c-fos activation by hypoxia. We next determined downstream pathways activated by intracellular Ca(2+) concentration. Immunoblot analysis revealed Ca(2+)/calmodulin-dependent kinase II (CaMKII) protein in PC-12 cells and revealed that hypoxia increased the enzyme activity. KN-93, a CaMK inhibitor, blocked CaMKII activation and c-fos promoter stimulation by hypoxia. Ectopic expression of an active mutant of CaMKII (pCaMKII290) stimulated c-fos promoter activity under normoxia. Hypoxia increased phosphorylation of CREB at the serine residue 133 (Ser-133), and KN-93 attenuated this effect. Point mutations at the Ca(2+)/cAMP-responsive cis-element (Ca/CRE) attenuated, whereas point mutations in the serum-responsive cis-element (SRE) abolished transcriptional activation of c-fos by hypoxia. These results demonstrate that c-fos activation by hypoxia involves CaMK activation and CREB phosphorylation at Ser-133 and requires Ca/CRE and SRE. These observations demonstrate that Ca(2+)-dependent signaling pathways play a crucial role in induction of c-fos gene expression, which may underlie long-term adaptive responses to hypoxia.

http://www.ncbi.nlm.nih.gov/pubmed/10797155

1 interesting to take note of is that weight gain(though not that severe when compared to GC agonists) is a common side effect of CCBs- and this is a hallmark of GC agonists as well(like betamethasone). I can attest this because i am experimenting with https://en.wikipedia.org/wiki/Nifedipine now in accordance with this old patent http://www.google.com/patents/US5407944 that discovered the balding scalp is chronically and significantly hypoxic when compared to non-balding scalp.

While i do not agree with it's premise that suggested the usage of E2(Beta-estradiol) for hair growth(because of the huge tremendous sides that i've been through)- it makes sense that that the balding scalp is hypoxic, which translate to a localised form peripheral hypertension, as I can feel this chronic tightness on my head.

TheKingofFighters
06-01-2016, 04:25 AM
Further on, look@ LGR5( centre/right) of the same diagram in http://www.wikipathways.org/index.php/Pathway:WP2840 , then look @ Dr Cotsareli's patent http://www.google.com/patents/US20110021599 - this time round on the most upregulated genes in non-balding scalp when compared to balding scalp. LGR5 is aka GPR49. It's the 9th most upregulated and a WNT target gene:

http://www.ncbi.nlm.nih.gov/pubmed/18849992

Lgr5 marks cycling, yet long-lived, hair follicle stem cells.
Jaks V1, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgård R.
Author information
Abstract
In mouse hair follicles, a group of quiescent cells in the bulge is believed to have stem cell activity. Lgr5, a marker of intestinal stem cells, is expressed in actively cycling cells in the bulge and secondary germ of telogen hair follicles and in the lower outer root sheath of anagen hair follicles. Here we show that Lgr5(+) cells comprise an actively proliferating and multipotent stem cell population able to give rise to new hair follicles and maintain all cell lineages of the hair follicle over long periods of time. Lgr5(+) progeny repopulate other stem cell compartments in the hair follicle, supporting the existence of a stem or progenitor cell hierarchy. By marking Lgr5(+) cells during trafficking through the lower outer root sheath, we show that these cells retain stem cell properties and contribute to hair follicle growth during the next anagen. Expression analysis suggests involvement of autocrine Hedgehog signaling(In the context of AGA, anything that involves hedgehog signalling, as discussed above to your previous post- involves PAX1) in maintaining the Lgr5(+) stem cell population.

Now look at this http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682727

Abstract:
Leucine rich repeat containing G-protein coupled receptor 5 (LGR5) is a well-established stem cell marker in the normal intestine. Recent evidence suggests LGR5 is also a marker of cancer stem cells in colorectal tumours. Cancer stem cells propagate and maintain tumours and are hypothesized to be refractory to therapy. Solid tumours frequently experience hypoxia and an unresolved question remains as to how the cancer stem cell population survives this environmental stress. Several regulatory links are known to exist between hypoxic and stem cell signalling pathways. However, the role of hypoxia in regulating LGR5 is yet to be elucidated. Here it is reported that hypoxia down-regulates LGR5 expression. Both protein and mRNA expression is reduced in hypoxia. LGR5 down regulation was observed in cells derived from adenoma, primary carcinoma and metastases, suggesting this process occurs throughout tumourigenesis. [U]LGR5 was found to be re-expressed following re-oxygenation,[/U[(aka 'normoxia') demonstrating tumour cells ability to switch between expressing LGR5 in normoxic conditions and reducing expression in hypoxia. LGR5 is an established target gene of the WNT signalling pathway and hypoxia has been reported previously to regulate the WNT pathway. Results presented here suggest hypoxic down-regulation of the WNT pathway mediates the hypoxic regulation of LGR5. Topflash WNT reporter activity and expression of a selection of additional WNT target genes decreased in hypoxia in the cell lines tested here. Preliminary ChiP experiments suggest WNT signalling effectors Beta-catenin and TCF4 are lost from the LGR5 promoter in hypoxia. It has been reported previously that HIF-1 interacts with the WNT pathway in hypoxia to down-regulate WNT target gene expression. However HIF-1 does not regulate LGR5 in the cell lines tested here. Highly related HIF-2, though, is critical in the hypoxic regulation of LGR5 in the LoVo cell line and not in other cell lines tested here. The reversible down regulation of stem cell markers during hypoxia may have important implications for targeting cancer stem cells in vivo where tumours are heterogeneous with fluctuating areas of hypoxia.

TheKingofFighters
06-01-2016, 04:32 AM
Finally, Hypoxia increases intracelluar calcium levels(which is why the patent i linked suggested the usage of Nifedipine- it blocks L-type calcium channels and results in vasodilation- the latter a process similar to Minoxidil)- which c-fos and inflammatory processes are heavily dependent on.

Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: role of the Na(+)-glucose cotransporter.
Berna N1, Arnould T, Remacle J, Michiels C.
Author information
Abstract
Hypoxia is a common denominator of many vascular disorders, especially those associated with ischemia. To study the effect of oxygen depletion on endothelium, we developed an in vitro model of hypoxia on human umbilical vein endothelial cells (HUVEC). Hypoxia strongly activates HUVEC, which then synthesize large amounts of prostaglandins and platelet-activating factor. The first step of this activation is a decrease in ATP content of the cells, followed by an increase in the cytosolic calcium concentration ([Ca(2+)](i)) which then activates the phospholipase A(2) (PLA(2)). The link between the decrease in ATP and the increase in [Ca(2+)](i) was not known and is investigated in this work. We first showed that the presence of extracellular Na(+) was necessary to observe the hypoxia-induced increase in [Ca(2+)](i) and the activation of PLA(2). This increase was not due to the release of Ca(2+) from intracellular stores, since thapsigargin did not inhibit this process. The Na(+)/Ca(2+) exchanger was involved since dichlorobenzamil inhibited the [Ca(2+)](i) and the PLA(2) activation. The glycolysis was activated, but the intracellular pH (pH(i)) in hypoxic cells did not differ from control cells. Finally, the hypoxia-induced increase in [Ca(2+)](i) and PLA(2) activation were inhibited by phlorizin, an inhibitor of the Na(+)-glucose cotransport. The proposed biochemical mechanism occurring under hypoxia is the following: glycolysis is first activated due to a requirement for ATP, leading to an influx of Na(+) through the activated Na(+)-glucose cotransport followed by the activation of the Na(+)/Ca(2+) exchanger, resulting in a net influx of Ca(2+).
Copyright 2001 Wiley-Liss, Inc.

TheKingofFighters
06-01-2016, 04:51 AM
Finally, Hypoxia increases intracelluar calcium levels(which is why the patent i linked suggested the usage of Nifedipine- it blocks L-type calcium channels and results in vasodilation- the latter a process similar to Minoxidil)- which c-fos and inflammatory processes are heavily dependent on.

Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: role of the Na(+)-glucose cotransporter.
Berna N1, Arnould T, Remacle J, Michiels C.
Author information
Abstract
Hypoxia is a common denominator of many vascular disorders, especially those associated with ischemia. To study the effect of oxygen depletion on endothelium, we developed an in vitro model of hypoxia on human umbilical vein endothelial cells (HUVEC). Hypoxia strongly activates HUVEC, which then synthesize large amounts of prostaglandins and platelet-activating factor. The first step of this activation is a decrease in ATP content of the cells, followed by an increase in the cytosolic calcium concentration ([Ca(2+)](i)) which then activates the phospholipase A(2) (PLA(2)). The link between the decrease in ATP and the increase in [Ca(2+)](i) was not known and is investigated in this work. We first showed that the presence of extracellular Na(+) was necessary to observe the hypoxia-induced increase in [Ca(2+)](i) and the activation of PLA(2). This increase was not due to the release of Ca(2+) from intracellular stores, since thapsigargin did not inhibit this process. The Na(+)/Ca(2+) exchanger was involved since dichlorobenzamil inhibited the [Ca(2+)](i) and the PLA(2) activation. The glycolysis was activated, but the intracellular pH (pH(i)) in hypoxic cells did not differ from control cells. Finally, the hypoxia-induced increase in [Ca(2+)](i) and PLA(2) activation were inhibited by phlorizin, an inhibitor of the Na(+)-glucose cotransport. The proposed biochemical mechanism occurring under hypoxia is the following: glycolysis is first activated due to a requirement for ATP, leading to an influx of Na(+) through the activated Na(+)-glucose cotransport followed by the activation of the Na(+)/Ca(2+) exchanger, resulting in a net influx of Ca(2+).
Copyright 2001 Wiley-Liss, Inc.

Then continuing on hypoxia reducing expression of pro-hair growth genes:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827269/

Abstract
Low oxygen tension (hypoxia) contributes critically to pluripotency of human embryonic stem cells (hESCs) by preventing spontaneous differentiation and supporting self-renewal. However, it is not well understood how hESCs respond to reduced oxygen availability and what are the molecular mechanisms maintaining pluripotency in these conditions. In this study we characterized the transcriptional and molecular responses of three hESC lines (H9, HS401 and HS360) on short (2 hours), intermediate (24 hours) and prolonged (7 days) exposure to low oxygen conditions (4% O2). In response to prolonged hypoxia the expression of pluripotency surface marker SSEA-3 was increased. Furthermore, the genome wide gene-expression analysis revealed that a substantial proportion (12%) of all hypoxia-regulated genes in hESCs, were directly linked to the mechanisms controlling pluripotency or differentiation. Moreover, transcription of MYC oncogene was induced in response to continuous hypoxia. At the protein level MYC was stabilized through phosphorylation already in response to a short hypoxic exposure. Total MYC protein levels remained elevated throughout all the time points studied. Further, MYC protein expression in hypoxia was affected by silencing HIF2α, but not HIF1α. Since MYC has a crucial role in regulating pluripotency we propose that induction of sustained MYC expression in hypoxia contributes to activation of transcriptional programs critical for hESC self-renewal and maintenance of enhanced pluripotent state.


To clarify the mechanisms how hypoxic growth conditions contribute to pluripotency and differentiation of hESCs, we surveyed the transcriptome data for all transcripts associated with regulation of hESC physiology. Importantly, 12% of all oxygen-regulated transcripts detected were linked to mechanisms controlling pluripotency and differentiation [42] (Figure 3C). The majority of transcriptional responses were detected in prolonged hypoxic culture. From these genes of particular interest are HEY2 with a role in notch signaling [43], LEFTY2 involved in TGFβ-signaling [44] and IGFBP2 which is overexpressed in the stem cell compartment of glioblastomas promoting proliferation and survival of brain tumors [45]. Moreover, the levels of MYC that contributes to induction and maintenance of pluripotency [21]–[24] were elevated.

Hypoxic culture conditions also modified the expression of genes driving cell differentiation (Figure 2C), further supporting an idea that hypoxia directly influences the differentiation potential of cells. Among these genes were neuroectoderm marker PAX6 [46], trophoblast and placenta associated transcription factor MSX2 [47], and a primitive streak marker FLRT3 [48], which all showed less expression in response to prolonged hypoxic culturing compared to normoxic cultures.

Look @ the diagram again in http://www.wikipathways.org/index.php/Pathway:WP2840 . Check out 'FLRT3'(not in the diagram) and 'MSX2'(centre-right). Than look@ Dr Cotsareli's patent @ http://www.google.com/patents/US20110021599 . 'FLRT3' and 'MSX2' are the 34th and 47th most upregulated gene, respectively- in non-balding scalp(normoxic) when compared to balding scalp(hypoxic)

MSX2:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386654/

‘Cyclic alopecia’ in Msx2 mutants: defects in hair cycling and hair shaft differentiation
Liang Ma,1,2 Jian Liu,3 Tobey Wu,3 Maksim Plikus,3 Ting-Xin Jiang,3 Qun Bi,2 Yi-Hsin Liu,4 Sven Müller-Röver,5 Heiko Peters,1 John P. Sundberg,6 Rob Maxson,7 Richard L. Maas,1,* and Cheng-Ming Chuong3,*
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available free at Development
See other articles in PMC that cite the published article.
Go to:
SUMMARY
Msx2-deficient mice exhibit progressive hair loss, starting at P14 and followed by successive cycles of wavelike regrowth and loss. During the hair cycle, Msx2 deficiency shortens anagen phase, but prolongs catagen and telogen. Msx2-deficient hair shafts are structurally abnormal. Molecular analyses suggest a Bmp4/Bmp2/Msx2/Foxn1 acidic hair keratin pathway is involved. These structurally abnormal hairs are easily dislodged in catagen implying a precocious exogen. Deficiency in Msx2 helps to reveal the distinctive skin domains on the same mouse. Each domain cycles asynchronously – although hairs within each skin domain cycle in synchronized waves. Thus, the combinatorial defects in hair cycling and differentiation, together with concealed skin domains, account for the cyclic alopecia phenotype.

Keywords: Alopecia, Hair cycle, Hair differentiation, Homeobox genes, Msx2, Foxn1, Ha3, Fgf5, Mouse

FLRT3:

Flrt2 and Flrt3 have overlapping and non-overlapping expression during craniofacial development.
Gong SG1, Mai S, Chung K, Wei K.
Author information
1Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ont., Canada M5G 1G6. sg.gong@dentistry.utoronto.ca
Abstract
Craniofacial morphogenesis is a complex multi-step process that involves numerous biological processes to coordinate the growth, proliferation, migration, and subsequent differentiation of the cranial neural crest cells. Members of the Fibronectin Leucine-Rich Transmembrane (Flrt) gene family have been previously reported to be widely expressed in the developing embryo. We mapped the expression of Flrt2 and Flrt3 at critical stages of craniofacial development and found that, during early craniofacial development, Flrt2 was highly expressed initially in the cranial neural crest cells and Flrt3 in the midbrain. Later both genes were expressed in the developing pharyngeal region. Flrt2 expression predominated in the neural crest-derived mesenchyme in the medial aspect of the developing frontonasal region in close relationships with the expression of Fgfr2, Shh, and Msx1, three genes shown previously to play critical roles in craniofacial development. Flrt2 was also present in the vomero-nasal organ, mandibular primodia, and the posterior aspects of the unfused and fused secondary palatal shelves. Flrt3, however, had a more restrictive expression, being present in the mesenchyme underlying the ectoderm of the medial nasal process and in the mandibular primordium and in regions undergoing outgrowth, in a pattern that overlapped with Bmp4 expression. Both Flrt2 and Flrt3 were later found to be present at sites of epithelial-mesenchymal interactions such as the developing tooth buds, hair follicles, and eye. Together the data suggested important roles for Flrt2 and Flrt3 in mediating events such as NCC migration, chondrogenesis and epithelial-mesenchymal interactions during craniofacial development.

PAX1 is heavily expressed in the https://en.wikipedia.org/wiki/Pharyngeal_pouch_(embryology) all the way to the cranium. our neck and skull anatomy is defined by the PAX genes.

MSX1, MSX2's family member- is the 51 most upregulated gene in non-balding scalp when compared to balding scalp @ http://www.google.com/patents/US20110021599 . It is also, just like MSX2- a BMP signalling target gene(atually, both of them are also WNT signalling's target genes) as can be seen here again http://www.wikipathways.org/index.php/Pathway:WP2840 (topleft)

TheKingofFighters
06-01-2016, 05:09 AM
Inbeforethecure please give me ur valuable input on the above

TheKingofFighters
06-01-2016, 05:25 AM
Nifedipine:

http://i63.tinypic.com/2vbjtix.jpg

The powder is yellow and not a conventional white, as in the case of all https://en.wikipedia.org/wiki/Dihydropyridine -derivatives.

It is also described here in another patent(aside from the 1 on hypoxia which 1 linked earlier)

http://www.patentsencyclopedia.com/app/20150005291

This study (not sure if it's done by the same inventors to the patent above) talks about calcium channels and the hair follcile:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690395/

Abstract
The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Cav1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Cav1.2, they lack detectable voltage-dependent calcium currents. Cav1.2TS acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Cav1.2 to induce anagen and overcome the TS phenotype. Cav1.2 regulates production of the bulge-derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration.

Keywords: hair follicle stem cells, bulge, calcium channel, VGCC

HMDWN
06-01-2016, 06:06 AM
Atually, the possible cure- is in our vomit
well, that would be abundant and MPB makes its sufferers sick enough!

Swooping
06-01-2016, 07:42 AM
FYI, in a recent study by Philpott et al. (http://www.ncbi.nlm.nih.gov/pubmed/27060448), they did not find any differences of PAX1 between balding DPC and non-balding. Interestingly, FOXA2 wasn't even expressed.

At the susceptibility loci 7p21.1 (HDAC9 & TWIST1) they found only TWIST1 to be differentially expressed in balding DPC vs non-balding DPC (upregulated), not HDAC9.

Knockout of TWIST1 in a mice model (BLEGH) was found to dramatically enhance the anagen phase in a study. Also TWIST1 has shown to be able to upregulate AR by binding to E-boxes in the AR promoter.

At susceptibility loci 2q37 they found TWIST2 do be deferentially expressed rather than HDAC4.

In the AGA major risk locus Xq12 they found evidence for AR instead of EDA2R.

Interesting study.

I remember a study pointing out a interaction between HDACs and Twists, I'll look it up later, but I have the picture here;

http://s33.postimg.org/63mk0vh0v/geness.jpg



I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.

@InBeforeTheCure,

Great man, keep it up. I have troubles understanding how you would be able to underline a strong hypothesis based on the current genetic data? I compare it to walking around in a very big complex labyrinth where one is drunk without a map. I might be wrong though. Very curious to your findings. The biggest problem in my opinion also resides with what you mention and that is the "experiment". We lack a proper model. We only have and use rodent models. Every researcher now finally is aware that it's a horrible model for AGA and we desperately need a proper one. Harsher regulations etc. made it impossible to test on a macaque model like in the past (correct decision imo, but that aside). So how are you going to be able to cope with this problem? Slap stuff on your scalp?

Speaking of SHH, the SHH agonist that was in development by Curis and Procter & Gamble back in 2005 for androgenetic alopecia had huge excitement, but didn't proceed to human clinical trial testing as it was touted to be to dangerous. After all AGA is seen as a cosmetic disease and not a life threatening one, which hugely added to their decision. That was a black point. That being said I'm still intrigued by the SHH pathway simply because a SHH antagonist induces alopecia in approximately 70% of subjects as a side effects from the top of my head, which might even be very long lasting after discontinuation (longer than a year). Based on this observation alone one could at least argue that the pathway seems to have a huge role in hair follicle function.


I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype.

@Mlamber5

No I don't think so. In fact I believe it almost to be certain that a JAK inhibitor isn't going to do a great deal for AGA. I don't see why one would even be hyped for this. It's based on a rodent model. Find me one person who shows reversal with AGA on a JAK inhibitor. I'll give you the answer in advance; It ain't going to happen, and if it will happen it will be a huge miracle. For which I hope obviously. Also why do you mention that AR stoppage won't stop the progression of AGA, but only will slow it down? Are the people suffering from complete androgen insensitivity just lucky people who always retain their luxurious hair until old age? Btw, recently a case report has shown a guy suffering from alopecia universalis who was put on tofacitinib 10mg with + methotxerate and the regimen failed to reverse his condition. Perhaps it's not even going to be that great for everyone suffering from AA related conditions...

TheKingofFighters
06-01-2016, 09:38 AM
thank you for your reply swooping. Would you care to post the entire study here? i cant access it.

TheKingofFighters
06-01-2016, 08:16 PM
well, that would be abundant and MPB makes its sufferers sick enough!

Im afraid it would'nt be enough. You're gonna have to purify your vomit and apply it daily.

Luckily, some researcher have already came up with something a long time ago.

http://www.google.com/patents/WO1990011075A1?cl=en

A decreased vascularity of the scalp is considered to be a contributing factor to baldness since a good vascular supply is required for healthy hair follicles. Topically administered monobutyrin should penetrate the skin of the scalp and enhance the vascularity of the area containing hair follicles. This would result in the arrest qf hair loss. Formulations of the compounds of the invention are prepared using generally known excipients and carriers according to methods known in the art, such as those set forth in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (latest edition). For topical administration, especially for superficial lesions, standard topical formulations are employed using, for example, 10 -4-1% solutions of the compounds of the invention, with or without added growth factor, such as FGF, PDGF or EDGF. The topical prepara- tions would be applied daily or 2-3 times per week to the affected area. The concentration of the solution or other formulation depends on the severity of the wound and the nature of the subject. Formulations can be in a variety of known forms such as ointments, salves, gels, sprays, creams and lotions. For bone and tissue* repair, local and depot administration is preferred, or administration by sub¬ cutaneous or localized implant. Slow release forms can be included in polymers such as Hydron (Langer, R. , et al., Nature (1976) 263:797-799) or Elvax 40P (DuPont) (Murray, J.B., et al., In Vitro (1983) _19_:743-747) . Other sustained release systems have been suggested by Hsieh, D.S.T., et al., J Pharm Sci (1983) 72:17-22.

The patent above was done submitted in 1990. 26 years later, latest research still collaborates with that old patent's findings:

Thanks Swooping:

J Invest Dermatol. 2016 Apr 6. pii: S0022-202X(16)31024-7. doi: 10.1016/j.jid.2016.03.032. [Epub ahead of print]
Differential expression between human dermal papilla cells from balding and non-balding scalps reveals new candidate genes for androgenetic alopecia.
Chew EG1, Tan JH1, Bahta AW2, Ho BS3, Liu X1, Lim TC4, Sia YY1, Bigliardi PL5, Heilmann S6, Wan AC4, Nöthen MM6, Philpott MP2, Hillmer AM7. <=== this guy is the researcher who discovered the PAX1/FOXA2 balding locus for AGA
Author information
Abstract
Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPC) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPC in hair-related studies often lack dermal papilla (DP) characteristics. In contrast, immortalised DPC have high resemblance to intact DP. We derived immortalised human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retain high proportions of DP signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially-expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 and SSPN to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularisation around the hair follicle may contribute to the development of AGA.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

TheKingofFighters
06-01-2016, 08:44 PM
Im afraid it would'nt be enough. You're gonna have to purify your vomit and apply it daily.

Luckily, some researcher have already came up with something a long time ago.

http://www.google.com/patents/WO1990011075A1?cl=en

A decreased vascularity of the scalp is considered to be a contributing factor to baldness since a good vascular supply is required for healthy hair follicles. Topically administered monobutyrin should penetrate the skin of the scalp and enhance the vascularity of the area containing hair follicles. This would result in the arrest qf hair loss. Formulations of the compounds of the invention are prepared using generally known excipients and carriers according to methods known in the art, such as those set forth in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (latest edition). For topical administration, especially for superficial lesions, standard topical formulations are employed using, for example, 10 -4-1% solutions of the compounds of the invention, with or without added growth factor, such as FGF, PDGF or EDGF. The topical prepara- tions would be applied daily or 2-3 times per week to the affected area. The concentration of the solution or other formulation depends on the severity of the wound and the nature of the subject. Formulations can be in a variety of known forms such as ointments, salves, gels, sprays, creams and lotions. For bone and tissue* repair, local and depot administration is preferred, or administration by sub¬ cutaneous or localized implant. Slow release forms can be included in polymers such as Hydron (Langer, R. , et al., Nature (1976) 263:797-799) or Elvax 40P (DuPont) (Murray, J.B., et al., In Vitro (1983) _19_:743-747) . Other sustained release systems have been suggested by Hsieh, D.S.T., et al., J Pharm Sci (1983) 72:17-22.

The patent above was done submitted in 1990. 26 years later, latest research still collaborates with that old patent's findings:

Thanks Swooping:

J Invest Dermatol. 2016 Apr 6. pii: S0022-202X(16)31024-7. doi: 10.1016/j.jid.2016.03.032. [Epub ahead of print]
Differential expression between human dermal papilla cells from balding and non-balding scalps reveals new candidate genes for androgenetic alopecia.
Chew EG1, Tan JH1, Bahta AW2, Ho BS3, Liu X1, Lim TC4, Sia YY1, Bigliardi PL5, Heilmann S6, Wan AC4, Nöthen MM6, Philpott MP2, Hillmer AM7. <=== this guy is the researcher who discovered the PAX1/FOXA2 balding locus for AGA
Author information
Abstract
Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPC) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPC in hair-related studies often lack dermal papilla (DP) characteristics. In contrast, immortalised DPC have high resemblance to intact DP. We derived immortalised human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retain high proportions of DP signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially-expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 and SSPN to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularisation around the hair follicle may contribute to the development of AGA.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.


Why monobutyrin?

I've said that the possible cure is in our vomit- and that active ingredient is Butyric acid. Monobutyrin is a prodrug(of Butyric acid) and it contains 1 molecule of Butyric acid and 1 molecule of Glycerin. When it enters a cell, Butyric acid is separated from the compound. Butyric acid by itself has only a few mins of half life- and it's the reason why we cant use it .

The patent contains a rather easyily-produced vehicle and the biggest advantage is that it contains NO ethanol. Ethanol(metabolised to acetaldehyde) is what contributes to the pathology of AGA- as seen in:

http://www.google.com/patents/US20110021599 . ALDH1A1 and AOX1
(9th and 11th most upregulated gene in balding scalp when compared to non-balding scalp, Cotsareli's patent), amongst other genes as well.

Formulation B:

A monobutyrin gel composition is prepared from the following:

Ingredient Amount

Monobutyrin 0.1 g

Hydroxyethylcellulose 250H 2.0 g

Glycerine 15.0 g

Chlorhexidine gluconate 0.25 g

Water q.s. 100.0 g

Inbeforethecure, please tell me what you think of all these.

Swooping
06-02-2016, 05:22 AM
Hunting the genes in male-pattern alopecia: how important are they, how close are we and what will they tell us? - http://onlinelibrary.wiley.com/doi/10.1111/exd.12965/epdf

I have sent you a pm for the other study (which is more important to you probably).

TheKingofFighters
06-02-2016, 05:31 AM
Hunting the genes in male-pattern alopecia: how important are they, how close are we and what will they tell us? - http://onlinelibrary.wiley.com/doi/10.1111/exd.12965/epdf

I have sent you a pm for the other study (which is more important to you probably).

Atually, i've just got it(the 2016 study) via the deepweb. Im reading through it now and it is giving me a headache because the microarray genes they ahve seems to be the opposite of the 1s in Cotsareli's patent. I have. I have to rethink everything all over again and these will probably take a few days for me to digest and figure out a good solution. Anyway, 1 thing seems for sure- and that is balding hair follicles have a deficient vasculature system( vasculature development,
blood vessel development and blood vessel
morphogenesis ) serving them.

The good news is I probably do not have to stray far because the belief that upregulating angiogenesis is the key to regrowing hair has been in my direction all along(Minoxidil is under-performing in this area).

Swooping
06-02-2016, 06:01 AM
Indeed, no doubt that a phenomenon of AGA is the lack of vascularization of the miniaturized hair follicles. BUT, one must also see that a healthy hair follicle in telogen clearly lacks vascularization in comparison to anagen. Yet, a healthy hair follicle which is sitting in telogen vascularizes itself tremendously and does this constantly between anagen, catagen and telogen. Jahoda describes this well in a study of him.

It's exactly the same with adipose tissue. So all in all it's like this

Healthy hair follicle telogen (non-AGA) - lack of vascularization, lack of adipose tissue.

Miniaturized hair follicle (AGA) - lack of vascularization, lack of adipose tissue.

Healthy hair follicle anagen (NON-AGA) - vascularized, increased adipose tissue.

http://s18.postimg.org/52pfla3zt/cycling.jpg

Anyway, I have a question for you and it's based on the following observation;


A third factor is aging. In normal men, advancing age is accompanied by increase in the incidence and extent of baldness. In eunuchs who were castrated prepubertally and given androgenic treatment at a later date,
those who are in the second decade of life when treatment is begun tend to lose hair slowly over a period of years, as in most normal young men of their age. In contrast, the eunuch who reaches the sixth decade of life
before receiving androgenic treatment loses his hair within a few months of the beginning of treatment. Evidently the susceptibility to alopecia increases with age but is not expressed in the absence of inciting agents like androgens (Hamilton, 1942).

So, both groups of eunuchs are perfect NW 1's. You inject them with androgens for the first time in their life. The older group tends to bald extremely fast, way faster than the younger group. Why? What's your view on this.

TheKingofFighters
06-02-2016, 06:35 AM
MANUS CRIP T
ACCEP TED
A
CCEPTED MANUSCRIPT
21
Table 2:
List of vasculature-related genes that are down-re
gulated in balding DPC (BAB) compared to
non-balding DPC (BAN)
Gene Name
Median fold change
Gene Name
Median fold change
1nM DHT
10nM DHT
1nM DHT
10nM DHT
ACTC1
2.628
2.532
GNA13
-
1.885
ADORA2A
1.924
1.752
GUCY1A3
1.832
1.846
ADRA1B
1.833
1.749
HEY1
2.046
2.402
ADRB2 <== ok it's official. Those who are familiar with Steroids will have an idea what this is. Bambuterol, Clenbuterol, Salmaterol, etc. They are also anti-asthmatic agents and they exert vasodilatory effects.
2.106
2.590
HIF1A
2.557
2.670
AGT
2.008
1.881
HIF1A
2.806
2.850
AGTR1
2.788
2.643
HIF1A
2.822
2.546
AGTR1
2.803
2.621
HMOX1
1.895
1.934
AMOT
1.851
1.910
HTATIP2
6.764
6.038
ANGPTL4
2.054
2.220
ITGA1
2.008
1.956
ANXA2
2.500
2.211
ITGA4
1.784
1.748
APOLD1
2.371
2.661
JUNB
2.325
2.002
BGN
2.314
2.324
KLF5
1.738
1.802
CAV1
2.884
2.708
LEPR
2.042
1.987
CAV2
1.857
1.954
LOX
3.116
2.974
CAV2
1.819
1.775
MMP14
2.090
2.003
CAV2
1.827
1.741
NOS3
2.154
1.955
CCBE1
2.250
2.171
NOTCH1
1.713
1.813
CDH13
1.829
1.867
P2RX4
1.830
1.806
CDH2
1.734
1.782
PDE5A
2.809
2.697
CHD7
2.047
2.187
PDPN
1.931
1.957
CITED2
2.967
2.623
PLAU
1.788
1.882
COL1A1
5.069
4.926
PLCD3
1.750
1.770
COL1A2
1.808
1.757
PLXDC1
1.992
1.846
COL3A1
3.723
3.615
PPAP2B
1.879
1.870
COL18A1
16.750
15.675
PPAP2B
2.235
2.225
CTGF
3.546
3.587
RECK
2.463
2.351
CTGF
3.963
4.229
RECK
2.458
2.314
CXCL12
2.635
2.631
SCG2
5.365
5.938
CXCL12
2.391
2.151
SGPL1
1.910
1.828
CXCL12
2.518
2.643
SMAD7
1.841
1.729
CYR61
3.167
3.023
SMO
1.783
1.830
DHCR7
23.464
20.353
SOD2
-
1.752
DHCR7
17.994
14.520
SOD2
2.306
2.355
DICER1
1.860
1.800
SOD2
1.969
2.367
DICER1
1.896
1.898
TGFA
3.281
3.060
EDNRA
1.831
1.978
TGFA
2.146
2.328
EREG
1.986
2.303
THY1
2.871
2.781
FGF2
2.087
2.018
TNFAIP2
3.180
2.792
FGF2
1.971
1.954
ZC3H12A
1.890
2.237
GCH1
2.957
3.348
ZFP36L1
3.244
3.055
GNA13
1.784
1.755
ZMIZ1
1.835
1.746

The good news here for those of Anglo-saxon descent:

MATERIALS AND METHODS
Isolation and immortalisation of human balding and
non-balding primary DPC
Between one and three DP were isolated from each ma
tched 2 mm punch biopsies of balding (frontal) and
non-balding (occipital) scalps of male AGA patients
who were undergoing hair transplant surgery and no
t
currently on hair loss medications, as described pr
eviously (Bahta
et al.
, 2008; Philpott
et al.
, 1994;
Upton
et al.
, 2015). Ethics approval was obtained from East Lon
don and City health authority (T/98/008)
and all biopsies were taken with full patient writt
en consent. All experiments adhered to the Declarat
ion
of Helsinki Principles. Isolated primary DPCs were
cultured up to passage 3 (
Supplementary Materials
and Methods
) and immortalised with hTERT using pBABEhygro-hTER
T. Hygromycin-resistant clones
with stable hTERT expression were then cultured as
described in the
Supplementary Materials and
Methods
. We were able to derive one immortalized balding (
BAB) and one non-balding (BAN) cell line
originating from two different male individuals due
to limitation in tissue materials, difficulties in
establishing pure primary DPC cultures and low tran
sformation efficiencies. Both BAB and BAN have
been established from Anglo-Saxon males with Hamilt
on scale 4 AGA.

That list above applies to these group of men.

TheKingofFighters
06-02-2016, 06:49 AM
Indeed, no doubt that a phenomenon of AGA is the lack of vascularization of the miniaturized hair follicles. BUT, one must also see that a healthy hair follicle in telogen clearly lacks vascularization in comparison to anagen. Yet, a healthy hair follicle which is sitting in telogen vascularizes itself tremendously and does this constantly between anagen, catagen and telogen. Jahoda describes this well in a study of him.

It's exactly the same with adipose tissue. So all in all it's like this

Healthy hair follicle telogen (non-AGA) - lack of vascularization, lack of adipose tissue.

Miniaturized hair follicle (AGA) - lack of vascularization, lack of adipose tissue.

Healthy hair follicle anagen (NON-AGA) - vascularized, increased adipose tissue.

http://s18.postimg.org/52pfla3zt/cycling.jpg

Anyway, I have a question for you and it's based on the following observation;



So, both groups of eunuchs are perfect NW 1's. You inject them with androgens for the first time in their life. The older group tends to bald extremely fast, way faster than the younger group. Why? What's your view on this.

I do not and wont be able to give any comments without any data or genes to examine

InBeforeTheCure
06-02-2016, 08:01 PM
Looking forward to it. I can see we both have started from the same point, the genes it looks like. If indeed JAK/STAT inhibition does end up reversing AGA it would only make sense that the team that discovered the key pieces of information and cure to hair loss ( Christiano's team ) is a team that focuses on the genetics behind all types of hair loss.

I was looking more at gene expression data and major pathways, but I've been looking more at GWAS again lately too.



BTW, i greatly appreciate yours and mlamber5's valuable input into this topic(PAX1).

Well, thank you. :)


Inbeforethecure- Give me your valuable input on this:

http://www.wikipathways.org/index.php/Pathway:WP2840

Look at 'NR3C1'(centre/south of the diagram)- that's the Gluccocorticoid receptor and it's in a direct relationship with FOS(aka c-FOS) and FOSB

Then look at this http://www.google.com/patents/US20110021599 - Dr Cotsareli's patent on the most downregulated genes in non-balding scalp when compared to balding scalp. FOS and FOSB are the 3rd and 4th most downregulated genes in non-balding scalp, respectively.

What do you think? Gluccocorticoid underexpression or overexpression in AGA? Gluccocorticoid resistance?

According to the Chew/Philpott data, there's no difference in NR3C1 expression in balding vs. non-balding DPCs, while c-fos is downregulated in balding DPCs. Don't know about epithelial parts of the HF for NR3C1. But a lot of things can regulate c-fos and most other genes, so a computational approach is really best-suited for guessing at relationships among vast amounts of data.

As for the rest of it, I don't think I can keep up with you. :p

Also, a lot of these things I don't really know well enough to comment. I need to study the epithelial HF interactions a lot more, and I think when dealing with the complex details of this, computational approaches would be necessary. I will ask this about MSX2 though: Since MSX2 is a signature gene for matrix cells and transit amplifying cells, could it be that MSX2 is lower in balding scalp simply because the follicles are miniaturized?


FYI, in a recent study by Philpott et al. (http://www.ncbi.nlm.nih.gov/pubmed/27060448), they did not find any differences of PAX1 between balding DPC and non-balding. Interestingly, FOXA2 wasn't even expressed.

They didn't really detect PAX1 either beyond "background" levels. I would guess that it's only a transiently expressed gene, either embryonic or during a particular part of the hair cycle (early anagen is a good candidate for that).


At the susceptibility loci 7p21.1 (HDAC9 & TWIST1) they found only TWIST1 to be differentially expressed in balding DPC vs non-balding DPC (upregulated), not HDAC9.

Knockout of TWIST1 in a mice model (BLEGH) was found to dramatically enhance the anagen phase in a study. Also TWIST1 has shown to be able to upregulate AR by binding to E-boxes in the AR promoter.


Yes, the HDAC9 spot is probably a regulatory region for TWIST1.
Variants in an Hdac9 intronic enhancer plasmid impact Twist1 expression in vitro (http://www.ncbi.nlm.nih.gov/pubmed/26721262)


@InBeforeTheCure,

Great man, keep it up. I have troubles understanding how you would be able to underline a strong hypothesis based on the current genetic data? I compare it to walking around in a very big complex labyrinth where one is drunk without a map. I might be wrong though. Very curious to your findings.

I wouldn't call it a "strong" hypothesis, because to me a strong hypothesis would need to have the following properties:

1) It must explain all or at least most aspects of what we know about AGA.
2) It must explain the role of most of the genes that show up in GWAS.
3) Obviously, it must give definite predictions that could in practice be falsifiable (otherwise, it's pseudoscience)

Then if many experiments are done that confirm the predictions of the hypothesis, it would be elevated to the status of a theory.

I would say that what I've got only partially provides 1) (it needs more development and refinement). It only partially matches 2) -- a couple of the major risk genes do have definite roles in the model, one of which I wasn't even aware was in the GWAS results until afterwards, and the others don't really have definite roles. PAX1 is known to interact with a key transcription factor of the model and change its binding sites, but I can't say what the nature of that change would be. Other genes I haven't investigated closely enough yet. It does provide 3), and should provide more predictions with further development.

I do think though that I'm going to post the most important things of what I've got so far right away, because I hate talking about it in vague terms. ;)


The biggest problem in my opinion also resides with what you mention and that is the "experiment". We lack a proper model. We only have and use rodent models. Every researcher now finally is aware that it's a horrible model for AGA and we desperately need a proper one. Harsher regulations etc. made it impossible to test on a macaque model like in the past (correct decision imo, but that aside). So how are you going to be able to cope with this problem? Slap stuff on your scalp?

True. The best we have now is...what? Tissue samples with the hairs inside?


Speaking of SHH, the SHH agonist that was in development by Curis and Procter & Gamble back in 2005 for androgenetic alopecia had huge excitement, but didn't proceed to human clinical trial testing as it was touted to be to dangerous. After all AGA is seen as a cosmetic disease and not a life threatening one, which hugely added to their decision. That was a black point. That being said I'm still intrigued by the SHH pathway simply because a SHH antagonist induces alopecia in approximately 70% of subjects as a side effects from the top of my head, which might even be very long lasting after discontinuation (longer than a year). Based on this observation alone one could at least argue that the pathway seems to have a huge role in hair follicle function.

Yes, definitely. The Shh pathway is known to have a huge role in hair follicle function. I don't think Shh agonists would do anything miraculous for AGA though.


Anyway, I have a question for you and it's based on the following observation;



So, both groups of eunuchs are perfect NW 1's. You inject them with androgens for the first time in their life. The older group tends to bald extremely fast, way faster than the younger group. Why? What's your view on this.

I have a question. Do you know if when those older eunuchs are injected with androgens, do they also show accelerated facial hair growth? If so, it would hint that AGA is a programmed developmental event. If not, it's more likely that this phenomenon could be the result of increased sensitivity of DPCs to stress with increasing age.

Also, the data for the Chew/Philpott paper are available on GEO. It's GSE66663 and GSE66664.

InBeforeTheCure
06-02-2016, 09:00 PM
Also, the data for the Chew/Philpott paper are available on GEO. It's GSE66663 and GSE66664.

I've also filtered the data for those transcripts strongly detected in balding DPCs or non-balding DPCs or both, and calculated the fold change between the average of the balding samples and the average of the non-balding samples for each gene. I've uploaded that here: https://www.dropbox.com/s/k8t4aaa6enx8nkv/chew_data.csv?dl=0

I also ran a quick pathway analysis for the top 1,000 upregulated genes in balding DPCs with DAVID:

http://s33.postimg.org/7sthbobq7/david1.png

...and for the top 1,000 downregulated genes:

http://s33.postimg.org/ivupyb3hb/david2.png

karxxx
06-03-2016, 05:41 AM
my opinion .
DHT resistant hair makes it very difficult.
Beard stem cells is the solution.
beard stem cells transplants are one solution.

TheKingofFighters
06-03-2016, 06:47 AM
I've also filtered the data for those transcripts strongly detected in balding DPCs or non-balding DPCs or both, and calculated the fold change between the average of the balding samples and the average of the non-balding samples for each gene. I've uploaded that here: https://www.dropbox.com/s/k8t4aaa6enx8nkv/chew_data.csv?dl=0

I also ran a quick pathway analysis for the top 1,000 upregulated genes in balding DPCs with DAVID:

http://s33.postimg.org/7sthbobq7/david1.png

...and for the top 1,000 downregulated genes:

http://s33.postimg.org/ivupyb3hb/david2.png

7 68,611,960 rs69455416 7q11.22 []---AUTS2 AUTS2 down - - - - 2.801 2.868

AUTS2 is a gene downregulated in BAB(balding scalp. So we need to upregulate it)

read this:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468360/

Possible functional links among brain- and skull-related genes selected in modern humans

The sequencing of the genomes from extinct hominins has revealed that changes in some brain-related genes have been selected after the split between anatomically-modern humans and Neanderthals/Denisovans. To date, no coherent view of these changes has been provided. Following a line of research we initiated in Boeckx and Benítez-Burraco (2014a), we hypothesize functional links among most of these genes and their products, based on the existing literature for each of the gene discussed. The genes we focus on are found mutated in different cognitive disorders affecting modern populations and their products are involved in skull and brain morphology, and neural connectivity. If our hypothesis turns out to be on the right track, it means that the changes affecting most of these proteins resulted in a more globular brain and ultimately brought about modern cognition, with its characteristic generativity and capacity to form and exploit cross-modular concepts, properties most clearly manifested in language.

Keywords: language-ready brain, skull morphology, human evolution, Neanderthals/Denisovans, anatomically modern humans, AUTS2, FOXP2, RUNX2

TheKingofFighters
06-03-2016, 03:51 PM
7 68,611,960 rs69455416 7q11.22 []---AUTS2 AUTS2 down - - - - 2.801 2.868

AUTS2 is a gene downregulated in BAB(balding scalp. So we need to upregulate it)

read this:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468360/

Possible functional links among brain- and skull-related genes selected in modern humans

The sequencing of the genomes from extinct hominins has revealed that changes in some brain-related genes have been selected after the split between anatomically-modern humans and Neanderthals/Denisovans. To date, no coherent view of these changes has been provided. Following a line of research we initiated in Boeckx and Benítez-Burraco (2014a), we hypothesize functional links among most of these genes and their products, based on the existing literature for each of the gene discussed. The genes we focus on are found mutated in different cognitive disorders affecting modern populations and their products are involved in skull and brain morphology, and neural connectivity. If our hypothesis turns out to be on the right track, it means that the changes affecting most of these proteins resulted in a more globular brain and ultimately brought about modern cognition, with its characteristic generativity and capacity to form and exploit cross-modular concepts, properties most clearly manifested in language.

Keywords: language-ready brain, skull morphology, human evolution, Neanderthals/Denisovans, anatomically modern humans, AUTS2, FOXP2, RUNX2

This means our skull shape has got something to do with AGA. This fits in with the 'skull expansion theory'.

burtandernie
06-03-2016, 08:01 PM
"So, both groups of eunuchs are perfect NW 1's. You inject them with androgens for the first time in their life. The older group tends to bald extremely fast, way faster than the younger group. Why?

Doesnt this though perfectly explain why in most men as they get older fin seems to stop working? There rate of sensitivity increases as they get older, and the androgens left over are enough to continue the balding process. It also explains why men as they age even when androgen levels naturally decline actually keep balding sometimes it even speeds up. Of course why is hair sensitive to begin with is the million dollar question, and the answer is probably pretty complicated.

TheKingofFighters
06-04-2016, 11:18 AM
1)MAPT is 1 of the root causative AGA gene downregulated in balding scalp=> need to UP(Estradiol)
2)SSPN is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(PPAR Alpha)
3)AUTS2 is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(PPAR Alpha)
4)TWIST1 is 1 of the root causative AGA gene upregulated in balding scalp => need to DOWN(Estradiol)
5)RNF145 is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(Phenobarbital)
6)TWIST2 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(Estradiol)
7)PER2 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(Estradiol)

8)UBIAD1 is 1 of the causative AGA gene upregulated in balding scalp => need to DOWN(Dibutyl Phthalate, Caffeine)
9)SRM is 1 of the causative AGA gene upregulated in balding scalp => Need to DOWN(Estradiol) <=== this gene stands for 'Spermidine synthase'. seems like those that carry the AGA variant of this gene has too much of Spermidine production in the balding scalp:

At the 1p36 locus, non-differentially-expressed candidate gene TARDBP (TAR DNA binding protein) is
unlikely to be causative. Instead, SRM, previously mentioned as a potential candidate gene due to its
proximity to rs12565727 (Li et al., 2012), was up-regulated in BAB(balding scalp) compared to BAN. SRM is involved
in the synthesis of spermidine which acts on matrix keratinocytes to promote hair elongation and prolong
anagen (Ramot et al., 2011). However, the effect of SRM activity and the resultant spermidine
synthesized in DPC is unknown. Further, we found CASZ1, EXOSC10, FRAP1, and UBIAD1 to be
differentially-expressed at this locus. They provide new potential candidate genes for hair loss/growth
modulation.

10)FRAP1 is 1 of the causative AGA gene upregulated in balding scalp => Need to DOWN(?)
11)EXOSC10 => is 1 of the causative AGA gene upregulated in balding scalp => need to DOWN(Dibutyl Phthalate)
12)CASZ1 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(PPAR ALpha, Butyraldehyde)
13)AR is 1 of the causative gene upregulated in balding scalp => need to DOWN(AR blockers) <== the AGA-variants of this gene are not present in East Asians.

Total = 17 AGA locus genes known so far. 4 of them were not differentially-regulated when exposed to DHT:

14)WNT10A
15)Between SUCNR1 and MBNL1
16)SETBP1
17)Between PAX1 and FOXA2. FOXA2's expression were not detected in balding scalp and PAX1's expression was not found to be differentially expressed when DPCs were exposed to DHT.


Seems like a PPAR Alpha agonist and Estradiol are what we need to regrow hair

TheKingofFighters
06-04-2016, 11:36 AM
1)MAPT is 1 of the root causative AGA gene downregulated in balding scalp=> need to UP(Estradiol)
2)SSPN is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(PPAR Alpha)
3)AUTS2 is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(PPAR Alpha)
4)TWIST1 is 1 of the root causative AGA gene upregulated in balding scalp => need to DOWN(Estradiol)
5)RNF145 is 1 of the root causative AGA gene downregulated in balding scalp => need to UP(Phenobarbital)
6)TWIST2 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(Estradiol)
7)PER2 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(Estradiol)

8)UBIAD1 is 1 of the causative AGA gene upregulated in balding scalp => need to DOWN(Dibutyl Phthalate, Caffeine)
9)SRM is 1 of the causative AGA gene upregulated in balding scalp => Need to DOWN(Estradiol) <=== this gene stands for 'Spermidine synthase'. seems like those that carry the AGA variant of this gene has too much of Spermidine production in the balding scalp:

At the 1p36 locus, non-differentially-expressed candidate gene TARDBP (TAR DNA binding protein) is
unlikely to be causative. Instead, SRM, previously mentioned as a potential candidate gene due to its
proximity to rs12565727 (Li et al., 2012), was up-regulated in BAB(balding scalp) compared to BAN. SRM is involved
in the synthesis of spermidine which acts on matrix keratinocytes to promote hair elongation and prolong
anagen (Ramot et al., 2011). However, the effect of SRM activity and the resultant spermidine
synthesized in DPC is unknown. Further, we found CASZ1, EXOSC10, FRAP1, and UBIAD1 to be
differentially-expressed at this locus. They provide new potential candidate genes for hair loss/growth
modulation.

10)FRAP1 is 1 of the causative AGA gene upregulated in balding scalp => Need to DOWN(?)
11)EXOSC10 => is 1 of the causative AGA gene upregulated in balding scalp => need to DOWN(Dibutyl Phthalate)
12)CASZ1 is 1 of the causative AGA gene downregulated in balding scalp => need to UP(PPAR ALpha, Butyraldehyde)
13)AR is 1 of the causative gene upregulated in balding scalp => need to DOWN(AR blockers) <== the AGA-variants of this gene are not present in East Asians.

Total = 17 AGA locus genes known so far. 4 of them were not differentially-regulated when exposed to DHT:

14)WNT10A
15)Between SUCNR1 and MBNL1
16)SETBP1
17)Between PAX1 and FOXA2. FOXA2's expression were not detected in balding scalp and PAX1's expression was not found to be differentially expressed when DPCs were exposed to DHT.


Seems like a PPAR Alpha agonist and Estradiol are what we need to regrow hair

Furthermore, the identification of MAPT as the relevant AGA candidate gene at 17q21.31
instead of SPPL2C suggests that changes in MAPT function connect the risk for AGA with the risk for
Parkinson’s disease (Li et al., 2012).

Those who have a family history of Parkinson's could be a carrier of the AGA variant of MAPT.

TheKingofFighters
06-04-2016, 11:56 AM
Furthermore, the identification of MAPT as the relevant AGA candidate gene at 17q21.31
instead of SPPL2C suggests that changes in MAPT function connect the risk for AGA with the risk for
Parkinson’s disease (Li et al., 2012).

Those who have a family history of Parkinson's could be a carrier of the AGA variant of MAPT.

4 of them were not differentially-regulated when exposed to DHT:

14)WNT10A
15)Between SUCNR1 and MBNL1
16)SETBP1
17)Between PAX1 and FOXA2. FOXA2's expression were not detected in balding scalp and PAX1's expression was not found to be differentially expressed when DPCs were exposed to DHT.

This could mean that these AGA-causing locus are androgen pathway-independent in the DPCs of the balding scalp.

In any case:

1)WNT10A = Estradiol(UP), Butyraldehyde =(UP)- assuming that WNT10A is downregulated in balding scalp

2a)SUCNR1, from genecards:

This gene encodes a G-protein-coupled receptor for succinate, an intermediate molecule of the citric acid cycle. It is involved in the promotion of hematopoietic progenitor cell development, and it has a potential role in renovascular hypertension which has known correlations to renal failure, diabetes and atherosclerosis. [provided by RefSeq, Oct 2009]

2b)MBNL1, from genecards:

This gene encodes a member of the muscleblind protein family which was initially described in Drosophila melanogaster. The encoded protein is a C3H-type zinc finger protein that modulates alternative splicing of pre-mRNAs. Muscleblind proteins bind specifically to expanded dsCUG RNA but not to normal size CUG repeats and may thereby play a role in the pathophysiology of myotonic dystrophy. Mice lacking this gene exhibited muscle abnormalities and cataracts. Several alternatively spliced transcript variants have been described but the full-length natures of only some have been determined. The different isoforms are thought to have different binding specificities and/or splicing activities. [provided by RefSeq, Sep 2015]

3)SETBP1, from genecards:

This gene encodes a protein which contains a several motifs including a ski homology region and a SET-binding region in addition to three nuclear localization signals. The encoded protein has been shown to bind the SET nuclear oncogene which is involved in DNA replication. Mutations in this gene are associated with Schinzel-Giedion midface retraction syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]


4)Pax1(Estradiol=UP, Butyraldehyde=UP), from genecards:

This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. This gene plays a role in pattern formation during embryogenesis and may be essential for development of the vertebral column. This gene is silenced by methylation in ovarian and cervical cancers and may be a tumor suppressor gene. Mutations in this gene are also associated with vertebral malformations. [provided by RefSeq, Mar 2012]

Swooping
06-06-2016, 12:05 PM
@InBeforeTheCure,

I agree.

I'm very curious to your findings/thoughts! I need to educate myself better on literature and methods so I can stay relevant in this discussion though :p. I have PM'ed you and it would be cool if you can teach me some things and give me more insight into your thought process etc.

I can't recall if Hamilton describes anything about facial hair growth in these two groups, don't think so to be honest. Speaking of "stress", check out this recent study guys;

"Comparative Transcriptome profiling provides new insights into mechanisms of androgenetic alopecia progression: Whole transcriptome discovery study identifies altered oxidation-reduction state in hair follicles of androgenetic alopecia patients"

http://onlinelibrary.wiley.com/doi/10.1111/bjd.14767/abstract;jsessionid=6D87B15F1DB95025982274A6C41B62 BA.f03t02


"The up-regulation of genes in the respiratory chain (CYB5R3, SDHA) may impact on the redox state in AGA-affected hairs 7, 8. Furthermore, the up-regulation of anti-oxidation genes (GPX4 and PRX3) suggests that patient vertex scalps may be exposed to greater oxidative stress than control scalps, possibly resultant from increased respiratory chain activity 9, 10. Increased levels of GPX4 would also protect the increased amount of lipid synthesized in the patient vertex scalp from phospholipid hydroperoxides-mediated oxidation 11. The occurrence of oxidative stress in DP cells may account for impaired hair growth in AGA as elevated reactive oxidative species in balding DP cells are known to cause elevated secretion of hair growth inhibitors TGFβ1/TGFβ2 and cell senescence"

Underlines the possibility of oxidative stress being implicated in AGA again.

TheKingofFighters
06-06-2016, 12:59 PM
The vast majority of the genes below are not the causative AGA locus genes mentioned in the study- but they are the 1s that are expressed selectively in balding/non-balding scalp follicles just after being freshly dissected. So, it is likely the AGA causative locus genes influences the appropriate expression of hair growth genes in the DPC.

Derma papilla signature genes expressed only in non-balding scalp follicles:

APOD = Estradiol, VPA,
ARHGEF3 = VPA
BMP4 = Estradiol via ESR2, but downs it via ESR1, VPA
DIO2 = Estradiol
FOXO1 = Estradiol via ESR1, VPA
GAS7 = VPA, Ascorbic acid,
GMFG = Butyraldehyde , VPA
GUCY1A3 = Estradiol, VPA
IFI27 = Ascorbic acid, Estradiol, Butyraldehyde,
LXN = Ascorbic acid,
LZTS1 = Butyraldehyde, VPA
NOG = Estradiol via ESR1 but downs it via ESR2, Butyraldehyde, VPA
PLCG2 = Estradiol, VPA, Ethanol
RBP1 = Estradiol via ESR1, Butyraldehyde, VPA, Ethanol,

Derma pailla signature genes expressed only in balding scalp follicles

BMP2 = VPA half/half
CCND2 =VPA half/half, Ethanol
GPM6B = VPA half/half,
MEF2C = ?
SOSTDC1 = Estradiol
STON1 = Butyraldhye is safe, VPA is half/half

It should be noted that the discoveries made by this study are almost completely at odds with those in made in Dr Cotsarelis's study.

Example:

IFI27 is a gene upregulated in balding scalp- but is expressed in non-balding scalps instead in http://www.ncbi.nlm.nih.gov/pubmed/27060448 <=== The researcher that participated in this study, AM Hilmer- is also the 1 that discovered the PAX1/FOXA2 AGA locus along with several other AGA causative gene locus.

And becos we know that Vitamin C and its derivatives inhibits DKK1(L-threonate, L ascorbyl 2 phosphate, etc)- it is IMO that this study seems to have more credibility n makes more sense.

However, it is also plausible that the subjects Dr Cotsarelis used in his study were carrying different AGA causative genes than those listed in this study.

InBeforeTheCure
06-06-2016, 04:53 PM
@InBeforeTheCure,

I agree.

I'm very curious to your findings/thoughts! I need to educate myself better on literature and methods so I can stay relevant in this discussion though :p. I have PM'ed you and it would be cool if you can teach me some things and give me more insight into your thought process etc.

Unfortunately, it looks like I can't access my inbox...? I get the following message:


InBeforeTheCure, you do not have permission to access this page. This could be due to one of several reasons:

Your user account may not have sufficient privileges to access this page. Are you trying to edit someone else's post, access administrative features or some other privileged system?
If you are trying to post, the administrator may have disabled your account, or it may be awaiting activation.


I can't recall if Hamilton describes anything about facial hair growth in these two groups, don't think so to be honest.

That sucks. Facial hair develops in a pattern too, of course, so it would be interesting to know.


Speaking of "stress", check out this recent study guys;

"Comparative Transcriptome profiling provides new insights into mechanisms of androgenetic alopecia progression: Whole transcriptome discovery study identifies altered oxidation-reduction state in hair follicles of androgenetic alopecia patients"

http://onlinelibrary.wiley.com/doi/10.1111/bjd.14767/abstract;jsessionid=6D87B15F1DB95025982274A6C41B62 BA.f03t02


Furthermore, the up-regulation of anti-oxidation genes (GPX4 and PRX3) suggests that patient vertex scalps may be exposed to greater oxidative stress than control scalps, possibly resultant from increased respiratory chain activity 9, 10.

Actually, the interesting thing is that the expression of anti-oxidation genes are not necessarily "upregulated". In fact, they fluctuate over time. For example...

GPX4 expression vs. hours of DHT exposure, for Balding DPCs of Subject A:
http://s33.postimg.org/kjs7br75b/GPX4a.png

Subject B:
http://s33.postimg.org/4k9js7b3j/GPX4b.png

Subject C:
http://s33.postimg.org/uwj3bkq27/GPX4c.png

Now, you probably know about FoxO genes and mTOR, right?

Link to pathway diagram: mTOR signaling at a glance (http://d1dvw62tmnyoft.cloudfront.net/content/joces/122/20/3589/F1.large.jpg)

Here are the most upregulated genes in balding DPCs with 100 nM DHT added from that study by Kwack et. al that focused on DKK1:

http://s33.postimg.org/pny9j099r/kwack.png

DHT induces expression of SLC3A2 and SLC7A5, which you can see in the mTOR pathway diagram. These are amino acid transporters that act upstream of mTORC1-mediated anabolic processes. Also, SGK is 4.53x upregulated, which you can also see in the diagram is a substrate of mTORC2. SGK is similar in structure and function to Akt. FoxO1/FoxO3 enforce quiescence of cells and play a critical role in homeostasis and stress resistance -- they transcribe a lot of ROS scavenger genes, for example.

So Akt/SGK, to promote cell proliferation, phosphorylate FoxO. This allows a protein called 14-3-3 to bind it and move it from the nucleus into the cytoplasm where it undergoes proteasomal degradation. It's also important to note that in response to ROS, MST1 and JNK phosphorylate FoxO to keep it in the nucleus, and this signal overrides the Akt/SGK-induced nuclear exclusion signal.

Now imagine what would happen if you were to take this system in its "ground state" (low ROS, low Akt/SGK). Add DHT and you induce FoxO nuclear exclusion and proteasomal degradation through mTORC2 -> Akt + highly upregulated SGK. ROS start to accumulate, but since FoxO protein levels are low, the cells are unable to respond despite the MST1/JNK override signal. Then there's a lag time while new FoxO mRNA are being transcribed and then translated while ROS accumulate, and the newly produced nuclear FoxOs transcribe ROS scavenger genes and the ROS levels drop. Now it's in the ground state once more, and the process repeats itself. If it's an oscillating system like this, static measurements might be misleading and give contradictory results between different experiments.

BTW, here's a nice review paper on FoxOs from Nature: https://www.dropbox.com/s/fpwoka8h9n9e61i/eijkelenboom2013.pdf?dl=0

PAX1 has been shown to interact directly with FOXO1, especially under hypoxic stress, while an interaction between PAX9 (a PAX1 paralog) was not detected (see Section 3.6 (http://www.hindawi.com/journals/bmri/2014/309385/)). But maybe PAX1 could play in a role in coordinating homeobox genes as well. Speaking of that, I ran another quick analysis with oPossum (http://opossum.cisreg.ca/oPOSSUM3/) on the top 1000 upregulated genes in balding DPCs. What this does is search for enriched transcription factor binding motifs in a list of genes, which gives clues as to which TFs may be differentially regulated. These were the results:


TF JASPAR ID Class Family Tax Group IC GC Content Target gene hits Target gene non-hits Background gene hits Background gene non-hits Target TFBS hits Target TFBS nucleotide rate Background TFBS hits Background TFBS nucleotide rate Z-score Fisher score
HOXA5 MA0158.1 Helix-Turn-Helix Homeo vertebrates 8.759 0.315 673 129 17629 7123 12090 0.0525 205993 0.0458 43.625 36.952
Nkx2-5 MA0063.1 Helix-Turn-Helix Homeo vertebrates 8.27 0.218 663 139 16973 7779 11546 0.0439 197210 0.0384 39.008 42.733
SRY MA0084.1 Other Alpha-Helix High Mobility Group vertebrates 9.193 0.238 603 199 14714 10038 6056 0.0296 101929 0.0255 35.306 45.351
Pdx1 MA0132.1 Helix-Turn-Helix Homeo vertebrates 9.04 0.194 618 184 15507 9245 8348 0.0272 140973 0.0235 33.057 39.832
ARID3A MA0151.1 Helix-Turn-Helix Arid vertebrates 9.896 0.062 619 183 16086 8666 9711 0.0316 166235 0.0277 32.395 29.867
FOXA1 MA0148.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.533 0.332 550 252 13355 11397 3731 0.0223 63112 0.0193 29.512 37.245
Foxd3 MA0041.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.945 0.223 491 311 11354 13398 2950 0.0192 49535 0.0165 28.77 39.588
FOXI1 MA0042.1 Winged Helix-Turn-Helix Forkhead vertebrates 13.183 0.263 505 297 11680 13072 2917 0.019 49366 0.0165 27.126 41.788
FOXO3 MA0157.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.734 0.298 561 241 13611 11141 4116 0.0179 69410 0.0154 26.948 39.221
Foxa2 MA0047.2 Winged Helix-Turn-Helix Forkhead vertebrates 13.268 0.315 493 309 11656 13096 2581 0.0168 43535 0.0145 26.08 35.049
CEBPA MA0102.2 Zipper-Type Leucine Zipper vertebrates 8.712 0.358 543 259 12828 11924 3306 0.0162 55606 0.0139 26.048 43.054
Sox5 MA0087.1 Other Alpha-Helix High Mobility Group vertebrates 10.831 0.199 541 261 13087 11665 4272 0.0162 72042 0.014 25.659 36.79
Nobox MA0125.1 Helix-Turn-Helix Homeo vertebrates 9.573 0.26 556 246 13558 11194 4512 0.0196 77190 0.0172 25.477 37.118
AP1 MA0099.2 Zipper-Type Leucine Zipper vertebrates 9.193 0.405 640 162 16390 8362 6497 0.0247 113253 0.022 24.617 37.724
Prrx2 MA0075.1 Helix-Turn-Helix Homeo vertebrates 9.063 0.027 595 207 15063 9689 7172 0.0195 123270 0.0171 24.5 33.384
ELF5 MA0136.1 Winged Helix-Turn-Helix Ets vertebrates 8.693 0.429 644 158 16547 8205 6604 0.0323 117435 0.0294 23.311 37.45
FOXD1 MA0031.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.926 0.275 551 251 13087 11665 3680 0.016 62921 0.014 23.068 43.075
NKX3-1 MA0124.1 Helix-Turn-Helix Homeo vertebrates 11.127 0.179 524 278 12654 12098 4026 0.0153 68823 0.0134 22.597 34.707
NFATC2 MA0152.1 Ig-fold Rel vertebrates 9.859 0.346 618 184 15176 9576 5597 0.0213 97757 0.019 22.418 46.546
TBP MA0108.2 Beta-sheet TATA-binding vertebrates 10.086 0.377 447 355 10389 14363 1966 0.016 33775 0.0141 22.265 32.386
Gfi MA0038.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.47 0.391 576 226 13731 11021 3747 0.0203 65844 0.0183 20.727 46.787
SPIB MA0081.1 Winged Helix-Turn-Helix Ets vertebrates 9.06 0.466 677 125 17547 7205 9699 0.0369 175639 0.0342 20.147 41.641
SOX9 MA0077.1 Other Alpha-Helix High Mobility Group vertebrates 9.079 0.358 491 311 11417 13335 2415 0.0118 41403 0.0104 19.385 38.365
Foxq1 MA0040.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.07 0.202 372 430 8007 16745 1308 0.00781 22088 0.00675 17.565 35.701
Gata1 MA0035.2 Zinc-coordinating GATA vertebrates 10.878 0.373 583 219 14350 10402 4194 0.025 75905 0.0232 16.64 39.077
SPI1 MA0080.2 Winged Helix-Turn-Helix Ets vertebrates 9.64 0.435 622 180 15792 8960 5329 0.0203 95792 0.0186 16.257 37.032
Sox17 MA0078.1 Other Alpha-Helix High Mobility Group vertebrates 10.502 0.384 584 218 13879 10873 3668 0.0179 65883 0.0165 15.419 49.338
TAL1::TCF3 MA0091.1 Zipper-Type Helix-Loop-Helix vertebrates 14.07 0.453 367 435 7491 17261 873 0.00569 14681 0.0049 15.401 43.825
RUNX1 MA0002.2 Ig-fold Runt vertebrates 10.401 0.502 557 245 13641 11111 3248 0.0194 58648 0.0179 15.045 36.189
YY1 MA0095.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.101 0.51 679 123 17190 7562 9001 0.0293 165054 0.0275 14.953 51.067
Pou5f1 MA0142.1 Helix-Turn-Helix Homeo vertebrates 14.808 0.308 187 615 3402 21350 329 0.00268 5205 0.00217 14.863 28.176
MEF2A MA0052.1 Other Alpha-Helix MADS vertebrates 15.709 0.179 328 474 7006 17746 930 0.00505 15631 0.00434 14.559 30.883
HLF MA0043.1 Zipper-Type Leucine Zipper vertebrates 11.147 0.394 263 539 5508 19244 604 0.00394 9969 0.00332 14.399 25.267
NFIL3 MA0025.1 Zipper-Type Leucine Zipper vertebrates 14.139 0.265 301 501 6731 18021 933 0.00557 15828 0.00484 14.352 22.145
FEV MA0156.1 Winged Helix-Turn-Helix Ets vertebrates 12.121 0.442 620 182 15402 9350 4505 0.0196 81722 0.0182 14.227 43.317
IRF1 MA0050.1 Winged Helix-Turn-Helix IRF vertebrates 16.008 0.383 285 517 6075 18677 689 0.00449 11517 0.00384 14.225 25.888
REL MA0101.1 Ig-fold Rel vertebrates 10.515 0.559 473 329 10514 14238 1670 0.00907 29250 0.00813 14.19 45.432
Nkx3-2 MA0122.1 Helix-Turn-Helix Homeo vertebrates 8.542 0.463 603 199 15425 9327 4996 0.0244 91612 0.0229 13.614 31.797
SRF MA0083.1 Other Alpha-Helix MADS vertebrates 17.965 0.466 66 736 908 23844 79 0.000515 1019 0.00034 12.86 19.299
Myb MA0100.1 Helix-Turn-Helix Myb vertebrates 9.883 0.591 579 223 13518 11234 3237 0.0141 58600 0.013 12.359 53.58
Pax6 MA0069.1 Helix-Turn-Helix Homeo vertebrates 13.798 0.432 85 717 1218 23534 98 0.000745 1377 0.000536 12.255 22.706
Ddit3::Cebpa MA0019.1 Zipper-Type Leucine Zipper vertebrates 11.652 0.483 267 535 5576 19176 578 0.00377 9754 0.00325 12.228 26.049
Pax4 MA0068.1 Helix-Turn-Helix Homeo vertebrates 11.004 0.441 11 791 112 24640 11 0.000179 113 9.42E-05 11.844 6.36
Sox2 MA0143.1 Other Alpha-Helix High Mobility Group vertebrates 12.951 0.361 151 651 2809 21943 238 0.00194 3844 0.0016 11.393 20.884
NR2F1 MA0017.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.924 0.478 198 604 3735 21017 304 0.00231 5073 0.00197 10.302 26.755
Lhx3 MA0135.1 Helix-Turn-Helix Homeo vertebrates 16.354 0.131 263 539 5806 18946 722 0.0051 12758 0.00461 9.758 19.918
TEAD1 MA0090.1 Helix-Turn-Helix Homeo vertebrates 15.678 0.507 254 548 5222 19530 487 0.00317 8446 0.00282 9.124 26.132
HNF1B MA0153.1 Helix-Turn-Helix Homeo vertebrates 16.821 0.222 201 601 4107 20645 403 0.00263 6910 0.0023 9.091 20.411
Tal1::Gata1 MA0140.1 Zipper-Type Helix-Loop-Helix vertebrates 11.297 0.451 280 522 6212 18540 622 0.00608 11200 0.0056 8.662 21.006
NF-kappaB MA0061.1 Ig-fold Rel vertebrates 13.345 0.621 390 412 8381 16371 1047 0.00568 18865 0.00524 8.308 38.621
RELA MA0107.1 Ig-fold Rel vertebrates 14.757 0.567 335 467 7171 17581 768 0.00417 13690 0.0038 8.053 31.49
NFE2L2 MA0150.1 Zipper-Type Leucine Zipper vertebrates 14.394 0.486 278 524 5635 19117 511 0.00305 8970 0.00274 8.039 30.909
MAX MA0058.1 Zipper-Type Helix-Loop-Helix vertebrates 12.685 0.571 375 427 7993 16759 886 0.00481 15900 0.00442 8.018 37.751
TLX1::NFIC MA0119.1 Helix-Turn-Helix::Other Homeo::Nuclear Factor I-CCAAT-binding vertebrates 19.665 0.598 63 739 1066 23686 76 0.000578 1162 0.000452 8.003 11.765
FOXF2 MA0030.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.824 0.334 195 607 4097 20655 369 0.0028 6459 0.00251 7.91 17.636
Stat3 MA0144.1 Ig-fold Stat vertebrates 13.601 0.505 437 365 9883 14869 1291 0.00701 23645 0.00657 7.367 36.189
Arnt::Ahr MA0006.1 Zipper-Type Helix-Loop-Helix vertebrates 9.532 0.715 564 238 13597 11155 3555 0.0116 66086 0.011 7.309 41.414
RORA_1 MA0071.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.19 0.424 383 419 8624 16128 1030 0.00559 18895 0.00525 6.412 29.963
HNF1A MA0046.1 Helix-Turn-Helix Homeo vertebrates 15.548 0.259 154 648 3044 21708 248 0.00188 4352 0.00169 6.329 17.375
NFYA MA0060.1 Other Alpha-Helix NFY CCAAT-binding vertebrates 12.925 0.523 302 500 5865 18887 519 0.00451 9476 0.00421 6.185 40.312
IRF2 MA0051.1 Winged Helix-Turn-Helix IRF vertebrates 21.134 0.412 50 752 844 23908 57 0.000557 923 0.000462 6.009 9.654
ELK1 MA0028.1 Winged Helix-Turn-Helix Ets vertebrates 8.812 0.568 588 214 13642 11110 2900 0.0157 54748 0.0152 5.893 57.662
Ar MA0007.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.703 0.498 31 771 534 24218 35 0.000418 554 0.000339 5.835 6.196
HNF4A MA0114.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 9.617 0.522 301 501 6389 18363 613 0.00433 11240 0.00406 5.677 28.301
USF1 MA0093.1 Zipper-Type Helix-Loop-Helix vertebrates 11.29 0.643 411 391 9330 15422 1197 0.00455 21993 0.00428 5.635 32.057
ELK4 MA0076.1 Winged Helix-Turn-Helix Ets vertebrates 14.123 0.583 307 495 6034 18718 519 0.00254 9342 0.00234 5.606 39.461
NR4A2 MA0160.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 10.165 0.491 569 233 13896 10856 3170 0.0138 60034 0.0133 5 38.825
CREB1 MA0018.2 Zipper-Type Leucine Zipper vertebrates 10.139 0.523 420 382 9204 15548 1064 0.00462 19712 0.00438 4.914 39.656
Hand1::Tcfe2a MA0092.1 Zipper-Type Helix-Loop-Helix vertebrates 10.144 0.507 550 252 13286 11466 2883 0.0157 54768 0.0152 4.807 38.545
T MA0009.1 Beta-Hairpin-Ribbon T vertebrates 17.863 0.452 99 703 1811 22941 123 0.000735 2114 0.000646 4.707 14.441
STAT1 MA0137.2 Ig-fold Stat vertebrates 13.119 0.452 292 510 6394 18358 591 0.00481 10990 0.00458 4.663 23.604
ESR2 MA0258.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.618 0.546 122 680 2219 22533 149 0.00146 2670 0.00134 4.474 18.01
RXR::RAR_DR5 MA0159.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 16.004 0.535 71 731 1313 23439 86 0.000794 1499 0.000708 4.356 10.296
EWSR1-FLI1 MA0149.1 Winged Helix-Turn-Helix Ets vertebrates 32.871 0.554 14 788 207 24545 14 0.000137 209 0.000105 4.249 4.571
E2F1 MA0024.1 Winged Helix-Turn-Helix E2F vertebrates 13.838 0.625 376 426 8113 16639 946 0.00411 17630 0.00392 4.115 35.871
PBX1 MA0070.1 Helix-Turn-Helix Homeo vertebrates 14.641 0.31 194 608 4107 20645 361 0.00235 6634 0.00221 4.032 16.986
MYC::MAX MA0059.1 Zipper-Type Helix-Loop-Helix vertebrates 14.237 0.602 174 628 3436 21316 249 0.00149 4535 0.00139 3.671 19.827
NR3C1 MA0113.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 14.749 0.432 123 679 2522 22230 172 0.00168 3161 0.00158 3.401 12.131
Arnt MA0004.1 Zipper-Type Helix-Loop-Helix vertebrates 10.992 0.642 335 467 7052 17700 742 0.00242 13904 0.00232 2.785 33.888
HIF1A::ARNT MA0259.1 Zipper-Type Helix-Loop-Helix vertebrates 9.74 0.657 485 317 10914 13838 1968 0.00855 37662 0.00837 2.611 44.747
Esrrb MA0141.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.806 0.524 424 378 10167 14585 1376 0.00896 26346 0.00878 2.61 24.477
NFKB1 MA0105.1 Ig-fold Rel vertebrates 15.627 0.758 201 601 3946 20806 340 0.00203 6372 0.00195 2.542 23.715
CTCF MA0139.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.205 0.645 171 631 3236 21516 212 0.00219 3982 0.0021 2.498 22.539
RREB1 MA0073.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 22.278 0.623 79 723 1520 23232 99 0.00107 1839 0.00102 2.238 10.037
Nr2e3 MA0164.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.028 0.373 291 511 6354 18398 650 0.00247 12287 0.00239 2.225 23.819
Evi1 MA0029.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.909 0.28 94 708 1931 22821 132 0.001 2457 0.000956 2.074 9.382
ESR1 MA0112.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.563 0.594 19 783 345 24407 20 0.000217 355 0.000197 1.895 3.819
MZF1_1-4 MA0056.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.586 0.725 660 142 16863 7889 10359 0.0337 201000 0.0335 1.757 42.724
MZF1_5-13 MA0057.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.4 0.588 560 242 13425 11327 4003 0.0217 77649 0.0216 1.46 42.21
Mycn MA0104.2 Zipper-Type Helix-Loop-Helix vertebrates 11.104 0.699 379 423 8332 16420 982 0.00533 18928 0.00526 1.344 33.248
Zfp423 MA0116.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.925 0.679 256 546 5691 19061 526 0.00428 10149 0.00423 1.112 18.634
ZEB1 MA0103.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.305 0.557 685 117 17454 7298 8797 0.0287 171132 0.0285 1.015 50.298
EBF1 MA0154.1 Zipper-Type Helix-Loop-Helix vertebrates 11.564 0.648 483 319 11288 13464 2013 0.0109 39149 0.0109 0.658 36.105
Pax5 MA0014.1 Helix-Turn-Helix Homeo vertebrates 12.432 0.575 65 737 1224 23528 71 0.000771 1364 0.000758 0.623 9.032
Spz1 MA0111.1 Other Other vertebrates 11.907 0.538 291 511 6658 18094 646 0.00386 12530 0.00383 0.611 18.812
PPARG::RXRA MA0065.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 11.663 0.547 262 540 6067 18685 558 0.00454 11080 0.00462 -1.486 15.473
ZNF354C MA0130.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.958 0.615 685 117 17566 7186 10559 0.0344 207738 0.0346 -1.773 47.78
REST MA0138.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 23.134 0.596 10 792 232 24520 11 0.000125 242 0.000141 -1.836 1.465
RORA_2 MA0072.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 17.425 0.369 171 631 3571 21181 252 0.00192 5079 0.00198 -1.855 15.711
Egr1 MA0162.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.456 0.739 306 496 6364 18388 609 0.00364 12188 0.00373 -1.974 31.55
NR1H2::RXRA MA0115.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 27.878 0.445 4 798 99 24653 4 3.69E-05 100 4.72E-05 -2.091 0.902
Myc MA0147.1 Zipper-Type Helix-Loop-Helix vertebrates 11.157 0.686 366 436 8288 16464 925 0.00502 18476 0.00513 -2.131 27.179
GABPA MA0062.2 Winged Helix-Turn-Helix Ets vertebrates 13.335 0.647 418 384 9355 15397 1049 0.00626 20927 0.0064 -2.248 35.475
MIZF MA0131.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.197 0.61 91 711 2080 22672 118 0.000641 2497 0.000694 -2.756 5.883
PLAG1 MA0163.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 19.352 0.798 91 711 1971 22781 117 0.000889 2462 0.000958 -3.016 7.429
TP53 MA0106.1 Zinc-coordinating Loop-Sheet-Helix vertebrates 26.239 0.603 0 802 8 24744 0 0 8 4.45E-06 -3.036 0
PPARG MA0066.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.365 0.523 2 800 62 24690 2 2.17E-05 64 3.56E-05 -3.214 0.509
RXRA::VDR MA0074.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.451 0.527 17 785 453 24299 20 0.000163 475 0.000198 -3.413 1.174
SP1 MA0079.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 11.129 0.82 559 243 12391 12361 4015 0.0218 79797 0.0222 -3.46 64.552
NHLH1 MA0048.1 Zipper-Type Helix-Loop-Helix vertebrates 14.132 0.674 261 541 5783 18969 479 0.00312 9874 0.00329 -4.075 19.385
Myf MA0055.1 Zipper-Type Helix-Loop-Helix vertebrates 15.914 0.609 428 374 10157 14595 1348 0.00878 27519 0.00918 -5.609 26.549
Klf4 MA0039.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 12.618 0.771 577 225 13645 11107 4418 0.024 88731 0.0247 -5.863 49.321
Tcfcp2l1 MA0145.1 Other CP2 vertebrates 11.65 0.609 445 357 10591 14161 1574 0.012 32190 0.0125 -6.823 27.865
INSM1 MA0155.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.862 0.667 331 471 7588 17164 835 0.00544 17685 0.0059 -8.104 22.059
znf143 MA0088.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.541 0.53 54 748 1301 23451 58 0.00063 1473 0.000819 -8.973 3.145
Zfx MA0146.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.077 0.749 429 373 9872 14880 1587 0.0121 33238 0.0129 -10.427 31.938


Interesting that lots of homeobox genes show up. Also, SRY (a Y-chromosomal gene responsible for male sex determination). AR is there, lots of FOX genes, AP1, STATs, NF-kB, and more.

Also, look at that region on Chr1 near TARDBP, one of the most significant AGA risk locuses:

http://s33.postimg.org/unmt2nf5b/rs12565727.png

In the Chew paper, they show four contiguous genes in that region are upregulated in balding DPCs, including MTOR (they call it "FRAP1", which is another name for the MTOR gene). I was investigating mTOR before I was even aware of this, so it was kind of cool to see that. But anyway, I think this corroborates the idea that mTOR is a key player in AGA pathology.


Underlines the possibility of oxidative stress being implicated in AGA again.

Yeah, I think oxidative stress plays a critical role not only in inducing senescence, but also in progressively increasing androgen sensitivity. For example, p38 MAPK is a major oxidative stress-induced senescence pathway, and its downstream target HSP27 can stabilize AR and therefore increase AR protein levels and androgen sensitivity (Zoubeidi et. al, 2007 (http://cancerres.aacrjournals.org/content/67/21/10455.long)). p38 MAPK also produces a lot of inflammatory cytokines (it plays a role in SASP), so maybe some of the inflammatory part of AGA is because of that pathway. Also, you mentioned Twist1 (another AGA risk gene) upregulating AR. Look at this (http://www.ncbi.nlm.nih.gov/pubmed/19802001):


There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR.

So these factors might cooperate in a vicious positive feedback loop, where once the genetic network hits a certain tipping point, it gains momentum and progresses toward the inevitable.

InBeforeTheCure
06-06-2016, 05:13 PM
God damn it. I screwed up the page and I can't edit it now.

TheKingofFighters
06-06-2016, 05:45 PM
Unfortunately, it looks like I can't access my inbox...? I get the following message:





That sucks. Facial hair develops in a pattern too, of course, so it would be interesting to know.





Actually, the interesting thing is that the expression of anti-oxidation genes are not necessarily "upregulated". In fact, they fluctuate over time. For example...

GPX4 expression vs. hours of DHT exposure, for Balding DPCs of Subject A:
http://s33.postimg.org/kjs7br75b/GPX4a.png

Subject B:
http://s33.postimg.org/4k9js7b3j/GPX4b.png

Subject C:
http://s33.postimg.org/uwj3bkq27/GPX4c.png

Now, you probably know about FoxO genes and mTOR, right?

Link to pathway diagram: mTOR signaling at a glance (http://d1dvw62tmnyoft.cloudfront.net/content/joces/122/20/3589/F1.large.jpg)

Here are the most upregulated genes in balding DPCs with 100 nM DHT added from that study by Kwack et. al that focused on DKK1:

http://s33.postimg.org/pny9j099r/kwack.png

DHT induces expression of SLC3A2 and SLC7A5, which you can see in the mTOR pathway diagram. These are amino acid transporters that act upstream of mTORC1-mediated anabolic processes. Also, SGK is 4.53x upregulated, which you can also see in the diagram is a substrate of mTORC2. SGK is similar in structure and function to Akt. FoxO1/FoxO3 enforce quiescence of cells and play a critical role in homeostasis and stress resistance -- they transcribe a lot of ROS scavenger genes, for example.

So Akt/SGK, to promote cell proliferation, phosphorylate FoxO. This allows a protein called 14-3-3 to bind it and move it from the nucleus into the cytoplasm where it undergoes proteasomal degradation. It's also important to note that in response to ROS, MST1 and JNK phosphorylate FoxO to keep it in the nucleus, and this signal overrides the Akt/SGK-induced nuclear exclusion signal.

Now imagine what would happen if you were to take this system in its "ground state" (low ROS, low Akt/SGK). Add DHT and you induce FoxO nuclear exclusion and proteasomal degradation through mTORC2 -> Akt + highly upregulated SGK. ROS start to accumulate, but since FoxO protein levels are low, the cells are unable to respond despite the MST1/JNK override signal. Then there's a lag time while new FoxO mRNA are being transcribed and then translated while ROS accumulate, and the newly produced nuclear FoxOs transcribe ROS scavenger genes and the ROS levels drop. Now it's in the ground state once more, and the process repeats itself. If it's an oscillating system like this, static measurements might be misleading and give contradictory results between different experiments.

BTW, here's a nice review paper on FoxOs from Nature: https://www.dropbox.com/s/fpwoka8h9n9e61i/eijkelenboom2013.pdf?dl=0

PAX1 has been shown to interact directly with FOXO1, especially under hypoxic stress, while an interaction between PAX9 (a PAX1 paralog) was not detected (see Section 3.6 (http://www.hindawi.com/journals/bmri/2014/309385/)). But maybe PAX1 could play in a role in coordinating homeobox genes as well. Speaking of that, I ran another quick analysis with oPossum (http://opossum.cisreg.ca/oPOSSUM3/) on the top 1000 upregulated genes in balding DPCs. What this does is search for enriched transcription factor binding motifs in a list of genes, which gives clues as to which TFs may be differentially regulated. These were the results:


TF JASPAR ID Class Family Tax Group IC GC Content Target gene hits Target gene non-hits Background gene hits Background gene non-hits Target TFBS hits Target TFBS nucleotide rate Background TFBS hits Background TFBS nucleotide rate Z-score Fisher score
HOXA5 MA0158.1 Helix-Turn-Helix Homeo vertebrates 8.759 0.315 673 129 17629 7123 12090 0.0525 205993 0.0458 43.625 36.952
Nkx2-5 MA0063.1 Helix-Turn-Helix Homeo vertebrates 8.27 0.218 663 139 16973 7779 11546 0.0439 197210 0.0384 39.008 42.733
SRY MA0084.1 Other Alpha-Helix High Mobility Group vertebrates 9.193 0.238 603 199 14714 10038 6056 0.0296 101929 0.0255 35.306 45.351
Pdx1 MA0132.1 Helix-Turn-Helix Homeo vertebrates 9.04 0.194 618 184 15507 9245 8348 0.0272 140973 0.0235 33.057 39.832
ARID3A MA0151.1 Helix-Turn-Helix Arid vertebrates 9.896 0.062 619 183 16086 8666 9711 0.0316 166235 0.0277 32.395 29.867
FOXA1 MA0148.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.533 0.332 550 252 13355 11397 3731 0.0223 63112 0.0193 29.512 37.245
Foxd3 MA0041.1 Winged Helix-Turn-Helix Forkhead vertebrates 12.945 0.223 491 311 11354 13398 2950 0.0192 49535 0.0165 28.77 39.588
FOXI1 MA0042.1 Winged Helix-Turn-Helix Forkhead vertebrates 13.183 0.263 505 297 11680 13072 2917 0.019 49366 0.0165 27.126 41.788
FOXO3 MA0157.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.734 0.298 561 241 13611 11141 4116 0.0179 69410 0.0154 26.948 39.221
Foxa2 MA0047.2 Winged Helix-Turn-Helix Forkhead vertebrates 13.268 0.315 493 309 11656 13096 2581 0.0168 43535 0.0145 26.08 35.049
CEBPA MA0102.2 Zipper-Type Leucine Zipper vertebrates 8.712 0.358 543 259 12828 11924 3306 0.0162 55606 0.0139 26.048 43.054
Sox5 MA0087.1 Other Alpha-Helix High Mobility Group vertebrates 10.831 0.199 541 261 13087 11665 4272 0.0162 72042 0.014 25.659 36.79
Nobox MA0125.1 Helix-Turn-Helix Homeo vertebrates 9.573 0.26 556 246 13558 11194 4512 0.0196 77190 0.0172 25.477 37.118
AP1 MA0099.2 Zipper-Type Leucine Zipper vertebrates 9.193 0.405 640 162 16390 8362 6497 0.0247 113253 0.022 24.617 37.724
Prrx2 MA0075.1 Helix-Turn-Helix Homeo vertebrates 9.063 0.027 595 207 15063 9689 7172 0.0195 123270 0.0171 24.5 33.384
ELF5 MA0136.1 Winged Helix-Turn-Helix Ets vertebrates 8.693 0.429 644 158 16547 8205 6604 0.0323 117435 0.0294 23.311 37.45
FOXD1 MA0031.1 Winged Helix-Turn-Helix Forkhead vertebrates 11.926 0.275 551 251 13087 11665 3680 0.016 62921 0.014 23.068 43.075
NKX3-1 MA0124.1 Helix-Turn-Helix Homeo vertebrates 11.127 0.179 524 278 12654 12098 4026 0.0153 68823 0.0134 22.597 34.707
NFATC2 MA0152.1 Ig-fold Rel vertebrates 9.859 0.346 618 184 15176 9576 5597 0.0213 97757 0.019 22.418 46.546
TBP MA0108.2 Beta-sheet TATA-binding vertebrates 10.086 0.377 447 355 10389 14363 1966 0.016 33775 0.0141 22.265 32.386
Gfi MA0038.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.47 0.391 576 226 13731 11021 3747 0.0203 65844 0.0183 20.727 46.787
SPIB MA0081.1 Winged Helix-Turn-Helix Ets vertebrates 9.06 0.466 677 125 17547 7205 9699 0.0369 175639 0.0342 20.147 41.641
SOX9 MA0077.1 Other Alpha-Helix High Mobility Group vertebrates 9.079 0.358 491 311 11417 13335 2415 0.0118 41403 0.0104 19.385 38.365
Foxq1 MA0040.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.07 0.202 372 430 8007 16745 1308 0.00781 22088 0.00675 17.565 35.701
Gata1 MA0035.2 Zinc-coordinating GATA vertebrates 10.878 0.373 583 219 14350 10402 4194 0.025 75905 0.0232 16.64 39.077
SPI1 MA0080.2 Winged Helix-Turn-Helix Ets vertebrates 9.64 0.435 622 180 15792 8960 5329 0.0203 95792 0.0186 16.257 37.032
Sox17 MA0078.1 Other Alpha-Helix High Mobility Group vertebrates 10.502 0.384 584 218 13879 10873 3668 0.0179 65883 0.0165 15.419 49.338
TAL1::TCF3 MA0091.1 Zipper-Type Helix-Loop-Helix vertebrates 14.07 0.453 367 435 7491 17261 873 0.00569 14681 0.0049 15.401 43.825
RUNX1 MA0002.2 Ig-fold Runt vertebrates 10.401 0.502 557 245 13641 11111 3248 0.0194 58648 0.0179 15.045 36.189
YY1 MA0095.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.101 0.51 679 123 17190 7562 9001 0.0293 165054 0.0275 14.953 51.067
Pou5f1 MA0142.1 Helix-Turn-Helix Homeo vertebrates 14.808 0.308 187 615 3402 21350 329 0.00268 5205 0.00217 14.863 28.176
MEF2A MA0052.1 Other Alpha-Helix MADS vertebrates 15.709 0.179 328 474 7006 17746 930 0.00505 15631 0.00434 14.559 30.883
HLF MA0043.1 Zipper-Type Leucine Zipper vertebrates 11.147 0.394 263 539 5508 19244 604 0.00394 9969 0.00332 14.399 25.267
NFIL3 MA0025.1 Zipper-Type Leucine Zipper vertebrates 14.139 0.265 301 501 6731 18021 933 0.00557 15828 0.00484 14.352 22.145
FEV MA0156.1 Winged Helix-Turn-Helix Ets vertebrates 12.121 0.442 620 182 15402 9350 4505 0.0196 81722 0.0182 14.227 43.317
IRF1 MA0050.1 Winged Helix-Turn-Helix IRF vertebrates 16.008 0.383 285 517 6075 18677 689 0.00449 11517 0.00384 14.225 25.888
REL MA0101.1 Ig-fold Rel vertebrates 10.515 0.559 473 329 10514 14238 1670 0.00907 29250 0.00813 14.19 45.432
Nkx3-2 MA0122.1 Helix-Turn-Helix Homeo vertebrates 8.542 0.463 603 199 15425 9327 4996 0.0244 91612 0.0229 13.614 31.797
SRF MA0083.1 Other Alpha-Helix MADS vertebrates 17.965 0.466 66 736 908 23844 79 0.000515 1019 0.00034 12.86 19.299
Myb MA0100.1 Helix-Turn-Helix Myb vertebrates 9.883 0.591 579 223 13518 11234 3237 0.0141 58600 0.013 12.359 53.58
Pax6 MA0069.1 Helix-Turn-Helix Homeo vertebrates 13.798 0.432 85 717 1218 23534 98 0.000745 1377 0.000536 12.255 22.706
Ddit3::Cebpa MA0019.1 Zipper-Type Leucine Zipper vertebrates 11.652 0.483 267 535 5576 19176 578 0.00377 9754 0.00325 12.228 26.049
Pax4 MA0068.1 Helix-Turn-Helix Homeo vertebrates 11.004 0.441 11 791 112 24640 11 0.000179 113 9.42E-05 11.844 6.36
Sox2 MA0143.1 Other Alpha-Helix High Mobility Group vertebrates 12.951 0.361 151 651 2809 21943 238 0.00194 3844 0.0016 11.393 20.884
NR2F1 MA0017.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.924 0.478 198 604 3735 21017 304 0.00231 5073 0.00197 10.302 26.755
Lhx3 MA0135.1 Helix-Turn-Helix Homeo vertebrates 16.354 0.131 263 539 5806 18946 722 0.0051 12758 0.00461 9.758 19.918
TEAD1 MA0090.1 Helix-Turn-Helix Homeo vertebrates 15.678 0.507 254 548 5222 19530 487 0.00317 8446 0.00282 9.124 26.132
HNF1B MA0153.1 Helix-Turn-Helix Homeo vertebrates 16.821 0.222 201 601 4107 20645 403 0.00263 6910 0.0023 9.091 20.411
Tal1::Gata1 MA0140.1 Zipper-Type Helix-Loop-Helix vertebrates 11.297 0.451 280 522 6212 18540 622 0.00608 11200 0.0056 8.662 21.006
NF-kappaB MA0061.1 Ig-fold Rel vertebrates 13.345 0.621 390 412 8381 16371 1047 0.00568 18865 0.00524 8.308 38.621
RELA MA0107.1 Ig-fold Rel vertebrates 14.757 0.567 335 467 7171 17581 768 0.00417 13690 0.0038 8.053 31.49
NFE2L2 MA0150.1 Zipper-Type Leucine Zipper vertebrates 14.394 0.486 278 524 5635 19117 511 0.00305 8970 0.00274 8.039 30.909
MAX MA0058.1 Zipper-Type Helix-Loop-Helix vertebrates 12.685 0.571 375 427 7993 16759 886 0.00481 15900 0.00442 8.018 37.751
TLX1::NFIC MA0119.1 Helix-Turn-Helix::Other Homeo::Nuclear Factor I-CCAAT-binding vertebrates 19.665 0.598 63 739 1066 23686 76 0.000578 1162 0.000452 8.003 11.765
FOXF2 MA0030.1 Winged Helix-Turn-Helix Forkhead vertebrates 14.824 0.334 195 607 4097 20655 369 0.0028 6459 0.00251 7.91 17.636
Stat3 MA0144.1 Ig-fold Stat vertebrates 13.601 0.505 437 365 9883 14869 1291 0.00701 23645 0.00657 7.367 36.189
Arnt::Ahr MA0006.1 Zipper-Type Helix-Loop-Helix vertebrates 9.532 0.715 564 238 13597 11155 3555 0.0116 66086 0.011 7.309 41.414
RORA_1 MA0071.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.19 0.424 383 419 8624 16128 1030 0.00559 18895 0.00525 6.412 29.963
HNF1A MA0046.1 Helix-Turn-Helix Homeo vertebrates 15.548 0.259 154 648 3044 21708 248 0.00188 4352 0.00169 6.329 17.375
NFYA MA0060.1 Other Alpha-Helix NFY CCAAT-binding vertebrates 12.925 0.523 302 500 5865 18887 519 0.00451 9476 0.00421 6.185 40.312
IRF2 MA0051.1 Winged Helix-Turn-Helix IRF vertebrates 21.134 0.412 50 752 844 23908 57 0.000557 923 0.000462 6.009 9.654
ELK1 MA0028.1 Winged Helix-Turn-Helix Ets vertebrates 8.812 0.568 588 214 13642 11110 2900 0.0157 54748 0.0152 5.893 57.662
Ar MA0007.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 15.703 0.498 31 771 534 24218 35 0.000418 554 0.000339 5.835 6.196
HNF4A MA0114.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 9.617 0.522 301 501 6389 18363 613 0.00433 11240 0.00406 5.677 28.301
USF1 MA0093.1 Zipper-Type Helix-Loop-Helix vertebrates 11.29 0.643 411 391 9330 15422 1197 0.00455 21993 0.00428 5.635 32.057
ELK4 MA0076.1 Winged Helix-Turn-Helix Ets vertebrates 14.123 0.583 307 495 6034 18718 519 0.00254 9342 0.00234 5.606 39.461
NR4A2 MA0160.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 10.165 0.491 569 233 13896 10856 3170 0.0138 60034 0.0133 5 38.825
CREB1 MA0018.2 Zipper-Type Leucine Zipper vertebrates 10.139 0.523 420 382 9204 15548 1064 0.00462 19712 0.00438 4.914 39.656
Hand1::Tcfe2a MA0092.1 Zipper-Type Helix-Loop-Helix vertebrates 10.144 0.507 550 252 13286 11466 2883 0.0157 54768 0.0152 4.807 38.545
T MA0009.1 Beta-Hairpin-Ribbon T vertebrates 17.863 0.452 99 703 1811 22941 123 0.000735 2114 0.000646 4.707 14.441
STAT1 MA0137.2 Ig-fold Stat vertebrates 13.119 0.452 292 510 6394 18358 591 0.00481 10990 0.00458 4.663 23.604
ESR2 MA0258.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.618 0.546 122 680 2219 22533 149 0.00146 2670 0.00134 4.474 18.01
RXR::RAR_DR5 MA0159.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 16.004 0.535 71 731 1313 23439 86 0.000794 1499 0.000708 4.356 10.296
EWSR1-FLI1 MA0149.1 Winged Helix-Turn-Helix Ets vertebrates 32.871 0.554 14 788 207 24545 14 0.000137 209 0.000105 4.249 4.571
E2F1 MA0024.1 Winged Helix-Turn-Helix E2F vertebrates 13.838 0.625 376 426 8113 16639 946 0.00411 17630 0.00392 4.115 35.871
PBX1 MA0070.1 Helix-Turn-Helix Homeo vertebrates 14.641 0.31 194 608 4107 20645 361 0.00235 6634 0.00221 4.032 16.986
MYC::MAX MA0059.1 Zipper-Type Helix-Loop-Helix vertebrates 14.237 0.602 174 628 3436 21316 249 0.00149 4535 0.00139 3.671 19.827
NR3C1 MA0113.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 14.749 0.432 123 679 2522 22230 172 0.00168 3161 0.00158 3.401 12.131
Arnt MA0004.1 Zipper-Type Helix-Loop-Helix vertebrates 10.992 0.642 335 467 7052 17700 742 0.00242 13904 0.00232 2.785 33.888
HIF1A::ARNT MA0259.1 Zipper-Type Helix-Loop-Helix vertebrates 9.74 0.657 485 317 10914 13838 1968 0.00855 37662 0.00837 2.611 44.747
Esrrb MA0141.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.806 0.524 424 378 10167 14585 1376 0.00896 26346 0.00878 2.61 24.477
NFKB1 MA0105.1 Ig-fold Rel vertebrates 15.627 0.758 201 601 3946 20806 340 0.00203 6372 0.00195 2.542 23.715
CTCF MA0139.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.205 0.645 171 631 3236 21516 212 0.00219 3982 0.0021 2.498 22.539
RREB1 MA0073.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 22.278 0.623 79 723 1520 23232 99 0.00107 1839 0.00102 2.238 10.037
Nr2e3 MA0164.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 12.028 0.373 291 511 6354 18398 650 0.00247 12287 0.00239 2.225 23.819
Evi1 MA0029.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.909 0.28 94 708 1931 22821 132 0.001 2457 0.000956 2.074 9.382
ESR1 MA0112.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 13.563 0.594 19 783 345 24407 20 0.000217 355 0.000197 1.895 3.819
MZF1_1-4 MA0056.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.586 0.725 660 142 16863 7889 10359 0.0337 201000 0.0335 1.757 42.724
MZF1_5-13 MA0057.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 9.4 0.588 560 242 13425 11327 4003 0.0217 77649 0.0216 1.46 42.21
Mycn MA0104.2 Zipper-Type Helix-Loop-Helix vertebrates 11.104 0.699 379 423 8332 16420 982 0.00533 18928 0.00526 1.344 33.248
Zfp423 MA0116.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.925 0.679 256 546 5691 19061 526 0.00428 10149 0.00423 1.112 18.634
ZEB1 MA0103.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.305 0.557 685 117 17454 7298 8797 0.0287 171132 0.0285 1.015 50.298
EBF1 MA0154.1 Zipper-Type Helix-Loop-Helix vertebrates 11.564 0.648 483 319 11288 13464 2013 0.0109 39149 0.0109 0.658 36.105
Pax5 MA0014.1 Helix-Turn-Helix Homeo vertebrates 12.432 0.575 65 737 1224 23528 71 0.000771 1364 0.000758 0.623 9.032
Spz1 MA0111.1 Other Other vertebrates 11.907 0.538 291 511 6658 18094 646 0.00386 12530 0.00383 0.611 18.812
PPARG::RXRA MA0065.2 Zinc-coordinating Hormone-nuclear Receptor vertebrates 11.663 0.547 262 540 6067 18685 558 0.00454 11080 0.00462 -1.486 15.473
ZNF354C MA0130.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 8.958 0.615 685 117 17566 7186 10559 0.0344 207738 0.0346 -1.773 47.78
REST MA0138.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 23.134 0.596 10 792 232 24520 11 0.000125 242 0.000141 -1.836 1.465
RORA_2 MA0072.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 17.425 0.369 171 631 3571 21181 252 0.00192 5079 0.00198 -1.855 15.711
Egr1 MA0162.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.456 0.739 306 496 6364 18388 609 0.00364 12188 0.00373 -1.974 31.55
NR1H2::RXRA MA0115.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 27.878 0.445 4 798 99 24653 4 3.69E-05 100 4.72E-05 -2.091 0.902
Myc MA0147.1 Zipper-Type Helix-Loop-Helix vertebrates 11.157 0.686 366 436 8288 16464 925 0.00502 18476 0.00513 -2.131 27.179
GABPA MA0062.2 Winged Helix-Turn-Helix Ets vertebrates 13.335 0.647 418 384 9355 15397 1049 0.00626 20927 0.0064 -2.248 35.475
MIZF MA0131.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.197 0.61 91 711 2080 22672 118 0.000641 2497 0.000694 -2.756 5.883
PLAG1 MA0163.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 19.352 0.798 91 711 1971 22781 117 0.000889 2462 0.000958 -3.016 7.429
TP53 MA0106.1 Zinc-coordinating Loop-Sheet-Helix vertebrates 26.239 0.603 0 802 8 24744 0 0 8 4.45E-06 -3.036 0
PPARG MA0066.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.365 0.523 2 800 62 24690 2 2.17E-05 64 3.56E-05 -3.214 0.509
RXRA::VDR MA0074.1 Zinc-coordinating Hormone-nuclear Receptor vertebrates 20.451 0.527 17 785 453 24299 20 0.000163 475 0.000198 -3.413 1.174
SP1 MA0079.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 11.129 0.82 559 243 12391 12361 4015 0.0218 79797 0.0222 -3.46 64.552
NHLH1 MA0048.1 Zipper-Type Helix-Loop-Helix vertebrates 14.132 0.674 261 541 5783 18969 479 0.00312 9874 0.00329 -4.075 19.385
Myf MA0055.1 Zipper-Type Helix-Loop-Helix vertebrates 15.914 0.609 428 374 10157 14595 1348 0.00878 27519 0.00918 -5.609 26.549
Klf4 MA0039.2 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 12.618 0.771 577 225 13645 11107 4418 0.024 88731 0.0247 -5.863 49.321
Tcfcp2l1 MA0145.1 Other CP2 vertebrates 11.65 0.609 445 357 10591 14161 1574 0.012 32190 0.0125 -6.823 27.865
INSM1 MA0155.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 14.862 0.667 331 471 7588 17164 835 0.00544 17685 0.0059 -8.104 22.059
znf143 MA0088.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 17.541 0.53 54 748 1301 23451 58 0.00063 1473 0.000819 -8.973 3.145
Zfx MA0146.1 Zinc-coordinating BetaBetaAlpha-zinc finger vertebrates 13.077 0.749 429 373 9872 14880 1587 0.0121 33238 0.0129 -10.427 31.938


Interesting that lots of homeobox genes show up. Also, SRY (a Y-chromosomal gene responsible for male sex determination). AR is there, lots of FOX genes, AP1, STATs, NF-kB, and more.

Also, look at that region on Chr1 near TARDBP, one of the most significant AGA risk locuses:

http://s33.postimg.org/unmt2nf5b/rs12565727.png

In the Chew paper, they show four contiguous genes in that region are upregulated in balding DPCs, including MTOR (they call it "FRAP1", which is another name for the MTOR gene). I was investigating mTOR before I was even aware of this, so it was kind of cool to see that. But anyway, I think this corroborates the idea that mTOR is a key player in AGA pathology.



Yeah, I think oxidative stress plays a critical role not only in inducing senescence, but also in progressively increasing androgen sensitivity. For example, p38 MAPK is a major oxidative stress-induced senescence pathway, and its downstream target HSP27 can stabilize AR and therefore increase AR protein levels and androgen sensitivity (Zoubeidi et. al, 2007 (http://cancerres.aacrjournals.org/content/67/21/10455.long)). p38 MAPK also produces a lot of inflammatory cytokines (it plays a role in SASP), so maybe some of the inflammatory part of AGA is because of that pathway. Also, you mentioned Twist1 (another AGA risk gene) upregulating AR. Look at this (http://www.ncbi.nlm.nih.gov/pubmed/19802001):



So these factors might cooperate in a vicious positive feedback loop, where once the genetic network hits a certain tipping point, it gains momentum and progresses toward the inevitable.

From where was the 'top 1000 genes in balding DPCs' from?

TheKingofFighters
06-06-2016, 05:54 PM
Inbeforethecure:

This is the holy bible.

http://ctdbase.org/detail.go?type=gene&acc=2475&view=ixn for mTOR(and all other genes)

TheKingofFighters
06-06-2016, 06:35 PM
IMO, I have come to the conclusion that we have 2 factors causing AGA:

1)The prominence of androgenic factors instead of estrogenic 1s in the balding scalp(likely involving some androgen pathway-independent factors as well)
2)Oxidative stress


Estrogenic signalling involves oxidation. Perhaps while Estradiol is(likely) part of the solution to AGA- there's still another half that is required to regrow hair- and this requires a certain factor to neutralise the oxidation brought on by estrogenic and androgenic signalling.
Without oxidative elements in the first place(like STAT3 involving il-6 in NFKB)- hair growth cannot happen- yet without anti-oxidative elements to neutralise that oxidative element - hair cannot grow further and die off.

TheKingofFighters
06-06-2016, 08:04 PM
inbeforethecure:

If we were to look@ page 21 of the study- the only https://en.wikipedia.org/wiki/Chemokine gene that we can see that appears in the ENTIRE list of downregulated genes in balding scalp(when compared to non-balding scalp) for vasculature- is https://en.wikipedia.org/wiki/Stromal_cell-derived_factor_1 aka CXCL12. This means this gene is extremely crucial for promoting hair growth.

Dihydrotestosterone results in decreased expression of CXCL12 mRNA
Dihydrotestosterone results in decreased expression of CXCL12 protein

Estradiol results in increased expression of CXCL12 mRNA
Estradiol results in increased expression of CXCL12 protein
Estrogens results in increased expression of CXCL12 mRNA

Oxygen deficiency results in increased expression of CXCL12 mRNA
Oxygen deficiency results in increased expression of CXCL12 protein

Valproic Acid results in decreased expression of CXCL12 mRNA
Valproic Acid results in increased expression of CXCL12 mRNA

butyraldehyde results in increased expression of CXCL12 mRNA

InBeforeTheCure
06-07-2016, 12:11 AM
From where was the 'top 1000 genes in balding DPCs' from?

It's from the Chew/Philpott study (accession GSE66663 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66663) for untreated cells, GSE66664 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66664) for DHT-treated cells).


Inbeforethecure:

This is the holy bible.

http://ctdbase.org/detail.go?type=gene&acc=2475&view=ixn for mTOR(and all other genes)

Really cool site, thanks. And about mTOR...I forgot to mention in my last post that since mTORC1 inhibits autophagy, overactivation of mTORC1 could cause mitochondrial damage and consequent oxidative stress over time. So perhaps mTORC1 and mTORC2 are both implicated in AGA.


IMO, I have come to the conclusion that we have 2 factors causing AGA:

1)The prominence of androgenic factors instead of estrogenic 1s in the balding scalp(likely involving some androgen pathway-independent factors as well)
2)Oxidative stress

One of the interesting thing about estrogen is that it has specific effects on different types of hair follicles -- it suppressed facial hair growth but promotes head hair growth. This is different from say Minoxidil, which promotes hair growth everywhere.

I would say that the most likely barrier to regrowing hair would be degeneration and senescence of dermal papilla cells, and possibly increased androgen sensitivity due to AR upregulation, increased activity of co-activators like HSP27, and post-translational modifications.


Estrogenic signalling involves oxidation. Perhaps while Estradiol is(likely) part of the solution to AGA- there's still another half that is required to regrow hair- and this requires a certain factor to neutralise the oxidation brought on by estrogenic and androgenic signalling.
Without oxidative elements in the first place(like STAT3 involving il-6 in NFKB)- hair growth cannot happen- yet without anti-oxidative elements to neutralise that oxidative element - hair cannot grow further and die off.

Yeah, the intricate systems of cross-talk between different pathways in hair follicles (and other systems) are fascinating. And I remember some people talking about how, if you want to induce new follicles, you need Jak-Stat pathway (and therefore not to use Jak inhibitors when trying to do that).


inbeforethecure:

If we were to look@ page 21 of the study- the only https://en.wikipedia.org/wiki/Chemokine gene that we can see that appears in the ENTIRE list of downregulated genes in balding scalp(when compared to non-balding scalp) for vasculature- is https://en.wikipedia.org/wiki/Stromal_cell-derived_factor_1 aka CXCL12. This means this gene is extremely crucial for promoting hair growth.

Dihydrotestosterone results in decreased expression of CXCL12 mRNA
Dihydrotestosterone results in decreased expression of CXCL12 protein

Estradiol results in increased expression of CXCL12 mRNA
Estradiol results in increased expression of CXCL12 protein
Estrogens results in increased expression of CXCL12 mRNA

Oxygen deficiency results in increased expression of CXCL12 mRNA
Oxygen deficiency results in increased expression of CXCL12 protein

Valproic Acid results in decreased expression of CXCL12 mRNA
Valproic Acid results in increased expression of CXCL12 mRNA

butyraldehyde results in increased expression of CXCL12 mRNA

Here's the entire list of expression levels of CXCLs in balding DPCs.

ILMN_1779234 CXCL6 2.176765229
ILMN_2161577 CXCL6 1.772099149
ILMN_1682636 CXCL2 1.421599429
ILMN_1787897 CXCL1 1.001257032
ILMN_1791447 CXCL12 0.452343235
ILMN_1689111 CXCL12 0.424927863
ILMN_1728478 CXCL16 0.298548249
ILMN_1791759 CXCL10 0.291211017
ILMN_1752562 CXCL5 0.212344214
ILMN_1803825 CXCL12 0.205825531
ILMN_2171384 CXCL5 0.118066746

So CXCL6 and CXCL2 are upregulated, CXCL1 is unchanged, while CXCL12, CXCL16, CXCL10, and CXCL5 are downregulated. But I get lost when it comes to the complex details and interactions of several thousand genes -- that's why I'm playing with computational approaches to analyzing these networks. :p

InBeforeTheCure
06-07-2016, 07:17 AM
Another ROS scavenger and FoxO target gene is SOD2. There are three SOD2 transcripts, and all three are underexpressed in balding DPCs (47.2%, 28.7%, and 27.0% expression compared to non-balding DPCs in untreated cells).

ILMN_2336781 SOD2 0.472452155
ILMN_2406501 SOD2 0.286869356
ILMN_1792922 SOD2 0.269849418

BAB-A shows an interesting periodic expression pattern when treated with DHT, which would be expected based on the mechanism I described earlier. There's also a slow overall reduction over time.

http://s32.postimg.org/5er6asa2d/sod2a.png

BAB-B also oscillates, but with a longer and uneven period:

http://s32.postimg.org/xdlc1nbp1/sod2b.png

BAB-C drops precipitously at the start and has no clear oscillation pattern (but perhaps a pattern would be apparent with more frequent measurements?):

http://s32.postimg.org/90wznfgfp/sod2c.png

The non-balding DPCs also fluctuate. For example, here's BAN-A:

http://s32.postimg.org/bgyt19yid/sod2a2.png

The steep drop-off in SOD2 in each case happens within 15-30 minutes, which suggests that AR is acting through a non-genomic pathway, I suppose? So maybe the pathway shown here which acts through the Akt/mTOR/FoxO axis:

http://lsresearch.thomsonreuters.com/static/maps/2203_map.png

Another things is that AR binding to beta-catenin might also inhibit FoxO-mediated transcription, since FoxO uses beta-catenin as a co-activator when cells are under stress.

TheKingofFighters
06-07-2016, 07:40 AM
ILMN_1779234 CXCL6 2.176765229
ILMN_2161577 CXCL6 1.772099149
ILMN_1682636 CXCL2 1.421599429
ILMN_1787897 CXCL1 1.001257032
ILMN_1791447 CXCL12 0.452343235
ILMN_1689111 CXCL12 0.424927863
ILMN_1728478 CXCL16 0.298548249
ILMN_1791759 CXCL10 0.291211017
ILMN_1752562 CXCL5 0.212344214
ILMN_1803825 CXCL12 0.205825531
ILMN_2171384 CXCL5 0.118066746

simplified:

CXCL6:

Ascorbic Acid deficiency results in increased expression of CXCL6 mRNA
Ascorbic Acid results in decreased expression of CXCL6 mRNA

CXCL2:

Estradiol affects the expression of CXCL2 mRNA
Estradiol inhibits the reaction [Halothane results in increased expression of CXCL2 mRNA]
Estradiol results in decreased expression of CXCL2 mRNA
fulvestrant inhibits the reaction [Estradiol inhibits the reaction [Halothane results in increased expression of CXCL2 mRNA]

butyraldehyde results in increased expression of CXCL2 mRNA

CXCL16:

lysophosphatidic acid results in increased expression of CXCL16 protein https://en.wikipedia.org/wiki/LPAR6

Valproic Acid results in increased expression of CXCL16 mRNA


CXCL10:

tofacitinib inhibits the reaction [IFNG protein results in increased expression of CXCL10 mRNA]
tofacitinib results in decreased expression of CXCL10 mRNA
tofacitinib results in decreased secretion of CXCL10 protein <== I have already trialled Tofacitinib 2 years back. It doesnt work and made my scalp very itchy. a possible reason could be that the Th response was swifted to Th2.

Valproic Acid results in increased expression of CXCL10 mRNA

Quercetin results in decreased expression of CXCL10 mRNA <== same goes for Quecertin and Resveratrol- they are double-edged swords.
Quercetin results in decreased secretion of CXCL10 protein

resveratrol results in decreased expression of CXCL10 mRNA
resveratrol results in decreased expression of CXCL10 protein

Ethanol results in increased expression of CXCL10 mRNA

butyraldehyde results in increased expression of CXCL10 mRNA

Estradiol results in increased expression of CXCL10 mRNA
Estradiol results in increased expression of CXCL10 protein

Ascorbic Acid deficiency results in increased expression of CXCL10 mRNA
Ascorbic Acid results in decreased expression of CXCL10 mRNA







CXCL5:

Antirheumatic Agents results in decreased expression of CXCL5 mRNA <== Sulfasalazine and Cox2 inhibitors are some examples. Thus, they are double-edged swords becos they down both pro-hair growth and pro-hair loss chemokine ligands.

Estradiol results in increased expression of CXCL5 mRNA

butyraldehyde results in increased expression of CXCL5 mRNA

Valproic Acid results in decreased expression of CXCL5 mRNA
Valproic Acid results in increased expression of CXCL5 mRNA

TheKingofFighters
06-07-2016, 08:33 AM
Another ROS scavenger and FoxO target gene is SOD2. There are three SOD2 transcripts, and all three are underexpressed in balding DPCs (47.2%, 28.7%, and 27.0% expression compared to non-balding DPCs in untreated cells).

ILMN_2336781 SOD2 0.472452155
ILMN_2406501 SOD2 0.286869356
ILMN_1792922 SOD2 0.269849418

BAB-A shows an interesting periodic expression pattern when treated with DHT, which would be expected based on the mechanism I described earlier. There's also a slow overall reduction over time.

http://s32.postimg.org/5er6asa2d/sod2a.png

BAB-B also oscillates, but with a longer and uneven period:

http://s32.postimg.org/xdlc1nbp1/sod2b.png

BAB-C drops precipitously at the start and has no clear oscillation pattern (but perhaps a pattern would be apparent with more frequent measurements?):

http://s32.postimg.org/90wznfgfp/sod2c.png

The non-balding DPCs also fluctuate. For example, here's BAN-A:

http://s32.postimg.org/bgyt19yid/sod2a2.png

The steep drop-off in SOD2 in each case happens within 15-30 minutes, which suggests that AR is acting through a non-genomic pathway, I suppose? So maybe the pathway shown here which acts through the Akt/mTOR/FoxO axis:

http://lsresearch.thomsonreuters.com/static/maps/2203_map.png

Another things is that AR binding to beta-catenin might also inhibit FoxO-mediated transcription, since FoxO uses beta-catenin as a co-activator when cells are under stress.

Estradiol results in increased activity of SOD2 protein
Estradiol results in increased expression of and results in increased activity of SOD2 protein
Estradiol results in increased expression of SOD2 mRNA
Estradiol results in increased expression of SOD2 protein

TheKingofFighters
06-07-2016, 08:41 AM
the angle im looking at is there must be some causative ROS-related gene(s) deficient in AGA that work(s) hand-in-hand with Estradiol(which we are already lacking in) to grow hair.

So it's Estradiol + ? =hair. Estradiol by itself is not enough. I have 1 gram of it in my fridge(and the dosage is in the mcgs/ml of vehicle).

I have not seen appreciable results 1 despite trying it out for weeks. It brings on numerous sides like gyno- though IMO, i assume this has something to do with the vehicle itself that results in more systemic penetration instead of remaining in the scalp.

TheKingofFighters
06-07-2016, 08:58 AM
Estradiol:

http://i66.tinypic.com/2z9i5it.jpg

http://i68.tinypic.com/2ql72pe.jpg

The powder is not in a conventional 'powdery' form- it's in a crystaline state that resembles table sugar

TheKingofFighters
06-07-2016, 09:42 AM
inbeforethecure:

Im not too sure about minoxidil 'growing hair everywhere' it doesnt seems to have any noticeable results on my scalp at all- while it did help grow my eyebrows

http://s32.postimg.org/3m5ezs581/CAM00411.jpg (http://postimg.org/image/3m5ezs581/)raw powder is a conventional, slightly bitter-tasting form

http://s32.postimg.org/xzf3fia9d/CAM00410.jpg (http://postimg.org/image/xzf3fia9d/)BTW, I should mention that SARMS like Ostarine still causes hairloss despite 'not affecting non-muscle tissues'. Perhaps muscle layers in the scalp are a factor to AGA? It gves me scalp itch everytime i use it:

http://s32.postimg.org/40ljifgc1/CAM00408.jpg (http://postimg.org/image/40ljifgc1/) helps alleviate oxidative stress- but it stop b-catenin. So again, ROS is defnitely a factor in AGA.
http://s32.postimg.org/op083q5wx/CAM00409.jpg (http://postimg.org/image/op083q5wx/)B2 adrenaagic agonists like Bambuterol are VERY anabolic(via cAMP upregulation). But I found that the more buffed up i became- the more hair i loss. and as mentioned before. Im not too sure about this 1 on whether it's helping or causing hairloss.

http://s32.postimg.org/5ndibwm0h/CAM00412.jpg (http://postimg.org/image/5ndibwm0h/)WORSENED my hairloss- it also gave me body odour and severe scalp itch. Something about the GABA receptors as well. It could be the N type voltage-gated calcium channels involved too.

TheKingofFighters
06-07-2016, 10:02 AM
Inbeforethecure:

http://s32.postimg.org/v8n0r1s35/CAM00413.jpg (http://postimg.org/image/v8n0r1s35/)helps my gyno. But the problem is while it inhibits DKK1;

Clomiphene results in decreased expression of DKK1 protein

http://ctdbase.org/detail.go?type=chem&acc=D002996&view=ixn

it worsens my hairloss and increased sebum secretion. This stuff agonises/antagonises Estrogen receptors, depending on the tissue. So my guess that it's a very good indicator that Estrogen receptors are deeply involved with AGA.

http://s32.postimg.org/kf9jio6lt/CAM00414.jpg (http://postimg.org/image/kf9jio6lt/)caused me whole body itch where there's hair- but amazingly, it doesnt seems to bother my scalp. It's an Estrogen receptor Beta agonist. I stopped this becos i switched to Estradiol itself.

http://s32.postimg.org/5yy9rd20h/CAM00415.jpg (http://postimg.org/image/5yy9rd20h/)increased sebum secretion and itch, despite being an anti-inflammatory. My guess tells me that Th response switches are caused by https://en.wikipedia.org/wiki/Cannabinoid_receptor receptors- in the context of AGA. That's why Tofacitinib(i binned it already) didnt work for me. Its about the appropriatehttps://en.wikipedia.org/wiki/Chemokine ligands in the scalp that brings hair growth. misexpress the wrong 1s and AGA occurs(as seen in the diagram u've linked)

SuicidalTraveler
06-07-2016, 11:47 AM
Inbeforethecure:

http://s32.postimg.org/v8n0r1s35/CAM00413.jpg (http://postimg.org/image/v8n0r1s35/)helps my gyno. But the problem is while it inhibits DKK1;

Clomiphene results in decreased expression of DKK1 protein

http://ctdbase.org/detail.go?type=chem&acc=D002996&view=ixn

it worsens my hairloss and increased sebum secretion. This stuff agonises/antagonises Estrogen receptors, depending on the tissue. So my guess that it's a very good indicator that Estrogen receptors are deeply involved with AGA.

http://s32.postimg.org/kf9jio6lt/CAM00414.jpg (http://postimg.org/image/kf9jio6lt/)caused me whole body itch where there's hair- but amazingly, it doesnt seems to bother my scalp. It's an Estrogen receptor Beta agonist. I stopped this becos i switched to Estradiol itself.

http://s32.postimg.org/5yy9rd20h/CAM00415.jpg (http://postimg.org/image/5yy9rd20h/)increased sebum secretion and itch, despite being an anti-inflammatory. My guess tells me that Th response switches are caused by https://en.wikipedia.org/wiki/Cannabinoid_receptor receptors- in the context of AGA. That's why Tofacitinib(i binned it already) didnt work for me. Its about the appropriatehttps://en.wikipedia.org/wiki/Chemokine ligands in the scalp that brings hair growth. misexpress the wrong 1s and AGA occurs(as seen in the diagram u've linked)

Yep. Estrogen receptor beta is really great for hair. It's protective. Estrogen receptor alpha is the one that harms the hair and causes gyno. When ER-alpha increased for me, I've gotten a lot more body hair but lost hair on my scalp. I've also developed very mild gyno.

Where have you got your Clomifene citrate?

Are you selling it if you don't use it anymore? Do you have any e-mail from where of I can contact you?

SuicidalTraveler

TheKingofFighters
06-07-2016, 11:57 AM
go to HGR

SuicidalTraveler
06-07-2016, 12:00 PM
Ok. :)

TheKingofFighters
06-07-2016, 12:42 PM
inbeforethecure:

If we look@ page 21, there are a few genes that are significantly differentiated between balding and non-balding scalp DPCs:

1)COL18A1 16.750 15.675 <== downregulated in balding scalp when compared to non-balding scalp by more than a whopping 15 fold

Estradiol promotes the reaction [ESR2 protein affects the expression of COL18A1 mRNA]
Estradiol results in increased expression of COL18A1 mRNA

This means the https://en.wikipedia.org/wiki/Estrogen_receptor_beta (aka ESR2) is downregulated in balding scalp. Also, the ESR2 inhibits AR's expression.

2)DHCR7 23.464 20.353 <=== more than 20 fold

Acetaminophen results in decreased expression of DHCR7 mRNA <=== Panadol
Estradiol results in increased expression of DHCR7 mRNA
Caffeine results in decreased expression of DHCR7 mRNA
Copper results in decreased expression of DHCR7 mRNA <== we've got copper toxicity in the balding scalp- and it's 1 of the effectors in Parkinson's
Ethanol results in increased expression of DHCR7 mRNA

3)HTATIP2 6.764 6.038 <== more than 6 fold

Valproic Acid results in increased expression of HTATIP2 mRNA
epigallocatechin gallate results in decreased expression of HTATIP2 mRNA <=== EGCG
Finasteride results in increased expression of HTATIP2 mRNA
Flutamide results in increased expression of HTATIP2 mRNA
Antirheumatic Agents results in decreased expression of HTATIP2 mRNA

4)SCG2 5.365 5.938 <=== more than 5 fold

Valproic Acid results in increased expression of SCG2 mRNA
8-Bromo Cyclic Adenosine Monophosphate results in increased expression of SCG2 mRNA <== cAMP (Bambuterol, Forskolin, etc)

5)COL1A1 5.069 4.926 <=== Collagen type 1, by around 5 fold

Tons of common chemicals ups it

TheKingofFighters
06-07-2016, 12:54 PM
On Parkinson's and AGA

17 43,924,219 rs123731246 17q21.31 [SPPL2C]--MAPT MAPT down MAPT down MAPT down 1.930 1.835 <=== this gene is downregulated in balding scalp

Copper results in decreased expression of MAPT mRNA
Copper results in increased phosphorylation of MAPT protein(phosphorylation = silencing, for this gene)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364959/

Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases

Abstract
Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10⁻⁹-1.01×10⁻¹²). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10⁻³). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10⁻⁸⁸]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

Parkinson's disease is the second most common neurodegenerative disorder with a prevalence of one percent in individuals that are over 60 years old [40]. Despite the often-reported higher prevalence of Parkinson's disease in men, as compared to women [40], there are no previous reports investigating the relationship between AGA and Parkinson's disease. This novel association between Parkinson's disease and early-onset AGA indicated that there could be a shared genetic or environmental cause for both conditions.

[41], although most of the patients affected by drug-induced hair loss are females [41]. As noted above, a greater incidence of Parkinson's disease has been reported in elderly men than in women [40] and androgen mediated neurotoxicity has been proposed to contribute to the gender bias in Parkinson's disease [42]. Since this association is entirely novel, it is unlikely that our results have arisen due to recall bias. In addition, the AGA cases in 23andMe study had an age of onset less than 40 years old. The mean age at diagnosis of Parkinson's disease is 70.5 years [43]. Therefore it is highly unlikely that Parkinson's disease occurred before AGA, as defined in the 23andMe study. At present we are unaware of any prospective Parkinson's disease cohorts having collected AGA data to further explore this relationship, and our evidence provides rationale to undertake such studies.

= Early onset AGA first, then onset of Parkinson's during old age- mostly in men

Ascorbic Acid inhibits the reaction [cyanoginosin LR results in increased phosphorylation of MAPT protein] <== Vitamin C inhibits the silencing of MAPT

Aldehydes results in increased expression of MAPT mRNA <== Alchohols increases MAPT

Estradiol results in increased expression of MAPT protein
Estradiol results in increased phosphorylation of MAPT protein

Caffeine results in decreased phosphorylation of MAPT protein

fulvestrant results in decreased expression of MAPT protein <== Antiestrogens downs MAPT

Ketamine results in increased phosphorylation of MAPT protein <== so balding ketamine abusers should stop for good

Valproic Acid results in increased expression of MAPT

Most antioxidants increases MAPT

TheKingofFighters
06-07-2016, 01:14 PM
It also makes sense that Ketamine is bad for hair in AGA individuals because Parkinson's signature symptom is hypolocomotion aka https://en.wikipedia.org/wiki/Hypoactivity (aka 'robot-ification)- something which Ketamine induces

Anton5redA
06-07-2016, 03:23 PM
I read this thread about 7 pages back, so TheKingofFighters, it seems like Ethanol is a bad vehicle, Tofacitinib is counter-productive in AGA and Estradiol tends to be absorbed systemically and activates the dormant potential boobies to wake-up and want to see the light of day, but what is it that you would recommend, at this time, for us to use or quit using?

My current topical regimen is: Minoxidil 3%, Finasteride 0.05%, Emu oil, Pygeum Africanum, Litsea Glutinosa, Green Tea extract and Oleuropein all dissolved in water, Ethanol and Propylene Glycol. Plus occasional Ketoconazole every other day.

BTW I noticed more terminal hair over the two months while on this treatment but think that there is just too much in my mix.

TheKingofFighters
06-07-2016, 09:50 PM
inbeforethecure:

on Stat3:

based on the data from the study regarding the https://en.wikipedia.org/wiki/Chemokine, my opinion is we need the right kind of inflammation to grow hair.

CXCl2 and CXCl6 is probably the 'wrong' type of inflammatory ligands that are upregulated in AGA-affected scalps.

What is ur take on this?

TheKingofFighters
06-07-2016, 10:18 PM
ILMN_1779234 CXCL6 2.176765229
ILMN_2161577 CXCL6 1.772099149
ILMN_1682636 CXCL2 1.421599429
ILMN_1787897 CXCL1 1.001257032
ILMN_1791447 CXCL12 0.452343235
ILMN_1689111 CXCL12 0.424927863
ILMN_1728478 CXCL16 0.298548249
ILMN_1791759 CXCL10 0.291211017
ILMN_1752562 CXCL5 0.212344214
ILMN_1803825 CXCL12 0.205825531
ILMN_2171384 CXCL5 0.118066746

simplified:

CXCL6:

Ascorbic Acid deficiency results in increased expression of CXCL6 mRNA
Ascorbic Acid results in decreased expression of CXCL6 mRNA

CXCL2:

Estradiol affects the expression of CXCL2 mRNA
Estradiol inhibits the reaction [Halothane results in increased expression of CXCL2 mRNA]
Estradiol results in decreased expression of CXCL2 mRNA
fulvestrant inhibits the reaction [Estradiol inhibits the reaction [Halothane results in increased expression of CXCL2 mRNA]

butyraldehyde results in increased expression of CXCL2 mRNA

CXCL16:

lysophosphatidic acid results in increased expression of CXCL16 protein https://en.wikipedia.org/wiki/LPAR6

Valproic Acid results in increased expression of CXCL16 mRNA


CXCL10:

tofacitinib inhibits the reaction [IFNG protein results in increased expression of CXCL10 mRNA]
tofacitinib results in decreased expression of CXCL10 mRNA
tofacitinib results in decreased secretion of CXCL10 protein <== I have already trialled Tofacitinib 2 years back. It doesnt work and made my scalp very itchy. a possible reason could be that the Th response was swifted to Th2.

Valproic Acid results in increased expression of CXCL10 mRNA

Quercetin results in decreased expression of CXCL10 mRNA <== same goes for Quecertin and Resveratrol- they are double-edged swords.
Quercetin results in decreased secretion of CXCL10 protein

resveratrol results in decreased expression of CXCL10 mRNA
resveratrol results in decreased expression of CXCL10 protein

Ethanol results in increased expression of CXCL10 mRNA

butyraldehyde results in increased expression of CXCL10 mRNA

Estradiol results in increased expression of CXCL10 mRNA
Estradiol results in increased expression of CXCL10 protein

Ascorbic Acid deficiency results in increased expression of CXCL10 mRNA
Ascorbic Acid results in decreased expression of CXCL10 mRNA







CXCL5:

Antirheumatic Agents results in decreased expression of CXCL5 mRNA <== Sulfasalazine and Cox2 inhibitors are some examples. Thus, they are double-edged swords becos they down both pro-hair growth and pro-hair loss chemokine ligands.

Estradiol results in increased expression of CXCL5 mRNA

butyraldehyde results in increased expression of CXCL5 mRNA

Valproic Acid results in decreased expression of CXCL5 mRNA
Valproic Acid results in increased expression of CXCL5 mRNA

On Zinc and the chemokines discussed:

The AGA-downregulated chemokines:

Zinc deficiency results in decreased expression of CXCL12 mRNA

Zinc deficiency results in decreased expression of CXCL10 mRNA

Zinc deficiency results in increased expression of CXCL5 mRNA
Zinc deficiency results in increased expression of CXCL5 protein
Zinc chloride results in increased expression of CXCL5 mRNA
Zinc Sulfate results in increased expression of CXCL5 mRNA

Overall = Zinc upregulates the pro-hair growth inflammatory chemokines

The AGA-upregulated chemokines:

1)Zinc deficiency results in increased expression of CXCL2 mRNA
Zinc Sulfate results in decreased expression of CXCL2 mRNA
Zinc Sulfate results in increased expression of CXCL2 mRNA

2)zinc chloride results in decreased expression of CXCL6 mRNA

'Because CXCL1 and CXCL2 are known to mediate neutrophil influx into tissues (33), we next quantified their mRNA expression in epidermal sheets obtained from ZA and ZD mice after vehicle or CrO application in vivo. Quantitative real-time PCR demonstrated that Zn deficiency resulted in a significant increase of Cxcl1 mRNA 4 and 24 hours after CrO exposure and Cxcl2 mRNA at 4 hours (Figure 3, A and B). The same enhancing effects of Zn deficiency for the chemokine mRNA expression were observed when mice were treated with BAC (Supplemental Figure 5A). In addition, in vitro exposure of Pam-212 keratinocytes to CrO rapidly induced Cxcl1 and Cxcl2 mRNA (Figure 3C). When TPEN was added to the cultures, significant further augmentation of CrO-induced chemokine mRNA accumulation was observed, which was not seen with TPEN alone (Figure 3C). Similar results were obtained in BAC-treated keratinocytes (Supplemental Figure 5B). Furthermore, consistent with recent findings (34), exogenous ATPγS induced Cxcl1 and Cxcl2 mRNA expression by ZA Pam-212 keratinocytes (Figure 3D). Together, our results suggest that Zn deficiency indirectly augments Cxcl1 and Cxcl2 gene expression in CrO-stimulated keratinocytes via increased ATP release, as observed in Figure 2. Interestingly, Zn deficiency further augmented ATPγS-induced Cxcl2, but not Cxcl1, mRNA expression (Figure 3D)'

https://www.jci.org/articles/view/58618

Overall = Zinc downregulates the pro-hair loss inflamamtory chemokines

TheKingofFighters
06-07-2016, 10:29 PM
inbeforethecure:

so based on the data, Vitamin C and Zinc would be 2 simple chemicals for aiding hair growth- probably influenicng the ROS pathway.

forgottenwarrior
06-07-2016, 11:31 PM
I've read this thread and can certainly say that zinc plays a big role in androgen metabolism along with the expression of estrogen receptors.

http://www.ncbi.nlm.nih.gov/pubmed/8613886

We studied the effects of zinc deficiency on hepatic androgen metabolism and aromatization, androgen and estrogen receptor binding, and circulating levels of reproductive hormones in freely fed, pair-fed and zinc deficient rats. Hepatic conversion of testosterone to dihydrotestosterone was significantly less, but formation of estradiol from testosterone was significantly greater in rats fed the zinc-deficient diet compared with freely fed and pair-fed control rats. There were significantly lower serum concentrations of luteinizing hormone, estradiol and testosterone in rats fed the zinc-deficient diet. No difference in the concentration of serum follicle-stimulating hormone was observed between the zinc-deficient group and either control group. Scatchard analyses of the receptor binding data showed a significantly higher level of estrogen receptor in zinc-deficient rats (36.6 +/- 3.4 fmol/mg protein) than in pair-fed controls (23.3 +/- 2.2 fmol/mg protein) and a significantly lower level of androgen binding sites in rats fed the zinc-deficient diet (6.7 +/- 0.7 fmol/mg protein) than in pair-fed control rats (11.3 +/- 1.2 fmol/mg protein). There were no differences in hepatic androgen and estrogen receptor levels between freely fed and pair-fed controls. These findings indicate that zinc deficiency reduces circulating luteinizing hormone and testosterone concentrations, alters hepatic steroid metabolism, and modifies sex steroid hormone receptor levels, thereby contributing to the pathogenesis of male reproductive dysfunction.


This is not to say Zinc is bad at all but rather, needed to keep masculinity in check for us men and prevent gyno and other unwanted effects from estradiol.

The other thing I wanted to bring up to attention was the possibility of microbes altering estrogen and androgen metabolism.

http://immortalhair.forumandco.com/t9616-dental-work-stopped-my-hair-loss

I've recently had dental work done, and will continue to do so as I'm not satisfied with the filling I was given since headaches have been continually plaguing me. They occur only on the side where the amalgam filled tooth was.

I would like to expand on the pathogen possibility later with how gut flora can influence hormones and such.

TheKingofFighters
06-07-2016, 11:55 PM
Estradiol results in increased activity of SOD2 protein
Estradiol results in increased expression of and results in increased activity of SOD2 protein
Estradiol results in increased expression of SOD2 mRNA
Estradiol results in increased expression of SOD2 protein

inbeforethecure:

[FOXO1 protein results in increased expression of SOD2 mRNA]

FOXO1's target gene is SOD2- to remove ROS and improve cell survival. I have read the zebrafish pax1/pax9 study. Like u've mentioned- it states pax1 and Foxo1's interaction increases during hypoxia.

It is highly like due to the 20p11 AGA locus that this interaction is altered- and this is further evident that FOX01's expression is only present in non-balding scalp DPCs

SuicidalTraveler
06-08-2016, 07:05 AM
How's it going with UPS?

Anton5redA
06-08-2016, 07:39 AM
Hi KinfofFighters,

Great, I've read about zinc oxide being used to decrease chronic inflammation and increase rate of healing in macerated skin (pressure ulcers, fresh scars etc). Having Zinc in the mix would probably increase chances of a follicle switching to terminal hair, with stemming from that chemokine production towards the goal of increasing follicle size. I think that the follicle itself needs to be nudged towards the expression and downregulation of genes aimed at increasing the keratin output of each hair follicle.

There is an article (http://www.hindawi.com/journals/ecam/2011/985345/) describing the use of the mixture of liposterolic extract of Serenoa repens (LSESr), its glycoside -( β-sitosterol) and two anti-inflammatory agents (carnitine and thioctic acid) in downregulating the CCL17, CXCL6 and LTB(4) associated with pathways which are involved in the inflammation and apoptosis in and around the AGA hair follicles. This shows that what I am doing, via a different regimen, probably hits the cytokines that you've mentioned, in the appropriate fashion (up or down).

I have observed that the new hair that have sprouted on my scalp over the last month are whisky white for the first 3 mm or so and get thicker and darker towards the base, but are growing at 30-60 degree angles. (different from the old 90-degree hair an inch or two away). I think that happens because dermis there is not thick-enough for their height. Hopefully it will thicken with time. My scalp dermis thinned out because of TNF-Alpha and other chronic catabolic inflammatory markers affecting it for years. (akin to corticosteroidal increase effect on apoptosis of keratinocytes, adipocytes and endothelial cells).

Releasing the downwards pressure of the bad inflammatory factors, both mentioned by you and yet-unrecognized, should allow re-generation of some terminal hair follicles to full capacity, even in the absence of the external up-regulation of pro-anabolic chemokines, as the scalp has some resilience and recoil-pressure to return to its earlier, hairier state.

I am not aware of any substances that would pin-pointedly increase the expression of anabolic genes in the follicle papillae. There are however VEGF-promoters and other bloodflow-increasers via the hypoxia-simulating stimulation, massage and microneedling we can resort to, once the bad inflammation is in check. The latter has been shown to do more for hair thickening than just improve circulation to the scalp.

I am not well-versed in the cell biology, despite a bachelors in the field, so I am not sure of almost everything, the more I learn, the less I know, ha ha. Same thing with medicine, which I have a doctorate in, but if you want to try out something new in growing hair, I might want to look into it.

However, I am not into gynecomastia for example, so estradiol is not gonna get anywhere as high of a concentration as you have tried.

Anton5redA
06-08-2016, 07:54 AM
Amalgam is an alloy 50% mercury, which stops elongation of microtubules, which are needed to maintain and grow nerve cells. Sooooo....
It is recommended to take DMSA or IV EDTA immediately prior to and after an amalgam filling extraction so as to avoid Central Nervous System (Headache, poor memory, sleep etc) side effects of the pieces of the filling (microscopic ) going into the stomach and getting absorbed.
Also the dental and cranial nerves suffer from the mercury vapors from drilling etc. but it should pass when mercury gets evenly distributed in the body, but do you really want that?
Not sure why HA is one-sided, maybe you do have a plaque on an artery like Middle Meningeal, that renders that bottleneck ore sensitive to transient bacterial LPS (although LPS is usually vasodilatory), or mercury, who knows? Better go get checked before a clot forms on the bacteria-roughened endothelium (if that is the case of course)

Oh yeah, also, there is more of an urgency to get checked, if you have ever had Rheumatic fever, prosthetic heart valve, or even any foreign surgical material or shrapnel in your body. Or if you have intermittent fevers, unless you are on immunosuppressants. Anyways, take my advice with a grain of salt.

TheKingofFighters
06-08-2016, 07:57 AM
Hi KinfofFighters,

Great, I've read about zinc oxide being used to decrease chronic inflammation and increase rate of healing in macerated skin (pressure ulcers, fresh scars etc). Having Zinc in the mix would probably increase chances of a follicle switching to terminal hair, with stemming from that chemokine production towards the goal of increasing follicle size. I think that the follicle itself needs to be nudged towards the expression and downregulation of genes aimed at increasing the keratin output of each hair follicle.

There is an article (http://www.hindawi.com/journals/ecam/2011/985345/) describing the use of the mixture of liposterolic extract of Serenoa repens (LSESr), its glycoside -( β-sitosterol) and two anti-inflammatory agents (carnitine and thioctic acid) in downregulating the CCL17, CXCL6 and LTB(4) associated with pathways which are involved in the inflammation and apoptosis in and around the AGA hair follicles. This shows that what I am doing, via a different regimen, probably hits the cytokines that you've mentioned, in the appropriate fashion (up or down).

I have observed that the new hair that have sprouted on my scalp over the last month are whisky white for the first 3 mm or so and get thicker and darker towards the base, but are growing at 30-60 degree angles. (different from the old 90-degree hair an inch or two away). I think that happens because dermis there is not thick-enough for their height. Hopefully it will thicken with time. My scalp dermis thinned out because of TNF-Alpha and other chronic catabolic inflammatory markers affecting it for years. (akin to corticosteroidal increase effect on apoptosis of keratinocytes, adipocytes and endothelial cells).

Releasing the downwards pressure of the bad inflammatory factors, both mentioned by you and yet-unrecognized, should allow re-generation of some terminal hair follicles to full capacity, even in the absence of the external up-regulation of pro-anabolic chemokines, as the scalp has some resilience and recoil-pressure to return to its earlier, hairier state.

I am not aware of any substances that would pin-pointedly increase the expression of anabolic genes in the follicle papillae. There are however VEGF-promoters and other bloodflow-increasers via the hypoxia-simulating stimulation, massage and microneedling we can resort to, once the bad inflammation is in check. The latter has been shown to do more for hair thickening than just improve circulation to the scalp.

I am not well-versed in the cell biology, despite a bachelors in the field, so I am not sure of almost everything, the more I learn, the less I know, ha ha. Same thing with medicine, which I have a doctorate in, but if you want to try out something new in growing hair, I might want to look into it.

However, I am not into gynecomastia for example, so estradiol is not gonna get anywhere as high of a concentration as you have tried.

Hi, if im interpreting it right, u're basically asking 'what should i use to regrow hair'.

I would gladly love to help u if i can, but unfortunately- i cant- simply because I do not know the answer myself. Estradiol is only part of the equation and i am still trying to analyse the study(the 1 in discussion here with inbeforethecure) and figure out a solution combo to AGA.

I CAN tell you what NOT to use though. Take note it's just a rough, cliff note I have made myself and there would probably be more changes as time goes on :

Bisphenol A ===> NO, becos it downs MAPT, PLCG2, LZTS1
Copper => NO ===> becos it downs MAPT
Quecertin => NO
Resveratrol => NO
VPA = NO becos it downs VEGFA, LXN
Genistein => NO
Pentanal => NO
Phthalates => NO, becos it downs MAPT, GAS7, NOG, BMP4 and ups FRAP1
Progesterone => NO, becos it downs MAPT, BMP4
PPAR Alpha => NO- becos it downs NOG, DIO2, GUCY1a3, PLCG2, IFI27 and ups FRAP1
PPAR Gamma => NO- becos it downs LXN and ups FRAP1
Calcitriol = NO- becos it downs GAS7, IFI27
cAMP => No- becos it downs BMP4
Finasteride = NO- becos it downs IFI27
Retinoids => NO becos it downs IFI27
Folic acid => becos it downs IFI27
Palm oil => NO becos it downs IFI27 and ups FRAP1
Melantonin => NO becos it ups FRAP1
Zinc = Ambiguous. Downs ARHGEF3

Anton5redA
06-08-2016, 08:04 AM
Thanks, I will look at the research for several of these in the Cliff note that are of interest to me, later, after work

TheKingofFighters
06-08-2016, 08:12 AM
Thanks, I will look at the research for several of these in the Cliff note that are of interest to me, later, after work


So it's:

Estradiol +? + ? in a topical vehicle of Ethanol?% Water?% + Peg40 Castor oil ?% + Polyquaternium-16 ?%(a modified form of K&B solution)

Never Estradiol alone- its just not enough. The vehicle composition is important too because we are gonna need 1 that allows Estradiol to stay in the scalp for as much as possible with minimum amounts going systemic- and keeping ethanol at the bare minimum

TheKingofFighters
06-08-2016, 08:59 AM
http://s33.postimg.org/qqurayve3/CAM00407.jpg (http://postimg.org/image/qqurayve3/) I used it for colouring my skin. Induces massive scalp itch.