Pax1/Foxa2- 1 of the primary genetic reasons why we balding men- are balding

[eldarlmario]

Originally posted by: summersnow

Hi Mario yes I've a curved spine which causes me to need to be more self aware of my poster an consently correct when out in public. Nothing worse than looking like a slouch. My neck clicks when I breathe deeply, prior to the clicking it crunches in the laying down position and I can press what feels like the first 1 to 5 discs nlin my neck in an out without much discomfort. When the neck clicks during the night through forced deep breathing the noise is very loud and resonates through my skull an feels quite good when it happens. Other than that it's the best I can explain it.


seems like i guessed that correctly when u said u had seizures

i had many, many times almost went into 1 when i turn my neck suddenly within a achievable normal degree(not extreme) and there's this 'snap' INSIDE my head(not neck) that felt like some nerve were being twisted i felt like fainting in that split second- and it takes place multiple time in a day.
not to mentioned the recurring tinnitus in my ears i get once in awhile that goes:

"eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee for a GOOD 3 mins non stop."

and i also have a serious TMJ problem)the joint between the mandible and cranium as in there's this 'click' sounds take takes place whenever i moved my jaws.

[eldarlmario]

plus i cant stand upright at all. doing so takes extra effort and even then i cant maintain it for long without placing strain on my lumbar and guess what? im only 30.

[eldarlmario]

atually the best way to disecribe that 'snap' in my head would be more like a psuedo-stroke that comes in less than 1 sec before disappearing which often send me into a panic attack- thinking to myself: wtf was going on?"

ok and u r the 3rd person with AGA that has a curved spine that i have spoken to(excluding myself- and i have a curved spine since elemntary school)

my right shoulder is higher than my left. and i have a huge tendancy to place all my weight on my right leg when standing in a stationary postion.

[eldarlmario]

H6 family homeobox 2 (inner ear and vestibular function) <===== i suspect this to be the culprit for the tinnitus. it's 1 of the genes that altered by the pax1/foxa2 balding/scoliosis haplotype

http://www.ncbi.nlm.nih.gov/gene/3167

[eldarlmario]

ok so looks like i would be getting topical Calcipotriol then:

1)Topical Calcipotriol 0.0005% generic premade ointment
2)Topical Valproic acid (undecided on the dosage) DIY vehicle
3)Topical Dinoprostone 0.05% generic premade ointment
4)Topical Verapamil 3% DIY vehicle
5)Topical Tretinoin 0.0005% DIY vehicle
in addtion to my present regime of RU1%(might be replaced with valproic acid since i have only ~800mg left of it) TM 0.125% DIY vehicle, Minoxidil Sulfate 20mg/day oral, Dut 0.25% DIY vehicle.

Total = 8 items for my planned regime. Good enough cos overstacking is always something i want to avoid.

evaluating GHK-Cu(bought a 10ml bottle from Ebay- does nothing noticeable yet), Sirt 1 Activator(kills itch, but it's expensive and i have only 400mg of it left) and Tacrolimus(likely out- thank god i spent only 6 bucks for 3 tubes of it).

Might be getting Montelukast

Im just pondering on how i can measure 20mcg/4ml to create 0.0005% Tretinoin. That's next to impossible without the necessary scientific measuring instruments.

This is an extremely useful gene/chemical search engine cum encyclopedia for those who wants to help out to look for small molecules of the remaining genes that are in question marks

http://ctdbase.org/detail.go;j...&type=chem&acc=D014635

[eldarlmario]

http://www.ncbi.nlm.nih.gov/pubmed/20489134

Processing of pro-B-type natriuretic peptide: furin and corin as candidate convertases.
Semenov AG1, Tamm NN, Seferian KR, Postnikov AB, Karpova NS, Serebryanaya DV, Koshkina EV, Krasnoselsky MI, Katrukha AG.
Author information
Abstract
BACKGROUND:
B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are the products of the enzyme-mediated cleavage of their precursor molecule, proBNP. The clinical significance of proBNP-derived peptides as biomarkers of heart failure has been explored thoroughly, whereas little is known about the mechanisms of proBNP processing. We investigated the role of 2 candidate convertases, furin and corin, in human proBNP processing.

METHODS:
We measured proBNP expression in HEK 293 and furin-deficient LoVo cells. We used a furin inhibitor and a furin-specific small interfering RNA (siRNA) to explore the implication of furin in proBNP processing. Recombinant proBNPs were incubated with HEK 293 cells transfected with the corin-expressing plasmid. We applied mass spectrometry to analyze the products of furin- and corin-mediated cleavage.

RESULTS:
Reduction of furin activity significantly impaired proBNP processing in HEK 293 cells. Furin-deficient LoVo cells were unable to process proBNP, whereas coexpression with furin resulted in effective proBNP processing. Mass spectrometric analysis revealed that the furin-mediated cleavage of proBNP resulted in BNP 1-32, whereas corin-mediated cleavage led to the production of BNP 4-32. Some portion of proBNP in the plasma of heart failure patients was not glycosylated in the cleavage site region and was susceptible to furin-mediated cleavage.

CONCLUSIONS:
Both furin and corin are involved in the proBNP processing pathway, giving rise to distinct BNP forms. The significance of the presence of unprocessed proBNP in circulation that could be cleaved by the endogenous convertases should be further investigated for better understanding BNP physiology.

Conclusion => We need to downregulate CORIN in order to get the FURIN-induced form of BNP- which is 1-32 BNP

Sept 2012 patent: Natriuretic Peptides shows terminal hair growth in weeks
Here is a clip from the patent. We have the full study @ PHG with all the pics from the study. BNP and CNP gel grew thick terminal hair in just weeks! join our discussions on the latest hairloss treatments, just PM lilpauly. OR you can look at the trx2 thread on here for the 800,000th time....

57] As is clear from the case tests described below, the treatment agent of the present invention containing a natriuretic peptide (NP) as an active ingredient can outstandingly improve alopecia areata, androgenetic alopecia, female pattern alopecia, seborrheic alopecia, alopecia pityroides, postpartum alopecia, senile alopecia, and cancer chemotherapy drug-induced alopecia. Furthermore, the treatment agent of the present invention can restore white hair to black hair or its original color. Moreover, in accordance with use of the treatment agent of the present invention, dandruff is decreased. Furthermore, the treatment agent of the present invention does not have side effects such as an itching sensation, irritation, and feminization, and there is no recurrence of alopecia areata and cancer chemotherapy drug-induced alopecia for at least half a year even if its use is stopped.

[0158] The treatment agent of the present invention can be anticipated to be useful as a very effective treatment drug for androgenetic alopecia, for which sufficient therapeutic effects cannot be obtained by the conventional minoxidil or finasteride, and alopecia areata, for which there are hardly any effective treatment methods. Furthermore, the treatment agent of the present invention has marked hair growth, hair restoration, and hair thickening effects for female pattern alopecia, seborrheic alopecia, alopecia pityroides, postpartum alopecia, senile alopecia, cancer chemotherapy drug-induced alopecia, and alopecia due to radiation exposure, for which there are hardly any therapies, can dramatically decrease the amount of hair falling out, and can prevent the progress of hair loss.

[0159] Moreover, the treatment agent of the present invention can convert miniaturized hair root into large hair root that grows terminal hair and can change the hair quality so that it is harder and thicker. Furthermore, the treatment agent of the present invention promotes hair growth of terminal hair, prolongs the growth phase, and increases long hair. Moreover, the treatment agent of the present invention promotes hair restoration and hair lengthening and speeds up the hair lengthening rate.

[0160] Furthermore, the treatment agent of the present invention can increase the number of hairs per hair follicle. The treatment agent of the present invention promotes hair growth and hair restoration in the frontal region or M-shaped site, which is intractable, and has a hair growth effect, hair restoration effect, and hair thickening effect for alopecia that is classified as Va, VI, or VII on the Hamilton-Norwood scale, which is wide area, severe androgenetic alopecia. The treatment agent of the present invention restores hair for alopecia areata and has the effect of preventing restored hair from falling out such that newly grown hair does not fall out after its application is stopped.


Some Results.

[0225] FIG. 41 A photographic diagram showing the therapeutic effect when a BNP gel was applied to a hair loss site of the crown and the frontal region of androgenetic alopecia case B16 test subject. The test subject faced downward in the photograph. P denotes the hair loss site before application, T1 denotes the hair loss site of the same site after 100 ?g/g BNP gel was applied twice a day for 3 weeks, and T2 denotes the hair loss site of the same site when the application of 100 ?g/g BNP gel was stopped after 3 weeks and from the next day 200 ?g/g BNP gel was applied twice a day for 2 weeks. In P hair was scattered in the hair loss site within the range encircled by the dotted line, whereas in T1 hair with a feeling of volume grew densely in a central part within the range encircled by the dotted line, and in T2 the hair grew more densely and the so-called M-shaped hair loss site disappeared. In the photograph of T2, the reason why a central part within the range encircled by the dotted line, the so-called O-shaped hair loss site, was conspicuous is because the photograph was taken from a camera angle directly above the crown such that the crown, which was the remaining hair loss site, could be seen well.

Results in Weeks!
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[eldarlmario]

From another person:


"BNP 32 is nothing new for some of baldy brothers

https://www.baldtruthtalk.com/...growth-in-weeks/page33

And by reading this tread it seems that it is problematic, high molecule weight - over 3k, short half-time, and no visible result...



Of top:



I cant wait for Hair Loss Congres 13-17 November which one of the main sponsor is Samumed, small company, which is having SM3554 in phase 2 trial - it is supposedly b-catenin agonist (just like VPA)



Originally Posted by Tomtom21 View Post

I really feel that samumed has got a product that at the very least will be an additional to add to our arsenal. I was looking at their additional round of phase 2 study with the punch biopsy. I was curious to see what exactly they were looking to evaluate from the tissue biopsy in terms of biomarkers. straight from the clinical trials page they are aiming to evaluate the following:



Change in nuclear expression of beta-catenin

Change in nuclear expression of Ki-67 in epidermis and hair follicles.

Change in Ki-67 index in epidermis and hair follicles



First off beta catenin, I believe we all understand at this point if we follow the thread that it has direct affect on wnt pathway and therefore blah blah blah. Basically it can be very important in reactivating our dead beat hair follicle cells that don't want to do their job anymore.

However, I was curious to look into the Ki-67 biomarker they were interested in. I looked at what exactly Ki-67 protein is for and straight from wikipedia:



"The Ki-67 protein (also known as MKI67) is a cellular marker for proliferation.[5] It is strictly associated with cell proliferation. During interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. Ki-67 protein is present during all active phases of the cell cycle (G1, S, G2, and mitosis), but is absent from resting cells (G0)"



(G0) is = senescent phase where nothing is happening. Whereas previous studies have shown that our hair follicle cells experience longer and longer phases of G0 and shorter phases of interphase and mitosis, until ultimately permanently senescent and unfortunately slick bald.



All this coupled with the fact they recruited high norwoods, had a huge first phase 2 study, decided to run another smaller phase 2 study with biomarker biospy evaluation simultaneously with their first phase 2 study, and are evaluating these biomarkers which are directly linked to cell proliferation seem to all point to a positive opposed to a negative. Of course this is all speculative and we will have to wait a few more months to see just exactly the results are.

Thanks, valuable and interesting information. The consensus between many researchers is basically that senescence/cell cycle arrest and apoptosis (or combination of both) finds place in DPC. DPC size and amount modulates hair follicle size. A decline of DPC leads to a smaller hair follicle. In fact the DPC act as a master instructive niche for the whole hair follicle.



I have once illustrated this in a picture so it gets more clear. (Please do note that this isn't the exact pathway chain but just a overall general view)







Factually this explains why AGA is so extremely heard to reverse. A major pathway like P53 possibly sets in who is a master of diverse cellular processes and is a evolutionary ancient coordinator of stress responses. When damage is done it can literally lock down a cell for instance and keep it that way. These pathways are very complex and versatile though. P53 and P21 for instance can activate hundreds of downstream genes and have many functions.



However the beauty of a chemical like SM04554 is that while it acts directly on b-catenin (wnt pathway) it might actually crosstalk with major regulatory pathways like P53 and other major regulatory pathways.



Purely looking at it from a theoretical perspective is that it could work really good in my opinion. Furthermore we have no observational evidence of any direct b-catenin agonist simply because there has never been used one on humans ever. At least AFAIK.



Let's hope we will get positively surprised. Hopefully they will release their results asap.


yes it's old news. BUT the mechanism by how it gets upregulated in the first place is new. Nobody knew that CORIN was the 1 changing the pro-hair growth form of 1-32 BNP to the other form 4-32 BNP.

Until it was noticed that Cotsarelis patent indicated it as the most downregulated gene in haired-scalp(even more than PTGDS- the enzyme for making PGD2)

I i doubt it's not because of a lack of efficacy. Rather there could be a lack of FURIN in bald scalp Coupled with the overexpression of CORIN there- because if we were to check out its entry on wiki:

"Expression of furin in T-cells is required for maintenance of peripheral immune tolerance."

this means FURIN is rendering T cells to be more lax in its activity against the hair follicles on the scalp- and some AGA mechansims must be lowering its expression on the balding scalp AND regulating CORIn's expression instead

[eldarlmario]

It could also be that Recombinantly increasing 1-32 BNP might not be consistent enough to provide any effect long enough to see results.

So IMO upregulating FURIN https://en.wikipedia.org/wiki/Furin and downregulating CORIN https://en.wikipedia.org/wiki/CORIN by small molecules that could be applied daily would be the best strat for increasing 1-32 BNP consistently in the balding scalp

[failly]

Great that you're doing all this work. But why all these studies? What is the point you are trying to prove? Is there like a TL;DR?

[eldarlmario]

And i remember seeing patents on Furin being used for hair somewhere. i will try looking for it when im back home from work.

Off to work peeps.

[eldarlmario]

Great that you're doing all this work. But why all these studies? What is the point you are trying to prove? Is there like a TL;DR?

sorry english is not my first language- what is TL DR?

[charlie76761]

wow... that is some post! Great info.. .good man! Was just about to order some OC but will go for TM instead.

Also, will go for some Calcipotriol - any preferred/trusted supplier with pre-made (apologies if already stated)

Also, what are your thoughts on BIM? Should it be able to cause growth?

And Seti - do you hold much hope for it? I guess no need to order Seti if going to use TM as exactly the same action, or will both be better than one?


Lastly, minox sulfate - am i correct that orally it as dangerous of normal minox?

Thanks

[eldarlmario]

wow... that is some post! Great info.. .good man! Was just about to order some OC but will go for TM instead.

Also, will go for some Calcipotriol - any preferred/trusted supplier with pre-made (apologies if already stated)

Also, what are your thoughts on BIM? Should it be able to cause growth?

And Seti - do you hold much hope for it? I guess no need to order Seti if going to use TM as exactly the same action, or will both be better than one?


Lastly, minox sulfate - am i correct that orally it as dangerous of normal minox?

Thanks

i have personal surces(4 in fact) but im not sure if its ok to post it here

sorry but what's BIM?

TM works fine. Its stated to mount an insurmountable blockage of the CRTH2 inhibitor. Seti is developed for an oral route. not much info on its efficacy has been published yet.

Minoxidil sulfate is the active metabolite of minoxidil itself. it is more potent than its precursor@regrowing hair. 10mg/day orally nets better results than 10% minoxidil topically- and i am speaking from my own experience.

[charlie76761]

Thanks - i did try Minox 10mg day and got weird feelings in my heart so gave it a miss (got diuretic etc but thought best not risk it all.. if things get a lot worse, then will maybe try again)

This is BIM https://www.baldtruthtalk.com/thread...or-Bimatoprost -

i'm using at 0.3% a day (0.8ml) then applying 1.0% for 1ml to one spot of hair (1.0% is over 30 times stronger than used for growing eyelashes ..0.03%). Only a month in so too early for results

would love to know of those sources - it's fine to post here... everyone always references getting goods from Kane and no issue with the mods- be much appreciated

Thanks!

Charlie

[Hairismylife]

Eldarlmario, I use Seti+pge2 or plus some neogenic, will this work?
I inhibit pgd2, up pge2, this direction is correct and work? Would love to hear your opinion.