# Men's Hair Loss > Hair Loss Treatments > Cutting Edge / Future Treatments >  Pax1/Foxa2- 1 of the primary genetic reasons why we balding men- are balding

## eldarlmario

PAX1 gene: http://www.genecards.org/cgi-bin/carddisp.pl?gene=PAX1 

FOXA2 gene: http://www.genecards.org/cgi-b...=FOXA2&keywords=foxa2 

So to summarise my opinion on the all literature sources i have read in relation to the pathology of AGA: 

1)IMO, not all studies are accurate. Some older studies were even refuted by later studies. 
2)Not all proposed/suggested pharmalogical solutions in those studies were effective. Some were even refuted as being harmful to the hair follicles in later experiments. 
3)The best indicative and in IMO referral source on the pathology of AGA in my course of reading countless studies on literature relevant to AGA comes from the Scoliosis study. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365504/ The fact that Idiopathic Scoliosis http://en.wikipedia.org/wiki/S...tionary_considerations , and not AGA- was the (A)original intended topic of the study, along with the fact that the gene locus indicated by the study and supported by (B)others as being a genetic susceptibility locus in multiple ethnic groups for AGA further lends its findings enhanced credibilit(on AGA): 

(A)"Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition."* 

(B) Abstract 

Background 

Androgenetic alopecia (AGA) is a well-characterized type of progressive hair loss commonly seen in men, with different prevalences in different ethnic populations. It is generally considered to be a polygenic heritable trait. Several susceptibility genes/loci, such as AR/EDA2R, HDAC9 and 20p11, have been identified as being involved in its development in European populations. In this study, we aim to validate whether these loci are also associated with AGA in the Chinese Han population. 

Methods 

We genotyped 16 previously reported single nucleotide polymorphisms (SNPs) with 445 AGA cases and 546 healthy controls using the Sequenom iPlex platform. The trend test was used to evaluate the association between these loci and AGA in the Chinese Han population. Conservatively accounting for multiple testing by the Bonferroni correction, the threshold for statistical significance was P ?3.13×10?3. 

Results 

We identified that 5 SNPs at 20p11 were significantly associated with AGA in the Chinese Han population (1.84×10?11?P?2.10×10?6). 

Conclusions 

This study validated, for the first time, that 20p11 also confers risk for AGA in the Chinese Han population and implicated the potential common genetic factors for AGA shared by both Chinese and European populations. 

http://journals.plos.org/ploso.../journal.pone.0071771 

We carried out a genome-wide association study in 296 
individuals with male-pattern baldness (androgenetic alopecia) 
and 347 controls. We then investigated the 30 best SNPs in an 
independent replication sample and found highly significant 
association for five SNPs on chromosome 20p11 (rs2180439 
combined P ¼ 2.7  1015). No interaction was detected 
with the X-chromosomal androgen receptor locus, suggesting 
that the 20p11 locus has a role in a yet-to-be-identified 
androgen-independent pathway.(possibly why castrates dont regrow hair) 

http://neurogenetics.qimrbergh...llmer2008NatGenet.pdf 

Male-pattern baldness susceptibility locus at 20p11 

J Brent Richards,1,2 Xin Yuan,3 Frank Geller,4 Dawn Waterworth,3 Veronique Bataille,1 Daniel Glass,1 Kijoung Song,3 Gerard Waeber,5 Peter Vollenweider,5 Katja K H Aben,6,7 Lambertus A Kiemeney,8,9 Bragi Walters,4 Nicole Soranzo,1,10 Unnur Thorsteinsdottir,4 Augustine Kong,4 Thorunn Rafnar,4 Panos Deloukas,10 Patrick Sulem,4 Hreinn Stefansson,4 Kari Stefansson,4 Tim D Spector,1,11 and Vincent Mooser3,11 
Author information ? Copyright and License information ? 
The publisher's final edited version of this article is available at Nat Genet 
See other articles in PMC that cite the published article. 
Go to: 
Abstract 
We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 × 10?14 for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 × 10?15). 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672151/

----------


## eldarlmario

*Experimental small molecule pharmalogical solutions for AGA by topical/oral route administration in order of descending preference*_(would be updated from time to time):_ 

*1): 

All affected genes indicated in the Scoliosis study: 
*
TATA <= Topical *Calcitirol/Calcipotriol* 

HNF4 <= Topical *Carbamazepine*(direct activator of SHBG for disactivating circulating sex hormones with highest affinity for DHT=>increased bone resorption in the balding skull. Has sides), Topical *Valproic acid*(Androgen Receptor Blocker, Wnt/B-catenin agonist, CD34 upregulator and several other pro-hair growth properties. Has sides if taken orally), Topical *RU58841*(Androgen Receptor Blocker- less systemic side effects), topical *CB*(Androgen Receptor Blocker), topical/oral *Dutasteride*(5A Redutase Inhibitor to decrease circulating DHT. Used carefully- will dramatically slow down, but not stop- AGA and increase 'free' Testosterone levels for the muscles), topical/oral *Finasteride*(5A Redutase Inhibitor to decrease circulating DHT- almost the same profile as Dutasteride but with less potency), oral *Spironolactone*(Androgen Receptor Blocker, Aldosterone Inhibitor=> Less sodium reabsorption in kidneys=>less vasoconstriction=>increased blood supply to hair follicles. Has feminizing sides.)

RAR <= Ultra low dose topical *Tretinoin* (0.0005%. Ultra low doses of it  induces hair differentation at a stabilised rate with stem cells as the fuel while increasing dosages depletes stem cells rapidly and leads to apoptosis instead. Is also toxic when used in dosages above a certain threshold) 

RXRA <= Topical *Calcitriol/Calcipotirol*(Calcitriol-binded VDR is needed for full transcription of PPAR Alpha, Beta and Gamma. VDR-null cells on the scalp diverts pluripotent stem cells to the sebocyte(sebum) and sudoriferous(sweat) lineage)

STAT <= Topical *Calcitriol/Calcipotriol*(Calcitriol acts as a modulator of this central inflammation pathway- the JAK-STAT pathway.) 

BATF <= Topical *Calcitirol/Calcipotriol*(Calcitriol acts as a modulator of this TH17 cytokines regulatory gene) 

COMP <= Topical *Calcitirol/Calcipotriol*, topical *Valproic acid*(Both Calcitriol and Valproic acid increase expression of this gene- and it is upregulated only in haired-scalp.)

VDR <= Topical *Calcitirol/Calcipotriol*(Calcitriol's own receptor. It is a receptor that regulates, modulates and thus- controls hundreds of genes involved with Immunity, Calcium homeostasis, Bone formation/resorption(in synergy with BMPs) and many, many more in the human body.) 

HDAC2 <= Topical *Valproic acid*(inhibitor of HDAC2- which inhibits AGA-afflicted hair follicles stem cell renewal's function)

CART1 <= Topical *Calcitriol/Calcipotriol* 

FOXA <= ? 

FOXP1 <= Topical *Valproic acid*, Ultra low dose topical *Tretinoin*(0.0005%)

GATA3 <= Topical *Calcitriol/Calcipotriol*, *Oral Montelukast*, *Oral Zafirlukast* 

H6 family homeobox 2 <= ? 

IRF <= Topical *Calcitriol/Calcipotriol*[/B] 

PAX5 <= Topical *Calcitriol/Calcipotriol*[/B] 

P300 <= Topical *Calcitriol/Calcipotriol*[/B] 

*2): 

Top 5 upregulated genes in haired-scalp and Top 5 downregulated genes in haired-scalp as indicated by Dr Cotsarelis's patent in order of descending preference: 

Upregulated in haired-scalp:* 

GPRC5D <= Ultra low dose topical *Tretinoin*(0.0005% ) 

CDT6<= *Topical Calcitriol/Calcipotriol* 

LY6G6D<= ? 

S100A3<= Topical *Calcitriol/Calcipotriol* 

COMP<= Topical *Calcitriol/Calcipotriol*, topical *Valproic acid*

*3): 

Downregulated in haired-scalp:* 

CCL19<= Topical *Calcitriol/Calcipotriol*

FOSB<= Topical *Valproic acid*

c-FOS<= Topical *Valproic acid*, Topical/oral *Verapamil*, topical *D609* 

PTGDS<= Topical/oral *TM30089*(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral *Setipiprant*(Newest CRTH2 inhibitor in trials, topical/oral *Ramatroban*(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral *OC*(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.) 

CORIN<= Oral *Spironolactone*(indirectly by antagonising Aldosterone=> CORIN downregulation=> FURIN-Cleaved proBNP=> 1-32 BNP(the pro-hair growth form of BNP) => hair pigmentation + keratinization) 

*4): 

Three 'endpoint' genes indicated by Dr Cotsarelis's patent that are significantly-upregulated in haired-scalp: 
*
CD200<== Topical *Cacitirol/Calcipotriol* http://www.bloodjournal.org/content/...o-checked=true http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364365/ (Calcitriol increases both CD200's expression in the balding scalp and balding skull. In the latter's case, without adequate CD200's expression- bone resorption is severely-impaired that leads to ever-increasing bone formation in the balding skull.) 

CD34<== Topical *Valproic acid*(via existing cell self-renewal), Topical *16,16-Dimethly-PGE2*(via homing from bone marrow), Topical *PGE2*(PGE2=>EP2 Receptor=>Survivin=>CD34. Also- PGE2=>EP4 Receptor=>BMP-2=>SMAD1/5/8=>SMAD4=>DLX3=>RUNX2=>Hair shaft differentiation), Topical *Butaprost*(This is a selective EP2 receptor and EP4 receptor agonist. An PGE2 analog), topical/oral *Sulfasalazine*(Upregulates PGE2 while inhibiting COX-2) 

Intergrin A6<= Ultra low dose topical *Tretinoin*(0.0005%. Tretinoin is the only small molecule that could be found to upregulate IntergrinA6 with the other being the Parathyroid hormone-related protein(not a small molecule))

*END*

----------


## eldarlmario

I recommend any1 who sincerely wants to help himself with his hairloss to spend a couple of hours reading: 

1)The Scoliosis study http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365504/ 
2)Dr Cotsarelis patent http://www.google.com/patents/US20110021599 

These 2 studies are like the Old and New testament. it links up the puzzle of the pathological cause of AGA. If we were to look at the genes being altered in the Scoliosis study, it's very easy to understand why the genes mentioned in Dr Cotsarelis patent are being upregulated/downregulated.

----------


## eldarlmario

UV light will cause more hairloss. This was proven by Cotsarelis on how a 'surprising'(surprising because UV light exposure is supposed to decrease immunity) increase in leukocyte infiltration was observed in balding hair follicles after exposure to UV light and also by my own experience from suntanning) on the balding scalp- but cause hair growth else where. i noticed that the hairgrowth on my cheeks(induced by oral minox sulfate) was accelerated after the hrs spent suntanning raw. IMO, the balding scalp has a 'preference' due to the altered genes caused by the balding locus- to synthesise PTGDS- enzyme for making PGD2- over making PTGES-enzyme for making PGE2. This is not my own opinion because again- Dr Cotsarelis has already proven that PTGDS- enzyme for making PGD2 is indeed upregulated several times fold in hair from balding scalp.

----------


## eldarlmario

bump

----------


## eldarlmario

Accoriding to Dr Cotsarelis's patent, CD200's expression is significantly downregulated in bald-scalp. Here's an article on CD200 phenotypes:

CD200:CD200R-Mediated Regulation of Immunity 

1.1.2. Physical Interaction between CD200:CD200R 

Information concerning the physical interactions between CD200 and CD200R has come essentially from two methodologies. One has focused on studying the structural constraints and biophysical properties of the interacting molecules. Using site-directed mutagenesis of CD200R1 Hatherley and Barclay showed that, like CD200, this molecule interacts predominantly with CD200 through the GFCC? face of its N-terminal domain, suggesting in turn that the cell-cell interaction between a CD200+ and CD200R+ cell would thus span four Ig superfamily domains, a distance similar to many of the interactions found between T cells and antigen presenting cells [22]. The actual affinity of interaction between CD200 and CD200R(Cd200's receptor that is present on many cell types) is reportedly quite low (KD~2.5??M) [23], similar to that of many other interactions in the immune system which may imply that these serve to modulate cell activity in the context of other cell:cell interactions. 

Similar conclusions concerning the importance of interaction between the N-terminal domains of CD200/CD200R were reached from functional studies which focused on the ability of CD200 and CD200R-derived peptides to act as agonists or antagonists of the immune responses set in train by CD200:CD200R interactions [24, 25]. As an example, since CD200 was shown to attenuate inflammatory cytokine production following stimulation of lymphocytes by LPS(CD200 dampens inflammation) in vitro, or TNF? production in vivo after LPS injection, CD200 peptides which antagonized this activity, or alternatively acted independently as agonists, were characterized [24]. Regions in the N-terminal FR2CDR2 and CDR2FR3 domains of CD200 were most relevant for the functional effects seen [24]. 

Using murine peritoneal macrophages it was shown that the IFN? and IL-17-stimulated cytokine secretion was inhibited by CD200R1 engagement(once cd200 is activated, it inhibits interferon gamma and il-17 production), although surprisingly LPS-stimulated responses were apparently unaffected, unlike results reported elsewhere [40]. Tetanus toxoid-induced secretion of IL-5 and IL-13 from human PBMCs was also inhibited by CD200R1 agonists(Il-5 and Il-13, profibrotic Th2 cytokines, are also inhibited upon activation of cd200's receptor (1)- and many agonistic molecules can bind to it in CD200's place), but the effect was dependent upon cross-linking the CD200R1 on monocytes, but not on CD4 T cells, although CD200R1 is expressed on subsets of T cells [41]. As discussed in more details in the following, one of the earliest reported immunomodulatory effects of over-expression of CD200 in vivo was reported to be an alteration in the cytokine production profile following alloactivation, with preferential production of IL-4 and IL-10(an anti-autoimmune cytokine aka 'good' cytokine) at the expense of IFN? and IL-2 [42]. 

Sato et al. [43] analyzed the mechanisms(s) whereby CD200R1 expressed on dendritic cells (DCs) led to fine tuning of chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT). DCregs generated from bone marrow in vitro (BM-DCregs) expressed an alternate CD200R (CD200R3), resulting in a suppressive function in an antigen-specific CD4 T-cell response. Importantly, CD49+CD200R3+ cells were similar in phenotype and function to classical BM-DCregs, and, like the latter, adoptively transferred protection from cGVHD to mice after alloHSCT. Protection was associated with development of antigen-specific anergic CD4T cells and with CD4+CD25+Foxp3+Tregs, while depletion of CD49+CD200R3+ cells before alloHSCT enhanced cGVHD. Induction of Tregs following CD200:CD200R interactions(As mentioned before- Tregs are immunoregulatory t cells- they help prevent autoimmunity- and this happens when the CD200 receptor is activated by CD200) is, as will become evident in the following, a recurrent theme in CD200R-induced immunoregulation.

----------


## eldarlmario

On CD200's expression in the bones:

Provocative data has also been reported suggesting a functional role for CD200:CD200R interactions in influencing bone development [53]. Osteoclasts, important mediators of bone loss leading to osteoporosis, are CD200R1+.(osteoclasts have CD200 Receptor 1 on them) Osteoclasts from CD200KO mice differentiate at a reduced rate, with decreased activation of the NF-B and MAP kinase signaling pathways downstream of RANK, a receptor playing a key role in osteoclast differentiation.( http://en.wikipedia.org/wiki/Osteoclast differentiation is negatively affected when CD200R1 is underexpressed. this means bone resorption is reduced- just like what we can see on the balding skull. Bone keeps forming and forming with lesser-than-normal resorption and taking up space at the SubQ adipocyte layer's expense needed to maintain hair growth. Calcium is is needed to form bones. This probably explains why there we often see etopic harden tissue growth on slick-bald scalps. And VDR has got something to do with this because it is the master regulator of calcium homeostasis.) A soluble form of CD200 rescued macrophage fusion to form osteoclasts and macrophage activation downstream of RANK, while a soluble form of CD200R1 prevented this. CD200KO mice contained fewer osteoclasts and accumulated more bone than wt animals. (there you go)The importance of CD200 expression to bone development has also been investigated using a 2-dimensional and 3-dimensional culture systems, and monitoring expression of a number of mRNAs as well as growth of bone nodules and TRAP+ cells in culture, as surrogate markers for preferential osteoclastogenesis versus osteoblastogenesis [54]. These data favored a model in which osteoblast expression of CD200 delivered signals (through CD200R1) to attenuate activity in osteoclasts and promote expression of mRNAs associated with bone formation [55]. In support of this hypothesis, in a follow-up study in which cells were cultured under microgravity conditions in space orbit, preferential expression of CD200 (using cells) overcame the increased osteoclastogenesis seen under microgravity conditions [56].

----------


## eldarlmario

On Dr Cotsarelis patent http://www.google.com/patents/US20110021599

if we were to look at figure 3A of the patent- we can see 2 familar genes that has been indicated as being altered by the Scoliosis/AGA haplotype in the Scoliosis/AGA study: Comp(1)(Cooperates with myogenic proteins 1 RENAMED to: COMP aka Cartilage Oliogomeric Matrix Protein) and FGF18(via FOXp1- decides how long the telogen phase would lasts) 

GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. 

http://en.wikipedia.org/wiki/LGR5#Hair_Follicle 

FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G).(we know that Foxp1 is 1 of the gene altered by the AGA haplotype variant- and Foxp1 regulates FGF18) 
quoted from the FOXp1 study: 

We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent(telogen) phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression. 

This means: 

more stem cells recruited => longer hair growth(longer anagen phase) 
less stem cells recruited(via 'precocious activation' aka 'premature activation') =>faster anagen entry, BUT shorter hair growth(due to lesser stem cells recruited- And this fits the clinical presentations of AGA. Our hairs enter anagen fast- only to stop growing fast too, only to come back growing fast again- and dying off fast again=> rapid miniaturization. 

This is why IMO, minoxidil needs to be cycled once in a while- it uses up the "already-being-depleted-stem cells" in the hair follicle to fund that extra growth. This could be the reason why we have many users mentioning(including myself by my own experience with it) that cosmetically-visible minoxidl-fueled hair growth sheds all of a sudden after awhile.

----------


## eldarlmario

PTo those who are still pinning their hopeless hope on Bimatoprost:

From Dr Cotsarelis's findings:

GD2 was detected as 17 pg/mg of tissue in haired scalp and 75.5 pg/mg in bald scalp, representing a 4.4 fold increase in bald tissue. PGF2a also was slightly elevated in bald scalp with 6.7 pg/mg in haired scalp and 15.9 pg/mg in bald scalp. 

this might be the reason why bimatoprost(Latisse) don't work on the balding scalp

----------


## eldarlmario

Genes altered by the Pax1/Foxa2 Scoliosis/AGA balding haplotype variant 

TATA 
HNF4 
RAR 
RXRA 
STAT 
BATF 
COMP <==== Cooperates with myogenic protein renamed to Cartilage oligomeric matrix protein 
VDR 
HDAC2 
CART1 
FOXA 
FOXP1 
GATA3 
H6 family homeobox 2 (inner ear and vestibular function)
IRF 
PAX5 
P300

http://www.ncbi.nlm.nih.gov/pubmed/21355885 

Cartilage oligomeric matrix protein (COMP) forms part of the connective tissue of normal human hair follicles. 
Ariza de Schellenberger A1, Horland R, Rosowski M, Paus R, Lauster R, Lindner G. 
Author information 
Abstract 
Hair follicle cycling is driven by epithelial-mesenchymal interactions (EMI), which require extracellular matrix (ECM) modifications to control the crosstalk between key epithelial- and mesenchymal-derived growth factors and cytokines. The exact roles of these ECM modifications in hair cycle-associated EMI are still unknown. Here, we used differential microarray analysis of laser capture-microdissected human scalp hair follicles (HF) to identify new ECM components that distinguish fibroblasts from the connective tissue sheath (CTS) from those of the follicular dermal papilla (DP). These analyses provide the first evidence that normal human CTS fibroblasts are characterized by the selective in situ-transcription of cartilage oligomeric matrix protein (COMP). Following this up on the protein level, COMP was found to be hair cycle-dependent, suggesting critical role in this process: COMP is expressed during telogen and early anagen at regions of EMI and is degraded during catagen (only the CTS adjacent to the bulge remains COMP+ during catagen). Notably, COMP gene expression in vitro suggests direct correlation with the expression of TGFB2(Catagen inducing cytokine) in CTS fibroblasts. This raises the question whether COMP expression undergoes regulation by transforming growth factor, beta (TGFB) signalling. The intrafollicular COMP expression suggests to be functionally important and deserves further scrutiny in hair biology as indicated by the fact that altered COMP expression might be associated with scant fine hair(sounds familar) in the case of some chondrodysplasia and scleroderma patients.(and AGA 'patients' as well- because COMP is 1 of the genes being altered by the PAX/1Foxa2 AGA haplotype variant) Together these results reveal for the first time that COMP is part of the ECM and suggests its important role in normal human HF biology. 

© 2011 John Wiley & Sons A/S. 

And it fits in nicely with this: 

The top 30 upregulated genes in balding dermal papilla cells in response to 100 nM DHT determined by microarray hybridization. 


Gene Genebank ID Fold increase 

tyrosyl-tRNA synthetase (YARS) NM_003680 5.07 

dickkopf homolog 1 (DKK1) NM_012242 4.64 

serum/glucocorticoid regulated kinase (SGK) NM_005627 4.53 

a disintegrin-like and metalloprotease (ADAMTS5) NM_007038 3.75 

solute carrier family 19 (SLC19A2) NM_006996 3.31 

solute carrier family 2 (SLC2A3) NM_006931 2.99 

H2A histone family, member Z (H2AFZ) NM_002106 2.86 

RING1 and YY1 binding protein (RYBP) NM_012234 2.75 

nuclear receptor coactivator 3 (NCOA3) NM_181659 2.63 

adenosylmethionine decarboxylase 1 (AMD1) NM_001634 2.46 

LPS-induced TNF-alpha factor (LITAF) NM_004862 2.36 

ornithine decarboxylase 1 (ODC1) NM_002539 2.34 

myeloid cell leukemia sequence 1 (MCL1) NM_182763 2.32 

ATPase family homolog up-regulated in senescence cells (AFURS1) NM_024524 2.31 

ADP-ribosylation factor-like 4C (ARL4C) NM_005737 2.3 

cyclin-dependent kinase inhibitor 1A (p21) (CDKN1A) NM_000389 2.3 

aldo-keto reductase family 1, member C1 (AKR1C1) NM_001353 2.29 

DEAD (Asp-Glu-Ala-Asp) box polypeptide 5 (DDX5) NM_004396 2.27 

fibroblast growth factor 7 (FGF7) NM_002009 2.26 

solute carrier family 3 (SLC3A2) NM_002394 2.22 

VAMP-associated membrane protein B (VA0AP) NM_003574 2.1 

HSPC048 protein (HSPC048) NM_014148 2.09 

syndecan binding protein (syntenin) (SDCBP) NM_005625 2.08 

matrix metalloproteinase 3 (MMP3) NM_002422 2.08 

cyclin-dependent kinase inhibitor 1A (p21) (CDKN1A) NM_078467 2.07 

Kruppel-like factor 10 (KLF10) NM_005655 2.02 

heme oxygenase (decycling) 1 (HMOX1) NM_002133 2.02 

UDP-glucose ceramide glucosyltransferase (UGCG) NM_003358 2.01 

solute carrier family 7 (SLC7A5) NM_003486 1.99 

transforming growth factor, beta 2 (TGFB2) NM_003238 1.98 


And also tallies with what Dr Cosarelis discovered: 

http://www.google.com/patents/US20110021599 [/L] page 89- on the genes expression differences in haired-scalps vs bald scalps 

And looking back at the COMP study: 

Table 1. ?Human pathologies related with cartilage oligomeric matrix protein (COMP) disorders and hair follicle phenotypes in humans 
Syndrome	Mutation	Phenotype	Reference 
Cartilage hair hypoplasia Metaphyseal chondrodysplasia- McKusick type 132 400	Autosomal recessive 9. Cartilage oligomeric matrix protein (COMP)	Short-limbed dwarfism, general hypoplasia. Phenotype: Hair hypoplasia Immunodeficiency Short limbed	(54,55) 
Connective tissue and rheumatic disease Scleroderma	COMP is over-expressed probably because of autocrine transforming growth factor stimulation. Induction of pathogenic matrix deposition	Early hair greying followed by hair loss Localized scleroderma gives patchy hair loss	(29,30,56,5 


And when we read about the pathology description of http://en.wikipedia.org/wiki/Sclerod...athophysiology , save for the necrosis-like symptoms aside(and once again, implicating Calcitriol(Vitamin D) and calcium homeostatsis)- it seems to be what we are having, progressively- on the balding scalp: 

Pathophysiology[edit] 
It is characterised by increased synthesis of collagen (leading to the sclerosis), damage to small blood vessels, activation of T lymphocytes and production of altered connective tissues.[12] Its proposed pathogenesis is the following:[13][14][15][16][17] 
It begins with an inciting event at the level of the vasculature, probably the endothelium. The inciting event is yet to be elucidated, but may be a viral agent, oxidative stress or autoimmune. Endothelial cell damage and apoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissue oedema. At this stage it is predominantly a Th1 and Th17-mediated disease. 
After this the vasculature is further compromised by impaired angiogenesis and impaired vasculogenesis (fewer endothelial progenitor cells), likely related to the presence of anti-endothelin cell antibodies. Despite this impaired angiogenesis, elevated levels of pro-angiogenic growth factors like PDGF and VEGF is often seen in persons with the condition. The balance of vasodilation and vasoconstriction becomes off-balance and the net result is vasoconstriction. The damaged endothelium then serves as a point of origin for blood clot formation and further contributes to ischaemia-reperfusion injury and the generation of reactive oxygen species. These later stages are characterised by Th2 polarity. 
The damaged endothelium upregulates adhesion molecules and chemokines to attract leucocytes, which enables the development of both innate and adaptive immune responses,including loss of tolerance to various oxidised antigens, which includes topoisomerase I. B cells mature into plasma cells, which furthers the autoimmune component of the condition. T cells differentiate into various subsets, including Th2 cells, which play a vital role in tissue fibrosis. Anti - topoisomerase 1 antibodies, in turn, stimulate type I interferon production. 
Fibroblasts are recruited and activated by multiple cytokines and growth factors to generate myofibroblasts. Dysregulated transforming growth factor ? (TGF-?) signalling in fibroblasts and myofibroblasts has been observed in multiple studies of scleroderma-affected individuals. Activation of fibroblasts and myofibroblasts leads to excessive deposition of collagen and other related proteins, leading to fibrosis. B cells are also implicated in this stage, IL-6 and TGF-? produced by the B cells decrease collagen degradation and increase extracellular matrix production. Endothelin signalling is also implicated in the pathophysiology of fibrosis.[18] 
Vitamin D is also implicated in the pathophysiology of the disease, for one an inverse correlation between plasma levels of vitamin D and scleroderma severity has been noted and vitamin D is known to play a crucial role in regulating (usually suppressing) the actions of the immune system.(there you go)[19]

----------


## eldarlmario

back to the Cotsarelis patent: 

"GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth." 

This receptor is an adult stem cell biomarker. it formes a complex with http://en.wikipedia.org/wiki/LRP6 , which http://en.wikipedia.org/wiki/DKK1 inhibits- and we would only want this to be upregulated on the balding scalp- not skull.

----------


## eldarlmario

Cotsarelis's patent:

*"Preservation of hair follicle stem cells in AGA.* 

The preservation of KRT15hiITGA6hi cells in AGA is consistent with the current clinical concept that AGA is a nonscarring type of alopecia. Dermatologists classify alopecias into scarring and nonscarring categories. Some types of alopecia (e.g., lichen planopilaris, discoid lupus erythematosus, and graft-versus-host disease) are associated with destruction of hair follicle stem cells in the bulge and permanent hair loss. Ablation of the stem cell compartment leading to scarring alopecia has been replicated experimentally in mice through transgene expression of a cytotoxic gene in the bulge (2). In reversible types of alopecia (e.g., alopecia areata), inflammation targets hair follicle progenitor cells but spares hair follicle stem cells. In these disorders, regrowth occurs with suppression of inflammation and subsequent regeneration of the hair follicle from uninjured stem cells (5). Our finding that AGA, in the clinical category of nonscarring alopecia, demonstrated preservation of hair follicle stem cells suggests potential reversibility of this condition."

*(CD34 https://en.wikipedia.org/wiki/CD34 +CD200 https://en.wikipedia.org/wiki/ CD200 + CD49F https://en.wikipedia.org/wiki/ITGA6 )*==>Full Terminal Hair regrowth

*so slick-bald guys should not give up hope*

----------


## eldarlmario

Off topic for awhile. Some AGA individuals might suffer from some inner ear disorders(like chronic recurring tinnitus that goes:
"eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee  eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee  eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee  eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee  eeeeeeeeeeeeeeeeeeeeeeeeeee" that last several minutes- and im 1 of them): 

H6 family homeobox 2<== gene altered by the pax1/Foxa2 balding haplotpye variant 

Molecular (SNP) Analyses of Overlapping Hemizygous Deletions of 10q25.3 to 10qter in Four Patients: Evidence for HMX2 and HMX3 as Candidate Genes in Hearing and Vestibular Function 

on http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743949/ 

INTRODUCTION 
Deletions of chromosome 10qter were first reported by Lewandowski et al. in 1978. Subsequently, Wulfsberg et al. [1989] reported three new patients and reviewed 15 previous patients and proposed a 10qter deletion syndrome. Cytogenetically, these patients had deletions of bands 10q25 or 10q26 to the terminus, as well as interstitial deletions and translocations within this region. Additionally, both familial and de novo patients have been reported [Irving et al., 2003]. Irving et al. [2003] reported 15 new patients involving interstitial and terminal deletions of chromosome bands 10q25.2?26.3, and reviewed 17 patients from the literature, supporting wide clinical variability for deletions in this region yet common features including strabismus, facial asymmetry, prominent chin, down-slanting palpebral fissures, hypertelorism, malformed or large ears, and a thin upper lip. Kehrer-Sawatzki et al. [2005] also described the phenotype of a patient with an interstitial del(10)(q25.2q25.3?q26.11) and reviewed four previously described interstitial deletion patients involving bands 10q25.2-q26.1. Courtens et al. [2006] reported a subterminal deletion del(10)(q26.2) and reviewed the literature, describing the phenotype of subterminal deletions. Subterminal patients were noted to commonly have low birth weight, microcephaly at birth, short stature in childhood/adulthood, genital anomalies in males, and behavioral problems. Their craniofacial anomalies included broad/prominent nasal bridges, prominent nose, strabismus, thin upper lip, and fifth finger clinodactyly. Overall, there is variability in the sizes and positions of distal 10q deletions, presumably causing haploinsufficiency of many different genes in this large region and therefore contributing to significant variation in phenotype.

----------


## eldarlmario

ok found the possible reason for the underexpression of Ephrin A3 in balding hair follicles: 

Different gene expression profile observed in dermal papilla cells related to androgenic alopecia by DNA macroarray analysis. 
Midorikawa T1, Chikazawa T, Yoshino T, Takada K, Arase S. 
Author information 
Abstract 
BACKGROUND: 
Androgenic alopecia (AGA) is the most common type of baldness in men. Although etiological studies have proved that androgen is one of the causes of this symptom, the defined molecular mechanism underlying androgen-related actions remains largely unknown. 

OBJECTIVES: 
To clarify the difference in the gene expression profile of dermal papilla cells (DPCs) in skin affected by baldness. 

METHODS: 
DNA macroarray study was carried out on cultured DPCs from AGA skin comparing with DPCs from skin that is not affected by baldness. 

RESULTS: 
From DNA macroarray analysis, we observed that 107 of the 1185 analyzed genes had differing expression levels. A marked difference was observed in the decreased gene expression of BMP2 and ephrin A3 and up-regulated in NT-4 gene. In order to clarify the roles of BMP2 and ephrin A3 in the hair follicles, we examined the proliferation of hair follicle keratinocyte and expression of a hair acidic keratin gene. Both BMP2 and ephrin A3 raised the proliferation rate of the outer root sheath cells (ORSCs) and induced gene expression in acidic hair keratin 3-II. 

CONCLUSION: 
These results lead us to the hypothesis that both BMP2 and ephrin A3 function as hair growth promoting factors in the hair cycle. 

http://www.ncbi.nlm.nih.gov/pubmed/15488702 

Primary human CD34 hematopoietic stem and progenitor cells express 
functionally active receptors of neuromediators 
Ulrich Steidl, Simone Bork, Sebastian Schaub, Oliver Selbach, Janette Seres, Manuel Aivado, Thomas Schroeder, 
Ulrich-Peter Rohr, Roland Fenk, Slawomir Kliszewski, Christian Maercker, Peter Neubert, Stefan R. Bornstein, 
Helmut L. Haas, Guido Kobbe, Daniel G. Tenen, Rainer Haas, and Ralf Kronenwett 
Recently, overlapping molecular phenotypes 
of hematopoietic and neuropoietic 
cells were described in mice. Here, we examined 
primary human CD34 hematopoietic 
stem and progenitor cells applying specialized 
cDNA arrays, real-time reverse-transcriptase - polymerase 
chain reaction (RTPCR), 
and fluorescent-activated cell sorter 
(FACS) analysis focusing on genes involved 
inneurobiologicfunctions.Wefoundexpression 
of vesicle fusion and motility genes, 
ligand- and voltage-gated ion channels, receptorkinasesandphosphatases,and,most 
interestingly, mRNA as well as protein expression 
of G protein - coupled receptors of 
neuromediators(corticotropin-releasinghormone 
1 [CRH 1] and CRH 2 receptors, orexin/ 
hypocretin 1 and 2 receptors, GABAB receptor, 
adenosine A2B receptor, opioid 1 and 
1 receptors, and 5-HT 1F receptor). As 
shown by 2-color immunofluorescence, the 
protein expression of these receptors was 
higher in the more immature CD38dim than in 
the CD38bright subset within the CD34 population, 
and completely absent in fully differentiated 
blood cells, suggesting that those 
receptors play a role in developmentally 
early CD34 stem and progenitor cells. The 
intracellular concentration of cyclic adenosine 
monophosphate (cAMP) in CD34 cells 
was diminished significantly upon stimulation 
of either CRH or orexin receptors, indicating 
that those are functionally active and 
coupled to inhibitory G proteins in human 
hematopoietic cells. In conclusion, these 
findings suggest a molecular interrelation 
of neuronal and hematopoietic signaling 
mechanisms in humans. (Blood. 2004;104: 
81-88) 
© 2004 by The American Society of Hematology 


http://www.bloodjournal.org/co...l.pdf?sso-checked=true

----------


## eldarlmario

looking back at Cotsarelis findings of the gene differences in haired-scalp, we can see that the gene CORIN is the most under-regulated gnene(even lower than PTGDS- enzyme for synthesising PGD2) http://www.google.com/patents/US20110021599 page 92 

The serine protease Corin is a novel modifier of the Agouti pathway. 
Enshell-Seijffers D1, Lindon C, Morgan BA. 
Author information 
Abstract 
The hair follicle is a model system for studying epithelial-mesenchymal interactions during organogenesis. Although analysis of the epithelial contribution to these interactions has progressed rapidly, the lack of tools to manipulate gene expression in the mesenchymal component, the dermal papilla, has hampered progress towards understanding the contribution of these cells. In this work, Corin was identified in a screen to detect genes specifically expressed in the dermal papilla. It is expressed in the dermal papilla of all pelage hair follicle types from the earliest stages of their formation, but is not expressed elsewhere in the skin. Mutation of the Corin gene reveals that it is not required for morphogenesis of the hair follicle. However, analysis of the ;dirty blonde' phenotype of these mice reveals that the transmembrane protease encoded by Corin plays a critical role in specifying coat color and acts downstream of agouti gene expression as a suppressor of the agouti pathway. 

This suggest it has probably got something to do with hair colojur- probably the hair greying phenomenon or the kind of faint/weak colour we see in baby hairs(miniaturized) 

Also, we can see in the entire lists of gene differences that the only Bmp that appears in it- is BMP-2(upregulated in haired-scalps than bald scalps) on page 89, agreeing with the findings of the Japanese study in the post above this.

----------


## eldarlmario

ok- taking an angle from this study(scoliosis) and combining the information from Dr Cotsarelis own research on PGD2(from where the concept of using a CRTh2 inhibitor for AGA came from- and proven indeed accurate by others and myself through feeling the difference it made to our scalps) and Cd34/IntergrinA6/CD200(the study that lists out the differences between balding- scalp and haired scalped from the same indidivuals(s)) plus some individual studies like the korean and japanese 1s that showed how Dkk1 inhibits hair growth, how tgf beta 2 induces catagen, how bmp-2 and ephrin a3 is downregulated in balding hair follicles, etc; 

I find that the findings(on genes involved, upregulated/downregulated, etc) from them: 

1)The Scoliosis study 
2)Dr Cotasarelis PGD2 and Cd34/IntergrinA6/CD200 studies 
3)Some individual studies by others 

correlates with each other rather accurately. 

In other words, like i have mentioned before: 

Whatever all these truckload of binding site-altered genes(caused by the disruption of a so-called "PEC7 Enhancer" at the PAX1/FOXA2 locus) are doing: 

TATA 
HNF4 
RAR 
RXRA 
STAT 
BATF 
COMP 
VDR 
HDAC2 
CART1 
FOXA 
FOXP1 
GATA3 
H6 family homeobox 2 
IRF 
PAX5 
P300 

is leading to this downregulation of CD34, IntergrinA6(i ommited this in the post a few pages back) and CD200 on the balding scalp + Cd200 on the balding skull(and eyebrows for me) 

Coupled with the fact that i myself indeed have a natural v-shape hairline before i started receding, slightly-curved spine and frequently-occuring parotitis of my parotid glands(just below the ears) and frequently-ocurring tinittus in my ears(mentioned very early in this thread months ago before i even stumbled on the scoliosis study) plus slight tingling sensation on my scalp temple when i massaged the lymph nodes below my jawline, ears and parathyroid glands on my neck made me feel the findings from the scoliosis study are extremely accurate. 

P.S I also have occasional 'twiches" in my head that felt like some nerves were being 'twisted' whenever i adjusted my jaw or moved my neck- and again, this started during puberty but i am unsure of what the cause is and if there is any link to the balding haplotype variants. 

-------------------------

----------


## eldarlmario

PPAR receptors and their relationship with RXRA:

Pax1(-)RXRA (DOWN) => RXRA/PPAR alpha + PPAR beta/RXRA + RXRA/PPAR gamma coactivation (DOWN) => Vitamin D Receptor:



The diagram shows how individual PPARs binds with RXRA 

PPAR Beta is the 'master regulator' of sebocyte profileration and differentiation. IMO, there is nothing wrong with PPAR Beta expression. But due to certain modified functions in PPAR Alpha and/or PPAR gamma via interactions with RXRA- final gene transcription thru the VDR receptor favors sebocyte differentiation at the expense of adipocyte differentiation = more sebum and less fats on the balding scalp 




Whatever the mechanism is, there is for certain(atually, it's already been indicated as being the genes with their binding sites altered by the Scoliosis study- so it's not just my own opinion), a modified function of the genes implicated in this section of the pathway that is a major cause of AGA- because they influence how downstream pathways behave- including but not limited to WNT/signalling pathway like DKK1, BMP-signalling like BMP-2, TGF Beta signalling like TGF Beta 1, TH1/Th2 cytokines ratio and activity, intracellular calcium levels, etc, etc 
Calcitirol => VDR =>Vitamin D binding protein(this step can be bypassed by using topical Calcitirol directly to the scalp http://en.wikipedia.org/wiki/Vitamin_D-binding_protein ) => RXRA + RXRB(not stated as being altered in the balding haplo type) => VDR Activation => VDR target genes (VDR activation/inactivation has significant consequences on the immune system) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597838/ 

VDR TARGET GENES Classical VDR Targets The most striking effect of severe vitamin D defi-ciency is rickets. Rickets can also result from mutations in theCYP27B1 or theVDR gene. 1,25(OH)2D3 is essen-tial for adequate Ca2þand Pi absorption from the intes-tine and hence for bone formation [112]. Liganded VDR has been shown to induce expression of the gene encod-ing for the major Ca2þ channel in intestinal epithelial cell, transient receptor potential cation channel, subfamily V, member 6 (TRPV6), by direct binding to a VDRE at 1.2, 2.1 and 4.3 kb from the TSS [113]. The sodium-phos-phate transport protein 2B (SLC34A2) gene was also found to be induced by 1,25(OH)2D3although no VDREs have yet been identified for this gene [114]. 1,25(OH)2D3 also down-regulates the expression of the PTH gene that opposes 1,25(OH)2D3 in regulation of serum Ca2þ and Pi levels, but up-regulates the fibroblast growth factor 23 (FGF23) gene(as posted before, this unheard of FGF has atually got alot to do with the hair), whose gene product, like PTH, lowers serum Pi levels [115]. The induction of the tumor necrosis factor ligand superfamily, member 11 (TNFSF11, also called RANKL) gene by liganded VDR via multiple distant VDREs (up to 76 kb from the TSS) leads to stimulation of osteoclast precursors to fuse and form new osteoclasts, resulting in enhanced resorption of bone [116]. Thus, this study also confirms that functional VDREs can be a large distance from the target gene TSS.

----------


## eldarlmario

ok i know people hate staring at a huge wall of text- so here goes: 

VDR Targets in Cell Cycle Regulation 

The main antiproliferative effect of 1,25(OH)2D3 on cells is a cell cycle block at the G1 phase. This can be explained by changed expression of multiple cell cycle regulator genes. Among the first targets described, expression of cyclin-dependent kinase inhibitor (CDKI) genes CDKN1A (also called p21) and CDKN1B (also called p27)(upregulates cell cycle arrest genes) were found to be up-regulated by ligand treatment [117,118]. For theCDKN1A gene, a VDRE in the proximal promoter was characterized, thus estab-lishing CDKN1A as a direct 1,25(OH)2D3 target gene [119]. More recently, it has been questioned whether CDKN1A actually represents a primary or a secondary target, the latter process via up-regulation of TGF-b or IGFBP3, and whether the described VDRE is truly func-tional [120,121]. Indeed, by screening 7 kb of the CDKN1A promoter with overlapping ChIP regions, three novel regions with 1,25(OH)2D3-induced VDR enrichment were identified, two of which also bound p53 as well [80]. The functionality of these characterized 1,25(OH)2D3-responsive regions relative to CDKN1A expression was illustrated through ChIP and 3C anal-yses [25,29]. Additional CDKIs, such asCDKN2B (p15), CDKN2A (p16), CDKN2C (p18), and CDKN2D (p19), also show transcriptional response to 1,25(OH)2D3, although the CDKN2A response appears to be secondary as it can be blocked by protein synthesis inhibitors [119,122]. In addition, the genes cyclin E1 (CCNE1), cyclin D1 (CCND1), and cyclin-dependent kinase 2 (CDK2) were also found to be down-regulated by 1,25 (OH)2D3 [120].(downregulated cell cycle progression genes) It remains to be elucidated whether these effects are primary and occur via functional VDREs on regulatory regions of these genes. Another interesting 1,25(OH)2D3 target gene isCCNC. The cyclin C-CDK8 complex was found to be associated with the RNA polymerase II basal transcriptional machinery [123] and is considered to be a functional part of mediator protein complexes that are involved in gene repression [124]. The fact that the CCNC gene, being located inchromosome6q21, is deleted in a subset of acute lymphoblasticleukemias,suggeststhatitmaybeinvolved in tumorigenesis [125]. In addition,growth arrest and DNA-damage-inducible, alpha (GADD45A) and members of the IGFBP gene family also respond to 1,25(OH)2D3 [81,126]. GADD45A plays an essential role in DNA repair and GADD45 proteins displace cyclin B1 from Cdc2 and hus inhibit the formation of M phase-promoting factor that is essential for G2/M transition [127].GADD45Ahas been shown to be a direct transcriptional target of 1,25 (OH)2D3 with a functional VDRE within the fourth exon of the gene [128]. IGFBPs modulate the activity of the circulating insulin-like growth factors (IGF) I and II. The IGFBP3 gene was first discovered to be up-regulated by 1,25(OH)2D3 and contains a functional VDRE [129]. As described above, IGFBP1 and IGFBP5 are also primary 1,25(OH)2D3 target genes [81]. Another interesting primary 1,25(OH)2D3 target is the PPARD gene(PPAR Beta, 'master regulator' of sebocyte profileration and differentiation), which contains a potent DR3-type VDRE in close proximity to its TSS [130]. PPARd and VDR proteins are widely expressed and in an apparent overlap in the physiological action of the two nuclear receptors, both are involved in the regulation of cellular growth, particularly neoplasms. HighPPARDexpression in tumor seems to be positive for the prognosis of associated cancers [131]. Overall, 1,25(OH)2D3 restricts cell cycle progression in several phases via multiple and partially redundant targets on parallel pathways that when combined provide a robust antiproliferative effect. 

Relative Expression of VDR Target Genes The steady state mRNA expression levels of some VDR target genes, such as that of the CYP24A1 gene, are very low in the absence of ligand, but are induced up to 1000-fold by stimulation with 1,25(OH)2D3 [36]. Most other known primary 1,25(OH)2D3 target genes, such asCCNCandCDKN1A, often show an inducibility of twofold or less after short-term treatment with 1,25 (OH)2D3 [132,133]. These latter genes, however, exhibit 10 000e100 000-fold higher(the enzyme that converts Calcitirol to its inactive metabolite- thus rendering circulating Calcitirol biologically incapable of doing anything- even though there has been a study that stated that the inactive metabolite has a still unknown receptor of its own in the bones) basal expression levels as compared to that of theCYP24A1 gene. Thus, when the relative levels are taken into account, two- to 20-fold moreCCNCandCDKN1A thanCYP24A1mRNA mole-cules are produced after induction with 1a,25(OH)2D3.

----------


## eldarlmario

Why only TOPICAL calcitirol or Calcipotriol should be used: 

Topical applications WILL go systemic- but they will affect hair follicles the balding scalp first before some of it goes into the bloodstream and affect the balding skull to enhance bone resorption. 

Oral go both ways but we will all want the hair follciles to be affected first AND this http://en.wikipedia.org/wiki/Vitamin_D-binding_protein is a concern because the scoliosis study stated that VDR has an altered binding site- the above could potentially be the binding sit altered and it might result in calcitirol in the blood stream NOT getting transported to the hair follicles on the balding scalp and http://en.wikipedia.org/wiki/Osteoclast in the balding skull to upregulate CD200 and hence- causing the possible pathologic reason why CD200 is unexpressed in the balding scalp and balding skull. 

So to be safe- topical application will be a better option because it bypasses that step and allows calcitirol(hence- CD200) to be delivered directly to the hair follices.

----------


## eldarlmario

1 potential downside(if any) i can envision from this protocol(Topical Calcitirol+ Leukotriene Antagonists like Singulair aka Montelukast + Crth2 blocker like TM/Seti/Rama?OC)- would be that we might be more susceptible to fungal infections and common ailments like flu, etc- because we are basically weakening our immune system. That is why we want to limit as much of the de-immunising effects to the balding scalp for as much as possible. 

*And i believe that's how our body intended it to be anyway- a more forgiving immune environment on our heads to let our hair grow in peace while protecting the rest of our entire body with upmost due diligence from invaders.*

----------


## eldarlmario

On Calcitirol:

http://www.medscape.com/viewarticle/776915_3 

Thus, VD inhibits the polarization of Th0 cells to either Th1 or -2 cells(inhibits both TH1 and Th2 production) and simultaneously facilitates the converison of naive Th0 cells to Tregs ones, which protect the organism from autoimmune diseases(promotes t cell differentiation to Regulatory t cells instead) (vide supra). Therefore, it is not surprising that Cantorna et al. have found the number of TGF-? transcripts multiplied upon treating mice with D3 simultaneously with blockade of experimentally induced encephalomyelitis.[112] Evidently, the ratio of differentiation of naive T0 cells to Th1 or Treg cells has tremendous clinical significance[113 - 117] since, as discussed above, the formers induce autoimmune disease, while the latter (Treg cells) exert their tolerogenic action by reducing the production of IL-2, as discussed above. Also, the transcription factor Foxp3 and the above mentioned CTL-4 are involved in this process since the inactivation of the latter factor abolishes the tolerogenic action of Tregs, downregulation of the MHC class II complexes and costimulatory ligands as B1, B2 and CD40.[87,88,113 - 117] Interestingly, one of the latter groups found the IL-4, -5, -13 and IFN-? levels decreased during allergic inflammation upon VD treatment.(Calcitirol treatment decreased il-4(the 'master' cytokine in charge of differentiating other cytokines in the TH2 type . Not to be confused with GATA3- who is the master regulator)[113] 

As for the regulatory, that is, tolerogenic T cells, it is important that the 'immunomodulant'[118] VDR favors the differentiation to 'tolerogenic' Tregs, more precisely to CD4+ CD25+ Fox3+ cells producing mainly IL-10, TGF-? but less NF-?B and AP-1 than other T cells.[93,119] Infact, VD also upregulates the expression of CTLA-4 and Foxp3 more exactly CD4+ CD25+ Fox3+ cells.[80] Finally, it is probably worth mentioning that VDR shifts the balance of Th1 versus -2 cells toward the latter(that was the common consensus reached by other studies too). This fact is amply proven by the clinical findings discussed in the second part of the review and some experimental data (vide infra). Nevertheless, this phenomenon does not seem to be quite evident, since VDR inhibits the activity of both the Th1 and -2 cells as discussed below.(This study found that consensus to be contrary) It might probably be explained by the radical reduction of Th1-type cells (vide infra), which under physiological conditions tonically inhibit the Th2 cells, that is, the altered balance might be due to desinhition of Th2 cells.

----------


## eldarlmario

The sum of these events might result in the enhancement of certain Th2 cell functions, that is, an enhanced propensity toward asthma, allergy, eczema and related disorders at least under experimental conditions,[131] but as discussed in the next part of this review, under clinical conditions VD rather suppresses the atopic disorders.(Calcitirol suppresses TH2-mediated immune responses instead of promoting it. Taken in context- this means it suppresses the majority of immune responses in AGA) 

According to several early studies in human T lymphocytes, VD inhibits the production of IgM and IgE(pro-inflammatory Immunogoblin B cells in the blood that mediates allergy responses) by the B cells,[132 - 134] though VD upregulates the GATA-3[135] one of the main transcription factors of Th2 cells. It is tempting to use these experimental findings for interpretation of clinical findings but these studies have not been either repeated or confirmed during the last 20 years. 

Further immune effects of calcitriol include suppression of T lymphocyte proliferation in humans,[129] presumably by inhibition of IL-2 production, inhibition of B-cell proliferation and antibody production by them in humans and animals,[40,134 - 136] and inhibition of chemokine-mediated migration and homing (into the lymph nodes) of naive and effector CD4+ T cells and macrophages due to blocking upregulation of E selectin ligands.[136 - 138] 

A final earlier neglected point is inhibition by VD Th17 cells and IL-17 production. IL-17 as a newly described cytokine was isolated from TCR-C4-CD8- mouse thymocytes by Kennedy et al.[139] still in 1996, but its physiological and pathological significance has been recognized only a decade later. The IL-17-producing CD4+ cells are termed Th17 cells and are considered pathogenic.[140 - 144] Discussed above, Th17 cells are cytotoxic like the Th1 cells but this lineage is not identical to previously known lineages.[140,141,144] The mature Th17 cells are not suppressed by either Th1 or Th2 cytokines and they are independent of the transcription factors of the former T cells.[140] The development of these Th17 cells is inhibited by both IFN-? and IL-4.[140] In one study, the Th1 pathway antagonized the Th17 one[135] but this work has not yet been confirmed. In mice, Treg cells inhibit Th17 cell responses by IL-10.[145] Thus, Th1 and -17 represent different lineages, but their physiological functions are similar and both are antagonized by Treg cells.[140] That is, Treg cells might be physiological antagonists of both subsets of cytotoxic T cells.

----------


## eldarlmario

btw a trivial: 

This seems to fit the theory of those who preach that AGA is atually a condition induced by bacteria on the scalp: 

http://en.wikipedia.org/wiki/Cathelicidin

----------


## eldarlmario

Now as for VD, IL-17 enhances the expression of cathelicidin in human keratinocytes but only in the presence of this vitamin. Otherwise according to some very recent studies, VD also inhibits the Th17-mediated immune functions.[86,155,156] Chang et al. found that in mice, VD inhibited the expression of IL-17 at the level of translation, more precisely via enhanced expression of C/EBP homologous proteins known to inhibit the process of translation and ameliorated experimental encephalomyelitis.[155] VD also inhibits experimental autoimune uveitis by suppressing TH17 polarization.[156] In another study made on stimulated peripheral blood mononuclear cells taken from patients in the early stage of rheumatoid arthritis, VD inhibited the expression of IL-17A, IFN-? and IL-4.[157] VD combined with vitamin A blocked the expression of IL-17 and -23 in both naive and in human CD4+ memory cells.[158] The physiological significance of these findings is proven by the study of Bruce et al. who found that in VDR knockout mice, the number of Th17 cells was higher and the experimentally induced bowel disease was aggravated.[159](in summary- Cacitirol suppresses Th17-mediated autoimmune responses too)

----------


## eldarlmario

Epidemiological & Genetic Data 

Acccording to some recent studies and meta-analyses, serum VD level is reduced in asthma patients and in other diseases accompanied with reduced FEV1, for example, according to the meta-analysis of Paul et al., in the USA 61% of young asthmatics have VD deficiency.[183] Nevertheless, they concluded that "VD supplementation as a preventive or secondary treatment is advisable and must await results of ongoing trials...".[183] Recently, Morales et al. reported that higher maternal circulating VD concentrations were associated with a lower risk of respiratory tract infection in childhood but not with less wheezing and asthma.[184] Thus, the etiological role of VD is not fully proven. However, two groups noted recently that low serum VD level in asthma was associated with impaired lung function, FEV1, airway hyperresponsiveness and reduced therapeutic efficacy of inhaled corticosteroids.[185,186] Wjst et al. came to the conclusion that in spite of the significant influence of external factors such as dietary intake and exposure to sunshine, the serum 25-OH-D3 (calcitriol) level seems to be a heritable trait in families with asthma.[45] *Their conclusion was confirmed by several other groups.*[28,187] Thus, VD hypovitaminosis is really an etiological factor in asthma, which is, however, also dependent on genetic disposition. Therefore, VD supplementation is apparently at the threshold of becoming a standard component of asthma prevention and its secondary/adjunct treatment as put forward by Majak et al..[185] Nevertheless, the situation is complicated by several further confounding factors: 

Low VD serum level is associated with increased airway smooth muscle mass, which is not secondary to asthmatic inflammation, nevertheless it may aggravate the eventually coexisting asthma;[188,189] 

Solar exposure in the vicinity of the equator might be beneficial for increasing the synthesis of VD but the same climate per se favors to allergic sensitization;[190,191] 

VD as an overall immunosuppressant agent might be favorable in asthma treatment but the shift of the Th1/2 balance toward the latter could facilitate the development of asthma; 

Both too low and too high VD levels have been found to enhance sensitization to aeroallergens;[191] 

Finally, an unexplained finding that in the brochoalvelar lavage, but not in the serum, the level of VD binding protein is particularly high in severe therapy-resistant asthma.[192] 

If VD is really linked to the genesis of asthma, the eventual polymorphism of the VDR gene is expected to be associated with the prevalence of asthma. In most related studies, the polymorphism of the VDR gene was examined by restriction enzymes (Bsml, Apal, TaqI and so on).[193] In some studies, the polymorphism of genes coding for the enzymes involved in the synthesis of VD[8,194] has been observed. Certain variants identified by restriction length polymorphism of VDR showed statistically significant but modest correlation with the prevalence of asthma.[195 - 199] Wjst et al. found a single-base variation in the VDR gene upon comparing asthmatic and their unaffected siblings.[198] Thus, they concluded that VDR exerts protective action against asthma. As mentioned above, the genetic polymorphism of VD binding protein in the plasma has been linked to airway diseases.[200] Others detected gene variants expressed in human activated NKT cells or CD8+ lymphocytes.[197] Finally, in a recent study by Bener et al., they found that more than a third of the asthmatic children had positive familial history of asthma and/or VD deficiency.[201] Truly in an earlier work[202] the VDR gene was found associated with asthma. Probably in this earlier work the technique used was not sophisticated enough. (*In summary- Vitamin D deficiency could be the pathological cause of asthma AND AGA because we ARE having 'asthma of the balding scalp. Rememeber- CRTH2 inhibitors are originally designed for asthma and the 'allergen' in AGA is sadly- our hair follicles.*' 

*and the study goes on and on and on(9 pages long) 

So please ready the study yourself and i will just post the conclusion of this study: 
*
Five-year View 
It can be hoped that the public health significance of undiagnosed VD hyopvitaminosis*(suggesting that pathology of AGA could be due to a lack of Cacitirol-activated Cacitirol Receptor levels on the balding scalp)* will be finally recognized first by the medical community then by society in general*(It might be- Multiple ethinc groups living north of the Equator has a lack of vitamin D levels in their body- not to mention that Vitamin D was only originally classed as a vitamin(the name of it already tells us so) before being reclassed as a critical nuclear hormone that has diverse fucntions in the human body- particularly Calcium homeostasis and the Immune system. Coupled with the fact that the Pax1 gene is in charge of sclerotome planning of the spine and skull, and is also expressed on the adult human scalp- there remains the possibility that variants in the region of the Pax1/foxa2 locus is influencing VDR's function(atually it is indeed doing so by altering VDR's 'binding site'- as indicated by the Scoliosis study)- localized to the balding scalp and skull)* Hopefully more and more lay people will understand that VD deficiency is a risk factor of many diseases affecting broad segments of society just as the lack of vitamin C, certain minerals, unhealthy nutrition and so on are detrimental. In an ideal scenario, complaint-free people will be regularly screened not only for hypertension, diabetes and various types of cancer but also for VD hypovitaminosis. Epidemiologists might provide more data on that which factors of living conditions and eating habits contribute to VD hypovitaminosis, which has already reached epidemic proportions.

----------


## eldarlmario

Guys remember i said i was certain i wasnt really imagining things about this chronic and annoying weird inner ear problem i have. Remember I said i had 1)chronic tinnitus, 2)had a nerve'twisted' in my head whenever i adjust my jaw or moved my neck, 3)inner ear pain: 

and i suspect this gene has got to do with it 

H6 family homeobox 2 <====Inner ear and vestibular function (altered gene by the Pax1/Foxa2 AGA/Scoliosis haplotype variant) 

and i've got a slightly-curved spine diagnosed by my school medical team during my elementary school days. 

look what i just found today: 

http://immortalhair.forumandco...oulders-are-misaigned 

"My left shoulder is higher then my right one(*Idiopathic Scoliosis*) and it could be the reason maybe why I had this ringing in my right ear(*Tinnitus*) for 2 years. I did a free chiropractic consultation." 

I thought they were BSing me just to say that for me to come in and make some coin, but I look in the mirror and its pretty noticable, had a family member comment on it the same day and I didnt even tell them about the consultation. 

Anyone here have any experience with one? 



"1)chronic tinnitus, 2)had a nerve'twisted' in my head whenever i adjust my jaw or moved my neck, 3)inner ear pain" 

http://www.youtube.com/watch?v=xoml9njNExI

----------


## eldarlmario

The position of the Atlas influences the entire body 

In a chain-reaction process, a misalignment of the Atlas may cause asymmetries of the entire skeleton, such as one shoulder being higher than the other with pain in the scapula, scoliosis, tilted pelvis with consequent danger of herniated discs (discopathy), pain in the back, hips, knees and even feet. 

As long as postural defects exist, permanent muscular tension develop which, as well as being painful, can cause other vertebrae in the column to become blocked (subluxations). 

The resulting subluxations may create persistent compression on certain nerve roots. More and more frequently doctors use cortisone against those irritations, which is indeed a useful medicament, but which causes severe, well noted side effects in the long term. 

Compression of certain nerves (leads to pins and needles) in arms and legs, while the pressure put on other nerves leads to malfunctions in the corresponding organs. This gives rise to a series of disturbances, even in apparently unrelated areas of the body. 

Enlarged, hardened muscles as a result of constant tension compress lymphatic structures as well as the arteries and veins which run between these muscles. This leads to decreased blood flow and a build-up of metabolic waste products in the tissue. This condition causes a vicious circle, making the muscles even more rigid. 

Certainly, there are other factors to be taken into account which can affect a symmetrical, upright posture of the body. However, misalignment of the Atlas can be absolutely decisive. Experience has shown that in many cases - after a simple correction of the Atlas - the skeleton consequently takes on a more correct and natural shape. 

If one shoulder is higher than the other or the pelvis is tilted, complaints are inevitable, sooner or later. 

everything is true. that's what i have been complaining about the lymph nodes below my jawline and under my ears for a longtime.

----------


## eldarlmario

Atlas Verterba:

----------


## eldarlmario

https://en.wikipedia.org/wiki/Vertebral_artery

----------


## eldarlmario

The topmost area with the veins coloured in yellow is where im having my lifelong-chronic discomfort that began during puberty Guess where 1 of the blood arteries lead to? Yes- the temples

----------


## eldarlmario

This is exciting(again- everything is IMO- and i will explain WHY it's exciting in my next post): 

It proves that we men bald men also have idiopathic scoliosis just as women who carry the pax1/foxa2 AGA/IS haplotype do- just that we have it at the http://en.wikipedia.org/wiki/Atlas_(anatomy) and for myself- i have it further down the spine as well- as in its effects extend downwards to my lower back near the http://en.wikipedia.org/wiki/Lumbar . 

I realised for a long time ago, but never thought much of- that: 

1)my right shoulder is slightly higher than my left and my right chest is bigger than my left 
2)gains from chest workouts is always more prominent on my right chest- to the point that i always do double amount of times to compensate for the left(e.g dumbell lifts for for right = X10, left = x20, pushups = right foot off the ground to focus all the body's weight on the left side to exert more resistance for my left chest) 

3)I could never stand upright 90 degrees- as in i cant do it without exerting extra effort and even so- i cant maintain it for long without experiencing constant strain. Thus, i have a natural tendency to slouch.

----------


## eldarlmario

Malformations in the Atlas verterba could be the origin of AGA. http://en.wikipedia.org/wiki/Vertebral_artery , http://en.wikipedia.org/wiki/Dorsal_root_ganglion and http://en.wikipedia.org/wiki/Lymphatic_vessel (where Lymphocytes are carried in) 

over the entire area where the:



over the top of the skull where it meets 
the http://en.wikipedia.org/wiki/Suture_(joint) for the http://en.wikipedia.org/wiki/Squamou...e_frontal_bone



The upper third of the frontal bone

----------


## eldarlmario

And i said it was exciting because(everything is IMO): 

A thorough examination of the entire http://en.wikipedia.org/wiki/Vertebral_column , especially the Atlas verterba(top of the spine) by a http://en.wikipedia.org/wiki/Neuropathology (Neurosurgeon)or http://en.wikipedia.org/wiki/Orthopedic_surgery (Orthopaedist) could even reveal some results. A correction allignment of the Atlas verterba(or https://en.wikipedia.org/wiki/Cervical_vertebrae) could even potentially 'cure' AGA by decompressing blood vessels, lymphatic vessels and nerves that transport growth factors, carries away lymphatic drainage includingwaste products and restoring ganglion cells functionality to the balding scalp and balding skull.

----------


## eldarlmario

I have difficulty doing this exercise- turning towards my right(but not the left)- specially if i were to move my shoulders too at the same time

----------


## eldarlmario

back to Calcitirol:

1)decreases epidermal kerotinocyte(the skin) differentiation through inhibition of B-catenin BUT; 
2)Increases the differentiation of hair follicles 

"Deletion of VDR resulted in defects in hair differentiation in vivo, with decreased expression of ?-catenin regulated hair differentiation genes such as PADI1, hair keratin KRT31 and calcium binding protein S100a3." <===deletion of VDR = downregulation of S100a3 in hair follicles 


"Thus the major finding of this study is that while 1,25(OH)2D3(Calcitirol)/VDR inhibits the actions of B-catenin to promote keratinocyte(skin cells) proliferation, 1,25(OH)2D3/VDR promotes the ability of B-catenin to stimulate hair follicle differentiation.(inhibits B-catenin destined for the epidermal lineage BUT promotes B-catenin destined for the hair follicle lineage) This article is part of a Special Issue entitled '16th Vitamin D Workshop'." 

http://www.ncbi.nlm.nih.gov/pubmed/24239508 

Taken in context, this mean: 

Calcitriol binded VDR (UP) => thinner skin(not to be confused with fats) and increased hair growth+ S100A3

----------


## eldarlmario

ok just found the reason why Tretinoin stops hair growth- when it will not under certain conditions- as indicated in this study: 

"We discovered that GPRC5D(this is the gene right at the top of Cotsarelis patent indicated as being regulated in haired-scalp- 19.553 folds) expression in HBC could be induced by ATRA*(All-trans-Retinoid-Acid- endogenous form of Tretinoin)* like other RAIG1 family genes Figure 4b (Cheng and Lotan, 1998;Brauner-Osborne and Krogsgaard-Larsen, 2000). We showed that 2 muM ATRA induced expression in a time-dependent manner (day 1, not detected; day 2, about 0.3-fold; day 3, 0.8-fold; day 4, 6.2-fold); however, the expression peaked 2 d after adding 10 muM ATRA and then decreased Figure 4b. The expression threshold was considerably higher than that in the original hair follicles (about 23-fold). The hair matrix cells (not expressing GPRC5D) are proliferating and differentiating into the cortical cells (expressing GPRC5D). When the rate of proliferation is higher than that of differentiation, the cortex continues to grow*(sufficient stem cells = maintained hair grow)*. On the other hand, when the rate of differentiation exceeds that of proliferation, *the growth was stopped because of depletion of stem cells* (=matrix cells). If GPRC5D is a differentiating marker in HBC analysis, its higher expression level might indicate considerably accelerated differentiation by ATRA, the rate of which exceeds that of proliferation. A high concentration of RA is toxic*( possibly why tretinoin inhibits hair growth)* (Beard et al, 2001). Retinoic acids are used to treat alopecia, and are used as a depilatory(*used in those minxodil-containing formulas to grow hair BUT is also used to REMOVE hair)*. Therefore, this transient induction may be due to excessive concentrations of ATRA and parallel the phenomena when ATRA is used as a depilatory.)" 

**So those who wants to remove their chest hair should use 10% tretinoin on their chest- on top of getting a burning itch + dry and painful skin* 

Extremely low dose = gprc5d-inducing- which translates as being beneficial to hair growth. dosage used in study was 2micromolar = 600nanograms/ml in a topical. Rounded up = the nearest would be 1mcg/ml(not even 1mg), assuming we use 1ml spread all over the balding scalp, once/day. 

Generic tretinoin has 0.025% as the lowest dose. Divided by per/ml, this equates to 250mcg/ml. So difference between hair growth-inhibiting + irritating to the skin versus hair growth is 249mcg 

*So basically Dosage is the critical factor that decides hair loss or hair growth.* 

The problem is: 

TATA 
HNF4 
*RAR <=====Retinoid acid Receptor* 
RXRA 
STAT 
BATF 
COMP 
VDR 
HDAC2 
CART1 
FOXA 
FOXP1 
GATA3 
H6 family homeobox 2 
IRF 
PAX5 
P300 

*For all we know, the altered RAR might be over-activated. that might translate into the fact that we have an overexpression of the RAR by ATRA(endogenous) aka Tretinoin(exogenous)- till the point that stem cells are depleted- leading to hair loss on top of causing inflammation and itch with dry skin. Which is why- Tretinoin is a very risky experimental to use- more riskier then calcitirol(which in fact by now- being inclined to overall being beneficial after going all those studies that support its role as being so) for the hair.*

----------


## Seuxin

So....what we should do ??

----------


## eldarlmario

Tissue and cell distribution of VDR 

Adipose Monocytes/Macrophages 
Adrenal Muscle, cardiac 
Bone, osteoblasts Muscle, embryonic 
Brain, general Muscle, smooth 
Brain, amygdale Ovary 
Brain, hypothalamus Pancreas ?-cell 
Brain, glial cells Parathyroid 
Breast Parotid 
Cartilage Pituitary 
Colon Placenta 
Dendritic cells Prostate 
Eggshell gland Retina 
Epididymus, seminiferous tubules Skin 
Gills (fish) Sperm 
Hair follicle Stomach 
Intestine Testis 
Kidney Thymus 
Liver Thyroid 
Lung Tonsils, dendritic cells 
Lymphocytes (B, T) Uterus 
Mast cells Yolk sac

----------


## eldarlmario

CD200(upregulated by calcitriol) +CD49F aka Intergrin A6(upregulated by Tretinoin) reexpression 

"was sufficient to reconstitute a whole follicle"- Dr Cotsarelis.

----------


## eldarlmario

ok i can see why nobody has thought of using topical calcitriol for AGA yet- there are only a few generic brands available. 

Quote Originally Posted by princessRambo View Post 
I am trying it, seeing small pigmented (not vellus, but very dark hair) in a 2 square inch area that was slick bald for years, and i mean slick bald, just buzzed head completely today as i am using the cream and it is difficult to apply when hair gets longer, (scalp solution seems always out of stock in that one online pharmacy), wife told me last night "you hair is getting very dark" and that made me happy [she is the actual princessRambo, her handle, when we play online games, i always thought it hilarious when she kills someone and it says: "you were killed by princessRambo" ] anyway, i think there is something to this, it has been 6 weeks so far, i will keep you posted in a couple months with pictures. I should note that I also take 3000 ml omega 3 (not fish oil amount, but actual quantity of omega 3 ingested), 6gram of evening primrose oil daily and multi vits, but i have been doing that for a while, not sure if that has interfered with the results i am seeing, i thought i would let you guys know that, as a full disclosure. Anyhow, here is a research I found noteworthy: http://www.ncbi.nlm.nih.gov/pubmed/15538745 


http://www.fertstert.org/artic...2(11)02791-9/abstract 

http://informahealthcare.com/doi/abs...90.2012.683079 

This is also an interesting video, please note how he talks about injecting vd3 around 12mn into the video. I think topical cream/solution of calcipotriol can actually reach the derma papilla cell. I am thinking derma roller + calcipotriol, would that work better without inducing hypercalcemia ? 
Really good post Princess! Keep us updated with the results! 


*this gets abit interesting*

----------


## eldarlmario

Regarding FOS- information from another person(not me): 

Definition: 
https://en.wikipedia.org/wiki/C-Fos 

It is involved in important cellular events, including cell proliferation, differentiation and survival; genes associated with hypoxia; and angiogenesis;[8] which makes its dysregulation an important factor for cancer development. It can also induce a loss of cell polarity and epithelial-mesenchymal transition, leading to invasive and metastatic growth in mammary epithelial cells.[9] 

This one is higly connected with cancer. 

The importance of c-fos in biological context has been determined by eliminating endogenous function by using anti-sense mRNA, anti-c-fos antibodies, a ribozyme that cleaves c-fos mRNA or a dominant negative mutant of c-fos. The transgenic mice thus generated are viable, demonstrating that there are c-fos dependent and independent pathways of cell proliferation, but display a range of tissue-specific developmental defects, including osteoporosis, delayed gametogenesis, lymphopenia and behavioral abnormalities.


Lack(and probably low level) of c-FOS leads to osteoporosis 

It was found that overexpression of c-fos from class I MHC promoter in transgenic mice leads to the formation of osteosarcomas due to increased proliferation of osteoblasts whereas ectopic expression of the other Jun and Fos proteins does not induce any malignant tumors. Activation of the c-Fos transgene in mice results in overexpression of cyclin D1, A and E in osteoblasts and chondrocytes, both in vitro and in vivo, which might contribute to the uncontrolled growth leading to tumor. Human osteosarcomas analyzed for c-fos expression have given positive results in more than half the cases and c-fos expression has been associated with higher frequency of relapse and poor response to chemotherapy


Overexpression increase proliferation of osteoblasts 

Several studies have raised the idea that c-Fos may also have tumor-suppressor activity, that it might be able to promote as well as suppress tumorigenesis. Supporting this is the observation that in ovarian carcinomas, loss of c-Fos expression correlates with disease progression. This double action could be enabled by differential protein composition of tumour cells and their environment, for example, dimerisation partners, co-activators and promoter architecture. It is possible that the tumor suppressing activity is due to a proapoptotic function. The exact mechanism by which c-Fos contributes to apoptosis is not clearly understood, but observations in human hepatocellular carcinoma cells indicate that c-Fos is a mediator of c-myc-induced cell death and might induce apoptosis through the p38 MAP kinase pathway. Fas ligand (FASLG or FasL) and the tumour necrosis factor-related apoptosis-inducing ligand (TNFSF10 or TRAIL) might reflect an additional apoptotic mechanism induced by c-Fos, as observed in a human T-cell leukaemia cell line. Another possible mechanism of c-Fos involvement in tumour suppression could be the direct regulation of BRCA1, a well established factor in familial breast and ovarian cancer.


This can also induce apoptosis by MAP kinase pathaway 

L-type Ca(2+) channel activation regulates induction of c-fos transcription by hypoxia. 
http://www.ncbi.nlm.nih.gov/pubmed/10797155 

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.jbc.org/content/266/12/7876.full.pdf 

The promoter region of the c-fos gene is known to contain 
specific regulatory elements that confer responsiveness to 
phorbol esters and calcium ionophores (24-27). Thus activation 
of protein kinase C and increases in cytosolic [Ca"] are 
both capable of inducing c-fos expression.


To assess the importance of Ca2+ mobilization resulting from 
mAChR activation, we used the Ca2+ chelator BAPTA to 
buffer the rise in cytosolic [Ca"]. When cells are loaded with 
20 p~ BAPTA for 30 min, carbachol no longer induces an 
increase in cytosolic calcium (37). In BAPTA-loaded cells, the 
mAChR-mediated increase in c-fos mRNA levels is reduced 
by at least 75% (compare lanes 2 and 4, Fig. 5). These data 
suggest that the increase in cytosolic [Ca'+] resulting from 
stimulation of the mAChR is required to maximally induce cfos 
expression. 
In experiments using PMA and ionomycin we confirm that 
both activation of protein kinase C and increases in intracellular 
[Ca'+] are needed to maximally increase c-fos expression. 
Ionomycin at a concentration of 100 nM causes a rapid and 
transient increase in cytosolic [Ca'+] comparable with that 
induced by carbachol (44).


Increase of intracellular Ca2+ -> increase in c-fos 

Regarding BAPTA- (potential inhibitor of c-fos) 

http://research-repository.uwa...3f7-fb6384dbc8b7).html 

The results confirmed the relationship between EP increase and the fall of scala media CM. One interpretation of these results is that lowering the Ca2+ concentration of endolymph with BAPTA inhibits mechano-electrical transduction in outer hair cells (OHCs) and leaves the hair cell transduction channels in a closed state, thus increasing the resistance across OHCs and increasing the EP.


It seems that BAPTa is bad for tansduction and... 

Effects of extracellular Ca2+ concentration on hair-bundle stiffness and gating-spring integrity in hair?cells 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC23657/ 

When a hair cell is stimulated by positive deflection of its hair bundle, increased tension in gating springs opens transduction channels, permitting cations to enter stereocilia and depolarize the cell. Ca2+ is thought to be required in mechanoelectrical transduction, for exposure of hair bundles to Ca2+ chelators eliminates responsiveness by disrupting tip links, filamentous interstereociliary connections that probably are the gating springs. Ca2+ also participates in adaptation to stimuli by controlling the activity of a molecular motor that sets gating-spring tension. Using a flexible glass fiber to measure hair-bundle stiffness, we investigated the effect of Ca2+ concentration on stiffness before and after the disruption of gating springs. The stiffness of intact hair bundles depended nonmonotonically on the extracellular Ca2+ concentration; the maximal stiffness of ?1200 ?N?m?1 occurred when bundles were bathed in solutions containing 250 ?M Ca2+, approximately the concentration found in frog endolymph. For cells exposed to solutions with sufficient chelator capacity to reduce the Ca2+ concentration below ?100 nM, hair-bundle stiffness fell to ?200 ?N?m?1 and no longer exhibited Ca2+-dependent changes. Because cells so treated lost mechanoelectrical transduction, we attribute the reduction in bundle stiffness to tip-link disruption. The results indicate that gating springs are not linearly elastic; instead, they stiffen with increased strain, which rises with adaptation-motor activity at the physiological extracellular Ca2+ concentration


and now the bad news 

Intracellular calcium chelator BAPTA protects cells against toxic calcium overload but also alters physiological calcium responses. 
Collatz MB1, Rüdel R, Brinkmeier H. 
Author information 
Abstract 
The effect of the membrane-permeant calcium chelator 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA/AM) on ionomycin-induced cellular calcium overload was studied in single differentiated NH15-CA2 neuroblastoma x glioma hybrid cells. To monitor [Ca2+]i we used the fluorescent indicator Fura-2. Preincubation of the cells with 3 microM BAPTA/AM reduced the number of cells showing deregulation of [Ca2+]i during ionomycin-induced calcium influx. The calcium transients elicited by application of KCl were also severely affected by the chelator. These transients, although varying from cell to cell in shape, amplitude and duration, are well reproducible in individual cells. After incubation of cells for 1 h with 0.3-30 microM BAPTA/AM the time course of these cellular transients was markedly slowed. At 1 microM BAPTA/AM, the time constant of decline of [Ca2+]i was increased by a factor of 4.1 +/- 2.4 (n = 14) and the amplitude was reduced to about 50%. With 30 microM BAPTA/AM, the K(+)-induced calcium transients were almost completely inhibited. We conclude that intracellularly loaded calcium chelators may be used for the prevention of [Ca2+]i-induced cell damage, however, at the expense of a disturbed calcium signalling


*In summary: I have found that BAPTA inhibit c-fos and that Ca2+ induce c-fos, unfotunetely BAPTA disturbe calcium signaling, thus BAPTA is Calcitriol antagonist - it inhibit intracelular Ca2+ :/ I ve also found that Ca2+ is crucial for mechanoelectrical tranduction of hair cells, so this is another + for calcitiol <*

*c-FOS(pro-apoptotic protein) is regulated in bald-scalp
high Ca2(intracellular calcium) levels => c-FOS upregulation*

----------


## eldarlmario

there are tons and tons and tons and tons of generic calcitriol easily available everywhere: 

38 pages of generic ORAL calcitirol here in the Indian generics pharmaceuticals industry 

http://www.mims.com/India/drug.../?q=calcitriol&page=0 

YET until the post anecdote linked above from ***alk, we have not head of calcitirol-induced hair regrowth in AGA-individuals anywhere- what does this tells us?? 

it proves that the hypothesis about this http://en.wikipedia.org/wiki/Vitamin_D-binding_protein might indeed be the reason why Calcitirol-binded VDR on the balding scalp is downregulated- It's not getting transported to the balding scalp/skull(but is normally expressed else where in the body) in AGA individuals. 

Vitamin D-bind protein:

----------


## eldarlmario

_"This is also an interesting video, please note how he talks about injecting vd3 around 12mn into the video. I think topical cream/solution of calcipotriol(http://en.wikipedia.org/wiki/Calcipotriol) can actually reach the derma papilla cell. I am thinking derma roller + calcipotriol, would that work better without inducing hypercalcemia ? 
Really good post Princess! Keep us updated with the results!" 
_
Calcipotriol 
From Wikipedia, the free encyclopedia 
Calcipotriol 
Calcipotriol.svg 
Systematic (IUPAC) name 
(1R,3S,5E)-5-{2-[(1R,3aS,4Z,7aR)-1-[(2R,3E)-5-cyclopropyl-5-hydroxypent-3-en-2-yl]-7a-methyl-octahydro-1H-inden-4-ylidene]ethylidene}-4-methylidenecyclohyytyexane-1,3-diol 
Clinical data 
Trade names	Daivobex, Dovobex, Sorilux 
AHFS/Drugs.com	monograph 
MedlinePlus	a608018 
Pregnancy 
category	
AU: B3 
US: C (Risk not ruled out) 
Legal status	
AU: Prescription Only (S4) 
CA: ?-only 
UK: Prescription-only (POM) 
US: ?-only 
Routes of 
administration	Topical 
Pharmacokinetic data 
Bioavailability	5 to 6% 
Metabolism	Hepatic 
Excretion	Biliary 
Identifiers 
CAS Registry Number	112965-21-6 Yes 
ATC code	D05AX02 
PubChem	CID: 5288783 
IUPHAR/BPS	2778 
DrugBank	DB02300 Yes 
ChemSpider	4450880 Yes 
UNII	143NQ3779B Yes 
KEGG	D01125 Yes 
ChEBI	CHEBI:50749 Yes 
ChEMBL	CHEMBL100918 
Chemical data 
Formula	C27H40O3 
Molecular mass	412.605 g/mol 
SMILES[show] 
InChI[show] 
(what is this?) (verify) 
Calcipotriol (INN) or calcipotriene (USAN) is a synthetic derivative of calcitriol, a form of vitamin D. It is used in the treatment of psoriasis, marketed under the trade name "Dovonex" in the United States, "Daivonex" outside of North America, and "Psorcutan" in Germany. This medication is safe for long-term application in psoriatic skin conditions. 
Contents [hide] 
1 Medical uses 
2 Adverse effects 
2.1 Contraindications 
2.2 Interactions 
3 Mechanism 
4 References 
5 External links 
Medical uses[edit] 
Chronic plaque psoriasis is the chief medical use of calcipotriol.[1] It has also been used successfully in the treatment of alopecia areata.[2] 

Adverse effects[edit] 
Adverse effects by frequency:[1][3][4][5] 
Very common (> 10% frequency) 
Burning 
Itchiness 
Skin irritation 
Common (1 - 10% frequency) 
Dermatitis 
Dry skin 
Erythema 
Peeling 
Worsening of psoriasis including facial/scalp 
Rash 
Uncommon (0.1 - 1% frequency) 
Exacerbation of psoriasis 
Rare (< 0.1% frequency) 
Allergic contact dermatitis 
Hypercalcaemia 
Photosensitivity 
Changes in pigmentation 
Skin atrophy 

Mechanism[edit] 
The efficacy of calcipotriol in the treatment of psoriasis was first noticed by the observation of patients receiving various forms of vitamin D in an osteoporosis study. Unexpectedly, some patients who also suffered from psoriasis experienced dramatic reductions in lesion counts.[6] 
The precise mechanism of calcipotriol in remitting psoriasis is not well understood. However, it has been shown to have comparable affinity with calcitriol for the vitamin D receptor (VDR), while being less than 1% as active as the calcitriol in regulating calcium metabolism. The vitamin D receptor belongs to the steroid/thyroid receptor superfamily, and is found on the cells of many different tissues including the thyroid, bone, kidney, and T cells of the immune system. T cells are known to play a role in psoriasis, and it is thought that the binding of calcipotriol to the VDR modulates the T cells gene transcription of cell differentiation and proliferation related genes. 




*Normally, from my own experience of reading up information on experimental meds that might help hairloss- you would expect it's warnings/cautions section to include 'hair loss' as a potential side/adverse effect. 

Surprisingly- Calcipotriol doesnt. 
*

----------


## eldarlmario

ok perhaps this is why ketoconazole makes hair thin and brittle after the initial illusive-thickness-giving effect: 

http://www.ncbi.nlm.nih.gov/pubmed/20870877 

"regulation of the hypoxic response in Candida albicans. 
Synnott JM1, Guida A, Mulhern-Haughey S, Higgins DG, Butler G. 
Author information 
Abstract 
The regulation of the response of Candida albicans to hypoxic (low-oxygen) conditions is poorly understood. We used microarray and other transcriptional analyses to investigate the role of the Upc2 and Bcr1 transcription factors in controlling expression of genes involved in cell wall metabolism, ergosterol synthesis, and glycolysis during adaptation to hypoxia. Hypoxic induction of the ergosterol pathway is mimicked by treatment with sterol-lowering drugs (ketoconazole) and requires UPC2. Expression of three members of the family CFEM (common in several fungal extracellular membranes) of cell wall genes (RBT5, PGA7, and PGA10) is also induced by hypoxia and ketoconazole and requires both UPC2 and BCR1. Expression of glycolytic genes is induced by hypoxia but not by treatment with sterol-lowering drugs, whereas expression of respiratory pathway genes is repressed. However, Upc2 does not play a major role in regulating expression of genes required for central carbon metabolism. Our results indicate that regulation of gene expression in response to hypoxia in C. albicans is complex and is signaled both via lowered sterol levels and other unstudied mechanisms. We also show that induction of filamentation under hypoxic conditions requires the Ras1- and Cdc35-dependent pathway." 

*It increases c-fos expression because of high Ca2 levels in balding scalp despite inducing hypoxia- and that leads down the pro-apoptosis pathway instead of the pro-survival pathway*

----------


## eldarlmario

From another person(not me)

Prolonged Expression of c-fos Suppresses Cell Cycle Entry of Dormant Hematopoietic Stem Cells 

http://www.bloodjournal.org/co...3/816?sso-checked=true 

The proto-oncogene c-fos was transiently upregulated in primitive hematopoietic stem (Lin?Sca-1+) cells stimulated with stem cell factor, interleukin-3 (IL-3), and IL-6. To investigate a role of the c-fos in hematopoietic stem cells, we used bone marrow (BM) cells from transgenic mice carrying the c-fos gene under the control of the interferon-?/? - inducible Mx-promoter (Mx - c-fos), and fetal liver cells from c-fos - deficient mice. Prolonged expression of the c-fos in Lin?Sca-1+ BM cells inhibited factor-dependent colony formation and hematopoiesis on a stromal cell layer by keeping them at G0/G1 phase of the cell cycle. These Lin?Sca-1+ BM cells on a stromal layer entered into the cell cycle whenever exogenous c-fos was downregulated. However, ectopic c-fos did not perturb colony formation by Lin?Sca-1+ BM cells after they entered the cell cycle. Furthermore, endogenous c-fos is not essential to cell cycle progression of hematopoietic stem cells because the factor-dependent and the stroma-dependent hematopoiesis by Lin?Sca-1+ fetal liver cells from c-fos - deficient mice was not impaired. These results suggest that the c-fos induced in primitive hematopoietic stem cells negatively controls cell cycle progression and maintains them in a dormant state 

The c-fos proto-oncogene, one of the immediate early genes, is transiently expressed on stimulation by external stimuli leading to cell cycle progression.10 Its product (c-Fos) forms a complex with the product of another proto-oncogene c-jun (AP-1) that regulates expression of AP-1 - binding genes at their transcriptional level.10-12 Thus, c-Fos may play a key role in the transduction of signals induced by external stimuli.12-14 c-Fos is known to be critical for the G0/G1 transition and cell cycle progression in fibroblasts.13 14The overexpression of c-fos in transgenic mice leads to a deregulated bone growth and results in sarcomas,15 16 and the overexpression in several cell lines leads to acceleration of cell cycle progression.17 18 On the contrary, overexpression of c-Fos negatively regulates cell cycle progression in some cell types.19 Thus, functions of c-Fos in cell cycle progression have remained open to question..


So this one definitely needs to be downregulated. However I was hoping that there wont be a need for that - c-fos is closely connected to cancer and after reading many studies - it should be balanced becouse under and overexpression leads to tumor... 

Because prolonged expression of c-fos inhibits G0/G1 transition of dormant hematopoietic stem cells in both cytokine-dependent (Figs 2 to 5) and stroma-dependent (Fig 8) hematopoiesis, downregulation of the c-fos may initiate G0/G1 transition. Indeed, cell proliferation began in the stem cell culture from Mx - c-fos mice whenever addition of IFN-?/? to the culture was stopped (Fig 8). Therefore, c-Fos may be a gate keeper for cell cycle entry of dormant hematopoietic stem cells.


In summary, the c-fos was transiently induced in primitive hematopoietic stem cells stimulated with SCF, IL-3, and IL-6. The prolonged expression of c-fos inhibited cell-cycle entry of primitive hematopoietic stem cells stimulated with SCF, IL-3, and IL-6 as well as in case of cultures on a stromal cell layer. Hematopoietic stem cells with the c-fos expression in culture survived in a dormant state and entered the cell cycle after c-fos was downregulated. We propose that c-Fos plays the role of gate keeper in cell cycle progression of dormant hematopoietic stem cells.

----------


## eldarlmario

This is exciting: 

From Dr Cotsarelis's patent: 

Example 2 Suprabasal Bulge Cells, But Not HF Stem Cells, are Depleted in Bald Scalp 
To determine whether destruction of HF stem cells accounted for follicle miniaturization, immuno-histochemical staining was performed on bald scalp with an antibody to KRT15, a marker for follicle stem cells. KRT15(Keratin15- hair follcile progenitor stem cell marker) expression was detected in the miniaturized follicles (FIG. 1C). To determine whether bald scalp exhibited changes in stem cell number, keratinocyte suspensions were stained for KRT15 and FST protein (both intracellularly) and were subjected to flow cytometry to identify bulge follicle stem cells. FST is also a marker for HF stem cells. Cells were also stained for the basal cell marker alpha-6 integrin. 

Cells were effectively permeabilized, as evidenced by the staining of over 90% of cells with antibodies against actin, in contrast to minimal staining from an unrelated isotype antibody (FIG. 2A). A high degree of overlap was observed between KRT15 and FST staining, with comparatively fewer single positive cells (KRT15+/FST? or KRT15?/FST+) than double positive or double negative cells (KRT15+/FST+ or KRT15?/FST?) as shown by the slope of the KRT15 vs. FST plot, which was close to 1 (FIG. 2B). Haired samples from each patient yielded similar results. 

Percentages of HF stem cells in the basal layer of the bulge, defined as KRT15+ or FST+ and alpha-6 integrin+, were similar between haired and bald scalp for all three paired samples (FIG. 2). The percentage of the KRT15+/alpha-6 integrin+ population in the haired and bald scalp was, respectively, 2.12 vs. 2.39 in the 1st patient (FIG. 2C); 2.05 vs. 2.55 in the 2nd patient. Similarly, in the 3rd patient, the percentage of the FST+/alpha-6 integrin+ populations in haired and bald scalp were 1.52% vs. 1.38% (FIG. 2D). Thus, the number of follicular stem cells in bald versus non-bald scalp was essentially constant. 

The KRT15+ and FST+ populations differed between the bald and haired scalp with respect to the distribution of alpha-6 integrin+ cells. Fewer alpha-6 integrin? cells were found in the stem cell compartment of bald scalp. The percentages of the KRT15+/alpha-6 integrin? population were 0.7% and 0.26% in haired and bald scalp, respectively, and the FST+/alpha-6 integrin? population were 0.96% to 0.45%, respectively. Thus the ratio of KRT15+/alpha-6 integrin+ to KRT15+/alpha-6 integrin? increased from 2.17 to 5.3 between haired and bald scalp, and the ratio of FST+/alpha-6 integrin+ to FST+/alpha-6 integrin? cells increased from 2.2 to 5.3. The 3rd subject exhibited a similar 2-fold increase in the ratio of KRT15+/alpha-6 integrin+ to KRT15+/alpha-6 integrin? cells (1.55 vs. 2.97). 

Thus, bald scalp exhibited a relative decrease in the proportion of alpha-6 integrin negative cells within the stem cell compartment. 

And look at this:

----------


## eldarlmario

http://www.ncbi.nlm.nih.gov/pubmed/17199579 

A double-blind, randomized quantitative comparison of calcitriol ointment and calcipotriol ointment on epidermal cell populations, proliferation and differentiation. 
Körver JE1, Vissers WH, van Rens DW, Pasch MC, van Erp PE, Boezeman JB, van De Kerkhof PC. 
Author information 
Abstract 
BACKGROUND: 
Calcitriol and calcipotriol are widely used in the topical treatment of psoriasis. However, studies comparing both treatment modalities are scarce. Especially, there are almost no studies comparing the effects on epidermal cell populations in a quantitative manner. 

OBJECTIVES: 
The aim of this study was to quantitatively compare the effects of topical calcitriol and topical calcipotriol on clinical scores and epidermal subpopulations. 

PATIENTS AND METHODS: 
From five patients with stable plaque psoriasis, skin biopsies were taken from two symmetrical regions on the trunk or extremities before and after treatment with either calcitriol or calcipotriol. Frozen sections were labelled immunofluorescently using direct immunofluorescence for beta-1 integrin and the Zenon labelling technique for keratin (K) 6, K10 and K15. The digital photographs of the stained sections were quantitatively analysed and the results of both treatments were compared. 

RESULTS: 
The clinical SUM-score improved significantly for both the calcitriol- and the calcipotriol-treated lesions. In the calcipotriol-treated group the expression of K10 and *K15increased**(hair follicle stem cell marker)* and the expression of K6 decreased significantly. No changes were seen for the marker beta-1 integrin. In the calcitriol-treated group none of the markers changed significantly. A tendency towards significance was seen for the changes in the expression of K6 and K15 in favour of calcipotriol. 

CONCLUSIONS: 
Both calcitriol and calcipotriol gave a significant improvement in clinical scores. However, treatment with calcipotriol resulted in a normalization of K6, K10 and K15, whereas treatment with calcitriol did not. Comparison of both treatments showed a tendency towards significance for the above-mentioned markers for calcipotriol only.

----------


## eldarlmario

more exciting news: 

http://www.ncbi.nlm.nih.gov/pubmed/17517646 

Vitamin D receptor is essential for normal keratinocyte stem cell function. 
Cianferotti L1, Cox M, Skorija K, Demay MB. 
Author information 
Abstract 
The major physiological role of the vitamin D receptor (VDR) is the maintenance of mineral ion homeostasis. Mutation of the VDR, in humans and mice, results in alopecia. Unlike the effects of the VDR on mineral ion homeostasis, the actions of the VDR that prevent alopecia are ligand-independent. Although absence of the VDR does not prevent the development of a keratinocyte stem cell niche in the bulge region of the hair follicle, it results in an inability of these stem cells to regenerate the lower portion of the hair follicle in vivo and impairs keratinocyte stem cell colony formation in vitro. *(CD34 impairment)* VDR ablation is associated with a gradual decrease in keratinocyte stem cells, accompanied by an increase in sebaceous activity*(sounds familar)*, a phenotype analogous to that seen with impaired canonical Wnt signaling*(familiar also)*. Transient gene expression assays demonstrate that the cooperative transcriptional effects of beta-catenin and Lef1 are abolished in keratinocytes isolated from VDR-null mice, revealing a role for the unliganded VDR in canonical Wnt signaling. Thus, absence of the VDR impairs canonical Wnt signaling in keratinocytes and leads to the development of alopecia due to a defect in keratinocyte stem cells.

----------


## eldarlmario

"However, by 9 months of age, while CD34 immunoreactivity was preserved in the bulge region of the hair follicles of the wild-type mice (Fig. 3D), it was not present in VDR-null mice"(hair follces becomes 34(-)) 

Because these bulge cells make up a small percentage of the keratinocyte population in the skin of mice and are characterized by the expression of both CD34 and A-6 integrin(there u go), cell sorting was performed to address whether the marked impairment of colony formation in the keratinocytes of the 28-day-old VDR-null mice was due to a decrease in the number of KSCs residing in the bulge or a functional abnormality of these cells. Consistent with the normal CD34 immunoreactivity (Fig. 3) of the bulge area in the VDR-null mice at 1 month of age, the number of doubly labeled cells detected by FACS analysis at this age was not significantly altered (Fig. 4A). These data strongly suggest that the KSCs in the VDR-null mice have an altered lineage progression or an altered ability to proliferate (or self-renew or survive) because they are unable to give rise to large stem cell colonies in vitro when placed in culture and are unable to generate functional hair follicles in vivo at a point in time when their numbers are apparently unaffected. It is notable that, with aging, there is a progressive decline in the number of doubly labeled cells in the VDR-null mice due to a marked decrease in CD34-positive cells (Fig. 4 A and C), confirming the lack of CD34 immunoreactivity seen at 9 months of age in the skin of the VDR-null mice (Fig. 3E). These data suggest that KSC self-renewal is impaired by the lack of a functional VDR. To determine whether the lack of VDR expression specifically in the keratinocyte component of the hair follicle is responsible for this reduction in CD34/A-6 integrin-positive cells with age, the KSC number was evaluated in VDR-null mice expressing the K-14 VDR transgene. As indicated in Fig. 4 A and D, the number of doubly labeled KSCs in VDR-null mice expressing the K-14-VDR transgene is not significantly different from that of their wild-type littermates at 1, 3.5, or 9 months of age.

----------


## eldarlmario

Abstract 
BACKGROUND: 
Calcitriol and calcipotriol, two vitamin D derivatives, are available for topical treatment of psoriasis and have been shown to be effective. 

AIM: 
To compare the efficacy and safety of calcitriol 3 microg/g and calcipotriol 50 microg/g. 

METHODS: 
This was a multicentre, randomized, investigator-masked, and parallel comparison in subjects with mild to moderate chronic plaque-type psoriasis receiving either calcitriol or calcipotriol ointment twice daily for 12 weeks. Efficacy evaluations comprised global improvement (on a 4-point scale from 0: no change or worse, to 3: clear or almost clear) assessed by the investigator and by the subject. Efficacy further included the 'dermatological sum score' at each study visit. Safety evaluations included adverse event reporting, cutaneous safety assessed by the investigator and cutaneous discomfort assessment by the subject (both on a 5-point scale from 0: none, to 4: very severe). 

RESULTS: 
A total of 250 subjects of both gender were recruited. At week 12, the LSmean score of global improvement rated by the investigator was 2.27 for calcitriol and 2.22 for calcipotriol. This difference was not statistically significant, with calcitriol demonstrating to be non-inferior to calcipotriol for global improvement. This same parameter was scored by the subject, with a mean of 2.12 for calcitriol and 2.09 for calcipotriol. The percentage of patients with at least marked improvement tended to be in favour of calcitriol (95.7% vs. 85% for calcipotriol). However, differences were not statistically significant. The mean worst score for the cutaneous safety assessment was higher in the calcipotriol group (0.3 vs. 0.1 and 0.4 vs. 0.2, by the investigator and the patient, respectively). These differences were statistically significant in favour of a better safety profile for calcitriol (P=0.0035). Fourteen dermatological and treatment-related adverse events were reported with calcipotriol vs. only five with calcitriol for a total of 22 adverse events reported throughout the study. 

CONCLUSION: 
Calcitriol administered twice daily over a 12-week treatment period demonstrated similar efficacy to calcipotriol, while showing a significantly better safety profile. 

*Conclusion = Both are effective with insignificant differences with regards to efficacy- but Calcitriol was better tolerated than Calcipotriol*

----------


## eldarlmario

ok i believe i know the reason why topical calcitirol hasnt been throughly investigated for AGA yet- its only indication is psoriasis- a chronic itch condition. and others studies have stated that it has a very low systemic profile when used topically(so low chances for the active to reach the balding scalp- if any). this means the subjects using it were using it on their bodies instead of the scalp(if any of them were having AGA-that is) and would hardly notice anything on their scalp.

----------


## eldarlmario

FOSB: 

FBJ murine osteosarcoma viral oncogene homolog B, also known as FOSB or FosB, is a protein that, in humans, is encoded by the FOSB gene.[1][2][3] 
The FOS gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation.[1] FosB and its truncated splice variants ?FosB and (further truncated) ?2?FosB are all involved in osteosclerosis(Elevated bone density- and FOSB is elevated in bald scalp), even though ?2?FosB lacks a known transactivation domain, preventing it from affecting gene transcription through the AP-1 complex.[4] 
The ?FosB splice variant has been identified as playing a central, crucial (necessary and sufficient)[5][6] role in the development and maintenance of pathological behavior and neural plasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions.[5][7][8] E.g., ?FosB overexpression causes the development addiction-related structural neuroplasticity to occur throughout the reward system.[9] ?FosB differs from the full length FosB and further truncated ?2?FosB in its capacity to produce these effects, as only accumbal ?FosB overexpression is associated with pathological responses to drugs.[10] 

In the animal kingdom(in humans with AGA too) there also exists a non-pathological form of osteosclerosis, resulting in unusually solid bone structure with little to no marrow. It is often seen in in aquatic vertebrates,(and on the heads of AGA-stricken men too) especially those living in shallow waters,[5] providing ballast as an adaptation for an aquatic existence. It makes bones heavier, but also more fragile. In those animal groups osteosclerosis often occurs together with bone thickening (pachyostosis). This joint occurrence is called pachyosteosclerosis.

----------


## eldarlmario

ok looks like FOSB is involved with addiction- increased urge and propensity to scratch our heads due to the good-feeling reward that it gives?(that's what im experiencing a couple of hours just before my next topical dose after i got home from work- the more i scratch- the better it feels and the more and more i wanna keep scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and scratching and srcatching and scratching

----------


## ppxrare

wow..... you need to take a break

----------


## eldarlmario

andddddd here's the solution: 

?FosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.[34] Current medical reviews of research involving lab animals have identified that a drug class - class I histone deacetylase inhibitors(Valproic acid- and it activates wnt/b-catenin pathway, but inhibits HDAC2) (HDACi)[note 2] - that indirectly inhibits the function and further increases in the expression of accumbal ?FosB by promoting accumbal G9a expression.[9][32][35][36] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid)(this is atually the precursor of the 'date-rape drug' http://en.wikipedia.org/wiki/Gamma-Hydroxybutyric_acid ) for an extended period indicate that class I HDACis, and butyrate salts in particular, have efficacy in reducing addictive behavior in lab animals[note 3] that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates;[32][36][37] however, as of August 2015 no clinical trials involving human addicts and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.

----------


## eldarlmario

lol wtf i have this: 

Neural and behavioral effects of validated FosB transcriptional targets[5][13] 
Target 
gene	Target 
expression	Neural effects	Behavioral effects 
c-Fos	Molecular switch enabling the chronic 
induction of FosB[note 4]	- 
dynorphin	? 
[note 5]	. Downregulation of ?-opioid feedback loop	. Increased drug reward 
NF-?B	?	. Expansion of Nacc dendritic processes 
. NF-?B inflammatory response in the NAcc 
. NF-?B inflammatory response in the CP 
. Increased drug reward 
. Increased drug reward 
. Locomotor sensitization ( http://en.wikipedia.org/wiki/Stereotypy - but mine's very mild- more like a tic as in i have an irresistable urge to make a 'sharp woo!' sound for no reason- and my family's used to me doing that ) 
GluR2	?	. Decreased sensitivity to glutamate	. Increased drug reward 
Cdk5	?	. GluR1 synaptic protein phosphorylation 
. Expansion of NAcc dendritic processes	. Decreased drug reward 
(net effect) 

http://en.wikipedia.org/wiki/Stereotypy

----------


## eldarlmario

Seems like we need to INHIBIT HDAC2(Valproic acid is a class 1 HDAC inhibitor) instead: 

http://journals.plos.org/ploso.../journal.pone.0034152 


Valproic Acid Induces Hair Regeneration in Murine Model and Activates Alkaline Phosphatase Activity in Human Dermal Papilla Cells 

Abstract 

Background 

Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA), a GSK3? inhibitor that activates the Wnt/?-catenin pathway, to promote hair re-growth in vitro and in vivo. 

Methodology/ Principal Findings 

Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP). VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/?-catenin pathway, whereas minoxidil (MNX), a drug commonly used to treat alopecia, did not significantly affect the Wnt/?-catenin pathway. VPA analogs and other GSK3? inhibitors that activate the Wnt/?-catenin pathway such as 4-phenyl butyric acid, LiCl*(Lithium chloride)*, and BeCl2 also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice. 

Conclusions/ Significance 

*Our findings indicate that small molecules that activate the Wnt/?-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth.* 

*Results 

Valproic Acid Promotes Hair Re-Growth and Induces Terminally Differentiated Hair Markers in Vivo* 

We tested the hair re-growth activity of LiCl and VPA, two chemical activators of the Wnt/?-catenin pathway [25], [26]. VPA or LiCl was topically applied daily onto the backs of C3H mice at different concentrations to determine the optimal concentration for each agent. MNX was separately applied as a positive control. The mice treated with 1 M LiCl or 500 mM VPA showed hair growth phenotypes (Figures S1A and S1B). Especially, VPA promoted hair re-growth as efficiently as MNX after 28 d (Figure 1A). The hair follicles of mice treated with VPA or MNX entered anagen phase, whereas hair follicles in the control group treated with vehicle solution remained in telogen phase (Figure 1A, data for different drug treatment times are shown in Figure S2A). The histomorphometrical analyses showed that VPA promoted telogen-anagen transition (Figure 1B). Especially, the hair follicles of mice treated with VPA were transformed to middle- or late-anagen (Figure 1B). Immunohistochemical analysis confirmed that expression of filaggrin and loricrin was increased by VPA or MNX (Figure 2A, data for different drug treatment times are shown in Figures S2B and S2C). We did not observe any significant abnormal phenotypes in the epidermis, hair follicles, or other skin structures aside from hair re-growth following application of VPA or MNX (Figure 1A). In contrast to the epidermis of mouse skin treated with VPA, skin that was treated with LiCl revealed critical abnormal changes including an increase in the thickness of the epidermis*(note that Topical Calcitriol/Calcipotriol inhibits skin thickness too)* (Figure S3), where expression of filaggrin, loricrin, and keratin 14 was also abnormally elevated as shown by immunohistochemistry (Figure S3). 

Valproic Acid Activates the Wnt/?-Catenin Pathway in Addition to the Erk and Akt Pathways 

The expression of ?-catenin in mouse skin was significantly increased by application of VPA, but only slightly increased by MNX*(So i guess we can assume this is gonna grow more than just baby hairs on the hairline- which is what Minoxidl sulfate is ONLY doing)* (Figure 2A). MNX is known to promote hair re-growth via the Erk and Akt pathways, which are involved in the regulation of proliferation in dermal papilla cells of the hair follicle [27]. Interestingly, the activities of both Erk and Akt*(Via Adenosine A2B Via IGF1 and IGF2 Via IGF-1 receptor 1 and 2)* were similarly enhanced by treatment with either VPA or MNX (Figure 2A). The expression level of the proliferation marker PCNA was increased by application of VPA or MNX compared to control skin (Figure 2A). Thus, VPA up-regulates the Wnt/?-catenin pathway in addition to the Erk and Akt pathways, but via a different mechanism*(maybe using a different pathway is the reason for the 'better growth' than Minoxidil?)*. 

To examine the short-term effects of VPA on hair re-growth, we analyzed the skin of C3H mice after application of VPA or MNX for 7 d. The thickness of the epidermis increased slightly and the number of hair follicles increased 7 d after application of VPA or MNX (Figure S4A, upper panel). Immunohistochemical analysis showed that keratin14 expression was increased following a 7 d application of VPA or MNX (Figure S4A, lower panel), although the level of keratin14 was not changed 28 d application of VPA or MNX (Figure 2A). Interestingly, VPA, but not MNX, greatly increased the expression of ?-catenin in the hair follicles of C3H mice (Figure 2B). We also observed significant induction of ALP in the dermal papilla following application of VPA, but not MNX (Figures 2B and S4B). Moreover, we confirmed specific activation of the Wnt/?-catenin pathway in the pre-cortex regions [4] of the skin of TOP-Gal Wnt reporter mice treated for 7 d with VPA, but not MNX (Figure S4C). *Interestingly, Keratin 15 and CD34, the hair follicular stem cell markers, were induced in bulge cells by application of VPA for 7 d* (Figure 2C), but not by application of MNX*(Inferring that results could be seen in a shorter amount of time than Minxodil-which is by my own experience- 3weeks for oral and 8weeks for topical for Minoxidil SULFATE)*. 

Valproic Acid, but not MNX, Up-Regulates the Wnt/?-Catenin Pathway and ALP Activity in Human Dermal Papilla Cells 

To identify whether VPA can activate the Wnt/?-catenin pathway in human systems, we used an in vitro culture system of human dermal papilla cells. The expression level of ?-catenin was greatly increased by treatment with VPA, but not MNX for 72 h (Figures 3A and S5). Similarly, expression of both BMP4 and ALP was increased by VPA, but not MNX (Figures 3A and S5). We also confirmed significant activation of ?-catenin and BMP4 in human dermal papilla cells treated with VPA by immunocytochemistry, and again those changes were not observed following treatment with MNX (Figure 3B). To evaluate the effect of VPA or MNX on the regulation of ALP activity, we used human dermal papilla cells at passage 11 that showed very weak ALP activity. We observed a significant increase in ALP activity following treatment with VPA, but not MNX (Figure 3C). Moreover, the induction of ALP activity by VPA was blocked by noggin, a BMP4 antagonist (Figure 3D). To confirm the role of the Wnt/?-catenin pathway in the activation of ALP, we measured the effects of Wnt3a, BMP4, or epidermal growth factor (EGF) ligand on ALP. Expression of both ALP and ?-catenin was significantly increased by treatment with Wnt3a or BMP4 in a concentration-dependent manner, whereas these changes were not significantly induced by treatment with EGF (Figure 3E). The specific activation of ALP by Wnt3a and BMP was also confirmed by a direct assay 

To confirm the role of the Wnt/?-catenin pathway in hair re-growth, we tested the effects of drugs that regulate the Wnt/?-catenin pathway on hair re-growth in mice. Beryllium chloride (BeCl2), LiCl (an alternative GSK3? inhibitor), and several derivatives of VPA including 4-phenyl butyric acid (PBA) and 2-ethyl butyric acid (EBA) were tested for their effects on hair re-growth. PBA or EBA induced hair re-growth after topical application to the back of C3H mice for 28 d (Figure 4A, first row panel). The levels of ?-catenin were increased by treatment with PBA, but not EBA (Figure 4A, second row panel). The hair follicles of skin tissues treated with PBA or EBA entered anagen phase as shown by H&E staining (Figure 4A, third row panel). Histomorphometrical analysis revealed that PBA and EBA also induced telogen-anagen transition (Figure 4B). LiCl or BeCl2 also induced hair re-growth after 35 d although its hair growing activity was mild (Figure S6A, first row panel). Treatment with LiCl or BeCl2 increased the levels of ?-catenin and accelerated hair cycle into the anagen phase (Figure S6A, second row panel and third row panel). However, the thickness of the epidermis was increased in skin treated with BeCl2 or PBA compared to control skin, as previously described for LiCl application. The expression of filaggrin and loricrin was abnormally increased by application of BeCl2, similar to the effect of LiCl (Figure S6B). However, the activities of Erk and Akt were increased by treatment with all of the drugs, including EBA (Figures S6C and S7). 

*Valproic Acid Promotes Hair Growth in Cutaneous Wounds in Mice* 

Activation of the Wnt/?-catenin pathway in epidermal keratinocytes can potentially induce hair growth in mouse skin that is damaged by wounding [29]. To test the effectiveness of VPA on wound-induced hair growth, we daily applied VPA to the wound area (diameter = 0.5 mm) of C3H mice. The presence of epithelial stem cells in hair follicles around wound areas induces spontaneous hair cycling as previously reported [30], and VPA further significantly enhanced hair growth (Figures 6A and S10A) and the transition from telogen phase to anagen phase at the wound site as revealed by histological analysis (Figure 6B). The expression levels of fillaggrin, loricrin, and keratin 14 in wounds was also specifically increased by application of VPA for 14 d by both immunoblot and immunohistochemical analyses (Figures 6C and 6D). Moreover, VPA specifically activated the Wnt/?-catenin pathway during hair growth at wound sites, as shown by increased ?-catenin expression (Figures 6C and 6D) and induction of ?-galactosidase in newly formed hair follicles of TOP-Gal Wnt reporter mice (Figure S10B; representative mice hairg growth phenotypes by drug application are shown in Figure S10C). Importantly, we also observed an increase in ALP activity in the hair follicles following application of VPA (Figure 6E). Keratin 15 and CD34, the hair follicular stem cell markers, were increased after 25 d of VPA application to the wounds(*Cd34 and K15- some of the stem cell genes mentioned by Dr Cotsarelis)* (Figure 6F). 

VPA is an antiepileptic drug frequently prescribed due to its safety and effectiveness [10], [11]. Prolonged use of VPA resulted in several side effects including hair loss by oral intake*(minimal amounts used should migitate this)*; these adverse effects are attributed to zinc and biotinidase depletion [31]. *We did not observe hair re-growth effects when VPA was orally administered to C57BL/6 mice* (Figures S11A and S11B). *However, topical application of VPA significantly promoted hair formation in murine models* The levels of ?-catenin in the mice skin were specifically increased by topical application of VPA *(topical applications is preferred to see optimal results- at least in mice)* (Figure S11C). 

In this study, we demonstrated that GSK3? inhibitors that activate the Wnt/?-catenin pathway [17], [18], [25], [32] could potentially be developed as drugs to treat hair loss and baldness involving defects in hair follicles. *Among these, VPA was identified as the most potent hair re-growth factor without causing skin abnormalities in mice)*. Alternative inhibitors of GSK3?, LiCl or BeCl2, also stimulated hair re-growth and returned the hair cycle to the anagen phase, but abnormally increased the thickness of the epidermis with hyper-activation of terminally differentiated epidermal markers. In contrast to the epidermis of mouse skin treated with other GSK3? inhibitor, skin of C3H mice treated with VPA didn't reveal any significant abnormal phenotypes in the epidermis. *(most effective hair growth stimulant without causing thickening of the skin amongst all the GSK3b inhibitors tested like Lithium, Belyrium, PBA and EBA. Also i checked Wiki for Valproic acid's halflife- it's 9-16hrs)* We found that ALP is a highly credible marker for activation of the Wnt/?-catenin pathway, and importance of the Wnt/?-catenin pathway in the activation of ALP was confirmed by the demonstration that ALP was not regulated by MNX or EBA, which did not induce expression of ?-catenin and BMP4*( that's because like i've mentioned before- Minoxidil does it through multiple indirect pathways like via Sulfonylurea receptor 2b via Adenosine via Adenosine a2b, and via mpge2 via PGE2 via the EP2 receptor via Survivin via and EP4 receptor for BMP-2)*. It is known that VPA stimulates neuronal differentiation of neural progenitors through the induction of BMP4 [33], [34], and the effect of BMP4 on hair-inducing activity was also previously reported [28]. Our study reporting that BMP4 plays a role as an activator of ALP further confirms the importance of the Wnt/?-catenin pathway in hair re-growth*(Ok this is something new to myself- i hope they are right because BMP-4 is what keeps the hair follicle in the telogen phase as shown in other studies)*. 

Although the relative effect was small compared to VPA or PBA, EBA (which did not activate ?-catenin and BMP4 or ALP), still induced hair formation. These results indicate that the hair-inducing activity of EBA may be independent of the Wnt/?-catenin pathway, and in fact we confirmed that EBA induced activation of Erk and Akt, which are in turn involved in keratinocyte proliferation. Interestingly, VPA induced expression of the hair follicular stem cell markers ketatin 15 and CD34 during hair formation and wound-induced growth.*(new protocol for dermarollers)* VPA is known to induce CD34 expression and enhance stemness [35], [36]. The bald scalps of men with androgenetic alopecia lack CD200-rich, CD34-positive hair follicle progenitor cells(taken form Dr Cotsareli's findings i assume), and have a defect in conversion of hair follicle stem cells to progenitor cells, which play a role in the pathogenesis of androgenetic alopecia [37]. The results of our study indicate that small molecules that activate the Wnt/?-catenin pathway, such as VPA, can potentially be applied for the development of drugs to accelerate hair cycle and stimulate hair re-growth.*(enough said)* 

M*Y THOUGHTS: 

Seems like that zebrafish study about promoting HDC2 for hair regeneration was either bogus or using a different model not applicable to AGA. IMO, Valproic acid, as a GSK3B, HDAC2 and FOSB inhibitor- should really show some results- since it's directly addressing HDAC2- 1 of the genes being directly altered by the Pax1/Foxa2 locus(unlike DKK1 which is atually further downstream of the pax1/foxa2 altered genes) or Minoxidil- which is growing hair via several indirect pathways. It is also inhibitng FOSB- which is the 4th most downregulated gene in haired-scalp as indicated in Dr Cotsarelis's patent. Hence- based on these: 

1)HDAC2 inhibitor 
2)FOSB inhibitor 
3)Half-life =9-16hrs. long enough for once/day applications. 

Valproic acid is onboard the ship*

----------


## eldarlmario

Oh and here's the most interesting part: 

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence a non-steroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[53] It was concluded that these actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[53] 

These could replace RU58841 in a regime while activating WNT signalling via GSK3B inhibition, antagonising HDAC2, Antagonising FOSB(involved in elevated bone densities and bone tumors) 

an on top of that by enhancing GABA- it's also a Nootropic.

----------


## eldarlmario

And that VPA also inhibit PKC. Thus- fulfilling the role as a another c-FOS inhibitor. 

Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients 

From another study by another person:

http://www.ncbi.nlm.nih.gov/pubmed/24533507 

Topical valproic acid increases the hair count in male patients with androgenetic alopecia: a randomized, comparative, clinical feasibility study using phototrichogram analysis. 

Valproic acid (VPA), a widely used anticonvulsant, inhibits glycogen synthase kinase 3? and activates the Wnt/?-catenin pathway, which is associated with hair growth cycle and anagen induction. To assess the efficacy of topical VPA for treating androgenetic alopecia (AGA), we performed a randomized, double-blind, placebo-controlled clinical trial. Male patients with moderate AGA underwent treatment with either VPA (sodium valproate, 8.3%) or placebo spray for 24 weeks. The primary end-point for efficacy was the change in hair count during treatment, which was assessed by phototrichogram analysis. Of the 40 patients enrolled in the study, 27 (n = 15, VPA group; n = 12, placebo group) completed the entire protocol with good compliance. No statistical differences in age, hair loss duration and total hair count at baseline were found between the groups. The mean change in total hair count was significantly higher in the VPA group than in the placebo group (P = 0.047). Both groups experienced mostly mild and self-limited adverse events, but their differences in prevalence rates were similar between the two groups (P = 0.72). A subject treated with topical VPA developed ventricular tachycardia, but it did not seem to be related to the VPA spray. Topical VPA increased the total hair counts of our patients; therefore, it is a potential treatment option for AGA.


It is definitly doing somethig good then.

----------


## eldarlmario

And like this study agrees with what the forementioned study stated: 

Abstract 

Background 

Use of peripheral blood- or bone marrow-derived progenitors for ischemic heart repair is a feasible option to induce neo-vascularization in ischemic tissues. These cells, named Endothelial Progenitors Cells (EPCs), have been extensively characterized phenotypically and functionally. The clinical efficacy of cardiac repair by EPCs cells remains, however, limited, due to cell autonomous defects as a consequence of risk factors. The devise of "enhancement" strategies has been therefore sought to improve repair ability of these cells and increase the clinical benefit. 

Principal Findings 

Pharmacologic inhibition of histone deacetylases (HDACs) is known to enhance hematopoietic stem cells engraftment by improvement of self renewal and inhibition of differentiation in the presence of mitogenic stimuli in vitro. In the present study cord blood-derived CD34+ were pre-conditioned with the HDAC inhibitor Valproic Acid. This treatment affected stem cell growth and gene expression, and improved ischemic myocardium protection in an immunodeficient mouse model of myocardial infarction. 

Conclusions 

Our results show that HDAC blockade leads to phenotype changes in CD34+ cells with enhanced self renewal and cardioprotection. 


http://journals.plos.org/ploso...1/journal.pone.0022158

----------


## 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! 
Attached Thumbnails Attached Thumbnails 
Click image for larger version 

Name:	20120238498_47-788018970.jpg 

Size:	6.1 KB 
ID:	19057

----------


## 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?
> 
> 
> ...


 i have personal s :Embarrassment: urces(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.

----------


## eldarlmario

> 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!
> ...


 about bim:

your answer is on page1 post 9. and by my own experience along with dr cotsarelis findings plus bimatoprost entry on wiki- pleade dont waste any more time on it. take note im only refering to hair on the balding scalp.

----------


## eldarlmario

> 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!
> ...


 about bim:

your answer is on page1 post 9. and by my own experience along with dr cotsarelis findings plus bimatoprost entry on wiki- pleade dont waste any more time on it. take note im only refering to hair on the balding scalp.

----------


## charlie76761

> about bim:
> 
> your answer is on page1 post 9. and by my own experience along with dr cotsarelis findings plus bimatoprost entry on wiki- pleade dont waste any more time on it. take note im only refering to hair on the balding scalp.


 Cheers for the guidance.. i've got the stuff now some might as well as keep in regime to see if Allergan know something Dr C doesnt plus this could be encouraging but no photos etc http://www.*****************/interact...lergan-Lumigan 

Any chance on your supplier for Calc.? Thanks

----------


## Hairismylife

Wow after a deeper reading I found that topical calcitirol and valproic acid is very powerful, targeting many aspects at the same time.  So any method we could get our hands on these?
Thanks for your finding and sharing!

----------


## charlie76761

Indeed.. .exciting stuff. Kane stocks both via Kouting but is off for a few days for the chinese holiday over there

Eldarlmario states the following for those two..  need to speak to Kane to understand if he can supply Calc. at that pre-made ointment and then ideally Eld will advise on Valproic acid % unless any one else knows or hav (i'll have a research later on)

1)Topical Calcipotriol 0.0005% generic premade ointment 
2)Topical Valproic acid (undecided on the dosage) DIY vehicle 

altho not too sure i want to experiment with Val Acid % ages https://www.nlm.nih.gov/medlineplus/...s/a682412.html

Has potential tho  http://www.ncbi.nlm.nih.gov/pubmed/24533507 altho just  found this http://www.currentpsychiatry.com/spe...cafce1fac.html 

google Calcipotriol Scalp solution - it's ready available for plaque psoriasis... surely if it was so good, it was have been very well noted by now esp those with AGA often have psoriasis so would be a very relevant grp of test cases..!?

----------


## Hairismylife

You've said what I think.  If Calc is so good for treating hairloss it would be well noted.  But I'd like to experiment by myself.  It's a vitamin D? So can I say it's quite safe to use?

----------


## Seuxin

I have difficulties to find a good and cheap Topical Calcipotriol ointment...
Any website or supplier please ? Inhouse ?
(I'm from Europa).

Valproic acid needs to be buy as powder right ?

----------


## charlie76761

> You've said what I think.  If Calc is so good for treating hairloss it would be well noted.  But I'd like to experiment by myself.  It's a vitamin D? So can I say it's quite safe to use?


 Seems safe http://www.ncbi.nlm.nih.gov/pubmed/8615060 although slightly worrying that this write up also states it's growth inhibiting (i'm assuming it stops cells replicating as over replicating leads to scalp plague). Hmmm

Ha... you now saying what i was thinking.. dropping it in to my topical mix for a 3 or so months cant hurt. 

Eldarlmario is stating 0.0005% mix although you seem to get it at 0.005% as standard solution so if going for E's % then would mean dropping in 0.1ml into every 1ml of my topical. Easy. 

*Eldarlmario*  pls can you let me know why 0.0005% solution?


Thanks

----------


## joachim

holy shit. 
can't keep up with all those infos and studies. too difficult to read and understand it all.

can someone summarize this? what's the news and the solution now? which topicals should we use? are we cured?  :Big Grin:

----------


## eldarlmario

sorry guys data reception is awfully  bad in the buikding where im in now. will reply when im back home

----------


## eldarlmario

> Seems safe http://www.ncbi.nlm.nih.gov/pubmed/8615060 although slightly worrying that this write up also states it's growth inhibiting (i'm assuming it stops cells replicating as over replicating leads to scalp plague). Hmmm
> 
> Ha... you now saying what i was thinking.. dropping it in to my topical mix for a 3 or so months cant hurt. 
> 
> Eldarlmario is stating 0.0005% mix although you seem to get it at 0.005% as standard solution so if going for E's % then would mean dropping in 0.1ml into every 1ml of my topical. Easy. 
> 
> *Eldarlmario*  pls can you let me know why 0.0005% solution?
> 
> 
> Thanks


 its a typo- n u r right, its 0.005% for calcipotriol, though tretinoin  is defintrly 0.0005%. 

and if its really ok- i will posts the sources later. i just don wan ppl to think imadvertising or something. im not being paid for doing all these. helping fellow AGA sufferers is my only goal

----------


## eldarlmario

> holy shit. 
> can't keep up with all those infos and studies. too difficult to read and understand it all.
> 
> can someone summarize this? what's the news and the solution now? which topicals should we use? are we cured?


 no we r not 'cured'- but i will my best- with the help of all of us here to find out how we can mimic this 'cure' as closely as possible(nothing is impossibl- at least in this context)- through a stable regime of a few small molecules consisting of:

1)topical calcipotriol or calcitriol.

Primary rationale: it induces the expression of CD200.

"Expression of CD200 and Integrin A6(CD49f) was sufficient to reconstitute a whole follicle"- Dr Cotsarellis

2)IF it indeed posseses ability to perform those functions relevant to multiple pathsays in regards to hair growth to what has been indicated for it on paper- then topical Valproic acid would be the next best thing(Gsk3. inhibitor, Androgen receptor inhibitor, FosB and c-fos inhibitor via inhibting PKC, CD34 expression inducer, HDAC2 inhibitor, Foxp1 activator, etc)

Primary rationale: It induces CD34 expression(PGE2 does so too).

3)topical tretinoin in an ultra low dose(0.0005%) upregulates Foxp1, GPRC5D, RAR and most importantly- Integrin A6

Primary rationale: It induces Integrin A6 expression( I could find only tretinoin and Parathyroid hormone-related protein(not a small molecule) that does so.

So magic formula => CD34 + CD200+ CD49f(Integrin A6) => hair regrowth. This is not my own opinion because Dr Cotsarelis has already stated this in his patent.

----------


## joachim

> no we r not 'cured'- but i will my best- with the help of all of us here to find out how we can mimic this 'cure' as closely as possible(nothing is impossibl- at least in this context)- through a stable regime of a few small molecules consisting of:
> 
> 1)topical calcipotriol or calcitriol.
> 
> Primary rationale: it induces the expression of CD200.
> 
> "Expression of CD200 and Integrin A6(CD49f) was sufficient to reconstitute a whole follicle"- Dr Cotsarellis
> 
> 2)IF it indeed posseses ability to perform those functions relevant to multiple pathsays in regards to hair growth to what has been indicated for it on paper- then topical Valproic acid would be the next best thing(Gsk3. inhibitor, Androgen receptor inhibitor, FosB and c-fos inhibitor via inhibting PKC, CD34 expression inducer, HDAC2 inhibitor, Foxp1 activator, etc)
> ...


 sounds interesting. thanks for that great work.
let's hope your theory pans out. it's time to cure this hairloss nightmare once and for all.

----------


## luca10

Interesting!

----------


## eldarlmario

Ok now that i have consolidated a list of the items to address each gene mentioned in the scoliosis study and Dr Cotsarelis patent- i will post the contacts again for the last time 

I have to stress yet again that 

1)i do not gain anything at all from posting these contacts(my own) other then having the pleasure of knowing I have helped a fellow AGA researcher in conducting his own experiments. 
2)i do not know the contacts and nor do I deal with them pertaining to a Business-Business relationship, other than being a Consumer myself in sourcing supplies for my research. 
3)My conduct at contributing information about AGA to our community should prove that 

These contacts are sourced from over the years while looking for research solutions for investigating AGA, Nootropics, Anabolics and even Myopia. My strategy for sourcing low-cost experimentals for my research is: 

1)http://www.mims.com/India/drug/AdvancedSearch/ to look for any Generic drug I want. Then: (Source A)gksales4@guokang8286.com.cn <==China-based Biochemical factory-based manufacturer for research chemicals(some)/generic drugs in raw powder form. I find most of their prices to be the lowest but some are grossly expensive. They respond to my queries fast, though OR : (Source B)leehpl900@gmail.com <==India-based direct dropshipper from the low-cost Generics Pharmaceutical Industry in India in premade form(gels/ointments/capsules/tabs). Alldaychemist and Inhouse get their stocks from the very same India-based Generics Pharmaceutical Industry base as the 1 mentioned above(but the latter 2 marks up their prices by several folds). This source takes 1 whole day to reply- so don't expect an immediate response. 

2)Santacruz Bio or Tocris website(these are commercial links and Im not gonna post them- so please google their homepage yourself) to look at a comprehensive search list of existing Research chemicals that i want . Then: (Source C)theKaneshop- and he gets his supplies/raw materials from the very same China-based Biochemicals Industry base as the other 2 listed here. Kane doesn't respond to queries sometimes. For all other research chemicals that thekaneshop do not have: (Source D)mail08@sciphar.com <==China-based Biochemical factory-based manufacturer. They provide recombinant products. The downside to this source is that they take a long time to reply, if they do- that is. If they don't', keep emailing them. 

3)Negotiate with them for the total price. 

Good luck conducting experiments for your research. Please report back if you've got positive results with photos of your mouse samples.

----------


## eldarlmario

_both are not available. all brands are discontinued in india. 

Dear LeeHpl, 

can you check if you can procure generic topical Calcitriol?(e.g Rolsical ointment by Sun(inca), Psorafuse by Mankind, etc)? 

very much appreciated if you could. 

Thanks_ 


Topical Calcitriol is discontinued in India

----------


## eldarlmario

And here's the good news: 

_dear, spelling is right 
Sodium Valproate (CAS:1069-66-5) 1kg is USD112 <=== sodium-chelated for oral 
Valproic acid (CAS 99-66-1) 1kg is USD136 <==topical 
best regards! 
katherine_

----------


## eldarlmario

VERAPAMIL 240 MG SR TABLET COMPANY- ABBOTT PRICE OF 1X10 = 10 PILLS $ 0.9<=== is the same as "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. " 

http://en.wikipedia.org/wiki/Calcium_channel_blocker 

and that they induces PGE2 expression(which i have already posted about) 

-------------------------
RU 1%, TM 0.125%, Minoxidil sulfate 20mg/day,Dut 0.25%<=these 4 r confirm working. GHK-Cu 1%, Sirt1 Activator 3 0.025%, Tacrolimus 0.03%<=evaluating these 3

----------


## eldarlmario

_Hi dear 
sulfasalazine x 800g is USD159 
best regards! 
katherine_

----------


## eldarlmario

_CAS 152-11-4 x 20g is USD100_ <====Verapamil

----------


## eldarlmario

Good morning! 
dear Terence 

_1)Dutasteride 1g is USD66 
2)Minoxidil Sulfate 10g is USD26 

plus shipping cost is USD30 

total is USD102 

Cas 22556-62-3 we have , but only have 5mg package 
5mg is USD80 <====Lysophosphatidic acid 

GHK-Cu is out of stock now 
_

----------


## eldarlmario

_Thanks for your valued mail. Details are as below, 

HEXIMAR CREAM 15 GM ( CALCIPOTRIOL 0.005 % ) PRICE OF EACH CREAM $ 7 

CERVIPRIME GEL( DINOPROSTONE ) COMPANY- ASTRA PRICE OF EACH CREAM $ 6(PGE2) 

MONTEK 4 MG ( MONTELUKAST ) TABLET COMPANY- SUN PRICE OF 1X10 = 10 PILLS $ 1.5 (<=TH2 inhibitor)

MONTEK 5 MG ( MONTELUKAST ) TABLET COMPANY- SUN PRICE OF 1X10 = 10 PILLS $ 2 

MONTEK 10 MG ( MONTELUKAST ) TABLET COMPANY- SUN PRICE OF 1X10 = 10 PILLS $ 3 

VERAPAMIL 40 MG TABLET COMPANY- ABBOTT PRICE OF 1X10 = 10 PILLS $ 0.15<==Calcium channel blocker. High doses induces PGE2 

VERAPAMIL 80 MG TABLET COMPANY- ABBOTT PRICE OF 1X10 = 10 PILLS $ 0.20 

VERAPAMIL 120 MG SR TABLET COMPANY- ABBOTT PRICE OF 1X10 = 10 PILLS $ 0.5 

VERAPAMIL 240 MG SR TABLET COMPANY- ABBOTT PRICE OF 1X10 = 10 PILLS $ 0.9 

Lonitab 10mg by Intas - 1X10 TAB $ 5 <===Oral Minoxidil

Dutas 0.5mg by Dr Reddy's - 1X30 PILLS $ 11 <==Dut

Aldactone 100mg by RPG - 1X15 PILLS $ 2 <==Spiro

THANKS 
_

----------


## eldarlmario

'cure'? that's too bold for me to claim- we can only try to mimic a 'cure' as closely to as possible but the atual cure would involve fixinf the cause first- and that's for qualified researcher/scientist to prove- not me

----------


## eldarlmario

> Seems safe http://www.ncbi.nlm.nih.gov/pubmed/8615060 although slightly worrying that this write up also states it's growth inhibiting (i'm assuming it stops cells replicating as over replicating leads to scalp plague). Hmmm
> 
> Ha... you now saying what i was thinking.. dropping it in to my topical mix for a 3 or so months cant hurt. 
> 
> Eldarlmario is stating 0.0005% mix although you seem to get it at 0.005% as standard solution so if going for E's % then would mean dropping in 0.1ml into every 1ml of my topical. Easy. 
> 
> 
> *Eldarlmario*  pls can you let me know why 0.0005% solution?
> 
> ...


 On Calcitirol stopping growth(in a way- u r right): ur answer is here: http://www.ncbi.nlm.nih.gov/pubmed/24239508

Its 0.005%- sorry for the typo

----------


## eldarlmario

From another person in another forum:

_Yeah sure. You're trying to bring the balding scalp back to the state of a healthy scalp. Perhaps it can work and you can trick your body with those ****tails but what about if we find the actual cause that brought the scalp to this situation?_

He got it all right.

By using chemicals to alter the way our scalp functions- we are 'tricking it' into behaving in a way that's not what Nature meant for us- and that is to be bald

----------


## eldarlmario

I have to reemphasize that the Pax1/Foxa2 theory(atually it's already proven by multiple studies to be a high risk susceptibility gene locus for AGA) is of my own. I have already posted links and studies coupled with my own spine and ear problems - that gave me the rationale to come to the conclussion accompanied by all those links and studies and the comparison of those genes indicated in the Scoliosis study with those indicated in Dr Cotsarelis patent.

True or not is left to your own judgement.

----------


## eldarlmario

_Good day! 
sorry for my late reply 
we have three days holiday 
Dimethicone Peg 10g is USD32 
Polimethylsilsequioxane I can't translate it , do you have CAS number ? 

thank you very much 
Polimethylsilsequioxane => Cas 68554-70-1 x10g is USD40 
best regards! 
katherine_ 

Prices for 2 liposomes suggested by another user in another forum when we talked about the importance of a good topical vehicle to use for delivering actives. PG induces contact dermititis for me and high ratio of ethanol dries my scalp badly while not staying on the scalp long enough to localise penetration of the actives to the scalp. DMSO is superbly efficient but has many undesirable side(e.g blood-borne halitosis,)

Liposomes helps the solution to stay on the scalp longer while not being harsh.

I enquiried for 10g as an average benchmark quantity. 1g-5g should be sufficient to last for a whole year.

----------


## eldarlmario

https://en.wikipedia.org/wiki/Human_..._to_bipedalism

The evolution of human bipedalism approximately four million years ago[1] has led to morphological alterations to the human skeleton including changes to the arrangement and size of the bones of the foot, hip size and shape, knee size, leg length, and the shape and orientation of the vertebral column(Spine).

----------


## eldarlmario

Vertebral column[edit]
Main article: Vertebral column
The vertebral column of humans takes a forward bend in the lumbar*(around the waist)* (lower) region and a backward bend in the thoracic( (upper) region around the upper chest) . Without the lumbar curve, the vertebral column would always lean forward, a position that requires much more muscular effort for bipedal animals. With a forward bend, humans use less muscular effort to stand and walk upright.[6] Together the lumbar and thoracic curves bring the body's center of gravity directly over the feet.[4] Also, the degree of body erection (the angle of body incline to a vertical line in a walking cycle) is significantly smaller[1] to conserve energy.

----------


## eldarlmario

https://en.wikipedia.org/wiki/Cervical_vertebrae

In vertebrates, cervical vertebrae (singular: vertebra) are those vertebrae immediately below the skull.

----------


## eldarlmario

https://en.wikipedia.org/wiki/Atlas_(anatomy)

In anatomy, the atlas (C1) is the most superior (first) cervical vertebra of the spine.

----------


## eldarlmario

[IMG]http://thepowerofposture.net/wp-content/uploads/2014/02/Forward-Head.jpg[?IMG]

"Significance[edit]
Even with much modification, some features of the human skeleton remain poorly adapted to bipedalism, leading to negative implications prevalent in humans today. The lower back and knee joints are plagued by osteological malfunction, lower back pain being a leading cause of lost working days,[14] because the joints support more weight. Arthritis has been a problem since hominids became bipedal: scientists have discovered its traces in the vertebrae of prehistoric hunter-gatherers.[14] Physical constraints have made it difficult to modify the joints for further stability while maintaining efficiency of locomotion.[4]"

https://en.wikipedia.org/wiki/Temporomandibular_joint



https://en.wikipedia.org/wiki/Tempor...oint_pathology

"A range of disorders may affect the temporomandibular joint (the joints which connect the mandible to the skull)."

----------


## eldarlmario

Notice how the veins and Arteries gets pressively narrower and narrower as they reach the:



and the:



and that these https://en.wikipedia.org/wiki/Lymphatic_vessel and https://en.wikipedia.org/wiki/Capillary in the area there could be easily choked and https://en.wikipedia.org/wiki/Atherosclerosis can take place there easily

----------


## eldarlmario

Thus, anything that vasodilates the blood vessels there is *partly*-helping to keep the hair follicles alive

and that we have a chronic state of vasocontriction there

----------


## NOhairNOlife

Bro you killed this thread. I didn't understand anything you wrote. I only read the first post

----------


## eldarlmario

It's ok, cos most of others did.

Hence- it's alive and kicking.

----------


## LMS

> Thus, anything that vasodilates the blood vessels there is *partly*-helping to keep the hair follicles alive
> 
> and that we have a chronic state of vasocontriction there


 if only it were that simple lol

----------


## Occulus

> It's ok, cos most of others did.
> 
> Hence- it's alive and kicking.


 A lot of this thread is way over my head, but what I can understand is interesting.  The biggest take away for me is just how complex the pathology is.  It's no wonder there are so few treatments, and that all of them are simply off-label, accidental discoveries (minox for blood pressure, finasteride for prostate, and ketoconazole for fungus).  Personally, given the complexity of the pathology, I think the closest thing to a cure will be some sort of hair cloning or growth outside the scalp, then surgical implantation; unraveling the solution in vivo looks too difficult.

----------


## champpy

> 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?
> 
> 
> ...


 Hey charlie, i see that you are going to give TM a try instead of OC.  What did u read in the post that made you come to this conclusion?

do you know if TM comes in a powder and if so how does it need to be prepared?
thanks man

----------


## charlie76761

> Hey charlie, i see that you are going to give TM a try instead of OC.  What did u read in the post that made you come to this conclusion?
> 
> do you know if TM comes in a powder and if so how does it need to be prepared?
> thanks man


 Hi Champpy, it's from the first page of the thread 

"PTGDS<= Topical/oral TM30089(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral Setipiprant(Newest CRTH2 inhibitor in trials, topical/oral Ramatroban(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral OC(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.) "

----------


## eldarlmario

> Hi Champpy, it's from the first page of the thread 
> 
> "PTGDS<= Topical/oral TM30089(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral Setipiprant(Newest CRTH2 inhibitor in trials, topical/oral Ramatroban(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral OC(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.) "


 i posted the sources already

----------


## Seuxin

And about PGD2, what is the better price quality ? TM ? OC ? other ?
I would like to add a pgd2 inhibitor.

----------


## Farkhairloss

> Hi Champpy, it's from the first page of the thread 
> 
> "PTGDS<= Topical/oral TM30089(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral Setipiprant(Newest CRTH2 inhibitor in trials, topical/oral Ramatroban(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral OC(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.) "


  If you use the internet search engine beginning with G and ending with E. And search for TM30089, the first link that comes up is HLH. Guys have experimented with this already in 2012. So im not sure how effective it is.

----------


## walrus

This thread is non-nonsensical research vomit.

----------


## champpy

Thanks charlie and eldarlmario. Right now i think the oc is slowing the loss a little. I might try n switch next month

----------


## barfacan

IT's just spambots talking to one another.

Nothing to see here

----------


## eldarlmario

> Bro you killed this thread. I didn't understand anything you wrote. I only read the first post


 


> This thread is non-nonsensical research vomit.


 


> IT's just spambots talking to one another.
> 
> Nothing to see here


 its ok, this thread is only for keen and sincere individuals who wants to help themselves with their own hairloss(their own- not other's)- and the fact that these group of individuals who r in here n not complaining that it's complicated proves the fact that:

1)they've learn something new AND/OR
2)they make the effort to go do some further research themselves on the information being stated here by using simple search engines like 'google search'- and reach a conclusion for themselves whether the said information here are accurate/plausible or not.

Thus- these are the people not complaining that the truckload of information is complicated  and hence- the reason why i started this thread in the cutting edge/future treatment section instead of the common 'hair loss treatment' section that are full of the same old stuff like minoxidil, dutasteride, finasteride, spiro, ketoconazole(if you've read my posts on keto- u would see that it's more harmful than it is beneficial to the hair with the reasons stated why backed up by studies and links), etc, etc.

*Conclusion- this thread is not for the laymen- especially LAZY 1s*

----------


## eldarlmario

Back to the Cotsarelis patent for promoting hair growth:

_Example 5 In Situ and Immuno-Histological Characterization of Novel HF Genes
In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data.

Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples (FIG. 5B). LRRC15 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC15 functions in cell migration, LRRC15 expression was measured in scalp samples by immuno-histochemistry. LRRC15 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (FIG. 6A), which is an area of rapid cell movement during hair growth. Thus, LRRC15 functions in cell mi__gration necessary for hair growth.

Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B).

GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. <==GPR49 forms a complex with LPR6(which DKK1 inhibits). DKK1 is inhibited by WAY262611, Magnesium L-threonate, Magnesium L ascorbyl 2 phosphate and Valproic acid.

The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular.<==Calcipotriol/Calcitriol

GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E).<===Ultra low dose Tretinoin(0.0005%-0.005%)

FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G).
<== <regulated by FOXP1- and FOXP1 is increased by Valproic acid and ultra low dose Tretinoin
The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth._

----------


## bornthisway

I know at least one person posted about using wounding and calcitriol and said it helped. It's likely worth a try and will probably take an extended time to notice any benefit like all treatments. Probably ideal when used in conjunction with minoxidil between rolling periods. The lowest dose for Tretinoin cream on a popular online pharmacy I've found is 0.025%. Is this concentration too high to get the intended outcome? Was the delivery topical for each of these substances that affected those genes? I wonder what the ideal application / frequency would be. When Follica disrupts the epidermis are they only applying calcitriol at that time? 


1,25-dihydroxyvitamin D3: a novel agent for enhancing wound healing.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), has diverse effects in a variety of tissues and cell types, including skin. Since 1,25(OH)2D3 affects both fibroblast and keratinocytes, we evaluated the effect of 1,25(OH)2D3 on wound healing. We investigated the effect of the topically applied 1,25(OH)2D3 or vehicle on the healing of cutaneous wounds in rats in a blinded manner. Wound areas were measured by planimetry technique. Healing was expressed as the percentage of the original wound area that was healed. 1,25(OH)2D3 at concentrations between 5 and 50 ng/day caused a dose-dependent acceleration of healing. Time course and specificity studies indicated that 1,25(OH)2D3 specifically promoted healing between 1-5 days after wounding as compared with vitamin D (0.5 microgram/day), which showed no significant improvement over control. Our results suggest that 1,25(OH)2D3 and its analogues may be a new class of compounds that could be developed to enhance wound healing.

http://www.ncbi.nlm.nih.gov/pubmed/8530536

----------


## eldarlmario

> I know at least one person posted about using wounding and calcitriol and said it helped. It's likely worth a try and will probably take an extended time to notice any benefit like all treatments. Probably ideal when used in conjunction with minoxidil between rolling periods. The lowest dose for Tretinoin cream on a popular online pharmacy I've found is 0.025%. Is this concentration too high to get the intended outcome? Was the delivery topical for each of these substances that affected those genes? I wonder what the ideal application / frequency would be. When Follica disrupts the epidermis are they only applying calcitriol at that time? 
> 
> 
> 1,25-dihydroxyvitamin D3: a novel agent for enhancing wound healing.
> 
> 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), has diverse effects in a variety of tissues and cell types, including skin. Since 1,25(OH)2D3 affects both fibroblast and keratinocytes, we evaluated the effect of 1,25(OH)2D3 on wound healing. We investigated the effect of the topically applied 1,25(OH)2D3 or vehicle on the healing of cutaneous wounds in rats in a blinded manner. Wound areas were measured by planimetry technique. Healing was expressed as the percentage of the original wound area that was healed. 1,25(OH)2D3 at concentrations between 5 and 50 ng/day caused a dose-dependent acceleration of healing. Time course and specificity studies indicated that 1,25(OH)2D3 specifically promoted healing between 1-5 days after wounding as compared with vitamin D (0.5 microgram/day), which showed no significant improvement over control. Our results suggest that 1,25(OH)2D3 and its analogues may be a new class of compounds that could be developed to enhance wound healing.
> 
> http://www.ncbi.nlm.nih.gov/pubmed/8530536


 for Tretinoin<== it's 0.0005% - 0.005% maximum. i have posted the study that stated:

tretinoin increases GPRC5D by using stem cells as fuel. in low doses(2macromolar) it induces hair follicle differentiation at a stabilized rate. With increasing doses, it depletes stem cells rapidly and stops growth once the stem cells run out. High doeses is also toxic to the hair follicles. and 0.025% is way too high for that. Hence 1mcg/ml is what is needed to be considered as minimally low dose. even with some generous adjustments- 25mcg(study used 600nanograms: rounded off to 1mcg for convenience with adjustments to 5mcg for topical applications) is all that is needed at the most to constitute  as low dose. no way generic 0.025% tretinoin is gonna be safe for that by the study and also- by my own experience. So 0.0025%-0.0005% would be the ideal range.

*So 5mcg/ml = 0.0005% to  25mcg/ml = 0.0025% would be the ideal range*

cumming from a user of tretinoin for 8years(on my face and once- experimentally on the scalp)

IMO, topical calpotriol and topical tretinoin in term of experimentally treating AGA should be used in ultra low doses.

----------


## eldarlmario

ok i still have not found a small molecule upregulator of:

1)*LY6G6D*<===3rd most upregulated gene in *haired-scalp* when compared to bald scalp.

and small molecule downregulator of(Spiro indirectly downregualtes CORIN via antagonsiing Aldosterone- but not1 every's gonna include oral Spiro as part of their regime, including myself)

2)*CORIN* <==*most* downregulated gene(even lower than PTGDS- the enzyme for making PGD2) in haired-scalp when compared to bald scalp. Cleaves Brain Natriuetic Peptide(BNP) into 4-32 BNP(non-beneficial for the hair) from 1-32BNP(pro-hair growth BNP)

Mind boogling- because i still do not know what it does to the hair on the balding scalp:

*H6 family homeobox 2*(i cant make out what the following does in regards to hair on the balding scalp yet(even though it has something to do with inner ear functions)
*FOXA*(3 forms of FOX genes with FOXA2 being the gene associated with the balding haplotype locus itself) i do not know what to make out of this yet.

perhaps folks here might wanna help out. Doing so, we would have found all the small molecule solutions(at least on paper) in regards to:

1)All the genes mentioned in the Scoliosis study affected by by some of the variants in the AGA/IS Pax1/Foxa2 haplotype  
2)Top 5 genes upregulated in haired-scalp
3)Top 5 genes downregulated in bald-scalp.

----------


## eldarlmario

ok: 

Valproic acid, Calicipotriol and Tretinoin tri-axis: 

Valproic acid => CD34(UP) but CD200(DOWN) 
Calcipotriol => CD200(UP) but CD49F(DOWN) 
Tretinoin=> CD49F(UP) but CD34(DOWN) 

some sort of balance here.

----------


## eldarlmario

From Dr Cotasarelis findings:

activator => CD34 positive progenitor stem cells
inhibitor => CD200 high(downregulation of immunoactivity)
resultant=>CD49F high Extra cellular Matrix

=> hair growth

----------


## walrus

> *Conclusion- this thread is not for the laymen- especially LAZY 1s*


 All you have demonstrated in this thread is an ability to type 'hair loss' into Google Scholar and use the copy and paste function of your computer. There is no new insight being offered. Tell me, what are your qualifications that make you not a layman yourself?

----------


## eldarlmario

"There is no new insight being offered."

Seriously- then why r u even here in this thread in the first place?

----------


## eldarlmario

ok guys had a sudden brainwave on CORIN. 

Spiro downregualtes CORIN levels indirectly via inhibiting Aldosterone. I remember back when i was on spiro and oral minox at the same time- the results i was getting was much better thaan what i have now. if i were to compare myself back than n now- i would had it's about 30%more results than when i was on spiro. so it seems that downregulation of CORIN is very important and unsurpringly- it's the most downregulated gene in ahired scalp as indicated by Dr Cotsarelis's aptent. 

ok Alpha-1 antitrypsin AKA Serpina1(upregulated in haired-scalp by several folds) http://en.wikipedia.org/wiki/Alpha-1_antitrypsin inhibits CORIN since it's a Trypsin inhibitor. So we need to find a small molecule Serpina1. Hitting 2 birds at the same time since Serpina1 probably inhibits other proteases that cause hair loss as well- as proven by the fact that it is upregulated several folds in haired-scalp.

----------


## Olmechairtransplant

www.hairtransplantdelhi.com 
Just see the Before and After quality of Hair Transplant
and decide your self

----------


## walrus

> "There is no new insight being offered."
> 
> Seriously- then why r u even here in this thread in the first place?


 Avoiding my question? Are you not a 'layman'?

----------


## bananana

@eldarlmario

this all sounds interesting, but complicated as hell.
pleas could you sum ALL FINDINGS IN ONE POST?
A sort of a "how-to" guide for us not-so-experienced here.

thank you

----------


## eldarlmario

> voiding my question? Are you not a 'layman'?


  lol dude- I DONT have to proof anything to you. 

the first page is all u need to look for the small molecule experiemtnals.

----------


## eldarlmario

> voiding my question? Are you not a 'layman'?


  lol dude- I dont think im 1 here and I DONT have to proof anything to you. 



> this all sounds interesting, but complicated as hell.
> pleas could you sum ALL FINDINGS IN ONE POST?
> A sort of a "how-to" guide for us not-so-experienced here.
> 
> thank you


 the first page is all u need to look for the small molecule experimentals.

----------


## eldarlmario

Simple terms(Dr Cotasarelis's findings):

Magic formula = Cd34 + CD200 +Cd49F

= hair growth

CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%
CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%)
CD49f: topical Tretinoin (generic creams/gels are available at 0.01%)

+ 1.5mm once/mth soft dermarolling

= hair growth

U need to stop DHT(higher potency) and Testerone first from exerting their acitions on further expanding your balding skull and inhibiting hair growth in AGA individuals. SO- it's:

1)*CD34*: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%
2)*CD200*: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%)
3)*CD49f*: topical Tretinoin (generic creams/gels are available at 0.01%)

AND

4)*An androgen receptor blocker* like RU58841 or Valproic acid, etc.

5)+ *1.5mm transient soft dermarolling*(optional)

_= hair growth_

----------


## eldarlmario

> Simple terms(Dr Cotasarelis's findings):
> 
> Magic formula = Cd34 + CD200 +Cd49F
> 
> = hair growth
> 
> CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%
> CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%)
> CD49f: topical Tretinoin (generic creams/gels are available at 0.01%)
> ...


 adding those stated below would be an added bonus:

6)Crth2 inhibitor- stops TH2 cytokines from attacking follicles.
7)Dutasteride- stops DHt. i dont think i have to explain this.
8)Curcumin- Gsk3B inhibitor. activates SERPINA1(upregulated 5.721 folds in haired scalp) which in turn- inhibits CORIN(most downregulated  gene in haired-scalp)
9)Cilnodipine- calcium channel blocker. decreases intracellular calcium levels- thereby widening blood vessels(vasodilation)

I hope this is simple enough. please google on the drugs effect and for their relationship with hair(e.g Cilnodipine is a calcium channel blocker- so google *calcium channel blockers hair*) IF you are keen to find out, Curcumin is a GSK3B inhibitor- google *Gsk3B Hair*, etc etc )

----------


## Hairismylife

Seti is a crth2 inhibitor?

----------


## eldarlmario

> Seti is a crth2 inhibitor?


 Yes it is.

----------


## hellouser

> Simple terms(Dr Cotasarelis's findings):
> 
> Magic formula = Cd34 + CD200 +Cd49F
> 
> = hair growth
> 
> CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%
> CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%)
> CD49f: topical Tretinoin (generic creams/gels are available at 0.01%)
> ...


 Lithium Chloride for CD200 expression.

You forgot that you need to inhibit PGD2, so setipiprant is necessary.

----------


## eldarlmario

ok here it goes again- all in 1 single post:

you will need the following:

1)CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%- nothing higher than that)
2)CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%- nothing higher than that)
3)CD49f: topical Tretinoin (generic creams/gels are available at 0.01%- nothing higher than that)
4)An Androgen Receptor blocker(preferably topical) like RU58841 or Valproic acid, etc. Stops further hair growth-inhibiting androgenic actions in AGA scalps.

to provide the basics to regrow hair

AND

5)optional 1.5mm once/mth *soft* dermarolling protocol(Just do till the scalp turns slightly red. It is absolutely *unnecessary* to whip things up into a bloody mess- _literally_).

WITH the following as an added bonus to achieve optimal results:

6)oral/topical Crth2 inhibitor- Stops TH2 cytokines from attacking hair follicles in the balding scalp. The name of the receptor already tells us it's function- 'Chemokine Receptor Expressed On T-Cell Helper 2'.
7)oral/topical Dutasteride- Decreases DHT(Steroid with higher potency to inhibit hair growth in AGA scalp)- but increases free Testerone levels(Steroid with much lower potency to inhibit hair growth in AGA scalps). i dont think i have to explain this.
8)topical Curcumin- GSK3B inhibitor. Activates SERPINA1(upregulated 5.721 folds in haired scalp) which in turn- inhibits CORIN(most downregulated gene in haired-scalp).
9)topical Cilnodipine- Calcium channel blocker. Decreases intracellular calcium levels(High levels of it leads to pathologies like fibrosis, soft tissue mineralization, etc)- thereby widening blood vessels(vasodilation) in the balding scalp.

AND IF you want to further add in something to guarantee at least some hair growth- our good ol' 10)topical/oral Minoxidil(preferbably sulfated- its active metabolite) is the prime candidate.

*9 experimental  components for a full regime(10 if you add in Minoxidil sulfate as a proven chemical for regrowing hair)*

----------


## Hairismylife

Eldar your help is very much appreciated.
I have faith in your golden formula but could you please suggest me a place to buy calcitirol/calcipotriol and tretinoin? Thanks in advance.

----------


## eldarlmario

> Eldar your help is very much appreciated.
> I have faith in your golden formula but could you please suggest me a place to buy calcitirol/calcipotriol and tretinoin? Thanks in advance.


 Source B in Post 90 of this thread

----------


## walrus

> lol dude- I dont think im 1 here and I DONT have to proof anything to you.


 Considering your claim of making insightful observations from the literature, it is entirely reasonable to ask what exactly makes you qualified. Especially given your outlandish claims about Scoliosis. The best you could muster was 'trust me I am'. Bro-science at its finest. 




> the first page is all u need to look for the small molecule experimentals.


 Or alternatively, people can view the primary literature for themselves without your added quack commentary: https://scholar.google.co.uk/scholar...ia%22&scisbd=1

----------


## eldarlmario

> Considering your claim of making insightful observations from the literature, it is entirely reasonable to ask what exactly makes you qualified. Especially given your outlandish claims about Scoliosis. The best you could muster was 'trust me I am'. Bro-science at its finest. 
> 
> 
> 
> Or alternatively, people can view the primary literature for themselves without your added quack commentary: https://scholar.google.co.uk/scholar...ia%22&scisbd=1


 Exactly and that leads back to my very first response to you, Mr Egoist. The second quote was an repeated error that was intended to be included in the post below it- and even then- just look how you have went into details towards responding to it.  Shows alot of your intention in this thread. U can always leave this thread if you find the information here 'insightful'. no1's stopping you. lol

----------


## Hairismylife

> Source B in Post 90 of this thread


 Also selling lithium chloride?

----------


## eldarlmario

> Also selling lithium chloride?


 Source A or Source D

----------


## eldarlmario

> Also selling lithium chloride?


 Source A or Source D

----------


## eldarlmario

.

----------


## eldarlmario

> Lithium Chloride for CD200 expression.
> 
> You forgot that you need to inhibit PGD2, so setipiprant is necessary.


 Hi, would u mind linking the source that stated lithium chloride upregulates CD200. Thanks.

----------


## Seuxin

What is better/cheaper between Calcitriol, Calcipotrio, and Lithium Chloride ?

----------


## Parsia

> ok here it goes again- all in 1 single post:
> 
> you will need the following:
> 
> 1)CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%- nothing higher than that)
> 2)CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%- nothing higher than that)
> 3)CD49f: topical Tretinoin (generic creams/gels are available at 0.01%- nothing higher than that)
> 4)An Androgen Receptor blocker(preferably topical) like RU58841 or Valproic acid, etc. Stops further hair growth-inhibiting androgenic actions in AGA scalps.
> 
> ...


 Hi Elder , How are u ?Thanks for the nice post .For Number 3 : topical Tretinoin 0.01% I think you mean 0.001% , Since I have read your other posts in the past. 

And Also for Valproic Acid you put that  in Both Categories of Topical PGE2  and also An 

Androgen Receptor blocker, So it works both ways? 

Thanks

----------


## eldarlmario

> What is better/cheaper between Calcitriol, Calcipotrio, and Lithium Chloride ?


 all 3 works to a certain degree. email the sources

----------


## eldarlmario

Tretinoin- it's 0.01% *maximum* and there ARE 0.01% premade generic creams around. you have to be VERY carefully using this by using only the lowest dose possible 

Mechanism of action[edit]
Although the mechanism of action of valproate is not fully understood,[39] it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[50] In addition, its anticonvulsant effect has been attributed to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[39] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[39] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.[39] It also possesses histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.[51][52]
Valproic acid has been found to be an *antagonist of the androgen and progesterone receptors, and hence a non-steroidal antiandrogen and antiprogestogen*, at concentrations much lower than therapeutic serum levels.[53] It was concluded that these actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[53]

Its upregulates CD34

http://www.ncbi.nlm.nih.gov/pubmed/15735039

Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells.
De Felice L1, Tatarelli C, Mascolo MG, Gregorj C, Agostini F, Fiorini R, Gelmetti V, Pascale S, Padula F, Petrucci MT, Arcese W, Nervi C.
Author information
Abstract
Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine ****tails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.

http://www.jci.org/articles/view/70313

Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin α6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune–deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.

----------


## eldarlmario

Experimental small molecule pharmalogical solutions for AGA by topical/oral route administration in order of descending preference(would be updated from time to time): 

1): 

All affected genes indicated in the Scoliosis study: 

TATA <= Topical Calcitirol/Calcipotriol 

HNF4 <= Topical Carbamazepine(direct activator of SHBG for disactivating circulating sex hormones with highest affinity for DHT=>increased bone resorption in the balding skull. Has sides), Topical Valproic acid(Androgen Receptor Blocker, Wnt/B-catenin agonist, CD34 upregulator and several other pro-hair growth properties. Has sides if taken orally), Topical RU58841(Androgen Receptor Blocker- less systemic side effects), topical CB(Androgen Receptor Blocker), topical/oral Dutasteride(5A Redutase Inhibitor to decrease circulating DHT. Used carefully- will dramatically slow down, but not stop- AGA and increase 'free' Testosterone levels for the muscles), topical/oral Finasteride(5A Redutase Inhibitor to decrease circulating DHT- almost the same profile as Dutasteride but with less potency), oral Spironolactone(Androgen Receptor Blocker, Aldosterone Inhibitor=> Less sodium reabsorption in kidneys=>less vasoconstriction=>increased blood supply to hair follicles. Has feminizing sides.) 

RAR <= Ultra low dose topical Tretinoin (0.01%-0.0005%. Ultra low doses of it induces hair shaft differentation at a stabilised rate with stem cells as the fuel while increasing dosages depletes stem cells rapidly and leads to apoptosis instead. Is also toxic when used in dosages above a certain threshold- and this 'threshold' is very low.) 

RXRA <= Topical Calcitriol/Calcipotirol(Calcitriol-binded VDR is needed for full transcription of PPAR Alpha, Beta and Gamma. VDR-null cells on the scalp diverts pluripotent stem cells to the sebocyte(sebum) and sudoriferous(sweat) lineage). 

STAT <= Topical Calcitriol/Calcipotriol(Calcitriol acts as a modulator of this central inflammation pathway- the JAK-STAT pathway.), topical/oral Sulfasalazine(via inhibiting TH1 cytokines) 

BATF <= Topical Calcitirol/Calcipotriol(Calcitriol acts as a modulator of this TH17 cytokines regulatory gene), topical/oral Sulfasalazine(via inhibiting TH17 cytokines). 

COMP <= Topical Calcitirol/Calcipotriol, topical Valproic acid(Both Calcitriol and Valproic acid increase expression of this gene- and it is upregulated only in haired-scalp.) 

VDR <= Topical Calcitirol/Calcipotriol(Calcitriol's own receptor. It is a receptor that regulates, modulates and thus- controls hundreds of genes(900+ genes) involved with Immunity, Calcium homeostasis, Bone formation/resorption(in synergy with BMPs) and many, many more in the human body.) 

HDAC2 <= Topical Valproic acid(inhibitor of HDAC2- which inhibits AGA-afflicted hair follicles stem cell renewal's function) 

CART1 <= Topical Calcitriol/Calcipotriol 

FOXA <= FOXA2 inhibits pre-adipocyte differentiation. topical Sirt 1 activators like Resveratrol inhibits Foxa2 expression. 

FOXP1 <= Topical Valproic acid, Ultra low dose topical Tretinoin(0.01% - 0.0005%)(FOXP1 regulates stem cells levels in the hair) 

GATA <= Topical Calcitriol/Calcipotriol, Oral Montelukast, Oral Zafirlukast(GATA3 is the master regulator TH2 cytokines profileration and differentiation.) 

H6 family homeobox 2 <= ? (Has got more to do with inner ear functions than to hair on the balding scalp) 

IRF <= Topical Calcitriol/Calcipotriol 

PAX5 <= Topical Calcitriol/Calcipotriol(PAX5 is the master regulator of B cells profileration and differentiation.). 

P300 <= Topical Calcitriol/Calcipotriol 

2): 

Top 5 upregulated genes in haired-scalp and Top 5 downregulated genes in haired-scalp as indicated by Dr Cotsarelis's patent in order of descending preference: 

Upregulated in haired-scalp: 

GPRC5D <= Ultra low dose topical Tretinoin(0.01% - 0.0005% ) 

CDT6<= Topical Calcitriol/Calcipotriol 

LY6G6D<= Closest that could be found for small molecules addressing this extremely-rarely-described gene is Valproic acid(seeing how Valproic acid has an overwhelming pro-hair growth effect when used topically, this means it probably upregulates it to a certain degree.). 

S100A3<= Topical Calcitriol/Calcipotriol 

COMP<= Topical Calcitriol/Calcipotriol, topical Valproic acid 

3): 

Downregulated in haired-scalp: 

CCL19<= Topical Calcitriol/Calcipotriol 

FOSB<= Topical Valproic acid 

c-FOS<= Topical Valproic acid(via inhibiting Protein Kinase C), Topical/oral Verapamil(Calicum channel blocker with lower half-life), topical Cilnidipine(Calcium cahnnel blocker with half-life of 24hrs), topical D609(research chemical). 

PTGDS<= Topical/oral TM30089(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral Setipiprant(Newest CRTH2 inhibitor in trials, topical/oral Ramatroban(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral OC(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.) 

CORIN<= Topical Curcumin(Upregulates Serpina1- another gene upregulated by 5.721 folds in haired-scalp which in turns inhibits the production of Corin that equautes to 1-32BNP(pro-hairgrowth) production instead of 4-32 BNP production- via trypsin inhibition. it is also a GSK3B inhibitor.), Oral Spironolactone(indirectly by antagonising Aldosterone=> CORIN downregulation=> FURIN-Cleaved proBNP=> 1-32 BNP(the pro-hair growth form of BNP) => hair pigmentation + keratinization) 

4): 

Three 'endpoint' genes indicated by Dr Cotsarelis's patent that are significantly-upregulated in haired-scalp: 

CD200<== Topical Cacitirol/Calcipotriol(Calcitriol increases both CD200's expression in the balding scalp and balding skull. In the latter's case, without adequate CD200's expression- bone resorption is severely-impaired that leads to ever-increasing bone formation in the balding skull.) 

CD34<== Topical Valproic acid(via existing cell self-renewal), Topical 16,16-Dimethly-PGE2(via homing from bone marrow), Topical PGE2(PGE2=>EP2 Receptor=>Survivin=>CD34. Also- PGE2=>EP4 Receptor=>BMP-2=>SMAD1/5/8=>SMAD4=>DLX3=>RUNX2=>Hair shaft differentiation), Topical Butaprost(This is a selective EP2 receptor and EP4 receptor agonist. An PGE2 analog), topical/oral Sulfasalazine(Upregulates PGE2 while inhibiting COX-2), Minoxidil sulfate(via mPGE2). 

Intergrin A6<= Ultra low dose topical Tretinoin(0.01%-0.0005%. Tretinoin is the only small molecule that could be found to upregulate IntergrinA6(CD49F) with the other being the Parathyroid hormone-related protein(not a small molecule)) 

*Dietary adjustments* 

IMO adjusting your diet will never have much of an impact on AGA. The only thing to look out for would be anything that will cause vasocontriction. 1)Caffeine antagonises the Adenosine receptors and 2)Calcium will not only cause vasocontriction- it also is used as fuel to form our ever growing bones in the balding skull and also as mineral deposits on our fibrosising balding-scalp. Keep it at not more than 1 cup of coffee a day(I know it's hard to not drink coffee-including myself) and /or best of all- avoid milk/cheese consumption. 

END 

































































































Ok now that i have consolidated a list of the items to address each gene mentioned in the scoliosis study and Dr Cotsarelis patent- i will post the contacts again for the last time 

I have to stress yet again that 

1)i do not gain anything at all from posting these contacts(my own) other then having the pleasure of knowing I have helped a fellow AGA researcher in conducting his own experiments. 
2)i do not know the contacts and nor do I deal with them pertaining to a Business-Business relationship, other than being a Consumer myself in sourcing supplies for my research. 
3)My conduct at contributing information about AGA to our community should prove that 

These contacts are sourced from over the years while looking for research solutions for investigating AGA, Nootropics, Anabolics and even Myopia. My strategy for sourcing low-cost experimentals for my research is: 

1)http://www.mims.com/India/drug/AdvancedSearch/ to look for any Generic drug I want. Then: (Source A)gksales4@guokang8286.com.cn <==China-based Biochemical factory-based manufacturer for research chemicals(some)/generic drugs in raw powder form. I find most of their prices to be the lowest but some are grossly expensive. They respond to my queries fast, though OR : (Source B)leehpl900@gmail.com <==India-based direct dropshipper from the low-cost Generics Pharmaceutical Industry in India in premade form(gels/ointments/capsules/tabs). Alldaychemist and Inhouse get their stocks from the very same India-based Generics Pharmaceutical Industry base as the 1 mentioned above(but the latter 2 marks up their prices by several folds). This source takes 1 whole day to reply- so don't expect an immediate response. 

2)Santacruz Bio or Tocris website(these are commercial links and Im not gonna post them- so please google their homepage yourself) to look at a comprehensive search list of existing Research chemicals that i want . Then: (Source C)theKaneshop- and he gets his supplies/raw materials from the very same China-based Biochemicals Industry base as the other 2 listed here. Kane doesn't respond to queries sometimes. For all other research chemicals that thekaneshop do not have: (Source D)mail08@sciphar.com <==China-based Biochemical factory-based manufacturer. They provide recombinant products. The downside to this source is that they take a long time to reply, if they do- that is. If they don't', keep emailing them. 

3)Make a list of the items that you want, drop them an email and negotiate with them for the total price(more items = lower prices). Dont' be afraid and ASK for ANYTHING that you want. Asking for quotes do not equate to commiting yourself into buying anything and cost you no $ for doing it. I have been ASKED alot of times whether these sources have this or that- I have provided contacts of these low-cost sources, so stop ASKING me whether they have this or that- ASK them(like i said- costs you next to nothing other then some finger work to type some sentences to send some emails and ASK them yourself). 

Good luck conducting experiments for your research and please report back if you've got positive results with photos of your mouse samples.

----------


## gainspotter

LETS DO SCIENCE BITCHES

Where's the RV?

----------


## eldarlmario

From Cotsarelis's patent: 

Example 5 In Situ and Immuno-Histological Characterization of Novel HF Genes 
In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data. 

Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples (FIG. 5B). LRRC15 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC15 functions in cell migration, LRRC15 expression was measured in scalp samples by immuno-histochemistry. LRRC15 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (FIG. 6A), which is an area of rapid cell movement during hair growth. Thus, LRRC15 functions in cell migration necessary for hair growth. <==topical Valproic acid 

Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B). <==oral Resveratol, topical Carbamazepine 

GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. <==Topical Valproic acid, Topical Trichostatin A 

The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular. <== Topical Calcitirol/Calcipotriol 0.005% 

GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E). <== Topical Tretinoin(0.01%-0.0005%) 

FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G). <== upregulated indirectly via FOXP1 by topical Valproic acid or topical Tretinoin(0.01%-0.0005%). 

The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth.

----------


## eldarlmario

_From Cotsarelis's patent:_ 

_Example 5 In Situ and Immuno-Histological Characterization of Novel HF Genes 
In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data. 

Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples (FIG. 5B). LRRC15 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC15 functions in cell migration, LRRC15 expression was measured in scalp samples by immuno-histochemistry. LRRC15 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (FIG. 6A), which is an area of rapid cell movement during hair growth. Thus, LRRC15 functions in cell migration necessary for hair growth. <==topical Valproic acid 

Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B). <==oral Resveratrol, topical Carbamazepine or any chemical that promotes Autophargy. PSI(Proteasome Inhibitor) works the same way as Serpina1.

GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. <==Topical Valproic acid, Topical Trichostatin A 

The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular. <== Topical Calcitirol/Calcipotriol 0.005% 

GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E). <== Topical Tretinoin(0.01%-0.0005%) 

FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G). <== upregulated indirectly via FOXP1 by topical Valproic acid or topical Tretinoin(0.01%-0.0005%)._ 

_The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth._

----------


## just2hairs

Eldar, 
I've only read part of this thread, but the curved spine and jaw cracking is exactly what i have.  My right side throughout my body is bigger than the left...even my skull.  My left arm and shoulder gets weak and numb especially when i'm stressed or don't get enough sleep.

Thanks for sharing your findings with us.  I think you maybe onto something. It's such a coincidence that i was googling possible links between hairloss and scoliosis earlier today, and now i just saw your thread.

----------


## eldarlmario

> Eldar, 
> I've only read part of this thread, but the curved spine and jaw cracking is exactly what i have.  My right side throughout my body is bigger than the left...even my skull.  My left arm and shoulder gets weak and numb especially when i'm stressed or don't get enough sleep.
> 
> Thanks for sharing your findings with us.  I think you maybe onto something. It's such a coincidence that i was googling possible links between hairloss and scoliosis earlier today, and now i just saw your thread.


 ic. i already know that there's definitely something with Scoliosis in connection with AGA cos you're the 4th person i have spoken to in hairloss forums who has almost the same symptoms as I.

----------


## just2hairs

I'm thinning diffusely throughout the scalp, even back and sides.

----------


## eldarlmario

> I'm thinning diffusely throughout the scalp, even back and sides.


 then u might have a special case of DUPA- Diffused and Unpatterned Alopecia http://www.bernsteinmedical.com/hair...oss-treatment/

----------


## eldarlmario

> ic. i already know that there's definitely something with Scoliosis in connection with AGA cos you're the 4th person i have spoken to in hairloss forums who has almost the same symptoms as I.


 We have people who find the idea of Scoliosis being connected with AGA being 'outlandish'. These people(with their kind of narrow-minded thinking) are the reason why the true cause of AGA has not being discovered. I hope the scientish and researchers working to find out are not like them.

----------


## charlie76761

Hi Eldarmario,

Picking up on a post from you earlier about sensitivity of your scalp to ethanol, i also have similar issues with dandruff and very dry scalp. Further, i think my hair has lost ground due to the toxic effects of ethanol as definitely thinned a bit when using RU and CB. 

I currently use 95% pure ethanol with DMI added so not more than 10% of total mix. 

Further to the options you listed in your post, what other vehicles and options for sensitive scalps have you come across? 

I've tried Jojoba and coconut oil with a bit of ethanol but it seems to un-dissolve the actives, and also it's too greasy to put on in the morning then go to work. Also, i've looked to stay clear of PG for obvious reasons. 

Lastly, how long do you think would need to leave on with DMI to get say 50% of absorption?

Thanks a lot 

Charlie

----------


## eldarlmario

> Hi Eldarmario,
> 
> Picking up on a post from you earlier about sensitivity of your scalp to ethanol, i also have similar issues with dandruff and very dry scalp. Further, i think my hair has lost ground due to the toxic effects of ethanol as definitely thinned a bit when using RU and CB. 
> 
> I currently use 95% pure ethanol with DMI added so not more than 10% of total mix. 
> 
> Further to the options you listed in your post, what other vehicles and options for sensitive scalps have you come across? 
> 
> I've tried Jojoba and coconut oil with a bit of ethanol but it seems to un-dissolve the actives, and also it's too greasy to put on in the morning then go to work. Also, i've looked to stay clear of PG for obvious reasons. 
> ...


 2hrs minimum- 4hrs to be optimum. im looking to get my hands on K&B solution from Kane. looks good on paper. 

From my experience with using so many experimentals- i have come to realise the importance of a good vehilce. It's like the gun u bring along with u into the battlefield.

Invest in a good vehicle.

----------


## breakbot

Check osteophytes in the neck.

----------


## walrus

> ic. i already know that there's definitely something with Scoliosis in connection with AGA cos you're the 4th person i have spoken to in hairloss forums who has almost the same symptoms as I.


 Correlation does not equal causation. This tenet applies to most of your ramblings  :Wink: .

eldarlmario logic:
"you are the 4th person I have spoken to with hairloss and big ears, there is definitely something to this"

----------


## just2hairs

> Correlation does not equal causation. This tenet applies to most of your ramblings .
> 
> eldarlmario logic:
> "you are the 4th person I have spoken to with hairloss and big ears, there is definitely something to this"


 So after reading through the research he's offered that's all you've gathered?

----------


## Soonbald

> I'm thinning diffusely throughout the scalp, even back and sides.


 I have to say yes me too..I have MORE hair on my Crown than the hair surounding the Crown and its like I have almost a bald spot on the side of my head on one side...you can see through the scalp easily...the other side is also thinning but not as much as the other side...

----------


## bandage

Very interesting research eldarlmario.  How do you propose to apply topical curcumin? Rub turmeric on the scalp? I see there is a product called psoria-gold, but it's very expensive

----------


## eldarlmario

> Very interesting research eldarlmario.  How do you propose to apply topical curcumin? Rub turmeric on the scalp? I see there is a product called psoria-gold, but it's very expensive


 buy the raw powder n mix into a topical

----------


## eldarlmario

> Correlation does not equal causation. This tenet applies to most of your ramblings .
> 
> eldarlmario logic:
> "you are the 4th person I have spoken to with hairloss and big ears, there is definitely something to this"


 Mr Egoist just needs to find something to do with his all free time on hand.

----------


## eldarlmario

*updated list:*

*Experimental small molecule pharmalogical solutions for AGA by topical/oral route administration in order of descending preference(would be updated from time to time): 

1): 

All affected genes indicated in the Scoliosis study: 
*
TATA <= Topical *Calcitirol/Calcipotriol* 

HNF4 <= Topical *Carbamazepine*(direct activator of SHBG for disactivating circulating sex hormones with highest affinity for DHT=>increased bone resorption in the balding skull. Has sides), Topical *Valproic acid*(Androgen Receptor Blocker, Wnt/B-catenin agonist, CD34 upregulator and several other pro-hair growth properties. Has sides if taken orally), Topical *RU58841*(Androgen Receptor Blocker- less systemic side effects), topical *CB*(Androgen Receptor Blocker), topical/oral *Dutasteride*(5A Redutase Inhibitor to decrease circulating DHT. Used carefully- will dramatically slow down, but not stop- AGA and increase 'free' Testosterone levels for the muscles), topical/oral *Finasteride*(5A Redutase Inhibitor to decrease circulating DHT- almost the same profile as Dutasteride but with less potency), oral *Spironolactone*(Androgen Receptor Blocker, Aldosterone Inhibitor=> Less sodium reabsorption in kidneys=>less vasoconstriction=>increased blood supply to hair follicles. Has feminizing sides.), topical *Ethyl Estradiol* (potently upregulates SHBG levels) 

RAR <= Ultra low dose topical *Tretinoin* (0.01%-0.0005%. Ultra low doses of it induces hair shaft differentation at a stabilised rate with stem cells as the fuel while increasing dosages depletes stem cells rapidly and leads to apoptosis instead. Is also toxic when used in dosages above a certain threshold- and this 'threshold' is very low.), topical *Valproic acid* 

RXRA <= Topical *Calcitriol/Calcipotirol*(Calcitriol-binded VDR is needed for full transcription of PPAR Alpha, Beta and Gamma. VDR-null cells on the scalp diverts pluripotent stem cells to the sebocyte(sebum) and sudoriferous(sweat) lineage). 

STAT <= Topical *Calcitriol/Calcipotriol*(Calcitriol acts as a modulator of this central inflammation pathway- the JAK-STAT pathway.), topical/oral *Sulfasalazine*(via inhibiting TH1 cytokines), most anti-inflammatory drugs modulates this pathway to a certain degree. 

BATF <= Topical *Calcitirol/Calcipotriol*(Calcitriol acts as a modulator of this TH17 cytokines regulatory gene), topical/oral *Sulfasalazine*(via inhibiting TH17 cytokines). 

COMP <= Topical *Calcitirol/Calcipotriol*, topical *Valproic acid*(Both Calcitriol and Valproic acid increase expression of this gene- and it is upregulated only in haired-scalp.) 

VDR <= Topical *Calcitirol/Calcipotriol*(Calcitriol's own receptor. It is a receptor that regulates, modulates and thus- controls hundreds of genes(900+ genes) involved with Immunity, Calcium homeostasis, Bone formation/resorption(in synergy with BMPs) and many, many more in the human body.) 

HDAC2 <= Topical *Valproic acid*(inhibitor of HDAC2- which inhibits AGA-afflicted hair follicles stem cell renewal's function), topical Trichostatin A 

CART1 <= Topical *Calcitriol/Calcipotriol* 

FOXA <= FOXA2 inhibits pre-adipocyte differentiation. oral Sirt 1 activators like *Resveratrol* inhibits Foxa2 expression. 

FOXP1 <= Topical *Valproic acid*, Ultra low dose topical *Tretinoin*(0.01% - 0.0005%)(FOXP1 regulates stem cells levels in the hair) 

GATA <= Topical *Calcitriol/Calcipotriol*, Oral *Montelukast*, Oral *Zafirlukast*(GATA3 is the master regulator TH2 cytokines profileration and differentiation.) 

H6 family homeobox 2 <= ? (Has got more to do with inner ear functions than to hair on the balding scalp) 

IRF <= Topical *Calcitriol/Calcipotriol* 

PAX5 <= Topical *Calcitriol/Calcipotriol*(PAX5 is the master regulator of B cells profileration and differentiation.). 

P300 <= Topical *Calcitriol/Calcipotriol* 

2): 

Top 5 upregulated genes in haired-scalp and Top 5 downregulated genes in haired-scalp as indicated by Dr Cotsarelis's patent in order of descending preference: 

Upregulated in haired-scalp: 

GPRC5D <= Ultra low dose topical *Tretinoin*(0.01% - 0.0005% ) 

CDT6<= Topical *Calcitriol/Calcipotriol* 

LY6G6D<= Closest that could be found for small molecules addressing this extremely-rarely-described gene is *Valproic acid*(seeing how Valproic acid has an overwhelming pro-hair growth effect when used topically, this means it probably upregulates it to a certain degree.). 

S100A3<= Topical *Calcitriol/Calcipotriol* 

COMP<= Topical *Calcitriol/Calcipotriol*, topical *Valproic acid* 

3): 

Downregulated in haired-scalp: 

CCL19<= Topical *Calcitriol/Calcipotriol* 

FOSB<= Topical *Valproic acid* 

c-FOS<= Topical* Valproic acid*(via inhibiting Protein Kinase C), Topical/oral *Verapamil*(Calicum channel blocker with lower half-life), topical *Cilnidipine*(Calcium cahnnel blocker with half-life of 24hrs), topical *D609*(research chemical). 

PTGDS<= Topical/oral *TM30089*(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral *Setipiprant*(Newest CRTH2 inhibitor in trials, topical/oral *Ramatroban*(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral *OC*(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.) 

CORIN<= Topical *Valproic acid*(indirectly via antagonising Progesterone), Topical *Carbamazepine*, topical *Phenytoin*(the active ingredient of Proxiphen. Phenytoin is also associated with drug-induced hypertrichosis of the face. Has some deadly sides in those predisposed to), topical *Curcumin*(Upregulates Serpina1- another gene upregulated by 5.721 folds in haired-scalp which in turns inhibits the production of Corin that equautes to 1-32BNP(pro-hairgrowth) production instead of 4-32 BNP production- via trypsin inhibition. it is also a GSK3B inhibitor.), Oral *Spironolactone*(indirectly by antagonising Aldosterone=> CORIN downregulation=> FURIN-Cleaved proBNP=> 1-32 BNP(the pro-hair growth form of BNP) => hair pigmentation + keratinization) 

4): 

Three 'endpoint' genes indicated by Dr Cotsarelis's patent that are significantly-upregulated in haired-scalp: 

CD200<== Topical *Cacitirol/Calcipotriol*(Calcitriol increases both CD200's expression in the balding scalp and balding skull. In the latter's case, without adequate CD200's expression- bone resorption is severely-impaired that leads to ever-increasing bone formation in the balding skull.) 

CD34<== Topical *Valproic acid*(via existing cell self-renewal), Topical *16,16-Dimethly-PGE2*(via homing from bone marrow), Topical *PGE2*(PGE2=>EP2 Receptor=>Survivin=>CD34. Also- PGE2=>EP4 Receptor=>BMP-2=>SMAD1/5/8=>SMAD4=>DLX3=>RUNX2=>Hair shaft differentiation), Topical *Butaprost*(This is a selective EP2 receptor and EP4 receptor agonist. An PGE2 analog), topical/oral *Sulfasalazine*(Upregulates PGE2 while inhibiting COX-2), *Minoxidil sulfate*(via mPGE2). 

Intergrin A6<= Topical *Valproic acid*, Ultra low dose topical *Tretinoin*(0.01%-0.0005%. Tretinoin is the only small molecule that could be found to upregulate IntergrinA6(CD49F) with the other being the Parathyroid hormone-related protein(not a small molecule)) 

_From Cotsarelis's patent:_ 

_Example 5 In Situ and Immuno-Histological Characterization of Novel HF Genes 
In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data. 
_
Microarray showed that LRRC15 was upregulated 4.5 fold in the haired samples (FIG. 5B). LRRC15 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC15 functions in cell migration, LRRC15 expression was measured in scalp samples by immuno-histochemistry. LRRC15 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (FIG. 6A), which is an area of rapid cell movement during hair growth. Thus, LRRC15 functions in cell migration necessary for hair growth. <==topical *Valproic acid* 

Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a Glade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (FIG. 6B). <==oral *Resveratol*, topical *Carbamazepine* 

GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth. <==Topical *Valproic acid*, Topical *Trichostatin A* 

The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno-histochemistry (FIG. 6D), which is also avascular. <== Topical *Calcitirol/Calcipotriol* 0.005% 

GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-1 (retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precortical cells of the hair, as shown by immuno-histochemistry (FIG. 6E). <== Topical *Tretinoin*(0.01%-0.0005%) 

FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G). <== upregulated indirectly via FOXP1 by topical *Valproic acid* or topical *Tretinoin*(0.01%-0.0005%). 

_The genes identified in this Example are all enriched in haired scalp, and are thus therapeutic targets for stimulating hair growth._ 

**Dietary adjustments** 

IMO adjusting your diet will never have much of an impact on AGA. The only thing to look out for would be anything that will cause vasocontriction. 1)Caffeine antagonises the Adenosine receptors and 2)Calcium will not only cause vasocontriction- it also is used as fuel to form our ever growing bones in the balding skull and also as mineral deposits on our fibrosising balding-scalp. Keep it at not more than 1 cup of coffee a day(I know it's hard to not drink coffee-including myself) and /or best of all- avoid milk/cheese consumption. 

*END* 

































































































Ok now that i have consolidated a list of the items to address each gene mentioned in the scoliosis study and Dr Cotsarelis patent- i will post the contacts again for the last time 

I have to stress yet again that 

1)i do not gain anything at all from posting these contacts(my own) other then having the pleasure of knowing I have helped a fellow AGA researcher in conducting his own experiments. 
2)i do not know the contacts and nor do I deal with them pertaining to a Business-Business relationship, other than being a Consumer myself in sourcing supplies for my research. 
3)My conduct at contributing information about AGA to our community should prove that 

These contacts are sourced from over the years while looking for research solutions for investigating AGA, Nootropics, Anabolics and even Myopia. My strategy for sourcing low-cost experimentals for my research is: 

1)http://www.mims.com/India/drug/AdvancedSearch/ to look for any Generic drug I want. Then: (Source A)gksales4@guokang8286.com.cn <==China-based Biochemical factory-based manufacturer for research chemicals(some)/generic drugs in raw powder form. I find most of their prices to be the lowest but some are grossly expensive. They respond to my queries fast, though OR : (Source B)leehpl900@gmail.com <==India-based direct dropshipper from the low-cost Generics Pharmaceutical Industry in India in premade form(gels/ointments/capsules/tabs). Alldaychemist and Inhouse get their stocks from the very same India-based Generics Pharmaceutical Industry base as the 1 mentioned above(but the latter 2 marks up their prices by several folds). This source takes 1 whole day to reply- so don't expect an immediate response. 

2)Santacruz Bio or Tocris website(these are commercial links and Im not gonna post them- so please google their homepage yourself) to look at a comprehensive search list of existing Research chemicals that i want . Then: (Source C)erin@ruishunchem.com <= China-based Biochemicals factory manufacturer. prices are equivalent or just slightly highly than Source A. Has some research chemicals, some recombinant products and most generics in raw powder form. They respond on the same day of enquiry(usually). (Source D): theKaneshop- he gets his supplies/raw materials from the very same China-based Biochemicals Industry base as the other 3 listed here. Kane doesn't respond to queries sometimes and he marks up his prices by several folds when compared to the other China-based manufacturers mentioned here. For all other research chemicals that thekaneshop do not have: (Source E)mail08@sciphar.com <==China-based Biochemical factory-based manufacturer. They provide recombinant products. The downside to this source is that they take a long time to reply, if they do- that is. If they don't', keep emailing them. 

3)Make a list of the items that you want, drop them an email and negotiate with them for the total price(more items = lower prices). Dont' be afraid and ASK for ANYTHING that you want. Asking for quotes do not equate to commiting yourself into buying anything and cost you no $ for doing it. I have been ASKED alot of times whether these sources have this or that- I have provided contacts of these low-cost sources, so stop ASKING me whether they have this or that- ASK them(like i said- costs you next to nothing other then some finger work to type some sentences to send some emails and ASK them yourself). 

Good luck conducting experiments for your research and please report back if you've got positive results with photos of your furry mouse samples.

----------


## Swooping

> Correlation does not equal causation. This tenet applies to most of your ramblings .
> 
> eldarlmario logic:
> "you are the 4th person I have spoken to with hairloss and big ears, there is definitely something to this"


 This.

----------


## baldybald

This thread is going to be useless

----------


## eldarlmario

> This thread is going to be useless


 thx for your opinion. you can always leave this thread if u find it 'useless'.

----------


## Guildenstern

In what concentration would you consider using oral setipiprant then? I have not found any data about bioavailability other than 50% being uselessly metabolized in the stomach. Is an affordable amount of mass even sufficient to make it to the follicle to inhibit CRTH2?

----------


## walrus

> you can always leave this thread if u find it 'useless'.


 Good thing you aren't a moderator.

----------


## eldarlmario

> Good thing you aren't a moderator.


 you're lucky that im not 1 indeed

----------


## eldarlmario

> In what concentration would you consider using oral setipiprant then? I have not found any data about bioavailability other than 50% being uselessly metabolized in the stomach. Is an affordable amount of mass even sufficient to make it to the follicle to inhibit CRTH2?


 'then'? that's what i would like to know too

----------


## bibi

Thank you eldarlmario for all these information.
I'm taking Montelukast for my asthma since 2 weeks and I've noticed a less itchy scalp during the past week.. I don't know if it's due to Montelukast or not, but can you tell me more precisly how it would work against mpb?
Thank you again

----------


## eldarlmario

> Thank you eldarlmario for all these information.
> I'm taking Montelukast for my asthma since 2 weeks and I've noticed a less itchy scalp during the past week.. I don't know if it's due to Montelukast or not, but can you tell me more precisly how it would work against mpb?
> Thank you again


 Montelukast and any other Leukotriene antagonists works by inhibiting IL-4(hence- blocking the differentiation of all TH2 cytokines) and blocking PGD2 and PGE2 synthesis. The CRTh2(*C*hemokine *R*eceptor expressed on *T* Cell *H*elper *2*) receptor is thus render incapable of attracting any TH2 cytokines from chemotaxing to where it's expressed in(like the mast cells in the hair) because there is none to begin with. You are going to need supplementing PGE2 to compensate for the loss of PGE2 production but then again- PGE2 production is already unexpressed(in fact- it's inversely expressed) in balding scalp.

So an comparison on the difference between a Leukotriene antagonist and a CRTh2 ihnbiitor:

CRTH2 inhibitor(TM/Seto/Rama/OC): blocks the receptor attracting TH2 cytokines to where it's expressed in by a homing mechanism called Chemotaxis. It can be expressed in any tissue in the body where PGD2 is expressed in.
Leukotriene antagonists: blocks the synthesis of TH2 cytokines in the first place by inhibiting production of IL-4(the 'master cytokine' of TH2 cytokines. Any production of other TH2 cytokines requires the upregulation of IL4 first)

----------


## Hairismylife

Eldarlmario in your opinion if I use Calci+pge2 only, can I expect some regrowth?

The Calci is so powerful that tackles so many genes? 

What dosage to use per day?

Thanks

----------


## bibi

Thank you for your answer Eldarlmario.
As english is not my native langage, It was diffucult for me to undestand 100% of these 19 pages of information.
Could you please briefly tell me the relation of TH2 with PGD2 and so AGA.
Thank you my friend.

----------


## eldarlmario

> Eldarlmario in your opinion if I use Calci+pge2 only, can I expect some regrowth?
> 
> The Calci is so powerful that tackles so many genes? 
> 
> What dosage to use per day?
> 
> Thanks


 U're gonna need 3 things + 1 more to even try and archive regrowth:

1)CD34 upregulator <== oral or topical PGE2 OR *topical* Valproic acid
2)CD200 upregulator<== *topical* Calcipotriol/Calcitriol
3)CD49F upregulator<== *topical* Tretinoin

+

4)Androgen Receptor inhibitor<== *topical* Valproic acid OR *topical* RU58841 OR any of the mainstream AR inhibitors(Spiro, etc)

just use the premade strength of 0.005% for topical Calcipotriol.

----------


## eldarlmario

> Thank you for your answer Eldarlmario.
> As english is not my native langage, It was diffucult for me to undestand 100% of these 19 pages of information.
> Could you please briefly tell me the relation of TH2 with PGD2 and so AGA.
> Thank you my friend.


 *Lazy poster alert*

----------


## Hairismylife

> U're gonna need 3 things + 1 more to even try and archive regrowth:
> 
> 1)CD34 upregulator <== oral or topical PGE2 OR *topical* Valproic acid
> 2)CD200 upregulator<== *topical* Calcipotriol/Calcitriol
> 3)CD49F upregulator<== *topical* Tretinoin
> 
> +
> 
> 4)Androgen Receptor inhibitor<== *topical* Valproic acid OR *topical* RU58841 OR any of the mainstream AR inhibitors(Spiro, etc)
> ...


 CB as AR inhibitor ok?

And 0.005% means how many mg in 1ml?

----------


## eldarlmario

> CB as AR inhibitor ok?
> 
> And 0.005% means how many mg in 1ml?


 50mcg. yes CB is ok

----------


## Hairismylife

> 50mcg. yes CB is ok


 Calcipo safe to use?
Any systematic or sex or any other else possible sides?

And tretinoin?

Thank in advance.  I'm ready to order some.

----------


## eldarlmario

> Calcipo safe to use?
> Any systematic or sex or any other else possible sides?
> 
> And tretinoin?
> 
> Thank in advance.  I'm ready to order some.


 Calcipotriol:

Medical uses[edit]
Chronic plaque psoriasis is the chief medical use of calcipotriol.[1] It has also been used successfully in the treatment of alopecia areata.[2]
Adverse effects[edit]
Adverse effects by frequency:[1][3][4][5]
Very common (> 10% frequency)
Burning
Itchiness
Skin irritation
Common (1–10% frequency)
Dermatitis
Dry skin
Erythema
Peeling
Worsening of psoriasis including facial/scalp
Rash
Uncommon (0.1–1% frequency)
Exacerbation of psoriasis
Rare (< 0.1% frequency)
Allergic contact dermatitis
Hypercalcaemia
Photosensitivity
Changes in pigmentation
Skin atrophy



Tretinoin:

Side effects[edit]
In dermatological use[edit]

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (December 2011)
When used, dryness or increased sensitivity to sunlight of the affected skin may occur.[13] More sensitive patients may also experience redness, scaling, itching, and burning.[14] A gradual increase in the frequency and amount of tretinoin application is best, as this allows one's skin to adequately adjust to the drug. Patients should be careful to follow their physician's recommendations when beginning a round of treatment.
As this product may cause irritation, it may indirectly increase sun sensitivity and fragility of the skin.[15] Patients who are using the drug should apply moisturizer and sunscreen to reduce the chance of developing sunburn while using tretinoin.[15] Additionally, patients using tretinoin should be cautious when simultaneously using other topical medications that contain salicylic acid, resorcinol, or sulfur because these medications may potentiate the drying and possibly irritating effects of tretinoin.[16] Topical tretinoin should be avoided during pregnancy because its use has been linked to birth defects in several case reports.[17]

----------


## bibi

> *Lazy poster alert*


 Oh please..
Or just tell me the page important I will try to translate it.
Thank you.

----------


## Hairismylife

Thanks Eldarl.
But tbh you have no sucess in regrowth, what's missing in your longlong regime!

----------


## eldarlmario

> Thanks Eldarl.
> But tbh you have no sucess in regrowth, what's missing in your longlong regime!


 is this considered regrowth?

[IMG][/IMG]

[IMG][/IMG]

----------


## awdtnr91

> is this considered regrowth?
> 
> [IMG][/IMG]
> 
> [IMG][/IMG]


 
Woahh....

After reading through all of this  and seeing results could we obtain a quick outline. I understand you have expressed everything needed above. But for those of us who haven't been in the hair game too long, something to simplify the process.  Buy these things, mix them with this, and to this daily... to acheive such results? It would be greatly appreciated.

----------


## baldybald

> is this considered regrowth?
> 
> [IMG][/IMG]
> 
> [IMG][/IMG]


 No, sorry.

----------


## bibi

WTF your eyebrow gonna be your hairline

----------


## bibi

Wait, I've already seen these pics on another hair loss forum, they are from 2013... What is your situation today? lol

----------


## baldybald

> Wait, I've already seen these pics on another hair loss forum, they are from 2013... What is your situation today? lol


  Lol, he wants to increase the number of his replies, well he is doing good so far !

----------


## TubZy

> Good thing you aren't a moderator.


 Lmfao

----------


## TubZy

> Oh please..
> Or just tell me the page important I will try to translate it.
> Thank you.


 Lol. He won't explain it to you don't worry.  He wants you to read through 20 pages of nonsense to act like he's smart. I'm not sure he had ever heard the term "summarize" or "cliff notes".  No one wants to read through all that summarize the important parts.  But doesn't matter to me I follow Swiss temples anyways who had way better results and success.

----------


## Parsia

> Lol. He won't explain it to you don't worry.  He wants you to read through 20 pages of nonsense to act like he's smart. I'm not sure he had ever heard the term "summarize" or "cliff notes".  No one wants to read through all that summarize the important parts.  But doesn't matter to me I follow Swiss temples anyways who had way better results and success.


 
Yes. As I always said , We are here to help . Not have the attitude against the other posters.

----------


## nameless

I've been ignoring this thread because it's a stupid waste of time. I was hoping that if we all ignored it, it would fade into the thread basement but people keep responding to it. This is my first, last, and only post in this thread and the only reason I'm posting it is to recommend that people stop responding to it so it goes down deep into the sh_tter where it belongs.

----------


## eldarlmario

> Wait, I've already seen these pics on another hair loss forum, they are from 2013... What is your situation today? lol


 yes u r right. my point for posting this pix is there IS a way to get regrowth(and de novo hairgrowth). The better-informed me that enabled me to get these results tells that it is mineral homeostasis and enhancement of bone resorption.

----------


## eldarlmario

> Lol. He won't explain it to you don't worry.  He wants you to read through 20 pages of nonsense to act like he's smart. I'm not sure he had ever heard the term "summarize" or "cliff notes".  No one wants to read through all that summarize the important parts.  But doesn't matter to me I follow Swiss temples anyways who had way better results and success.


 bye.

----------


## eldarlmario

> Lol, he wants to increase the number of his replies, well he is doing good so far !


 ty.

----------


## Hairismylife

> I've been ignoring this thread because it's a stupid waste of time. I was hoping that if we all ignored it, it would fade into the thread basement but people keep responding to it. This is my first, last, and only post in this thread and the only reason I'm posting it is to recommend that people stop responding to it so it goes down deep into the sh_tter where it belongs.


 Why? The science behind is not legit?

----------


## eldarlmario

> I've been ignoring this thread because it's a stupid waste of time. I was hoping that if we all ignored it, it would fade into the thread basement but people keep responding to it. This is my first, last, and only post in this thread and the only reason I'm posting it is to recommend that people stop responding to it so it goes down deep into the sh_tter where it belongs.


 see ya not again.

----------


## JSmith120

What? lol

----------


## Hairismylife

> U're gonna need 3 things + 1 more to even try and archive regrowth:
> 
> 1)CD34 upregulator <== oral or topical PGE2 OR *topical* Valproic acid
> 2)CD200 upregulator<== *topical* Calcipotriol/Calcitriol
> 3)CD49F upregulator<== *topical* Tretinoin
> 
> +
> 
> 4)Androgen Receptor inhibitor<== *topical* Valproic acid OR *topical* RU58841 OR any of the mainstream AR inhibitors(Spiro, etc)
> ...


 Premade?
Inhouse is selling Divotnex with 50mg/ml which is 5%, 1000 times higher than your suggestes dosage.  Can you recommend other source which makes this low dosage I gonna buy some.

----------


## jiggo

This guy wants to help us. Why are you all treating him so disrespectful? He is not posting bullshit. He posts scientific studies and literature and trys to create a treatment based on his research and as I can evaluate this it can work.

----------


## bibi

Well my "less itchy scalp" was certainly not due to Montelukast as the drug is not effective controlling allergic symptoms outside the airways : http://www.ncbi.nlm.nih.gov/pubmed/19127072

----------


## champpy

eldarlmario,

Can I ask, did you go thru a shedding period while on the oral minoxidil?

----------


## eldarlmario

forget it.

----------


## walrus

> forget it.


 Do you want people to beg you to come back and inflate your ego?

----------


## champpy

> forget it.


 Forget what?

----------


## barfacan

It's called a crash.  Give him a few days to recover

----------


## eldarlmario

> eldarlmario,
> 
> Can I ask, did you go thru a shedding period while on the oral minoxidil?


 not that i noticed.

----------


## eldarlmario

> Forget what?


 posted a list of something- but felt it's pointless to post it here

----------


## eldarlmario

> Do you want people to beg you to come back and inflate your ego?


 funny how this guy whines about this thread, yet cums back to check out the latest replies- apparently. Haha.

----------


## champpy

Thanks eldarlmario. If the shedding doesnt increase i may try it

----------


## galil1

wow!, you did your homework....hence, good job  :Wink: 
but, if I may, next time post some pics, I wanna see that hairline start just above the waist so you can make yourself a natural ''hairkini'' to cover what oralspiro did to you.

----------


## galil1

wow!, you did your homework....hence, good job  :Wink: 
but, if I may, next time post some pics, I wanna see that hairline start just above the waist so you can make yourself a natural ''hairkini'' to cover what oral spiro did to you.

----------


## ragnars

Hi Everyone,

I am a new guy on the board, I came here just from google pictures search result. I have checked this thread but ( maybe I missed something) can't see what caused your result eldermario ( forehead with full of tiny hairs ) ? is this what you mention before:

= hair growth

CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%
CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%)
CD49f: topical Tretinoin (generic creams/gels are available at 0.01%)

+ 1.5mm once/mth soft dermarolling

= hair growth

U need to stop DHT(higher potency) and Testerone first from exerting their acitions on further expanding your balding skull and inhibiting hair growth in AGA individuals. SO- it's:

1)CD34: topical PGE2 or topical Valproic acid(generic PGE2 gels is availble at 0.5%
2)CD200: topical Calcitirol or Calcipotriol(generic creams are available at 0.005%)
3)CD49f: topical Tretinoin (generic creams/gels are available at 0.01%)

AND

4)An androgen receptor blocker like RU58841 or Valproic acid, etc.

5)+ 1.5mm transient soft dermarolling(optional)

= hair growth

I am sorry if force you to tell this once again but if you could answer or give a link to this post I would be glad  :Wink: .

Regards

----------


## Getthroughthis

> its ok, this thread is only for keen and sincere individuals who wants to help themselves with their own hairloss(their own- not other's)- and the fact that these group of individuals who r in here n not complaining that it's complicated proves the fact that:
> 
> 1)they've learn something new AND/OR
> 2)they make the effort to go do some further research themselves on the information being stated here by using simple search engines like 'google search'- and reach a conclusion for themselves whether the said information here are accurate/plausible or not.
> 
> Thus- these are the people not complaining that the truckload of information is complicated  and hence- the reason why i started this thread in the cutting edge/future treatment section instead of the common 'hair loss treatment' section that are full of the same old stuff like minoxidil, dutasteride, finasteride, spiro, ketoconazole(if you've read my posts on keto- u would see that it's more harmful than it is beneficial to the hair with the reasons stated why backed up by studies and links), etc, etc.
> 
> *Conclusion- this thread is not for the laymen- especially LAZY 1s*


 Hey Eldarlmario, many thanks for all the very insightful info. Could you please point out the specific posts where you have written about the harmful effects of Keto? I'd really like to read it up on it. Many thanks

----------

