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

[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)

MY 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