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You forgot the link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/
Not only that, but PGD2 production is 12 times higher in bald vs. haired scalp in men with AGA:
Possibly. Interestingly enough, not everyone with hair loss is sensitive to PGD2's effects. A poster from the World Congress for Hair Research last month, courtesy of hellouser (right click and select "view image" or "open image in new tab" for a larger version):Originally posted by Chemical
As you can see, they identified a few SNPs (which appear to be in perfect linkage disequilibrium) in the CRTH2 (GPR44) gene associated with PGD2 sensitivity as well. I would guess that PGD2 is one problem (in those people who are sensitive to it), but not the only problem. Maybe PGD2 sensitivity accelerates things?
Sort of a side note, but I'd love to see more studies done into the genetics of AGA. In particular, differences in age, pattern, rate of loss, effectiveness of certain treatments, etc. associated with different genes. There's been some work done on which genes are associated with AGA, but nothing really on the details AFAIK.
Yeah, here's the graph that Cotsarelis presented:Originally posted by Chemical
So it steadily rises during anagen then spikes in very late anagen, soon followed by catagen.
The downside is that VPA is harder to get than minox.Originally posted by Chemical
BTW, your ideas about paracrine effects are interesting. I wonder if full regrowth would stop the nasty paracrine positive feedback loop, effectively returning the state of the follicles to what it was before hair loss started (you would still of course need maintenance drugs then), or whether certain genes/negative growth signals would remain upregulated?
In one week???Originally posted by ChemicalComment
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I m really interessed in your pictures Chemical. I would not judge sth before at least 2 months. Sounds really good. But is it not also possible that with your consequent usage of minox it can be its effect alone? Do you preclude that completely? Looking forward too your pictures soon then if you see its effects already go ahead
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Sorry about that, only realised after I couldnt edit my post anymore.Not only that, but PGD2 production is 12 times higher in bald vs. haired scalp in men with AGA:
Figure 2E is the averaged level of PGD2 from a greater sample, using a more accurate measurement method. Not as high as 12x but still high enough to retard hair growth. Paired with AR it will definitely cause balding.We discovered a significant increase in PGD2 in the balding scalp compared to haired scalp by immunoassay (Fig. 2D). The absolute level of PGD2 was 16.3 ng/g tissue in balding scalp and 1.5 ng/g tissue in haired scalp. PGD2 levels were then measured using ultra–high-performance liquid chromatography–mass spectrometry (UHPLC-MS) because of its reported superior accuracy in measuring prostaglandins compared to immunoassay (17). In a larger series of paired bald and haired samples from 17 men with AGA, we noted an increase in PGD2 in bald scalp compared to haired scalp (Fig. 2E).
"Approx half of Alopecia patients" - random sample and half were immune? My stats knowledge isnt the best but this is a clear indication that PGD2 isnt the holy grail after all. I would also like to see more research on genetic influence. It could be that we've all got different variations of AGA and respond only when the main individual-specific antagonists are suppressed.
PTGDS is being upregulated as anagen progresses, I cant figure out how. One theory is that its TCF/LEF dependent like Axin2 is, but is it an extracellular process? If so, then human hair should enter telogen in groups. Which isnt the case because they cycle independently. Furthermore:
The mouse model isnt entirely reliable for analysis. My guess is PTGDS is being increased in human scalp by AR or ERb.Firstly, the first two cycles of the mouse hair follicle are synchronized whereas in humans at a time when biopsies could be taken, neighbouring follicles cycle independently of each other. Secondly, the mouse hair cycle is short, taking about 3 weeks; in contrast, human scalp hairs have a cycle time of several years, and even vellus hairs take months. The short synchronized hair cycle thus allows hair follicles to be harvested and examined at specific time points in the cycle very easily.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571051/
Regarding VPA, sodium valproate is what you want. Not valproic acid because that'll burn (according to an anecdote). I use this pharmacy alot and they stock it. I'm tempted to buy some but I'll hold off for now.
DPC can release cytokines to the neighboring epidermis as a result of canonical WNT signalling. Including IGF-1 and KGF/VEGF which can bind to the originating cell surface receptors and possibly even nearby follicles. But the distance between the follicles might be too great for the factors to reach them. I dont understand fully how autocrine/paracrine signalling works with DPC but I do know that balding DPC produce DKK-1 and TGF-Beta1 that are released into the extracellular environment. The studies done with AGA DPC co-culture may not be an accurate representation of the scalp so its only speculation - but the theory of paracrine signalling is there. By removing the antagonist you return to baseline which is perfect for growth maintenance. But for regrowth you'll need to be more aggressive in increasing BetaCatenin. Increasing BetaCatenin in the skin/epidermis to high levels will automatically induce hair canal formation (post). The more positive growth factors you have floating around in the epidermis, the greater the chance it'll bind to DPC and not the thousands of other keratinocytes in between the hairs. It all boils down to a game of probability.
Another thing that I've been thinking about lately is angiogenesis. Hair follicles that have an a blood vessel attached grow larger in diameter and grow much faster:
However, if the blood vessel is directly serving the DPC with "nutrients"/glucose then wont that also mean androgens can easily enter the follicles? Its sort of a lose-lose. You'd need an AR suppressor with a very long half life to mitigate the constantly elevated T in the blood stream. Food for thought.
As for the growth I've seen, the follicles I saw last week were most likely anagen already, they were thin at the tips giving the impression of vellus hairs. They haven't fallen out, and they feel quite strong when pulled quite hard.
I know for a fact it was all minox. I was using 3x a day during christmas break. The OL probably had an additive effect. I think having sustained application of a treatment will overcome the body's constant growth retarding effects on hair, seeing as most topicals dont have a long half life. If for a few hours you increase BetaCatenin, and then its completely inhibited by AR for 6 hours, you'll never see growth. If I could use minox + OL 3x a day for a year I would be a nw0 gauranteed.
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I've been doing some more reading on PKC and understood a little better how it works with regards to hair growth. PKC caught my attention when I read this study on procyanidins (found in apple skin) increasing hair growth.
The confusing thing was that PKC can actually inactivate (phopsphorylate) gsk3b and we know gsk3b inhibition increases β-catenin. So procyanidins mediated PKC inhibition had to be working through a different mechanism.
Then I found this study:
Protein-kinase-C-mediated β-catenin phosphorylation negatively regulates the Wnt/β-catenin pathway
This is quite surprising. β-catenin can be degraded regardless of GSK-3β. This is not good news at all. So even PGE2 and minox's effectiveness will be greatly diminished if PKC is elevated.A23187 = PKC activator
A23187-mediated β-catenin degradation requires the β-catenin N-terminus but not GSK-3β activity
Since the phosphorylation of β-catenin by GSK-3β and its subsequent association with β-TrCP leads to β-catenin degradation, we examined whether A23187-mediated inhibition of CRT requires GSK-3β activity. To this end, HEK293 reporter cells were incubated with A23187 and LiCl, an inhibitor of GSK-3β. As shown in Fig. 2A, A23187 suppressed LiCl-induced CRT. Furthermore, Western blot analysis using anti-β-catenin antibody consistently showed that A23187 reduced the level of β-catenin that accumulated with LiCl treatment (Fig. 2B), indicating that A23187-mediated inhibition of the Wnt/β-catenin pathway is independent of GSK-3β.
And get this, PGD2 can activate PKC.
These results strongly suggest that PGD2 stimulates IL-6 synthesis through intracellular Ca2+ mobilization in osteoblasts, and that the PKC activation by PGD2 itself regulates the over-synthesis of IL-6.
http://www.ncbi.nlm.nih.gov/pubmed/10582659And PKC can in turn increase PTGDS expression:We previously showed that PGD2 stimulates the induction of heat shock protein 27 (HSP27) via protein kinase C (PKC)-dependent p38 mitogen-activated protein (MAP) kinase and p44/p42 MAP kinase in osteoblast-like MC3T3-E1 cells.
http://www.ncbi.nlm.nih.gov/pubmed/15743775
Protein kinase C activates human lipocalin-type prostaglandin D synthase gene expression through de-repression of notch-HES signaling and enhancement of AP-2 beta function in brain-derived TE671 cells.
Bear in mind these are in different cell types so its not 100% accurate.
If PGD2 increases PKC then it could mean that in some people the increase in PKC mediated β-catenin degradation may offset its GSK3b inhibiting effects (net yield of no change in β-catenin). PGD2 also inactivates AKT (InBeforeTheCure) so GSK3b is further increased doubling up on the PKC ¬ β-catenin.
Another related protein kinase is PKA that has the ability to prevent β-catenin degradation by occupying the SER675 position that the proteosomes require to carry out the ubiquitinition (study).
This is why forskolin can boost the effect of procyanidins on hair growth:
Apples are known to contain the highest concentration of procyanidin b-2, and the polyphenol extract is quite cheap from amazon uk. (Apple polyphenols contain procyanidin). Or alternatively grape seed extract.Nonselective protein kinase inhibitors, such as staurosporine and K252a, inhibit the growth of hair epithelial cells. 1,2-Dioctanoyl-sn-glycerol, a protein kinase C activator, dose-dependently decreases the growth of hair epithelial cells. Forskolin, an adenylate cyclase activator, promotes hair epithelial cell growth and boosts the growth-promoting effect of procyanidin B-2. It is speculated that the hair-growing activity of procyanidins is related to their protein kinase C-inhibiting activity.
I'm going to order some forskolin and apple/grape polyphenol to try on my right temple, versus the minox + Ol + EGCG on my left.
Update:
I've got significantly more new terminal follicles that are prickly to touch growing in the vertex area, behind the hairline.
I added more minox to my solution. I had 20ml left and added around 20ml more. The total original EGCG content in the 20ml is ~100mg. I also added another EGCG capsule since I wasnt seeing any irritation - if I keep my skin hydrated I dont get any redness at all or flaking. The total EGCG content is now around 350mg/40ml = 8.75%. The OL percent is less than 1mg now. I might not increase OL further. The mice study used 10% EGCG and they still saw slight Testosterone induced apoptosis. This leads me to believe 5% may not be enough, and like @BRIANBOY has stated, he's been able to use 10%+, hence my decision to use more. Everyone using EGCG can increase the EGCG dose at your own discretion or wait till I've gone 2 more weeks using this new dose without any sign of irritation. I've started using this new solution since today.
Also the left temple area is gradually taking on the hallmark scalp appearance (white skin tone) and texture - starting from the back. Its only been 3 weeks since using the mxol and 1 week using the EGCG. I wonder what will happen at the 3 month mark...Comment
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For informations, i use VPA ( the acid solution) without any problems ! PH is near the skin PH, i don't burn at all
PS : Anyone know why i cannot publish directly my messages there ? I'm not new member here.ThanksComment
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chemical so you think taking setipirant would be a good idea then if it reduces PKC with reduction of PGD2Comment
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What percentage of people have PGD2 sensitivity? Things like propecia and dut work in such a huge percentage of men it makes you think almost all balding men are sensitive to androgens to some degree. I wonder if PGD2 is similar or if its more a smaller group of men that it affects.
So right now someone losing hair should take or do what? It seems like we know a lot more than just DHT is an issue, but there are no practical physical treatments beyond just propecia. Its years and years to wait for something better.Comment
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Ah yes, I misread it. My bad.
Here's a recent study on risk alleles associated with AGA: http://journals.plos.org/plosone/art...l.pone.0127852Originally posted by Chemical
No association between the CRTH2 gene and AGA has yet been found AFAIK, and the allele frequencies of that gene were similar in the poster subset as they are in the population as a whole, so it seems as if variation in CRTH2 is not a risk factor for AGA. But PGD2 has been shown to lead to hair loss and miniaturization, so if you have AGA and are PGD2-sensitive, you may do better if you deal with PGD2 as part of your protocol, especially with what you've posted about PGD2 and PKC. Maybe.
Some interesting discussion from that paper:
From another paper:The polygenic nature of MPB was discovered in early studies [40,41] and confirmed in GWAS analyses that followed [9,12,14,16]. The role of androgens had also been established as an important part of the predisposition to MPB and its age-related onset. Therefore, the androgenetic pathway is a process certain to contribute to MPB variation [27,42]. The Xq12 region that includes androgen receptor (AR, OMIM: 313700) continues to show the best-documented and strongest association with MPB. This region also contains ectodysplasin A2 receptor (EDA2R, OMIM: 300276), but it is still not fully understood whether one or both genes play a role in the progression of AGA. Our study confirmed that the AR/EDA2R region forms the major risk factor for MPB with the highest significance shown by rs5919324 located upstream of AR. The same SNP was previously shown to have the most significant association with MPB in the study of Cobb et al, 2010 [11]. Cobb found the second strongest association with MPB from the 20p11 region between PAX1 encoding paired box protein 1 and FOXA2 encoding forkhead box protein A2 [9,14]. From seven SNPs located in this region and included in our study, the highest significance was recorded for rs1998076, which was previously shown to be associated with MPB in a German population sample [14]. Richards et al. reported that the risk of AGA increases substantially (OR = 7.12) in individuals having at least one risk allele at both the Xq12 and 20p11 loci. They further estimated that these two loci have very high sensitivity of MPB prediction (98.2%) but very low specificity (6.6%) [9]. Interestingly, different SNPs on Xq12 have been shown to be most significantly associated in various European populations, indicating a complex genetic architecture for the region [4,8,10,11]. Moreover, the AGA-associated region on 20p11 contains no recognized genes to date, so it can only be speculated whether variation in this area has a regulatory function for PAX1 and/or FOXA2 located at each of the region’s ends [43]. It is also worth emphasizing that in our study six SNPs from Xq12 and five SNPs from 20p11 were found to have positive influence on prediction accuracy and thus all were included in the extended 20-SNPs prediction model. Further studies are necessary to analyze in more detail whether multiple DNA variants may contribute to MPB development in these two major AGA loci. If this is the case, it will have a strong impact on prediction modeling. Allelic heterogeneity is already recognized as an important factor affecting trait prediction analyses [21,25,37,44].
Beyond Xq12 and 20p11, ten additional loci have been shown to contribute to the overall risk of developing MPB [12,15,16]. From these, the most significant associations with AGA in our study were found for SNPs located on chromosomes 1, 5 and 7. Beyond rs5919324 (Xq12) and rs1998076 (chr20), three additional SNPs indicated independent effects when assessed with multivariate regression analysis. First, we found strong association for rs929626 located in an intron of EBF1 (early B-cell factor 1), with this SNP originally identified in large meta-analysis of European males [16]. Transcription factor EBF-1 encoded by EBF1 is an important regulator of cell differentiation of adipocytes [45]; known to be involved in the regulation of hair follicle cycling [46]. SNP rs929626 was observed to have a positive impact on prediction in this study as well as interacting with rs1998076 (chr20). This interaction is novel and further studies on larger sample sets are necessary to confirm the effect and its biological mechanism. Implementation of the epistatic effect into the prediction model was found to have an ambiguous effect on accuracy and therefore was not included in the final 20-SNP prediction model. Second, rs12565727 close to TARDBP (TAR DNA binding protein) on chr1 gave the next highest association. This AGA determinant gene was recently identified by a meta-analysis performed by Li et al, in 2012. TARDBP codes for the 43 kDa transactive response DNA binding protein (TDP-43) and is involved in regulating gene expression and RNA splicing [47]. Third, the last SNP selected in our multivariate regression model was rs756853 located in an intron of HDAC9 (histone deacetylase 9) on chr7. This association was first discovered in a GWAS of German and Australian subjects [15]. The histone deacetylase 9 protein encoded by HDAC9 belongs to the extensive HDAC superfamily, which plays a critical role in the regulation of gene expression. HDAC proteins are responsible for deacetylation of histones leading to chromatin condensation and consequently to transcriptional repression [48]. Brockschmidt, et al. suggested that HDAC9 might interact with AR through MEF2C transcription factor modulating AR transcriptional activity [15]. Of six SNPs previously associated with hair morphology [30], none revealed independent association with MPB in our study. Only DNA variant rs7349332 in WNT10A showed a positive effect on prediction accuracy (a marginal AUC increase from 0.862 to 0.864) and was among markers included in the final 20-SNPs prediction model. This SNP was initially associated with hair morphology [30] and then also associated with MPB in a study of Heilmann et al. who suggested a possible link between hair curliness and hair loss [16].
Our results are in agreement with the genetic data obtained for AGA so far, indicating the involvement of multiple genetic loci with average or small individual effects. The study data indicates individuals carrying seven or more AGA risk alleles, in the five most associated loci, are significantly more susceptible to MPB.
EDA2R is capable of activating the NF-κB pathway and also through TRAF3,6, JNK (c-Jun N-terminal kinase) (Sinha et al., 2002), which activates c-Jun.EDA2R could influence the onset of AGA through the activation of the NF-κB pathway or by c-Jun, which has been shown to be critical for AR transactivation (Bubulya et al., 1996). Moreover, in adult mice, EDA2R is also expressed in the hair bulb and in differentiating hair matrix (Botchkarev and Fessing, 2005). Looking at the human expression data from the UniGene database (http://www.ncbi.nlm.nih.gov/sites/entrez), we noticed that it is expressed during embryonic life and, especially, in the first weeks after birth. Expression then seems to be absent until the 17th year of age, when it recurs in different tissues, including skin. This expression pattern fits very well with the course of AGA, with its onset around puberty.
EBF1 interacts with ERbeta: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738513/
Because the EBF1 binding motif was enriched at ERβ binding sites, the interaction between EBF1 protein and a few ERβ binding sites was investigated. When EBF1 was transiently expressed in C4–12/Flag.ERβ cells, it was recruited to several ERβ binding sites in an E2 dependent manner (Figures 6A). Moreover, the recruitment of ERβ at these sites was enhanced in the presence of EBF1 and E2 (figure 6B).
We then used co-immunoprecipitation to test for an interaction between these two proteins. As shown in figure 6C, V5-tagged EBF1 was detected in the ERβ immunoprecipitate, indicating an interaction between the two proteins. However, when V5-EBF1 was immunoprecipitated with V5 antibody, no ERβ was detected (data not shown). These results suggest a stoichiometry in which most of the ERβ interacts with EBF1, while only a small portion of EBF1 interacts with ERβ, indicating that ERβ levels are limiting. Notably, cells used in these assays were treated with MG132 because ERβ levels were very low (figure 6C).
Because the presence of EBF1 correlated with low ERβ protein levels, we wished to test the influence of EBF1 on ERβ protein levels and function. Due to the low ERβ expression in stably transfected C4–12/Flag.ERβ cells, transiently over-expressed ERβ was assayed in the presence and absence of EBF1. As shown in figure 7A, EBF1 significantly reduced ERβ protein stability while ERβ transcript levels remained unchanged (Figure 7B), indicating that EBF1 regulates ERβ stability at the protein level. ERβ transcriptional activity was also suppressed, as measured by an ERE-luciferase reporter assay (figure 7C). This suppressive effect was also observed for endogenous target genes. Thus, when C4–12/Flag.ERβ cells were transfected with EBF1, ERβ target gene expression in response to E2 was significantly reduced (figure 7D).The working hypothesis at Kythera was through AR:Originally posted by Chemical
Either way, certainly downstream of androgens.
I don't think most people have much of a problem with VPA, but we'll see...Originally posted by Chemical
Well, let's hope. Maintenance is much less inconvenient than regrowth lol.Originally posted by Chemical
Maybe we need some sort of DPC border control. Let in the nutrients, keep out the androgens. I assume that's many years away, sadly.Originally posted by ChemicalAnother thing that I've been thinking about lately is angiogenesis. Hair follicles that have an a blood vessel attached grow larger in diameter and grow much faster:
However, if the blood vessel is directly serving the DPC with "nutrients"/glucose then wont that also mean androgens can easily enter the follicles? Its sort of a lose-lose. You'd need an AR suppressor with a very long half life to mitigate the constantly elevated T in the blood stream. Food for thought.
60 percent in that sample.Comment
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Chemical - I believe an 8% solution of EGCG in 40ml would be 3.2 grams (3200 mg). So, 320 mg in 40ml is not 8.75%.Comment
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Speaking of NFkB (which EDA2R activates), NFkB is implicated in AR overexpression in androgen-independent prostate cancer...
Prostate cancers that progress during androgen-deprivation therapy often overexpress the androgen receptor (AR) and depend on AR signaling for growth. In most cases, increased AR expression occurs without gene amplification and may be due to altered transcriptional regulation. The transcription factor nuclear factor (NF)-κB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways. NF-κB is an important determinant of prostate cancer clinical biology, and therefore we investigated its role in the regulation of AR expression. We found that NF-κB expression in prostate cancer cells significantly increased AR mRNA and protein levels, AR transactivation activity, serum prostate-specific antigen levels, and cell proliferation. NF-κB inhibitors decrease AR expression levels, prostate-specific antigen secretion, and proliferation of prostate cancer cells in vitro. Furthermore, inhibitors of NF-κB demonstrated anti-tumor activity in androgen deprivation-resistant prostate cancer xenografts. In addition, levels of both NF-κB and AR were strongly correlated in human prostate cancer. Our data suggest that NF-κB can regulate AR expression in prostate cancer and that NF-κB inhibitors may have therapeutic potential.Comment
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Chemical, you say PGD2 does not play the major role, but what about the fact that genetically altered mice which overexpress Ptgs2 phenocopy AGA?
Transgenic mice overexpressing Ptgs2 in the epidermis phenocopy AGA
Given the correlation of increased levels of PGD2 with balding scalp in humans and the presumptive inhibitory role of PGD2 on the mouse follicle, we hypothesized that mice with high levels of PGD2 in the skin might develop features of AGA. Because Ptgs2 (cyclooxygenase 2, prostaglandin G/H synthase) is the enzyme upstream to Ptgds, we further hypothesized that mice overexpressing Ptgs2 would have elevated PGD2 levels. Transgenic mice that overexpress Ptgs2 in the epidermis had been developed previously for carcinogenesis studies. The hair follicles in these K14-Ptgs2 transgenic mice were noted to enter catagen prematurely, and these mice reportedly developed alopecia and sebaceous gland enlargement (14, 23).
We further analyzed the skin and hair follicles of the K14-Ptgs2 mouse. These mice developed alopecia, which was evident as a decrease in the normal murine pelage coat compared to control (Fig. 5, A and B). By histology, we also detected sebaceous gland hyperplasia as indicated by enlarged sebocytes clustered around the hair follicle (Fig. 5, C and D). The hair follicles in the K14-Ptgs2 mice were miniaturized compared to controls (Fig. 5, C and D), and these follicles bore a marked resemblance to the miniaturized follicles in human bald scalp.
To determine the prostaglandin content in the alopecic skin of the K14-Ptgs2 mice, we measured prostaglandin levels by HPLC-MS during the anagen phase of the hair follicle cycle. PGE2 was elevated in the K14-Ptgs2 mice compared to age-matched wild-type controls, as was previously shown using immunoassays measuring PGE2 and PGF2α content in biopsied mouse skin (14, 24). PGD2 was also elevated and was more abundant than PGE2 in both wild-type and K14-Ptgs2 mice. 15-dPGJ2 was elevated in K14-Ptgs2 mice compared to controls and demonstrated the largest fold increase (~14-fold), although baseline values were low (5.7 ng/g tissue) (Fig. 5E). We found low levels (18.4 ng/g tissue) of PGF2α, and an absence of prostacyclin (6k-PGF1α) and thromboxane (TxB2) (Fig. 5E), which are not known to be present in normal skin. Together, the balding phenotype in these mice is likely a result of the overwhelming PGD2 and 15-dPGJ2 inhibitory effects on the hair follicle, despite the presence of PGE2, a known promoter of hair growth (20).Comment
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How long have you been using VPA, and have you seen any change? Also where did you get the acid form?
PGD2 is quite important for REM sleep and I dont like the idea of messing with neurotransmitters. Thats why I dont like fin either (messes with pregnenolone). If seti can be used effectively topically then that might be ideal. You might also want to increase your EGCG dose too seeing as we're both using very low doses. I'm going to add another cap bumping up the total to 500mg/40ml = 1.25% EGCG.
Indeed, AGA is definitely an androgen mediated disease.
Sorry you're right. I'm using a 0.875% solution. How much EGCG are you using?DOSAGE EQUIVALENCE PERCENT
1mg/mL 0.1%
0.1mg/mL 0.01%
0.01mg/mL 0.001%
0.005mg/mL 0.0005%
@InBeforeTheCure
From those excerpts it seems they are saying having a combination of AR related alleles can predispose individuals to AGA, with EDAR/EDA2R being the most significant predictor. I dont particularly like lookng at nf-kb because its functions are so broad and it plays a hand in alot of signalling cascades which makes it difficult to see the bigger picture. But looking this picture from wikipedia I see PKC activating nf-kb.
I read previously that Andrpgens have the ability to upregulate or maintain AR transcriptional activity. There are feedback loops including GSK3b that try to inhibit AR, but we know PKC can phosphorylate GSK3b possibly preventing the feedback loop. AR also inhibits the PI3K/AKT pathway which prevents the additional degradation of GSK3b. However, inhibiting AR causes an increase in Pi3K/AKT signalling which is good. Without PI3K/AKT, PKA will not be as elevated (?) and PKA is known to upregulate AR. These feedback loops are ridiculously complex and we're only scratching the surface. I just wish it was simpler.The transcription factor nuclear factor (NF)-kappaB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways.
About EBF1, I remember making a post about the relationship between adipocytes and hair. EBF1 is expressed during anagen and also from the study you posted, inhibits ERb. In mice ERb is known to be hair growth suppressive so thats probably a good thing? Or perhaps EBF1 is doing something else behind the scenes.
Theres a disparity between mice ERb receptor distribution and male ERb receptor distribution in the scalp. (females have different ER distribution too) (post).Analysis of Ebf1 mRNA expression using in situ hybridization revealed that Ebf1 is expressed in the DP in mature, growing hair follicles at P4 (Rendl et al., 2005); however, bulge, hair germ, and DP cells lack Ebf1 expression during the initiation of a new anagen during the hair cycle (Figure S3B), when adipogenesis is active. This expression pattern was confirmed by real time PCR on isolated DP cells and epithelial cells (Figure S3C).
I was going over the research on 3b-Diol again and found something I'd missed:
In addition, 3β-adiol is considered a powerful DHT metabolite since its intraprostatic protein level is 100-fold higher than that of estradiol (E2) (29). Notably, 3β-adiol has antiproliferative actions which are not reproduced by 17β-estradiol (30). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212017/So Estrogen when applied topically in males doesnt inihibit hair unlike 3B Diol which has antiproliferative actions despite acting via ERb. Regardless of how AR is being increased, preventing the ability of AR to bind to the cell surface and also prevent the intracelluar nuclear trranslocation might be the answer we're looking for. I think given the variation in genetic components, theres a chance these treatments could be hit and miss.We found that 3beta-Adiol not only inhibits PC3-Luc cell migratory properties, but also induces a broader anti-tumor phenotype by decreasing the proliferation rate, increasing cell adhesion, and reducing invasive capabilities in vitro. All these 3beta-Adiol activities are mediated by ERbeta and cannot be reproduced by the physiological estrogen, 17beta-estradiol, suggesting the existence of different pathways activated by the two ERbeta ligands in PC3-Luc cells.
InBeforeTheCure has shown that PGD2 can increase GSK3b, and so it would be incorrect of me to say PGD2 doesnt have a role. I think it has a role but not as significant as the parent mediator of PTGDS, Androgens. I believe we should be focusing more on Androgen as that way we can eliminate multiple bad pathways with one big swoop.
Furthermore, I'd encourage you to read the previous page where I mention cotsarelises findings on actual real world PGD2 expression levels in bald scalp, which shows a modest 2.5-4 fold increase. InBeforeTheCure has also brought to light that 50% if AGA individuals are not sensitive to PGD2 further reinforcing my statement that PGD2 is not the only or most significant factor implicating AGA.
Although the analysis done on mice showed hair phenotype resembling AGA, you can see I've boded the bit that says "15-dPGJ2 was increased 14 fold" in the Ptgs2 overpressed mice. if you look at figure 2F: http://www.ncbi.nlm.nih.gov/pmc/arti...975/figure/F2/
You can see that 15-dPGJ2 is only a small fraction of PGD2, so a 14 fold increase in the metabolite would mean a ridiculously high concentration of PGD2 in the mice. Its not at all surprising that suraphysical levels of PGD2 can retard hair growth. But we have to be realistic here, in AGA humans its not that high anyway. If you inject mice with testosterone or DHT, they also show follicle miniturisation exactly like humans. In fact, anything that reduces BetaCatenin (antibody or what have you) will result in AGA phenotypes. I hope this has clarified my opinion on PGD2's effects on human hair.
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On the topic of AR, I found a study talking about synergistic effects of 5ar inibitors and AR antagonists:
So if I use a 5ar antagonist alongside EGCG theoretically there should be even greater AR suppression. EGCG can inhibit AR to an extent, but when DHT binds to AR its effects are order of magnitudes greater than T. I'm not taking anything strong enough to inhibit 5ar. I found out that Gamma Linoleic acid can inhibit 5ar quite well (study).Progesterone (P), a 5 alpha RI, and spironolactone (SL), an ARI, produced a dose responsive decrease in SGS at topical concentrations of 0.01% to 5.0%. At concentrations of 1, 3, and 5%, P and SL combinations produced neither an additive nor synergistic inhibition of SGS. At very low concentrations of up to 0.10%, neither P nor SL alone produced any effect on SGS. When combinations of these two steroids were applied at low concentrations, SGS decreased unilaterally to approximately 50%. This synergy occurred best at a P:SL ratio of 1:2. The lower effective concentrations of P may be explained by its greater percutaneous absorption. Synergy was also demonstrated at low concentrations with other antiandrogens: cyproterone acetate, canrenone, hydroxyflutamide, and N-N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane- 17 beta-carboxamide.
I've bought some Evening Primrose Oil gel capsules which I'll be adding to my Emu oil for use at night and in the morning before work after the MXOLCG has dried. Emu oil also has potential to reduce 5ar due its Beta-Sitosterol contents.Comment
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Hi chemical
1st thank you for your commitment to the thread.
All very technical and my knowledge of this stuff is next to nothing.
http://www.amazon.co.uk/gp/product/B00B2U9MW4?psc=1&redirect=true&ref_=oh_aui_detailp %20age_o00_s00[/url][/B]
Im in Ireland and cannot get the product above shipped from the U.K.
I have been taking the below as a supplement http://www.comvita.com/products/oliv...-natural/H5488
Would this do mixed with Emu oil?
Appreciate some feedback from all on the thread
Thank you and good luck.Comment
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Chemical,
I often find myself coming on this website hoping for some sort of miracle cure/new breakthrough treatment/some semblance of hope that I can hold on to. Your knowledge, willingness to explain things in detail and sheer pro-activeness with this awful affliction is great to read, and great to be aware of. Really hoping your hard work and dedication pays off and that you've answered some, if not all of the questions that this sort of hairloss poses.
Have ordered my first lot of EGCG and OL because of this thread. Fingers crossed it works!
Thanks again for your efforts; please post your pictures when you have any updates/progress! I'm not in a situation to post pictures for another 2 months but absolutely will when I can mix my new ingredients with minox.
Jackhammer.Comment
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