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Atually, the possible cure- is in our vomit
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Atually im trying to look from an angle with the viewpoint that the AR is not the culprit of AGA- but rather, it's either an underexpressed, overexpressed or no expression of PAX1 binding to it that is causing AGA. It is also the likely explanation why blocking the AR only halts AGA at best- but does'nt regrowth any hairThat's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):
(Bolton et. al, 2007, supplementary material)
Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).
By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/16...omms11616.html
So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this.
Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.
It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).
Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.
Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/
I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html
However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.
I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.
BTW, i greatly appreciate yours and mlamber5's valuable input into this topic(PAX1).Comment
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[q] Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh. [/q]
BTW, its:
SHH => Noggin <=> Pax1
Sonic hedgehog induces Noggin, which then induces Pax1's expression. But there was a study that stated Pax1 was upstream of Noggin.
So you are right in that Pax1 is a gene target of Hedgehog signallingComment
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part of the solution to the puzzle lies in the Gluccocorticoid receptor too.That's interesting that testosterone is known to decrease PAX1. In what context, and can you give us a source? That region just downstream of PAX1/FOXA2 (which is from about 21.5 Mb to 22.5 Mb) is loaded with androgen response elements (AREs):
(Bolton et. al, 2007, supplementary material)
Perhaps AR binds to that region and affects chromatin structure. Then the SNPs in between the AR binding site and PAX1 might alter an insulator sequence that stops those chromatin changes from propagating to PAX1. The effect could be either to prevent it from being upregulated (enhancer blocking element) or to prevent it from being downregulated (barrier element).
By the way, that exact same region between PAX1 and FOXA2 has showed up again in GWAS, this time in association with nose width. This was published just a couple weeks ago: http://www.nature.com/ncomms/2016/16...omms11616.html
So perhaps if someone were to look at it, they would find some correlation between nose width breadth and baldness because of this.
Anyway, since PAX genes are responsive to hedgehog signaling, I wonder if PAX1 does its damage (or protects from it) in early anagen, when transit amplifying cells are hitting the dermal papilla cells with Shh.
It's hard to say which way it might go, since for example MAPT is upregulated in Parkinson's disease but downregulated in AGA DPCs even though the SNPs associated with AGA are the same ones associated with Parkinson's. These elements interact in complex networks, so a change that might affect things one way in one context might affect things the opposite way in another. So who knows? The difference in expression might only be transient too, such as embryonic or at one part of the hair cycle (like early anagen).
Not necessarily. It could be that the process is similar in everyone, but the genes that show up in GWAS are like "resistance points" in the network that prevent the process from occurring or alters the speed at which it occurs, but once it gets enough momentum it snowballs.
Yeah, I love Rendl's site. And if you haven't seen it, here's the paper that goes along with the postnatal stuff: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826467/
I posted a paper earlier in this thread about non-coding RNA functions, but I'll post it here again: http://genesdev.cshlp.org/content/23/13/1494.full.html
However, those regions are probably regulatory regions for nearby genes for the most part. But non-coding RNAs could be playing a role even in that.
I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.Comment
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Inbeforethecure- Give me your valuable input on this:
Look at 'NR3C1'(centre/south of the diagram)- that's the Gluccocorticoid receptor and it's in a direct relationship with FOS(aka c-FOS) and FOSB
Then look at this http://www.google.com/patents/US20110021599 - Dr Cotsareli's patent on the most downregulated genes in non-balding scalp when compared to balding scalp. FOS and FOSB are the 3rd and 4th most downregulated genes in non-balding scalp, respectively.
What do you think? Gluccocorticoid underexpression or overexpression in AGA? Gluccocorticoid resistance?
Bear in mind that Calcium channel blockers directly inhibits FOS because:
L-type Ca(2+) channel activation regulates induction of c-fos transcription by hypoxia.
Premkumar DR1, Mishra RR, Overholt JL, Simonson MS, Cherniack NS, Prabhakar NR.
Author information
Abstract
In the present study we examined the intracellular pathways that link hypoxia to activation of c-fos gene expression. Experiments were performed on rat pheocromocytoma-12 (PC-12) cells. c-fos mRNA and promoter activities were analyzed by RT-PCR and reporter gene assays, respectively. BAPTA, a Ca(2+) chelator, inhibited c-fos mRNA and promoter activation by hypoxia. Nitrendipine, an L-type Ca(2+)-channel blocker, abolished, whereas BAY K 8644, an L-type channel agonist, enhanced c-fos activation by hypoxia. Ca(2+) currents were augmented reversibly by hypoxia, suggesting that Ca(2+) influx mediated by L-type Ca(2+) channels is essential for c-fos activation by hypoxia. We next determined downstream pathways activated by intracellular Ca(2+) concentration. Immunoblot analysis revealed Ca(2+)/calmodulin-dependent kinase II (CaMKII) protein in PC-12 cells and revealed that hypoxia increased the enzyme activity. KN-93, a CaMK inhibitor, blocked CaMKII activation and c-fos promoter stimulation by hypoxia. Ectopic expression of an active mutant of CaMKII (pCaMKII290) stimulated c-fos promoter activity under normoxia. Hypoxia increased phosphorylation of CREB at the serine residue 133 (Ser-133), and KN-93 attenuated this effect. Point mutations at the Ca(2+)/cAMP-responsive cis-element (Ca/CRE) attenuated, whereas point mutations in the serum-responsive cis-element (SRE) abolished transcriptional activation of c-fos by hypoxia. These results demonstrate that c-fos activation by hypoxia involves CaMK activation and CREB phosphorylation at Ser-133 and requires Ca/CRE and SRE. These observations demonstrate that Ca(2+)-dependent signaling pathways play a crucial role in induction of c-fos gene expression, which may underlie long-term adaptive responses to hypoxia.
1 interesting to take note of is that weight gain(though not that severe when compared to GC agonists) is a common side effect of CCBs- and this is a hallmark of GC agonists as well(like betamethasone). I can attest this because i am experimenting with https://en.wikipedia.org/wiki/Nifedipine now in accordance with this old patent http://www.google.com/patents/US5407944 that discovered the balding scalp is chronically and significantly hypoxic when compared to non-balding scalp.
While i do not agree with it's premise that suggested the usage of E2(Beta-estradiol) for hair growth(because of the huge tremendous sides that i've been through)- it makes sense that that the balding scalp is hypoxic, which translate to a localised form peripheral hypertension, as I can feel this chronic tightness on my head.Comment
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Further on, look@ LGR5( centre/right) of the same diagram in http://www.wikipathways.org/index.php/Pathway:WP2840 , then look @ Dr Cotsareli's patent http://www.google.com/patents/US20110021599 - this time round on the most upregulated genes in non-balding scalp when compared to balding scalp. LGR5 is aka GPR49. It's the 9th most upregulated and a WNT target gene:
Lgr5 marks cycling, yet long-lived, hair follicle stem cells.
Jaks V1, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgĺrd R.
Author information
Abstract
In mouse hair follicles, a group of quiescent cells in the bulge is believed to have stem cell activity. Lgr5, a marker of intestinal stem cells, is expressed in actively cycling cells in the bulge and secondary germ of telogen hair follicles and in the lower outer root sheath of anagen hair follicles. Here we show that Lgr5(+) cells comprise an actively proliferating and multipotent stem cell population able to give rise to new hair follicles and maintain all cell lineages of the hair follicle over long periods of time. Lgr5(+) progeny repopulate other stem cell compartments in the hair follicle, supporting the existence of a stem or progenitor cell hierarchy. By marking Lgr5(+) cells during trafficking through the lower outer root sheath, we show that these cells retain stem cell properties and contribute to hair follicle growth during the next anagen. Expression analysis suggests involvement of autocrine Hedgehog signaling(In the context of AGA, anything that involves hedgehog signalling, as discussed above to your previous post- involves PAX1) in maintaining the Lgr5(+) stem cell population.
Now look at this http://ethos.bl.uk/OrderDetails.do?u...l.ethos.682727
Abstract:
Leucine rich repeat containing G-protein coupled receptor 5 (LGR5) is a well-established stem cell marker in the normal intestine. Recent evidence suggests LGR5 is also a marker of cancer stem cells in colorectal tumours. Cancer stem cells propagate and maintain tumours and are hypothesized to be refractory to therapy. Solid tumours frequently experience hypoxia and an unresolved question remains as to how the cancer stem cell population survives this environmental stress. Several regulatory links are known to exist between hypoxic and stem cell signalling pathways. However, the role of hypoxia in regulating LGR5 is yet to be elucidated. Here it is reported that hypoxia down-regulates LGR5 expression. Both protein and mRNA expression is reduced in hypoxia. LGR5 down regulation was observed in cells derived from adenoma, primary carcinoma and metastases, suggesting this process occurs throughout tumourigenesis. [U]LGR5 was found to be re-expressed following re-oxygenation,[/U[(aka 'normoxia') demonstrating tumour cells ability to switch between expressing LGR5 in normoxic conditions and reducing expression in hypoxia. LGR5 is an established target gene of the WNT signalling pathway and hypoxia has been reported previously to regulate the WNT pathway. Results presented here suggest hypoxic down-regulation of the WNT pathway mediates the hypoxic regulation of LGR5. Topflash WNT reporter activity and expression of a selection of additional WNT target genes decreased in hypoxia in the cell lines tested here. Preliminary ChiP experiments suggest WNT signalling effectors Beta-catenin and TCF4 are lost from the LGR5 promoter in hypoxia. It has been reported previously that HIF-1 interacts with the WNT pathway in hypoxia to down-regulate WNT target gene expression. However HIF-1 does not regulate LGR5 in the cell lines tested here. Highly related HIF-2, though, is critical in the hypoxic regulation of LGR5 in the LoVo cell line and not in other cell lines tested here. The reversible down regulation of stem cell markers during hypoxia may have important implications for targeting cancer stem cells in vivo where tumours are heterogeneous with fluctuating areas of hypoxia.Comment
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Finally, Hypoxia increases intracelluar calcium levels(which is why the patent i linked suggested the usage of Nifedipine- it blocks L-type calcium channels and results in vasodilation- the latter a process similar to Minoxidil)- which c-fos and inflammatory processes are heavily dependent on.
Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: role of the Na(+)-glucose cotransporter.
Berna N1, Arnould T, Remacle J, Michiels C.
Author information
Abstract
Hypoxia is a common denominator of many vascular disorders, especially those associated with ischemia. To study the effect of oxygen depletion on endothelium, we developed an in vitro model of hypoxia on human umbilical vein endothelial cells (HUVEC). Hypoxia strongly activates HUVEC, which then synthesize large amounts of prostaglandins and platelet-activating factor. The first step of this activation is a decrease in ATP content of the cells, followed by an increase in the cytosolic calcium concentration ([Ca(2+)](i)) which then activates the phospholipase A(2) (PLA(2)). The link between the decrease in ATP and the increase in [Ca(2+)](i) was not known and is investigated in this work. We first showed that the presence of extracellular Na(+) was necessary to observe the hypoxia-induced increase in [Ca(2+)](i) and the activation of PLA(2). This increase was not due to the release of Ca(2+) from intracellular stores, since thapsigargin did not inhibit this process. The Na(+)/Ca(2+) exchanger was involved since dichlorobenzamil inhibited the [Ca(2+)](i) and the PLA(2) activation. The glycolysis was activated, but the intracellular pH (pH(i)) in hypoxic cells did not differ from control cells. Finally, the hypoxia-induced increase in [Ca(2+)](i) and PLA(2) activation were inhibited by phlorizin, an inhibitor of the Na(+)-glucose cotransport. The proposed biochemical mechanism occurring under hypoxia is the following: glycolysis is first activated due to a requirement for ATP, leading to an influx of Na(+) through the activated Na(+)-glucose cotransport followed by the activation of the Na(+)/Ca(2+) exchanger, resulting in a net influx of Ca(2+).
Copyright 2001 Wiley-Liss, Inc.Comment
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Then continuing on hypoxia reducing expression of pro-hair growth genes:
Abstract
Low oxygen tension (hypoxia) contributes critically to pluripotency of human embryonic stem cells (hESCs) by preventing spontaneous differentiation and supporting self-renewal. However, it is not well understood how hESCs respond to reduced oxygen availability and what are the molecular mechanisms maintaining pluripotency in these conditions. In this study we characterized the transcriptional and molecular responses of three hESC lines (H9, HS401 and HS360) on short (2 hours), intermediate (24 hours) and prolonged (7 days) exposure to low oxygen conditions (4% O2). In response to prolonged hypoxia the expression of pluripotency surface marker SSEA-3 was increased. Furthermore, the genome wide gene-expression analysis revealed that a substantial proportion (12%) of all hypoxia-regulated genes in hESCs, were directly linked to the mechanisms controlling pluripotency or differentiation. Moreover, transcription of MYC oncogene was induced in response to continuous hypoxia. At the protein level MYC was stabilized through phosphorylation already in response to a short hypoxic exposure. Total MYC protein levels remained elevated throughout all the time points studied. Further, MYC protein expression in hypoxia was affected by silencing HIF2α, but not HIF1α. Since MYC has a crucial role in regulating pluripotency we propose that induction of sustained MYC expression in hypoxia contributes to activation of transcriptional programs critical for hESC self-renewal and maintenance of enhanced pluripotent state.
To clarify the mechanisms how hypoxic growth conditions contribute to pluripotency and differentiation of hESCs, we surveyed the transcriptome data for all transcripts associated with regulation of hESC physiology. Importantly, 12% of all oxygen-regulated transcripts detected were linked to mechanisms controlling pluripotency and differentiation [42] (Figure 3C). The majority of transcriptional responses were detected in prolonged hypoxic culture. From these genes of particular interest are HEY2 with a role in notch signaling [43], LEFTY2 involved in TGFβ-signaling [44] and IGFBP2 which is overexpressed in the stem cell compartment of glioblastomas promoting proliferation and survival of brain tumors [45]. Moreover, the levels of MYC that contributes to induction and maintenance of pluripotency [21]–[24] were elevated.
Hypoxic culture conditions also modified the expression of genes driving cell differentiation (Figure 2C), further supporting an idea that hypoxia directly influences the differentiation potential of cells. Among these genes were neuroectoderm marker PAX6 [46], trophoblast and placenta associated transcription factor MSX2 [47], and a primitive streak marker FLRT3 [48], which all showed less expression in response to prolonged hypoxic culturing compared to normoxic cultures.
Look @ the diagram again in http://www.wikipathways.org/index.php/Pathway:WP2840 . Check out 'FLRT3'(not in the diagram) and 'MSX2'(centre-right). Than look@ Dr Cotsareli's patent @ http://www.google.com/patents/US20110021599 . 'FLRT3' and 'MSX2' are the 34th and 47th most upregulated gene, respectively- in non-balding scalp(normoxic) when compared to balding scalp(hypoxic)
MSX2:
‘Cyclic alopecia’ in Msx2 mutants: defects in hair cycling and hair shaft differentiation
Liang Ma,1,2 Jian Liu,3 Tobey Wu,3 Maksim Plikus,3 Ting-Xin Jiang,3 Qun Bi,2 Yi-Hsin Liu,4 Sven Müller-Röver,5 Heiko Peters,1 John P. Sundberg,6 Rob Maxson,7 Richard L. Maas,1,* and Cheng-Ming Chuong3,*
Author information ► Copyright and License information ►
The publisher's final edited version of this article is available free at Development
See other articles in PMC that cite the published article.
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SUMMARY
Msx2-deficient mice exhibit progressive hair loss, starting at P14 and followed by successive cycles of wavelike regrowth and loss. During the hair cycle, Msx2 deficiency shortens anagen phase, but prolongs catagen and telogen. Msx2-deficient hair shafts are structurally abnormal. Molecular analyses suggest a Bmp4/Bmp2/Msx2/Foxn1 acidic hair keratin pathway is involved. These structurally abnormal hairs are easily dislodged in catagen implying a precocious exogen. Deficiency in Msx2 helps to reveal the distinctive skin domains on the same mouse. Each domain cycles asynchronously – although hairs within each skin domain cycle in synchronized waves. Thus, the combinatorial defects in hair cycling and differentiation, together with concealed skin domains, account for the cyclic alopecia phenotype.
Keywords: Alopecia, Hair cycle, Hair differentiation, Homeobox genes, Msx2, Foxn1, Ha3, Fgf5, Mouse
FLRT3:
Flrt2 and Flrt3 have overlapping and non-overlapping expression during craniofacial development.
Gong SG1, Mai S, Chung K, Wei K.
Author information
1Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ont., Canada M5G 1G6. sg.gong@dentistry.utoronto.ca
Abstract
Craniofacial morphogenesis is a complex multi-step process that involves numerous biological processes to coordinate the growth, proliferation, migration, and subsequent differentiation of the cranial neural crest cells. Members of the Fibronectin Leucine-Rich Transmembrane (Flrt) gene family have been previously reported to be widely expressed in the developing embryo. We mapped the expression of Flrt2 and Flrt3 at critical stages of craniofacial development and found that, during early craniofacial development, Flrt2 was highly expressed initially in the cranial neural crest cells and Flrt3 in the midbrain. Later both genes were expressed in the developing pharyngeal region. Flrt2 expression predominated in the neural crest-derived mesenchyme in the medial aspect of the developing frontonasal region in close relationships with the expression of Fgfr2, Shh, and Msx1, three genes shown previously to play critical roles in craniofacial development. Flrt2 was also present in the vomero-nasal organ, mandibular primodia, and the posterior aspects of the unfused and fused secondary palatal shelves. Flrt3, however, had a more restrictive expression, being present in the mesenchyme underlying the ectoderm of the medial nasal process and in the mandibular primordium and in regions undergoing outgrowth, in a pattern that overlapped with Bmp4 expression. Both Flrt2 and Flrt3 were later found to be present at sites of epithelial-mesenchymal interactions such as the developing tooth buds, hair follicles, and eye. Together the data suggested important roles for Flrt2 and Flrt3 in mediating events such as NCC migration, chondrogenesis and epithelial-mesenchymal interactions during craniofacial development.
PAX1 is heavily expressed in the https://en.wikipedia.org/wiki/Pharyn...ch_(embryology) all the way to the cranium. our neck and skull anatomy is defined by the PAX genes.
MSX1, MSX2's family member- is the 51 most upregulated gene in non-balding scalp when compared to balding scalp @ http://www.google.com/patents/US20110021599 . It is also, just like MSX2- a BMP signalling target gene(atually, both of them are also WNT signalling's target genes) as can be seen here again http://www.wikipathways.org/index.php/Pathway:WP2840 (topleft)Comment
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Inbeforethecure please give me ur valuable input on the aboveComment
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Nifedipine:
The powder is yellow and not a conventional white, as in the case of all https://en.wikipedia.org/wiki/Dihydropyridine -derivatives.
It is also described here in another patent(aside from the 1 on hypoxia which 1 linked earlier)
This study (not sure if it's done by the same inventors to the patent above) talks about calcium channels and the hair follcile:
Abstract
The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Cav1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Cav1.2, they lack detectable voltage-dependent calcium currents. Cav1.2TS acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Cav1.2 to induce anagen and overcome the TS phenotype. Cav1.2 regulates production of the bulge-derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration.
Keywords: hair follicle stem cells, bulge, calcium channel, VGCCComment
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FYI, in a recent study by Philpott et al. , they did not find any differences of PAX1 between balding DPC and non-balding. Interestingly, FOXA2 wasn't even expressed.
At the susceptibility loci 7p21.1 (HDAC9 & TWIST1) they found only TWIST1 to be differentially expressed in balding DPC vs non-balding DPC (upregulated), not HDAC9.
Knockout of TWIST1 in a mice model (BLEGH) was found to dramatically enhance the anagen phase in a study. Also TWIST1 has shown to be able to upregulate AR by binding to E-boxes in the AR promoter.
At susceptibility loci 2q37 they found TWIST2 do be deferentially expressed rather than HDAC4.
In the AGA major risk locus Xq12 they found evidence for AR instead of EDA2R.
Interesting study.
I remember a study pointing out a interaction between HDACs and Twists, I'll look it up later, but I have the picture here;
@InBeforeTheCure,I agree completely, and for the past few weeks I've been working on a hypothesis as to how this thing could work. It's an incomplete model, and only experiment can say whether it's true or not true or partially true, but nevertheless I'll be posting a thread on that sometime in June. I've got the main idea, but I want to do a couple things first -- first I'm going to a bioinformatics analysis, and then I want look at mesenchymal-epithelial interactions more closely as well.
Great man, keep it up. I have troubles understanding how you would be able to underline a strong hypothesis based on the current genetic data? I compare it to walking around in a very big complex labyrinth where one is drunk without a map. I might be wrong though. Very curious to your findings. The biggest problem in my opinion also resides with what you mention and that is the "experiment". We lack a proper model. We only have and use rodent models. Every researcher now finally is aware that it's a horrible model for AGA and we desperately need a proper one. Harsher regulations etc. made it impossible to test on a macaque model like in the past (correct decision imo, but that aside). So how are you going to be able to cope with this problem? Slap stuff on your scalp?
Speaking of SHH, the SHH agonist that was in development by Curis and Procter & Gamble back in 2005 for androgenetic alopecia had huge excitement, but didn't proceed to human clinical trial testing as it was touted to be to dangerous. After all AGA is seen as a cosmetic disease and not a life threatening one, which hugely added to their decision. That was a black point. That being said I'm still intrigued by the SHH pathway simply because a SHH antagonist induces alopecia in approximately 70% of subjects as a side effects from the top of my head, which might even be very long lasting after discontinuation (longer than a year). Based on this observation alone one could at least argue that the pathway seems to have a huge role in hair follicle function.
@Mlamber5I think the combination of a topical JAK/STAT inhibitor and an androgen suppressor at the same time (such as finasteride ) could potentially cause GREAT reversal in AGA phenotype.
No I don't think so. In fact I believe it almost to be certain that a JAK inhibitor isn't going to do a great deal for AGA. I don't see why one would even be hyped for this. It's based on a rodent model. Find me one person who shows reversal with AGA on a JAK inhibitor. I'll give you the answer in advance; It ain't going to happen, and if it will happen it will be a huge miracle. For which I hope obviously. Also why do you mention that AR stoppage won't stop the progression of AGA, but only will slow it down? Are the people suffering from complete androgen insensitivity just lucky people who always retain their luxurious hair until old age? Btw, recently a case report has shown a guy suffering from alopecia universalis who was put on tofacitinib 10mg with + methotxerate and the regimen failed to reverse his condition. Perhaps it's not even going to be that great for everyone suffering from AA related conditions...Comment
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thank you for your reply swooping. Would you care to post the entire study here? i cant access it.Comment
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Im afraid it would'nt be enough. You're gonna have to purify your vomit and apply it daily.
Luckily, some researcher have already came up with something a long time ago.
A decreased vascularity of the scalp is considered to be a contributing factor to baldness since a good vascular supply is required for healthy hair follicles. Topically administered monobutyrin should penetrate the skin of the scalp and enhance the vascularity of the area containing hair follicles. This would result in the arrest qf hair loss. Formulations of the compounds of the invention are prepared using generally known excipients and carriers according to methods known in the art, such as those set forth in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (latest edition). For topical administration, especially for superficial lesions, standard topical formulations are employed using, for example, 10 -4-1% solutions of the compounds of the invention, with or without added growth factor, such as FGF, PDGF or EDGF. The topical prepara- tions would be applied daily or 2-3 times per week to the affected area. The concentration of the solution or other formulation depends on the severity of the wound and the nature of the subject. Formulations can be in a variety of known forms such as ointments, salves, gels, sprays, creams and lotions. For bone and tissue* repair, local and depot administration is preferred, or administration by sub¬ cutaneous or localized implant. Slow release forms can be included in polymers such as Hydron (Langer, R. , et al., Nature (1976) 263:797-799) or Elvax 40P (DuPont) (Murray, J.B., et al., In Vitro (1983) _19_:743-747) . Other sustained release systems have been suggested by Hsieh, D.S.T., et al., J Pharm Sci (1983) 72:17-22.
The patent above was done submitted in 1990. 26 years later, latest research still collaborates with that old patent's findings:
Thanks Swooping:
J Invest Dermatol. 2016 Apr 6. pii: S0022-202X(16)31024-7. doi: 10.1016/j.jid.2016.03.032. [Epub ahead of print]
Differential expression between human dermal papilla cells from balding and non-balding scalps reveals new candidate genes for androgenetic alopecia.
Chew EG1, Tan JH1, Bahta AW2, Ho BS3, Liu X1, Lim TC4, Sia YY1, Bigliardi PL5, Heilmann S6, Wan AC4, Nöthen MM6, Philpott MP2, Hillmer AM7. <=== this guy is the researcher who discovered the PAX1/FOXA2 balding locus for AGA
Author information
Abstract
Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPC) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPC in hair-related studies often lack dermal papilla (DP) characteristics. In contrast, immortalised DPC have high resemblance to intact DP. We derived immortalised human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retain high proportions of DP signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially-expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 and SSPN to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularisation around the hair follicle may contribute to the development of AGA.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.Comment
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