Updated Research and Knowledge - Cutting Edge

[AHMAD]

hy guys new to forum. are you still using oleuropien.

[Forestry]

5ar anti-androgen effect of ganoderma B / reishi

Chemical, why did you stop using oleuropein?

this 5ar research on ganoderma lucidum from 2007 is interesting, for guys in particular. reishi is easy to find / inexpensive:

The anti-androgen effect of ganoderol B isolated from the fruiting body of Ganoderma lucidum

I was able to search on the paper title and found a free pdf eventually, can't find the link now...

[InBeforeTheCure]

atually- the clue is something that u've have already read before:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365504/

SNP
marker
Position
(hg19)
Alleles IS
Genotype
IS Genotype
Frequency
1000G CEU
Genotype
Frequency
Disrupted TF binding site
rs11699227 21,961,920 C/T CC 1.00 0.259 TATA
rs6036003 21,961,964 A/G AA 1.00 0.259 4 altered motifs:HNF4, RAR, RXRA,
STAT
rs169311 21,962,333 A/C AA 1.00 0.259 4 altered motifs: BATF; COMP1, Irf, VDR
rs201545 21,962,422 A/C CC 1.00 1.000 N/A
rs5840940 21,962,533 -/T -/T 1.00 0.329 N/A
rs2424421 21,963,058 C/T CC .98* 0.259 10 altered motifs: Cart1, Foxa, Foxp1,
GATA, HDAC2, Hmx_2, Irf, Pax-5, RXRA,
P300

It's unlikely that both Hnf4a and Foxa2 would be involved in DPC differentiation because expression of those two together turns fibroblasts into hepatocytes. However, even if only one of them is involved, you would likely find that both show up in this sort of analysis because their target genes overlap, and of course we do see that.

BTW, on the BMPs part, not all BMPs are downregulated in balding DPCs. accoridng to a diagram in the study, BMP4's expression is only present in non-balding scalp DPCs where else BMP2's expression is only present in balding scalp DPCs.

SOX2 is mainly invovled with the shape of the individual hair follicle:

I haven't yet looked into Sox2 that carefully, but it's also possible that it's not upregulated or downregulated, but could instead be regulated "differently" due to binding by co-factors.

How about u list down each of the 10 most differentially-regulated genes for proteins, kinases and transcription factors

Kinases: https://www.dropbox.com/s/ldnww188yt...inase.csv?dl=0

Transcription Factors: https://www.dropbox.com/s/1yh34r1dir...ts_tf.csv?dl=0

Protein Network: https://www.dropbox.com/s/gtyrkljgwu...twork.sig?dl=0

Great job Inbeforethecure. You bring up an EXCELLENT point with pioneer factors. I have wondered this myself about 20p11. And in my opinion that is the number one enemy overall. It is the the region linked to AGA the strongest if all ethnicities are considered (Ar-Eda2r is monomorphic in Asian AGA). Upon reading on the two associates genes between the potential SNP's at 20p11 it would seem as if FOXA2, not PAX1 is the one that should be implicated. Foxa2 is know to be an androgen metabolic regulator, and another one of its many functions is response to interleukin 6, which has already been shown to be released in response to DHT in AGA DP and cause Catagen of actively growing follicle. So it really confounded me as to why foxa2 isn't expressed in AGA scalp (not in dp or in the rest of the hair follicle itself) but pax1 is. This seems to fit and clear that up. Awesome job. I really enjoy reading your computer data breakdowns as well.

Thank you. Actually though, I don't think it's cleared up at all. Pioneer factors are usually actively expressed in the cells they regulate AFAIK, so this would have to be some form of epigenetic memory if anything. As for IL6 and other inflammatory cytokines, I think it would be most natural to blame stress-induced p38 MAPK activity.

p38 and inflammation

A strong link has been established between the p38 pathway and inflammation. Rheumatoid arthritis, Alzheimer's disease and inflammatory bowel disease are all postulated to be regulated in part by the p38 pathway 87, 88, 89. The activation of the p38 pathway plays essential roles in the production of proinflammatory cytokines (IL-1beta, TNF-alpha and IL-6) 90; induction of enzymes such as COX-2 which controls connective tissue remodeling in pathological conditions 91; expression of intracellular enzymes such as iNOS, a regulator of oxidation 92, 93; induction of VCAM-1 and other adherent proteins along with other inflammatory related molecules 18. In addition, a regulatory role for p38 in the proliferation and differentiation of immune system cells such as GM-CSF, EPO, CSF and CD-40 has been established 16, 94.

(link)

MAPK14 in the network diagram = p38-alpha

so i dont understand a word in this thread, but when u guys guna cure this?

Chemical found the cure, but unfortunately the international conspiracy of hair transplant surgeons and minox vendors got to him. If he talks, he's a dead man. That's why he's disappeared.

inbeforethecure:

I do not know yet if Foxa2 is upregulated or downregulated in AGA individuals, not just necessarily in the scalp itself- but possibly in the organs that are vital to the scalp's functioning. (e.g thyroid, parathyroid, thymus- all of which Pax1 itself is heavily expressed in).

But what i do know from studies is that knockout of FOXa2 switches the response to TH2 cytokines- and this is the group of that is responsible for 'AGA itch' and is contained in sebocytes. So i will assume that FOXA2 is downregulated in AGA individuals. i might be wrong though.

Foxa2, if it's involved, would most likely confer risk to AGA by acting as a pioneer factor at AR target genes IMO. That's something it's known for.

In fact amongst Europeans, there are 3 different spots between foxa2 and pax1 that are at risk points for AGA.

Those SNPs are in high linkage disequilibrium with each other, so you would need a massive sample size to discern multiple risk points.

Ok, so for your info once again, the 2016 study also ruled out both HDAC4 and HDAC9 as AGA-causative genes. Instead, PER2 and TWIST2 in HDAC4's region were the true AGA-causative genes found to be downregulated in balding scalps.

TWIST1 in HDAC9's region was found to be the true AGA-causative gene- upregulated in balding scalps.

Focusing on the 5 SNP model from this study:



Best guesses for the functional variants at these sites: AR, PAX1 or FOXA2, RNF145, MTOR, TWIST1?

[TheKingofFighters]

Ok, so for your info once again, the 2016 study also ruled out both HDAC4 and HDAC9 as AGA-causative genes. Instead, PER2 and TWIST2 in HDAC4's region were the true AGA-causative genes found to be downregulated in balding scalps.

TWIST1 in HDAC9's region was found to be the true AGA-causative gene- upregulated in balding scalps.

Unsurprisingly, PER2 and TWIST2 is upregulated by Estradiol and Genistein while TWIST1 is downregulated by estrogenic compounds

[TheKingofFighters]

Ya I think you misinterpreted what I said, I am in agreeance with you. Other regions are involved for Asians besides 20p11, but the region on chromosome x effecting the Ar isn't one of them, and 20p11 is the single strongest at risk region. In fact amongst Europeans, there are 3 different spots between foxa2 and pax1 that are at risk points for AGA. There are only 2 at risk spots between eda2r and Ar (although the single highest at risk SNP is one of these nucleotide variants at one of those spots). Ago
Again the fact that Ar obviously has to do with androgen metabolism and foxa2 does as well fits the phenotype. Some other big spots are HDAC9 and HDAC4 (amongst many others). HDAC4 has been shown in some cell types to aid in Ar gene suppression so perhaps a certain variant in AGA doesn't allow this process to happen as effectively.

Ok, so for your info once again, the 2016 study also ruled out both HDAC4 and HDAC9 as AGA-causative genes. Instead, PER2 and TWIST2 in HDAC4's region were the true AGA-causative genes found to be downregulated in balding scalps.

TWIST1 in HDAC9's region was found to be the true AGA-causative gene- upregulated in balding scalps.

[mlamber5]

Not necessarily so. I use to think that East Asians(the study on 20p11 u read, i presume, was conducted on Han Chinese- East Asians to be exact.) are only affected by 20p11 too. But the 2016 study now reveals the possiblity of other similar AGA-causative genes affecting multi-ethnic groups. For your info, the study also ruled out EDAR's invovlement and stated that AR is the sole causative gene in that region. But what we do know is that the AR gene is not an AGA-causative 1 in East asians.

There is no defnite answer on il-6, especially when it's a https://en.wikipedia.org/wiki/Treg17_cells cytokine utilising the STAT3 pathway- and http://www.pnas.org/content/97/25/13824.full.pdf is critically involved in hair growth. U might be right, though- in a sense that there are 2 possible scenarios regarding IL-6:

1)There is atually an underexpression of STAT3/Th17 responses in the balding scalp , being replaced by TH1/Th2 cytokine responses instead- resulting in the upregulation of 'bad' inflammation genes in the context of hair growth.
2)There really is an overexpression(like what u think) of STAT3/Th17.

Ya I think you misinterpreted what I said, I am in agreeance with you. Other regions are involved for Asians besides 20p11, but the region on chromosome x effecting the Ar isn't one of them, and 20p11 is the single strongest at risk region. In fact amongst Europeans, there are 3 different spots between foxa2 and pax1 that are at risk points for AGA. There are only 2 at risk spots between eda2r and Ar (although the single highest at risk SNP is one of these nucleotide variants at one of those spots). Ago
Again the fact that Ar obviously has to do with androgen metabolism and foxa2 does as well fits the phenotype. Some other big spots are HDAC9 and HDAC4 (amongst many others). HDAC4 has been shown in some cell types to aid in Ar gene suppression so perhaps a certain variant in AGA doesn't allow this process to happen as effectively.

[kuba197]

So Replicel looks like a complete dud. They've stalled with trials to the point that earliest possible release date in Japan is now end of 2019/ 2020 and their stock is in steady decline. In all honesty if Histogen ends up being a disappointment as well, I just see Follica as a legitimate remedy. Other than that, anyone on this forum not maintaining with fin/DUT is a baldy before any new treatments actually come to fruition. Good luck making those gains in the gym fellas cuz we ain't woo'ing the ladies with our hair any time soon

Hoping for s-equol to bind the dht. It could give us a time. And fingers crossed for PSI being tested on private forum.

[Trouse5858]

So Replicel looks like a complete dud. They've stalled with trials to the point that earliest possible release date in Japan is now end of 2019/ 2020 and their stock is in steady decline. In all honesty if Histogen ends up being a disappointment as well, I just see Follica as a legitimate remedy. Other than that, anyone on this forum not maintaining with fin/DUT is a baldy before any new treatments actually come to fruition. Good luck making those gains in the gym fellas cuz we ain't woo'ing the ladies with our hair any time soon

[TheKingofFighters]

Not necessarily so. I use to think that East Asians(the study on 20p11 u read, i presume, was conducted on Han Chinese- East Asians to be exact.) are only affected by 20p11 too. But the 2016 study now reveals the possiblity of other similar AGA-causative genes affecting multi-ethnic groups. For your info, the study also ruled out EDAR's invovlement and stated that AR is the sole causative gene in that region. But what we do know is that the AR gene is not an AGA-causative 1 in East asians.

There is no defnite answer on il-6, especially when it's a https://en.wikipedia.org/wiki/Treg17_cells cytokine utilising the STAT3 pathway- and http://www.pnas.org/content/97/25/13824.full.pdf is critically involved in hair growth. U might be right, though- in a sense that there are 2 possible scenarios regarding IL-6:

1)There is atually an underexpression of STAT3/Th17 responses in the balding scalp , being replaced by TH1/Th2 cytokine responses instead- resulting in the upregulation of 'bad' inflammation genes in the context of hair growth.
2)There really is an overexpression(like what u think) of STAT3/Th17.

My take is that the MAPT gene, a gene that causes AGA and Parkinso's- is probably affecting other groups(than Caucasians) as well. i have a family history of neuro diseases- particularly Parkinson's and to my knowledge, all of my relatives who had it were bald.

[TheKingofFighters]

Great job Inbeforethecure. You bring up an EXCELLENT point with pioneer factors. I have wondered this myself about 20p11. And in my opinion that is the number one enemy overall. It is the the region linked to AGA the strongest if all ethnicities are considered (Ar-Eda2r is monomorphic in Asian AGA). Upon reading on the two associates genes between the potential SNP's at 20p11 it would seem as if FOXA2, not PAX1 is the one that should be implicated. Foxa2 is know to be an androgen metabolic regulator, and another one of its many functions is response to interleukin 6, which has already been shown to be released in response to DHT in AGA DP and cause Catagen of actively growing follicle. So it really confounded me as to why foxa2 isn't expressed in AGA scalp (not in dp or in the rest of the hair follicle itself) but pax1 is. This seems to fit and clear that up. Awesome job. I really enjoy reading your computer data breakdowns as well.

Not necessarily so. I use to think that East Asians(the study on 20p11 u read, i presume, was conducted on Han Chinese- East Asians to be exact.) are only affected by 20p11 too. But the 2016 study now reveals the possiblity of other similar AGA-causative genes affecting multi-ethnic groups. For your info, the study also ruled out EDAR's invovlement and stated that AR is the sole causative gene in that region. But what we do know is that the AR gene is not an AGA-causative 1 in East asians.

There is no defnite answer on il-6, especially when it's a https://en.wikipedia.org/wiki/Treg17_cells cytokine utilising the STAT3 pathway- and http://www.pnas.org/content/97/25/13824.full.pdf is critically involved in hair growth. U might be right, though- in a sense that there are 2 possible scenarios regarding IL-6:

1)There is atually an underexpression of STAT3/Th17 responses in the balding scalp , being replaced by TH1/Th2 cytokine responses instead- resulting in the upregulation of 'bad' inflammation genes in the context of hair growth.
2)There really is an overexpression(like what u think) of STAT3/Th17.

[TheKingofFighters]

inbeforethecure:

I do not know yet if Foxa2 is upregulated or downregulated in AGA individuals, not just necessarily in the scalp itself- but possibly in the organs that are vital to the scalp's functioning. (e.g thyroid, parathyroid, thymus- all of which Pax1 itself is heavily expressed in).

But what i do know from studies is that knockout of FOXa2 switches the response to TH2 cytokines- and this is the group of that is responsible for 'AGA itch' and is contained in sebocytes. So i will assume that FOXA2 is downregulated in AGA individuals. i might be wrong though.

[iaskdumbquestions]

so i dont understand a word in this thread, but when u guys guna cure this?

[mlamber5]

Thank you. Lots of work left to do though.



Size of circle (nodes) = number of other circles (nodes) connected to it

Anyway, the results are definitely interesting. I'll go over some quick observations before studying these things more deeply...

First, it seems that the computer likes FOXA2 rather than PAX1 as the causative gene at 20p11. Despite it not being expressed in dermal papilla cells, we see its "shadow", as well as the shadow of HNF4A (which is also not expressed in DPCs). Why? Is it a fictitious result? Some sort of statistical artifact? Here's a crazy idea: What if instead of dermal papilla cells, FOXA2 and HNF4A are expressed transiently in the precursors to dermal papilla cells (neural crest cells?). FOXA2 and HNF4A are pioneer factors -- they modify chromatin so that transcription factors bind particular sites and not others in particular cell types. FOXA2 and HNF4A are known to cooperate in differentiation of liver cells (link). Notice also that FOXA2 binds to the homeobox HOXA5, which in the oPossum results was one of the most enriched transcription factors in balding DPCs.

But can such an effect on chromatin persist even after FOXA2 and HNF4A are no longer expressed? Possibly. Something like this has been observed for another pioneer factor called NeuroD1:


(link)

As for the other stuff, MAPK1 (ERK2) and MAPK 3 (ERK1) are the two most altered kinases. CSNK2A1 (Casein Kinase 2) interacts with that pathway. MAPK14 is p38-alpha, a stress-activated pathway that is probably the major upstream regulator of senescence in AGA. CDK2 regulates G1/S cell cycle progression. GSK3beta inhibits beta-catenin of course, but phosphorylates a lot of other things as well. ATM is DNA damage response, and maybe HIPK2, although the latter is also involved in the ERK pathway and in regulating HIF1A. AKT1 we've talked about.

SOX2, a DP signature gene, is the most differentially regulated transcription factor. This plays a role in signaling to epithelial progenitor cells. Rendl et. al* showed that Sox2 knockout mice have higher BMP expression and slower migration of progenitor cells. Since BMPs are shown to be downregulated in balding DPCs, perhaps Sox2 is more active in AGA -- then the migration of progenitor cells would be faster? EGR1 is downstream of the ERK pathway. MITF is involved in DNA replication, DNA repair, mitosis, miRNA production, and mitochondrial metabolism. E2F1, SUZ12, PHF8, and MTF2 are involved in cell cycle regulation and senescence. POU5F1 (Oct-4) binds to Sox2...

*Avi Ma'ayan, an author of this paper, was also involved in writing the X2K program.

That's just rushing through of course. We'll get deeper into this stuff later on.

Great job Inbeforethecure. You bring up an EXCELLENT point with pioneer factors. I have wondered this myself about 20p11. And in my opinion that is the number one enemy overall. It is the the region linked to AGA the strongest if all ethnicities are considered (Ar-Eda2r is monomorphic in Asian AGA). Upon reading on the two associates genes between the potential SNP's at 20p11 it would seem as if FOXA2, not PAX1 is the one that should be implicated. Foxa2 is know to be an androgen metabolic regulator, and another one of its many functions is response to interleukin 6, which has already been shown to be released in response to DHT in AGA DP and cause Catagen of actively growing follicle. So it really confounded me as to why foxa2 isn't expressed in AGA scalp (not in dp or in the rest of the hair follicle itself) but pax1 is. This seems to fit and clear that up. Awesome job. I really enjoy reading your computer data breakdowns as well.

[SuicidalTraveler]

summer - 他正在找你。

[TheKingofFighters]

Thank you. Lots of work left to do though.



Size of circle (nodes) = number of other circles (nodes) connected to it

Anyway, the results are definitely interesting. I'll go over some quick observations before studying these things more deeply...

First, it seems that the computer likes FOXA2 rather than PAX1 as the causative gene at 20p11. Despite it not being expressed in dermal papilla cells, we see its "shadow", as well as the shadow of HNF4A (which is also not expressed in DPCs). Why? Is it a fictitious result? Some sort of statistical artifact? Here's a crazy idea: What if instead of dermal papilla cells, FOXA2 and HNF4A are expressed transiently in the precursors to dermal papilla cells (neural crest cells?). FOXA2 and HNF4A are pioneer factors -- they modify chromatin so that transcription factors bind particular sites and not others in particular cell types. FOXA2 and HNF4A are known to cooperate in differentiation of liver cells (link). Notice also that FOXA2 binds to the homeobox HOXA5, which in the oPossum results was one of the most enriched transcription factors in balding DPCs.

But can such an effect on chromatin persist even after FOXA2 and HNF4A are no longer expressed? Possibly. Something like this has been observed for another pioneer factor called NeuroD1:


(link)

As for the other stuff, MAPK1 (ERK2) and MAPK 3 (ERK1) are the two most altered kinases. CSNK2A1 (Casein Kinase 2) interacts with that pathway. MAPK14 is p38-alpha, a stress-activated pathway that is probably the major upstream regulator of senescence in AGA. CDK2 regulates G1/S cell cycle progression. GSK3beta inhibits beta-catenin of course, but phosphorylates a lot of other things as well. ATM is DNA damage response, and maybe HIPK2, although the latter is also involved in the ERK pathway and in regulating HIF1A. AKT1 we've talked about.

SOX2, a DP signature gene, is the most differentially regulated transcription factor. This plays a role in signaling to epithelial progenitor cells. Rendl et. al* showed that Sox2 knockout mice have higher BMP expression and slower migration of progenitor cells. Since BMPs are shown to be downregulated in balding DPCs, perhaps Sox2 is more active in AGA -- then the migration of progenitor cells would be faster? EGR1 is downstream of the ERK pathway. MITF is involved in DNA replication, DNA repair, mitosis, miRNA production, and mitochondrial metabolism. E2F1, SUZ12, PHF8, and MTF2 are involved in cell cycle regulation and senescence. POU5F1 (Oct-4) binds to Sox2...

*Avi Ma'ayan, an author of this paper, was also involved in writing the X2K program.

That's just rushing through of course. We'll get deeper into this stuff later on.

How about u list down each of the 10 most differentially-regulated genes for proteins, kinases and transcription factors