Last edited:
Androgenetic Alopecia Comparative Study- Gene Expression Differences
- Thread starter sktboiboi
- Start date
1 last thing i wanna highlight from the study:
ASHGV40021887 69.7530454 Up NM_001282275 PRAC2 17 Hs.236557 Prostate cancer susceptibility candidate 2
Prostate Cancer Susceptibility Candidate 2
This gene is highly expressed in prostate, rectum, colon, and testis. This gene may produce a non-coding RNA or may encode a short protein that might localize to the nucleus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
https://www.ncbi.nlm.nih.gov/pubmed/12746837
PRAC2: a new gene expressed in human prostate and prostate cancer.
Olsson P1, Motegi A, Bera TK, Lee B, Pastan I.
Author information
Abstract
BACKGROUND:
The database of human Expressed Sequence Tags was previously used to identify PRAC (Prostate 47:125-131, 2001), a novel gene specifically expressed in human prostate, prostate cancer, rectum, and distal colon. In this report, we have identified PRAC2, another gene with a similar expression pattern that is located adjacent to the original PRAC gene on chromosome 17q21.3.
METHODS:
Using a computer-based analysis, a cluster of sequence homologous ESTs was identified that is mainly derived from human prostate cDNA libraries. The tissue specificity was examined by multiple tissue RNA dot blots and RT-PCR. The PRAC2 transcript and protein were identified using Northern blot analysis, RACE-PCR, primer extension, and Western blots.
RESULTS:
PRAC2 encodes a 564 nucleotide RNA found in prostate, rectum, distal colon, and testis. Weak expression was also found in placenta, peripheral blood leukocytes, skin, and in two prostate cancer cell lines: LNCaP and PC-3. The transcript seems to encode a 10.5-kDa nuclear protein. The PRAC2 gene is located on chromosome 17 at position 17q21, between the Hoxb-13 gene and the recently discovered PRAC gene.
CONCLUSIONS:
Because of the higher expression of PRAC2 in prostate and its proximity to Hoxb-13, PRAC2 may have a function in prostate growth and development.
PRAC2 was the most upregulated gene in Androgenetic Alopecia tissues- 69+folds higher.
https://www.ncbi.nlm.nih.gov/pubmed/27125450
Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.
Chen R1, Yu Y2, Dong X3.
Author information
Abstract
Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management.
KEYWORDS:
Cell cycling; Microenvironment; Progesterone receptor; Prostate cancer; Reactive stroma; Stromal differentiation
so this is further implication of Progesterone in Androgenetic Alopecia and prostate cancer- it acts as a tumor suppressor in the prostate, but is a product of Hedgehog signalling in the hair follicle. it could also explain why androgen-deprivation eventually stops working in prostate cancer, as well as how 5AR inhibition also stops working after chronic treatment. There are other pathways besides the Androgen receptor at work in Androgenetic Alopecia(and prostate cancer)
Progesterone is anti-insulin/igf-1. Androgens are pro-insulin/igf-1
https://www.ncbi.nlm.nih.gov/pubmed/15753383
Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells.
Pandini G1, Mineo R, Frasca F, Roberts CT Jr, Marcelli M, Vigneri R, Belfiore A.
Author information
Abstract
In this study, we show that androgens up-regulate insulin-like growth factor-I receptor (IGF-IR) expression and sensitize prostate cancer cells to the biological effects of IGF-I. Both dihydrotestosterone and the synthetic androgen R1881 induced an approximately 6-fold increase in IGF-IR expression in androgen receptor (AR)-positive prostate cancer cells LNCaP. In accordance with IGF-IR up-regulation, treatment with the nonmetabolizable androgen R1881 sensitized LNCaP cells to the mitogenic and motogenic effects of IGF-I, whereas an IGF-IR blocking antibody effectively inhibited these effects. By contrast, these androgens did not affect IGF-IR expression in AR-negative prostate cancer cells PC-3. Reintroduction of AR into PC-3 cells by stable transfection restored the androgen effect on IGF-IR up-regulation. R1881-induced IGF-IR up-regulation was partially inhibited by the AR antagonist Casodex (bicalutamide). Two other AR antagonists, cyproterone acetate and OH-flutamide, were much less effective. Androgen-induced IGF-IR up-regulation was not dependent on AR genomic activity,(very likely via other hormonal receptors, because estrogen receptor A also increases igf-1 http://www.jbc.org/content/275/24/18447 ) because two AR mutants, AR-C619Y and AR-C574R, devoid of DNA binding activity and transcriptional activity were still able to elicit IGF-IR up-regulation in HEK293 kidney cells in response to androgens. Moreover, androgen-induced IGF-IR up-regulation involves the activation of the Src-extracellular signal-regulated kinase pathway, because it was inhibited by both the Src inhibitor PP2 and the MEK-1 inhibitor PD98059. The present observations strongly suggest that AR activation may stimulate prostate cancer progression through the altered IGF-IR expression and IGF action. Anti-androgen therapy may be only partially effective, or almost ineffective, in blocking important biological effects of androgens, such as activation of the IGF system.(same goes for hair. AAs are only partially-effective or ineffective- because igf-1 still gets activated via estrogen receptor A)
ASHGV40021887 69.7530454 Up NM_001282275 PRAC2 17 Hs.236557 Prostate cancer susceptibility candidate 2
Prostate Cancer Susceptibility Candidate 2
This gene is highly expressed in prostate, rectum, colon, and testis. This gene may produce a non-coding RNA or may encode a short protein that might localize to the nucleus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
https://www.ncbi.nlm.nih.gov/pubmed/12746837
PRAC2: a new gene expressed in human prostate and prostate cancer.
Olsson P1, Motegi A, Bera TK, Lee B, Pastan I.
Author information
Abstract
BACKGROUND:
The database of human Expressed Sequence Tags was previously used to identify PRAC (Prostate 47:125-131, 2001), a novel gene specifically expressed in human prostate, prostate cancer, rectum, and distal colon. In this report, we have identified PRAC2, another gene with a similar expression pattern that is located adjacent to the original PRAC gene on chromosome 17q21.3.
METHODS:
Using a computer-based analysis, a cluster of sequence homologous ESTs was identified that is mainly derived from human prostate cDNA libraries. The tissue specificity was examined by multiple tissue RNA dot blots and RT-PCR. The PRAC2 transcript and protein were identified using Northern blot analysis, RACE-PCR, primer extension, and Western blots.
RESULTS:
PRAC2 encodes a 564 nucleotide RNA found in prostate, rectum, distal colon, and testis. Weak expression was also found in placenta, peripheral blood leukocytes, skin, and in two prostate cancer cell lines: LNCaP and PC-3. The transcript seems to encode a 10.5-kDa nuclear protein. The PRAC2 gene is located on chromosome 17 at position 17q21, between the Hoxb-13 gene and the recently discovered PRAC gene.
CONCLUSIONS:
Because of the higher expression of PRAC2 in prostate and its proximity to Hoxb-13, PRAC2 may have a function in prostate growth and development.
PRAC2 was the most upregulated gene in Androgenetic Alopecia tissues- 69+folds higher.
https://www.ncbi.nlm.nih.gov/pubmed/27125450
Progesterone receptor in the prostate: A potential suppressor for benign prostatic hyperplasia and prostate cancer.
Chen R1, Yu Y2, Dong X3.
Author information
Abstract
Advanced prostate cancer undergoing androgen receptor pathway inhibition (ARPI) eventually progresses to castrate-resistant prostate cancer (CRPC), suggesting that (i) androgen receptor (AR) blockage is incomplete, and (ii) there are other critical molecular pathways contributing to prostate cancer (PCa) progression. Although most PCa occurs in the epithelium, prostate stroma is increasingly believed to play a crucial role in promoting tumorigenesis and facilitating tumor progression. In the stroma, sex steroid hormone receptors such as AR and estrogen receptor-α are implicated to have important functions, whereas the progesterone receptor (PR) remains largely under-investigated despite the high sequence and structural similarities between PR and AR. Stromal progesterone/PR signaling may play a critical role in PCa development and progression because not only progesterone is a critical precursor for de novo androgen steroidogenesis and an activator of mutant androgen receptors, but also PR functions in a ligand-independent manner in various important pathways. In fact, recent progress in our understanding of stromal PR function suggests that this receptor may exert an inhibitory effect on benign prostatic hyperplasia (BPH), reactive stroma development, and PCa progression. These early findings of stromal PR warrant further investigations as this receptor could be a potential biomarker and therapeutic target in PCa management.
KEYWORDS:
Cell cycling; Microenvironment; Progesterone receptor; Prostate cancer; Reactive stroma; Stromal differentiation
so this is further implication of Progesterone in Androgenetic Alopecia and prostate cancer- it acts as a tumor suppressor in the prostate, but is a product of Hedgehog signalling in the hair follicle. it could also explain why androgen-deprivation eventually stops working in prostate cancer, as well as how 5AR inhibition also stops working after chronic treatment. There are other pathways besides the Androgen receptor at work in Androgenetic Alopecia(and prostate cancer)
Progesterone is anti-insulin/igf-1. Androgens are pro-insulin/igf-1
https://www.ncbi.nlm.nih.gov/pubmed/15753383
Androgens up-regulate the insulin-like growth factor-I receptor in prostate cancer cells.
Pandini G1, Mineo R, Frasca F, Roberts CT Jr, Marcelli M, Vigneri R, Belfiore A.
Author information
Abstract
In this study, we show that androgens up-regulate insulin-like growth factor-I receptor (IGF-IR) expression and sensitize prostate cancer cells to the biological effects of IGF-I. Both dihydrotestosterone and the synthetic androgen R1881 induced an approximately 6-fold increase in IGF-IR expression in androgen receptor (AR)-positive prostate cancer cells LNCaP. In accordance with IGF-IR up-regulation, treatment with the nonmetabolizable androgen R1881 sensitized LNCaP cells to the mitogenic and motogenic effects of IGF-I, whereas an IGF-IR blocking antibody effectively inhibited these effects. By contrast, these androgens did not affect IGF-IR expression in AR-negative prostate cancer cells PC-3. Reintroduction of AR into PC-3 cells by stable transfection restored the androgen effect on IGF-IR up-regulation. R1881-induced IGF-IR up-regulation was partially inhibited by the AR antagonist Casodex (bicalutamide). Two other AR antagonists, cyproterone acetate and OH-flutamide, were much less effective. Androgen-induced IGF-IR up-regulation was not dependent on AR genomic activity,(very likely via other hormonal receptors, because estrogen receptor A also increases igf-1 http://www.jbc.org/content/275/24/18447 ) because two AR mutants, AR-C619Y and AR-C574R, devoid of DNA binding activity and transcriptional activity were still able to elicit IGF-IR up-regulation in HEK293 kidney cells in response to androgens. Moreover, androgen-induced IGF-IR up-regulation involves the activation of the Src-extracellular signal-regulated kinase pathway, because it was inhibited by both the Src inhibitor PP2 and the MEK-1 inhibitor PD98059. The present observations strongly suggest that AR activation may stimulate prostate cancer progression through the altered IGF-IR expression and IGF action. Anti-androgen therapy may be only partially effective, or almost ineffective, in blocking important biological effects of androgens, such as activation of the IGF system.(same goes for hair. AAs are only partially-effective or ineffective- because igf-1 still gets activated via estrogen receptor A)
Last edited:
https://www.ncbi.nlm.nih.gov/pubmed/22351751
Noggin is novel inducer of mesenchymal stem cell adipogenesis: implications for bone health and obesity.
Sawant A1, Chanda D, Isayeva T, Tsuladze G, Garvey WT, Ponnazhagan S.
Author information
Abstract
Noggin is a glycosylated-secreted protein known so far for its inhibitory effects on bone morphogenetic protein (BMP) signaling by sequestering the BMP ligand. We report here for the first time a novel mechanism by which noggin directly induces adipogenesis of mesenchymal stem cells independently of major human adipogenic signals through C/EBPδ, C/EBPα and peroxisome proliferator-activated receptor-γ. Evaluation of a possible mechanism for noggin-induced adipogenesis of mesenchymal stem cells identified the role of Pax-1 in mediating such differentiation. The relevance of elevated noggin levels in obesity was confirmed in a preclinical, immunocompetent mouse model of spontaneous obesity and in human patients with higher body mass index. These data clearly provide a novel role for noggin in inducing adipogenesis and possibly obesity and further indicates the potential of noggin as a therapeutic target to control obesity.
Noggin Mediates Adipocyte Differentiation via Pax-1
Next, we sought to understand the molecular pathway through which noggin mediated adipogenesis. It is known that mice with noggin haploinsufficiency exhibit reduced Paired box gene-1 (Pax-1) levels (20, 21). MSC from spontaneously obese mice, which exhibit high noggin levels, were found to have significantly elevated levels of Pax-1, thus raising the possibility of a novel adipocyte differentiation pathway of noggin through Pax-1 (Fig. 5A). To confirm the hypothesis that noggin-mediated adipocyte differentiation occurs via Pax-1, expression of Pax-1 in MSC derived from obese mice was abrogated in situ using Pax-1 shRNA (supplemental Fig. S4). As a control, MSC were transfected with a scramble shRNA construct. Adipocyte differentiation was carried out in the ADM along with inhibitors of classical adipocyte differentiation pathways. This segregated noggin-mediated adipogenesis from the canonical pathways and further facilitated to study if Pax-1 has any role in this process. Exogenous noggin was not added, as MSC from obese mice have elevated endogenous noggin. Obese MSC expressing either scr or shPax-1 differentiated into adipocytes as expected. But in the presence of inhibitors, when only noggin mediated pathway was active, obese MSC expressing shPax-1 failed to differentiate into adipocytes, whereas those expressing scrPax-1 differentiated into adipocytes (Fig. 5B). These data demonstrate that noggin-mediated adipocyte induction is through Pax-1 activation and thus provides evidence for a novel adipocyte differentiation pathway.
: Noggin Upregulation = Adipose tissue upregulation(fat layer), through pax1
https://www.ncbi.nlm.nih.gov/pubmed/11641247
Noggin is required for induction of the hair follicle growth phase in postnatal skin.
Botchkarev VA1, Botchkareva NV, Nakamura M, Huber O, Funa K, Lauster R, Paus R, Gilchrest BA.
Author information
Abstract
During postnatal development, the hair follicle (HF) shows cyclic activity with periods of relative resting, active growth (anagen), and regression. We demonstrate that similar to the HF induction in embryonic skin, initiation of a new hair growth phase in postnatal skin requires neutralization of the inhibitory activity of bone morphogenetic protein 4 (BMP4) by the BMP antagonist noggin. In the resting HF, BMP4 mRNA predominates over noggin in the epithelium and mesenchyme, and the BMP receptor IA is prominently expressed in the follicular germ. Anagen development is accompanied by down-regulation of the BMP4 and increased noggin mRNA in the HF. Furthermore, administration of noggin protein induces new hair growth phase in postnatal telogen skin in vivo. In contrast, BMP4 induces selective arrest of anagen development in the non-tylotrich (secondary) HF. As a hair growth inducer, noggin increases Shh mRNA in the HF whereas BMP4 down-regulates Shh. This suggests that modulation of BMP4 signaling by noggin is essential for hair growth phase induction in postnatal skin and that the hair growth-inducing effect of noggin is mediated, at least in part, by Shh.
Noggin upregulation = anagen induction, by activating hair follicle progenitor cells- which are present even in balding scalp(just lying dormant)
Because:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507425/
Unraveling hair follicle-adipocyte communication
Barbara Schmidt and Valerie Horsley
Author information ► Copyright and License information ► Disclaimer
The publisher's final edited version of this article is available at Exp Dermatol
See other articles in PMC that cite the published article.
Go to:
Abstract
Here, we explore the established and potential roles for intradermal adipose tissue in communication with hair follicle biology. The hair follicle delves deep into the rich dermal macroenvironment as it grows to maturity where it is surrounded by large lipid-filled adipocytes. Intradermal adipocytes regenerate with faster kinetics than other adipose tissue depots and in parallel with the hair cycle, suggesting an interplay exists between hair follicle cells and adipocytes. While adipocytes have well-established roles in metabolism and energy storage, until recently, they were overlooked as niche cells that provide important growth signals to neighboring skin cells. We discuss recent data supporting adipocytes as niche cells for the skin and skin pathologies that may be related to alterations in skin adipose tissue defects.
a healthy layer of subcutaneous fat is required to support the anagen phase of the hair cycle(hence the reason why many stem cells treatment all talked about using adipose tissue stemm cells to grow hair)
https://www.ncbi.nlm.nih.gov/pubmed/9409677
Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning.
Hirsinger E1, Duprez D, Jouve C, Malapert P, Cooke J, Pourquié O.
Author information
Abstract
In the vertebrate embryo, the lateral compartment of the somite gives rise to muscles of the limb and body wall and is patterned in response to lateral-plate-derived BMP4. Activation of the myogenic program distinctive to the medial somite, i.e. relatively immediate development of the epaxial muscle lineage, requires neutralization of this lateral signal. We have analyzed the properties of molecules likely to play a role in opposing lateral somite specification by BMP4. We propose that the BMP4 antagonist Noggin plays an important role in promoting medial somite patterning in vivo. We demonstrate that Noggin expression in the somite is under the control of a neural-tube-derived factor, whose effect can be mimicked experimentally by Wnt1. Wnt1 is appropriately expressed in the neural tube. Furthermore, we show that Sonic Hedgehog is able to activate ectopic expression of Noggin resulting in the blocking of BMP4 specification of the lateral somite. Our results are consistent with a model in which Noggin activation lies downstream of the SHH and Wnt signaling pathways.
:Noggin is downstream of Hedgehog signalling. Upregulation of hedgehog signalling = up regulation of Noggin.
So the first study in this thread has already discovered that hedgehog signalling is the most downregulated pathway in Androgenetic Alopecia tissue.
Thus:
https://www.ncbi.nlm.nih.gov/pubmed/16951680
Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus.
Lee K1, Jeong J, Kwak I, Yu CT, Lanske B, Soegiarto DW, Toftgard R, Tsai MJ, Tsai S, Lydon JP, DeMayo FJ.
Author information
Abstract
The hedgehog family of morphogens are regulators of cell proliferation, differentiation and cell-cell communication. These morphogens have been shown to have important roles in organogenesis, spermatogenesis, stem cell maintenance and oncogenesis. Indian hedgehog (encoded by Ihh) has been shown to be expressed in the uterine epithelium under the control of the steroid hormone, progesterone. Although in vivo and in vitro studies have shown that progesterone achieves its effects on uterine function through epithelial-stromal cross-talk, molecular mediator(s) for this cellular communication pathway have not been elucidated. Using new experimental approaches that ablate Ihh specifically in Pgr-positive uterine cells of the mouse, we demonstrate that Ihh is an essential mediator of Pgr action in the uterus, and expression of this factor is critical in mediating the communication between the uterine epithelium and stroma required for embryo implantation.
: Progesterone mediates Hedgehog signalling. Upregulation of Progesterone = upregulation of hedgehog signalling, which correlates with another study posted earlier in this thread:
Hedgehog signaling stimulates the conversion of cholesterol to steroids.
Tang C1, Pan Y1, Luo H1, Xiong W2, Zhu H3, Ruan H1, Wang J1, Zou C2, Tang L2, Iguchi T4, Long F5, Wu X6.
Author information
Abstract
Cholesterol modification of Hedgehog (Hh) ligands is fundamental for the activity of Hh signaling, and cholesterol biosynthesis is also required for intracellular Hh signaling transduction. Here, we investigated the roles and underlying mechanism of Hh signaling in metabolism of cholesterol. The main components of the Hh pathway are abundantly expressed in both human cytotrophoblasts and trophoblast-like cells. Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase. Moreover, inhibition of Hh signaling attenuates not only Hh-induced expression of steroidogenic enzymes but also the conversion of cholesterol to P4 and E2. Whereas Gli3 is required for Hh-induced P450scc expression, Gli2 mediates the induction of 3β-HSD1 and aromatase. Finally, in ovariectomized nude mice, systemic inhibition of Hh signaling by cyclopamine suppresses circulating P4 and E2 levels derived from a trophoblast-like choricarcinoma xenograft, and attenuates uterine response to P4 and E2. Together these results uncover a hitherto uncharacterized role of Hh signaling in metabolism of cholesterol.
Noggin is novel inducer of mesenchymal stem cell adipogenesis: implications for bone health and obesity.
Sawant A1, Chanda D, Isayeva T, Tsuladze G, Garvey WT, Ponnazhagan S.
Author information
Abstract
Noggin is a glycosylated-secreted protein known so far for its inhibitory effects on bone morphogenetic protein (BMP) signaling by sequestering the BMP ligand. We report here for the first time a novel mechanism by which noggin directly induces adipogenesis of mesenchymal stem cells independently of major human adipogenic signals through C/EBPδ, C/EBPα and peroxisome proliferator-activated receptor-γ. Evaluation of a possible mechanism for noggin-induced adipogenesis of mesenchymal stem cells identified the role of Pax-1 in mediating such differentiation. The relevance of elevated noggin levels in obesity was confirmed in a preclinical, immunocompetent mouse model of spontaneous obesity and in human patients with higher body mass index. These data clearly provide a novel role for noggin in inducing adipogenesis and possibly obesity and further indicates the potential of noggin as a therapeutic target to control obesity.
Noggin Mediates Adipocyte Differentiation via Pax-1
Next, we sought to understand the molecular pathway through which noggin mediated adipogenesis. It is known that mice with noggin haploinsufficiency exhibit reduced Paired box gene-1 (Pax-1) levels (20, 21). MSC from spontaneously obese mice, which exhibit high noggin levels, were found to have significantly elevated levels of Pax-1, thus raising the possibility of a novel adipocyte differentiation pathway of noggin through Pax-1 (Fig. 5A). To confirm the hypothesis that noggin-mediated adipocyte differentiation occurs via Pax-1, expression of Pax-1 in MSC derived from obese mice was abrogated in situ using Pax-1 shRNA (supplemental Fig. S4). As a control, MSC were transfected with a scramble shRNA construct. Adipocyte differentiation was carried out in the ADM along with inhibitors of classical adipocyte differentiation pathways. This segregated noggin-mediated adipogenesis from the canonical pathways and further facilitated to study if Pax-1 has any role in this process. Exogenous noggin was not added, as MSC from obese mice have elevated endogenous noggin. Obese MSC expressing either scr or shPax-1 differentiated into adipocytes as expected. But in the presence of inhibitors, when only noggin mediated pathway was active, obese MSC expressing shPax-1 failed to differentiate into adipocytes, whereas those expressing scrPax-1 differentiated into adipocytes (Fig. 5B). These data demonstrate that noggin-mediated adipocyte induction is through Pax-1 activation and thus provides evidence for a novel adipocyte differentiation pathway.
: Noggin Upregulation = Adipose tissue upregulation(fat layer), through pax1
https://www.ncbi.nlm.nih.gov/pubmed/11641247
Noggin is required for induction of the hair follicle growth phase in postnatal skin.
Botchkarev VA1, Botchkareva NV, Nakamura M, Huber O, Funa K, Lauster R, Paus R, Gilchrest BA.
Author information
Abstract
During postnatal development, the hair follicle (HF) shows cyclic activity with periods of relative resting, active growth (anagen), and regression. We demonstrate that similar to the HF induction in embryonic skin, initiation of a new hair growth phase in postnatal skin requires neutralization of the inhibitory activity of bone morphogenetic protein 4 (BMP4) by the BMP antagonist noggin. In the resting HF, BMP4 mRNA predominates over noggin in the epithelium and mesenchyme, and the BMP receptor IA is prominently expressed in the follicular germ. Anagen development is accompanied by down-regulation of the BMP4 and increased noggin mRNA in the HF. Furthermore, administration of noggin protein induces new hair growth phase in postnatal telogen skin in vivo. In contrast, BMP4 induces selective arrest of anagen development in the non-tylotrich (secondary) HF. As a hair growth inducer, noggin increases Shh mRNA in the HF whereas BMP4 down-regulates Shh. This suggests that modulation of BMP4 signaling by noggin is essential for hair growth phase induction in postnatal skin and that the hair growth-inducing effect of noggin is mediated, at least in part, by Shh.
Noggin upregulation = anagen induction, by activating hair follicle progenitor cells- which are present even in balding scalp(just lying dormant)
Because:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507425/
Unraveling hair follicle-adipocyte communication
Barbara Schmidt and Valerie Horsley
Author information ► Copyright and License information ► Disclaimer
The publisher's final edited version of this article is available at Exp Dermatol
See other articles in PMC that cite the published article.
Go to:
Abstract
Here, we explore the established and potential roles for intradermal adipose tissue in communication with hair follicle biology. The hair follicle delves deep into the rich dermal macroenvironment as it grows to maturity where it is surrounded by large lipid-filled adipocytes. Intradermal adipocytes regenerate with faster kinetics than other adipose tissue depots and in parallel with the hair cycle, suggesting an interplay exists between hair follicle cells and adipocytes. While adipocytes have well-established roles in metabolism and energy storage, until recently, they were overlooked as niche cells that provide important growth signals to neighboring skin cells. We discuss recent data supporting adipocytes as niche cells for the skin and skin pathologies that may be related to alterations in skin adipose tissue defects.
a healthy layer of subcutaneous fat is required to support the anagen phase of the hair cycle(hence the reason why many stem cells treatment all talked about using adipose tissue stemm cells to grow hair)
https://www.ncbi.nlm.nih.gov/pubmed/9409677
Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning.
Hirsinger E1, Duprez D, Jouve C, Malapert P, Cooke J, Pourquié O.
Author information
Abstract
In the vertebrate embryo, the lateral compartment of the somite gives rise to muscles of the limb and body wall and is patterned in response to lateral-plate-derived BMP4. Activation of the myogenic program distinctive to the medial somite, i.e. relatively immediate development of the epaxial muscle lineage, requires neutralization of this lateral signal. We have analyzed the properties of molecules likely to play a role in opposing lateral somite specification by BMP4. We propose that the BMP4 antagonist Noggin plays an important role in promoting medial somite patterning in vivo. We demonstrate that Noggin expression in the somite is under the control of a neural-tube-derived factor, whose effect can be mimicked experimentally by Wnt1. Wnt1 is appropriately expressed in the neural tube. Furthermore, we show that Sonic Hedgehog is able to activate ectopic expression of Noggin resulting in the blocking of BMP4 specification of the lateral somite. Our results are consistent with a model in which Noggin activation lies downstream of the SHH and Wnt signaling pathways.
:Noggin is downstream of Hedgehog signalling. Upregulation of hedgehog signalling = up regulation of Noggin.
So the first study in this thread has already discovered that hedgehog signalling is the most downregulated pathway in Androgenetic Alopecia tissue.
Thus:
https://www.ncbi.nlm.nih.gov/pubmed/16951680
Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus.
Lee K1, Jeong J, Kwak I, Yu CT, Lanske B, Soegiarto DW, Toftgard R, Tsai MJ, Tsai S, Lydon JP, DeMayo FJ.
Author information
Abstract
The hedgehog family of morphogens are regulators of cell proliferation, differentiation and cell-cell communication. These morphogens have been shown to have important roles in organogenesis, spermatogenesis, stem cell maintenance and oncogenesis. Indian hedgehog (encoded by Ihh) has been shown to be expressed in the uterine epithelium under the control of the steroid hormone, progesterone. Although in vivo and in vitro studies have shown that progesterone achieves its effects on uterine function through epithelial-stromal cross-talk, molecular mediator(s) for this cellular communication pathway have not been elucidated. Using new experimental approaches that ablate Ihh specifically in Pgr-positive uterine cells of the mouse, we demonstrate that Ihh is an essential mediator of Pgr action in the uterus, and expression of this factor is critical in mediating the communication between the uterine epithelium and stroma required for embryo implantation.
: Progesterone mediates Hedgehog signalling. Upregulation of Progesterone = upregulation of hedgehog signalling, which correlates with another study posted earlier in this thread:
Hedgehog signaling stimulates the conversion of cholesterol to steroids.
Tang C1, Pan Y1, Luo H1, Xiong W2, Zhu H3, Ruan H1, Wang J1, Zou C2, Tang L2, Iguchi T4, Long F5, Wu X6.
Author information
Abstract
Cholesterol modification of Hedgehog (Hh) ligands is fundamental for the activity of Hh signaling, and cholesterol biosynthesis is also required for intracellular Hh signaling transduction. Here, we investigated the roles and underlying mechanism of Hh signaling in metabolism of cholesterol. The main components of the Hh pathway are abundantly expressed in both human cytotrophoblasts and trophoblast-like cells. Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase. Moreover, inhibition of Hh signaling attenuates not only Hh-induced expression of steroidogenic enzymes but also the conversion of cholesterol to P4 and E2. Whereas Gli3 is required for Hh-induced P450scc expression, Gli2 mediates the induction of 3β-HSD1 and aromatase. Finally, in ovariectomized nude mice, systemic inhibition of Hh signaling by cyclopamine suppresses circulating P4 and E2 levels derived from a trophoblast-like choricarcinoma xenograft, and attenuates uterine response to P4 and E2. Together these results uncover a hitherto uncharacterized role of Hh signaling in metabolism of cholesterol.
Last edited:
Coincidentally:
Influence of estrogens on the androgen metabolism in different subunits of human hair follicles.
Niiyama S1, Happle R, Hoffmann R.
Author information
Abstract
The molecular pathways involved in estrogen-mediated induction of hair growth in androgenetic alopecia are unknown. Some authors found that estradiol (E) inhibited 5alpha-reductase (5alpha-R) activity and therefore we addressed the question whether 17alpha- or 17beta-E are able to modulate the activity of 5alpha-R, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) or 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in isolated compartments of human hair follicles. For this purpose, scalp biopsies from volunteers were taken and from each biopsy root sheaths, connective tissue sheaths and dermal papillae (DP) were dissected and incubated in the presence of 3H-testosterone (T) and, in addition, either 17alpha-E, 17beta-E, progesterone or finasteride for up to 48 hrs. Thereafter high-performance liquid chromatography analysis of culture supernatants was performed to detect T-metabolites. At the tested concentrations, finasteride was found to be a major inhibitor of dihydrotestosterone (DHT) formation. Even 1 nM finasteride inhibited DHT synthesis in DP by 86% and 1 nM progesterone by 75%. Estrogens were less able to inhibit the synthesis of DHT in DP (e.g. 100 nM 17alpha-E: 20%; 100 nM 17beta-E: 60%). Whether E directly inhibits 5alpha-R in DP's or whether the effect of estrogens might be explained by an increased conversion of T to the weaker androgens such as androstendione (via 17beta-HSD), androstenediol (via 3beta-HSD) or 17beta-E (via aromatase), thereby diminishing the amount of T available for the conversion to DHT, remains to be shown.
: Progesterone is the body's natural inhibitor of DHT's formation
A NOVEL MECHANISM FOR PANCREATIC Β-CELL DYSFUNCTION
Abstract
OBJECTIVE—Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic β-cells that is independent of the effects of FFAs.
RESEARCH DESIGN AND METHODS—Several methods were used to modulate cholesterol levels in intact islets and cultured β-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels. Acute and metabolic alteration of cholesterol was done using pharmacological reagents.
RESULTS—We found a direct link between elevated serum cholesterol and reduced insulin secretion, with normal secretion restored by cholesterol depletion. We further demonstrate that excess cholesterol inhibits secretion by downregulation of metabolism through increased neuronal nitric oxide synthase dimerization.
CONCLUSIONS—This direct effect of cholesterol on β-cell metabolism opens a novel set of mechanisms that may contribute to β-cell dysfunction and the onset of diabetes in obese patients.
: more insulin = less cholesterol
Insulin/IGF-1 secretion upregulation => Sebocyte lipogenesis upregulation +Cholesterol biosynthesis downregulation =>Sonic hedgehog downregulation => Progesterone + Estradiol downregulation => Noggin downregulation => Adipose tissue profileration downregulation => Anagen downregulation(but kept in dormancy because progenitor cells are retained)
Influence of estrogens on the androgen metabolism in different subunits of human hair follicles.
Niiyama S1, Happle R, Hoffmann R.
Author information
Abstract
The molecular pathways involved in estrogen-mediated induction of hair growth in androgenetic alopecia are unknown. Some authors found that estradiol (E) inhibited 5alpha-reductase (5alpha-R) activity and therefore we addressed the question whether 17alpha- or 17beta-E are able to modulate the activity of 5alpha-R, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) or 17beta-hydroxysteroid dehydrogenase (17beta-HSD) in isolated compartments of human hair follicles. For this purpose, scalp biopsies from volunteers were taken and from each biopsy root sheaths, connective tissue sheaths and dermal papillae (DP) were dissected and incubated in the presence of 3H-testosterone (T) and, in addition, either 17alpha-E, 17beta-E, progesterone or finasteride for up to 48 hrs. Thereafter high-performance liquid chromatography analysis of culture supernatants was performed to detect T-metabolites. At the tested concentrations, finasteride was found to be a major inhibitor of dihydrotestosterone (DHT) formation. Even 1 nM finasteride inhibited DHT synthesis in DP by 86% and 1 nM progesterone by 75%. Estrogens were less able to inhibit the synthesis of DHT in DP (e.g. 100 nM 17alpha-E: 20%; 100 nM 17beta-E: 60%). Whether E directly inhibits 5alpha-R in DP's or whether the effect of estrogens might be explained by an increased conversion of T to the weaker androgens such as androstendione (via 17beta-HSD), androstenediol (via 3beta-HSD) or 17beta-E (via aromatase), thereby diminishing the amount of T available for the conversion to DHT, remains to be shown.
: Progesterone is the body's natural inhibitor of DHT's formation
A NOVEL MECHANISM FOR PANCREATIC Β-CELL DYSFUNCTION
Abstract
OBJECTIVE—Type 2 diabetes is often accompanied by abnormal blood lipid and lipoprotein levels, but most studies on the link between hyperlipidemia and diabetes have focused on free fatty acids (FFAs). In this study, we examined the relationship between cholesterol and insulin secretion from pancreatic β-cells that is independent of the effects of FFAs.
RESEARCH DESIGN AND METHODS—Several methods were used to modulate cholesterol levels in intact islets and cultured β-cells, including a recently developed mouse model that exhibits elevated cholesterol but normal FFA levels. Acute and metabolic alteration of cholesterol was done using pharmacological reagents.
RESULTS—We found a direct link between elevated serum cholesterol and reduced insulin secretion, with normal secretion restored by cholesterol depletion. We further demonstrate that excess cholesterol inhibits secretion by downregulation of metabolism through increased neuronal nitric oxide synthase dimerization.
CONCLUSIONS—This direct effect of cholesterol on β-cell metabolism opens a novel set of mechanisms that may contribute to β-cell dysfunction and the onset of diabetes in obese patients.
: more insulin = less cholesterol
Insulin/IGF-1 secretion upregulation => Sebocyte lipogenesis upregulation +Cholesterol biosynthesis downregulation =>Sonic hedgehog downregulation => Progesterone + Estradiol downregulation => Noggin downregulation => Adipose tissue profileration downregulation => Anagen downregulation(but kept in dormancy because progenitor cells are retained)
Last edited:
So 1st study in this thread stated hedgehog signalling was the most downregulated pathway in balding scalp when compared to adjacent hair-bearing scalp:
"Of these, T-cell receptor signalling was the most upregulated pathway, and Hedgehog signalling pathway was the most downregulated pathway."
and Chromosome 20p11 is a universal balding variant in both Chinese and Europeans:
Abstract
Background
Androgenetic alopecia (Androgenetic Alopecia) is a well-characterized type of progressive hair loss commonly seen in men, with different prevalences in different ethnic populations. It is generally considered to be a polygenic heritable trait. Several susceptibility genes/loci, such as AR/EDA2R, HDAC9 and 20p11, have been identified as being involved in its development in European populations. In this study, we aim to validate whether these loci are also associated with Androgenetic Alopecia in the Chinese Han population.
Methods
We genotyped 16 previously reported single nucleotide polymorphisms (SNPs) with 445 Androgenetic Alopecia cases and 546 healthy controls using the Sequenom iPlex platform. The trend test was used to evaluate the association between these loci and Androgenetic Alopecia in the Chinese Han population. Conservatively accounting for multiple testing by the Bonferroni correction, the threshold for statistical significance was P ≤3.13×10−3.
Results
We identified that 5 SNPs at 20p11 were significantly associated with Androgenetic Alopecia in the Chinese Han population (1.84×10−11≤P≤2.10×10−6).
Genetic Variants at 20p11 Confer Risk to Androgenetic Alopecia in the Chinese Han Population
Chromosome 20p11 lies inbetween the Pax1 and Foxa2 genes. So the balding 20p11 variant influences how these 2 genes behave.
which is in line with:
Forkhead box protein A2 and T helper type 2-mediated pulmonary inflammation
Abstract
The transcription factor forkhead box protein A2 (FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2 (Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
Keywords: Forkhead box protein A2, T helper type 2 inflammation, Pulmonary, Development, Goblet cell hyperplasia.
:FOXA2 downregulation => Th2 upregulation
Th2 cinds to CRTh2(the main drug target of Setipiprant):
CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease.
Cosmi L1, Annunziato F, Galli MIG, Maggi RME, Nagata K, Romagnani S.
Author information
Abstract
Cells expressing the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the chemokine C receptor (CCR)4 were consistently detected in the circulation of healthy subjects, whereas numbers of cells expressing CCR3 were much lower. While all CCR4+ cells were T cells, a small proportion of CRTH2+, and about a half of the few CCR3+ cells were basophils. Only CRTH2+ T cells contained Th2 or Tc2 cells, but neither Th0 or Tc0, nor Th1 or Tc1 cells, although not all of them produced Th2-type cytokines. By contrast, CCR4+ T cells contained both Th2 or Tc2 and Th0 or Tc0 cells and even Th1 or Tc1 cells, whereas the few CCR3+ T cells were not clearly classifiable for their cytokine profile. CRTH2+ T lymphocytes were virtually devoid of chemokine CX receptor (CXCR)3+ and CCR5+ cells, but enriched in CCR3+ and CCR4+ cells. By contrast, CCR3+ or CCR4+ T cells did not show a similar clear-cut dichotomy in the expression of CCR5/CXCR3 or CCR3/ CCR4. Subjects with atopic dermatitis or HIV infection with low levels of circulating CD4+ T cells revealed a significant increase of CRTH2+ cells within both the CD4+ and the CD8+ T cell subset. These data support the concept that at present CRTH2 is the more reliable marker for detection of both human Th2 and Tc2 cells in health and disease.
: FOXA2 downregulation => Th2 upregulation => CRTh2 upregulation => Androgenetic Alopecia
so it's been established that progesterone and estradiol are the products of activated hegdehog signalling:
"Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase".
Now:
Decreased expression of FOXA2 promotes eutopic endometrial cell proliferation and migration in patients with endometriosis.
Lin A1, Yin J2, Cheng C3, Yang Z4, Yang H5.
Author information
Abstract
Endometriosis is characterized by eutopic endometrial cell 'metastasis' to ectopic foci. FOXA2 is a member of the forkhead transcription factor family, which may participate in transcriptional regulation in endometrial cells and contribute to the aetiology of endometriosis. This study investigated the roles played by FOXA2 in eutopic endometrium using endometriosis samples. Western blotting showed that the relative expression of FOXA2 was significantly reduced in eutopic endometrium from patients with endometriosis (n = 14) compared with endometriosis-free controls (n = 16) (0.69 ± 0.07 versus 1.24 ± 0.06, P < 0.05). To mimic eutopic endometrium of endometriosis, primary eutopic endometrial stromal cells (ESC) of controls were harvested and transfected with FOXA2 siRNA. MTT assay showed that cell viability of ESC with transfected FOXA2 siRNA increased significantly, whereas the apoptosis rate decreased as indicated by flow cytometry experiments (both P < 0.05). Wound healing assays revealed that transfection of FOXA2 siRNA promoted ESC migration. Moreover, real-time PCR analysis showed progesterone-induced FOXA2 expression in ESC under physiological conditions. In conclusion, these findings indicate that FOXA2 might be a progesterone-induced gene, which may participate in the 'metastatic' process of eutopic endometrium to ectopic loci in patients with endometriosis.
: Progesterone induces FOXA2 expression
Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia.
Wang DH, Tiwari A, Kim ME, Clemons NJ, Regmi NL, Hodges WA, Berman DM, Montgomery EA, Watkins DN, Zhang X, Zhang Q, Jie C, Spechler SJ, Souza RF.
Abstract
Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett's esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett's metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett's pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett's metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett's esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett's metaplasia.
so to cut things short, i have come across many studies that stated foxa2 activates hegdehog, while some says it's the other way round. whatever it is, it's:
whatever it is, it's:
FOXA2 <=> SHH(sonic hedgehog)
so the effects of FOXA2 downregulation = Sonic hedgehog downregulation + CRTh2 upregulation
All these means progesterone and estradiol are the hair-growing hormones in the balding scalp.
Progesterone stops the th2 inflammation while estradiol starts the pge2 cascade, because countless studies all states:
Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells.
Miao L1, Shi J, Wang CY, Zhu Y, Du X, Jiao H, Mo Z, Klocker H, Lee C, Zhang J.
Author information
Abstract
Estrogen receptor-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily of transcription factors. ERRalpha is highly expressed in the prostate, especially in prostate stromal cells. However, little is known about the regulation and function of ERRalpha, which may contribute to the progression of prostatic diseases. We previously found that prostaglandin E2 (PGE2) up-regulated the expression of aromatase in prostate stromal cells. Here we show that PGE2 also up-regulates the expression of ERRalpha, which, as a transcription factor, further mediates the regulatory effects of PGE2 on the expression of aromatase. ERRalpha expression was up-regulated by PGE2 in prostate stromal cell line WPMY-1, which was mediated mainly through the protein kinase A signaling pathway by PGE2 receptor EP2. Suppression of ERRalpha activity by chlordane (an antagonist of ERRalpha) or small interfering RNA knockdown of ERRalpha blocked the increase of expression and promoter activity of aromatase induced by PGE2. Overexpression of ERRalpha significantly increased aromatase expression and promoter activity, which were further augmented by PGE2. Chromatin immunoprecipitation assay demonstrated that ERRalpha directly bound to the aromatase promoter in vivo, and PGE2 enhanced the recruitment of ERRalpha and promoted transcriptional regulatory effects on aromatase expression in WPMY-1. 17Beta-estradiol concentration in WPMY-1 medium was up-regulated by ERRalpha expression, and that was further increased by PGE2. Our results provided evidence that ERRalpha contributed to local estrogen production by up-regulating aromatase expression in response to PGE2 and provided further insights into the potential role of ERRalpha in estrogen-related prostatic diseases.
Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior.
Amateau SK1, McCarthy MM.
Author information
Abstract
Adult male sexual behavior in mammals requires the neuronal organizing effects of gonadal steroids during a sensitive perinatal period. During development, estradiol differentiates the rat preoptic area (POA), an essential brain region in the male copulatory circuit. Here we report that increases in prostaglandin-E(2) (PGE(2)), resulting from changes in cyclooxygenase-2 (COX-2) regulation induced by perinatal exposure to estradiol, are necessary and sufficient to organize the crucial neural substrate that mediates male sexual behavior. Briefly preventing prostaglandin synthesis in newborn males with the COX inhibitor indomethacin permanently downregulates markers of dendritic spines in the POA and severely impairs male sexual behavior. Developmental exposure to the COX inhibitor aspirin results in mild impairment of sexual behavior. Conversely, administration of PGE(2) to newborn females masculinizes the POA and leads to male sex behavior in adults, thereby highlighting the pathway of steroid-independent brain masculinization. Our findings show that PGE(2) functions as a downstream effector of estradiol to permanently masculinize the brain.
"Of these, T-cell receptor signalling was the most upregulated pathway, and Hedgehog signalling pathway was the most downregulated pathway."
and Chromosome 20p11 is a universal balding variant in both Chinese and Europeans:
Abstract
Background
Androgenetic alopecia (Androgenetic Alopecia) is a well-characterized type of progressive hair loss commonly seen in men, with different prevalences in different ethnic populations. It is generally considered to be a polygenic heritable trait. Several susceptibility genes/loci, such as AR/EDA2R, HDAC9 and 20p11, have been identified as being involved in its development in European populations. In this study, we aim to validate whether these loci are also associated with Androgenetic Alopecia in the Chinese Han population.
Methods
We genotyped 16 previously reported single nucleotide polymorphisms (SNPs) with 445 Androgenetic Alopecia cases and 546 healthy controls using the Sequenom iPlex platform. The trend test was used to evaluate the association between these loci and Androgenetic Alopecia in the Chinese Han population. Conservatively accounting for multiple testing by the Bonferroni correction, the threshold for statistical significance was P ≤3.13×10−3.
Results
We identified that 5 SNPs at 20p11 were significantly associated with Androgenetic Alopecia in the Chinese Han population (1.84×10−11≤P≤2.10×10−6).
Genetic Variants at 20p11 Confer Risk to Androgenetic Alopecia in the Chinese Han Population
Chromosome 20p11 lies inbetween the Pax1 and Foxa2 genes. So the balding 20p11 variant influences how these 2 genes behave.
which is in line with:
Forkhead box protein A2 and T helper type 2-mediated pulmonary inflammation
Abstract
The transcription factor forkhead box protein A2 (FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2 (Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
Keywords: Forkhead box protein A2, T helper type 2 inflammation, Pulmonary, Development, Goblet cell hyperplasia.
:FOXA2 downregulation => Th2 upregulation
Th2 cinds to CRTh2(the main drug target of Setipiprant):
CRTH2 is the most reliable marker for the detection of circulating human type 2 Th and type 2 T cytotoxic cells in health and disease.
Cosmi L1, Annunziato F, Galli MIG, Maggi RME, Nagata K, Romagnani S.
Author information
Abstract
Cells expressing the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the chemokine C receptor (CCR)4 were consistently detected in the circulation of healthy subjects, whereas numbers of cells expressing CCR3 were much lower. While all CCR4+ cells were T cells, a small proportion of CRTH2+, and about a half of the few CCR3+ cells were basophils. Only CRTH2+ T cells contained Th2 or Tc2 cells, but neither Th0 or Tc0, nor Th1 or Tc1 cells, although not all of them produced Th2-type cytokines. By contrast, CCR4+ T cells contained both Th2 or Tc2 and Th0 or Tc0 cells and even Th1 or Tc1 cells, whereas the few CCR3+ T cells were not clearly classifiable for their cytokine profile. CRTH2+ T lymphocytes were virtually devoid of chemokine CX receptor (CXCR)3+ and CCR5+ cells, but enriched in CCR3+ and CCR4+ cells. By contrast, CCR3+ or CCR4+ T cells did not show a similar clear-cut dichotomy in the expression of CCR5/CXCR3 or CCR3/ CCR4. Subjects with atopic dermatitis or HIV infection with low levels of circulating CD4+ T cells revealed a significant increase of CRTH2+ cells within both the CD4+ and the CD8+ T cell subset. These data support the concept that at present CRTH2 is the more reliable marker for detection of both human Th2 and Tc2 cells in health and disease.
: FOXA2 downregulation => Th2 upregulation => CRTh2 upregulation => Androgenetic Alopecia
so it's been established that progesterone and estradiol are the products of activated hegdehog signalling:
"Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase".
Now:
Decreased expression of FOXA2 promotes eutopic endometrial cell proliferation and migration in patients with endometriosis.
Lin A1, Yin J2, Cheng C3, Yang Z4, Yang H5.
Author information
Abstract
Endometriosis is characterized by eutopic endometrial cell 'metastasis' to ectopic foci. FOXA2 is a member of the forkhead transcription factor family, which may participate in transcriptional regulation in endometrial cells and contribute to the aetiology of endometriosis. This study investigated the roles played by FOXA2 in eutopic endometrium using endometriosis samples. Western blotting showed that the relative expression of FOXA2 was significantly reduced in eutopic endometrium from patients with endometriosis (n = 14) compared with endometriosis-free controls (n = 16) (0.69 ± 0.07 versus 1.24 ± 0.06, P < 0.05). To mimic eutopic endometrium of endometriosis, primary eutopic endometrial stromal cells (ESC) of controls were harvested and transfected with FOXA2 siRNA. MTT assay showed that cell viability of ESC with transfected FOXA2 siRNA increased significantly, whereas the apoptosis rate decreased as indicated by flow cytometry experiments (both P < 0.05). Wound healing assays revealed that transfection of FOXA2 siRNA promoted ESC migration. Moreover, real-time PCR analysis showed progesterone-induced FOXA2 expression in ESC under physiological conditions. In conclusion, these findings indicate that FOXA2 might be a progesterone-induced gene, which may participate in the 'metastatic' process of eutopic endometrium to ectopic loci in patients with endometriosis.
: Progesterone induces FOXA2 expression
Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett's metaplasia.
Wang DH, Tiwari A, Kim ME, Clemons NJ, Regmi NL, Hodges WA, Berman DM, Montgomery EA, Watkins DN, Zhang X, Zhang Q, Jie C, Spechler SJ, Souza RF.
Abstract
Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett's esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett's metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett's pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett's metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett's esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett's metaplasia.
so to cut things short, i have come across many studies that stated foxa2 activates hegdehog, while some says it's the other way round. whatever it is, it's:
whatever it is, it's:
FOXA2 <=> SHH(sonic hedgehog)
so the effects of FOXA2 downregulation = Sonic hedgehog downregulation + CRTh2 upregulation
All these means progesterone and estradiol are the hair-growing hormones in the balding scalp.
Progesterone stops the th2 inflammation while estradiol starts the pge2 cascade, because countless studies all states:
Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells.
Miao L1, Shi J, Wang CY, Zhu Y, Du X, Jiao H, Mo Z, Klocker H, Lee C, Zhang J.
Author information
Abstract
Estrogen receptor-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily of transcription factors. ERRalpha is highly expressed in the prostate, especially in prostate stromal cells. However, little is known about the regulation and function of ERRalpha, which may contribute to the progression of prostatic diseases. We previously found that prostaglandin E2 (PGE2) up-regulated the expression of aromatase in prostate stromal cells. Here we show that PGE2 also up-regulates the expression of ERRalpha, which, as a transcription factor, further mediates the regulatory effects of PGE2 on the expression of aromatase. ERRalpha expression was up-regulated by PGE2 in prostate stromal cell line WPMY-1, which was mediated mainly through the protein kinase A signaling pathway by PGE2 receptor EP2. Suppression of ERRalpha activity by chlordane (an antagonist of ERRalpha) or small interfering RNA knockdown of ERRalpha blocked the increase of expression and promoter activity of aromatase induced by PGE2. Overexpression of ERRalpha significantly increased aromatase expression and promoter activity, which were further augmented by PGE2. Chromatin immunoprecipitation assay demonstrated that ERRalpha directly bound to the aromatase promoter in vivo, and PGE2 enhanced the recruitment of ERRalpha and promoted transcriptional regulatory effects on aromatase expression in WPMY-1. 17Beta-estradiol concentration in WPMY-1 medium was up-regulated by ERRalpha expression, and that was further increased by PGE2. Our results provided evidence that ERRalpha contributed to local estrogen production by up-regulating aromatase expression in response to PGE2 and provided further insights into the potential role of ERRalpha in estrogen-related prostatic diseases.
Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior.
Amateau SK1, McCarthy MM.
Author information
Abstract
Adult male sexual behavior in mammals requires the neuronal organizing effects of gonadal steroids during a sensitive perinatal period. During development, estradiol differentiates the rat preoptic area (POA), an essential brain region in the male copulatory circuit. Here we report that increases in prostaglandin-E(2) (PGE(2)), resulting from changes in cyclooxygenase-2 (COX-2) regulation induced by perinatal exposure to estradiol, are necessary and sufficient to organize the crucial neural substrate that mediates male sexual behavior. Briefly preventing prostaglandin synthesis in newborn males with the COX inhibitor indomethacin permanently downregulates markers of dendritic spines in the POA and severely impairs male sexual behavior. Developmental exposure to the COX inhibitor aspirin results in mild impairment of sexual behavior. Conversely, administration of PGE(2) to newborn females masculinizes the POA and leads to male sex behavior in adults, thereby highlighting the pathway of steroid-independent brain masculinization. Our findings show that PGE(2) functions as a downstream effector of estradiol to permanently masculinize the brain.
Last edited:
Estradiol enhances prostaglandin E2 receptor gene expression in luteinizing hormone-releasing hormone (LHRH) neurons and facilitates the LHRH response to PGE2 by activating a glia-to-neuron signaling pathway.
Rage F1, Lee BJ, Ma YJ, Ojeda SR.
Author information
Abstract
Prostaglandin E2 (PGE2) mediates the stimulatory effect of norepinephrine (NE) on the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling reproductive function. In rodents, this facilitatory effect requires previous exposure to estradiol, suggesting that the steroid affects downstream components in the cascade that leads to PGE2-induced LHRH release. Because astroglia are the predominant cell type contacting LHRH-secreting nerve terminals, we investigated the involvement of hypothalamic astrocytes in the estradiol facilitation of PGE2-induced LHRH release. A subpopulation of LHRH neurons was found to express the mRNA encoding the PGE2 receptor subtype EP1-R, which is coupled to calcium mobilization. The LHRH-producing cell line GT1-1 also contains EP1-R mRNA and, to a lesser extent, the three alternatively spliced forms of EP3-R mRNA (alpha, beta, and gamma) that encode receptors linked to inhibition and stimulation of cAMP formation. Hypothalamic astrocytes treated with estradiol produced a conditioned medium that when applied to GT1-1 cells resulted in a selective upregulation of EP1-R and EP3gamma-R mRNAs. The conditioned medium also enhanced the LHRH response to EP1-R and EP3-R agonists and the cAMP response to EP3-R activation. Thus, one mechanism by which estradiol facilitates the effect of neurotransmitters acting via PGE2 to stimulate LHRH release is by enhancing the glial production of substances that upregulate PGE2 receptors on LHRH neurons. The existence of such a mechanism underscores the emerging importance of glial-neuronal communication in the control of brain neurosecretory activity.
: Estradiol, through binding to Estrogen receptor Alpha(not Estrogen receptor beta- the target of Estriol)- is the body's natural PGE2 inducer
Binding and functional selectivity[edit]
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.[13][14]
Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
Estrogen receptor Alpha is the gene that induces PGE2 production. This is not to say that Estrogen receptor Beta is not important, because:
The distribution of estrogen receptor beta is distinct to that of estrogen receptor alpha and the androgen receptor in human skin and the pilosebaceous unit.
Thornton MJ1, Taylor AH, Mulligan K, Al-Azzawi F, Lyon CC, O'Driscoll J, Messenger AG.
Author information
Abstract
Both estrogens and androgens play important parts in skin and hair physiology, although studies of estrogen action in human skin have been rather limited. Recently, a second estrogen receptor (beta) has been identified in many nonclassical target tissues, including androgen-dependent tissues. Therefore, we have revisited the role of estrogens in human skin and hair by comparing the pattern of expression by immunohistochemistry for both estrogen receptors (alpha and beta) and the androgen receptor. Immunolocalization of androgen receptors was only seen in hair follicle dermal papilla cells and the basal cells of the sebaceous gland. Little specific staining of estrogen receptor alpha was seen anywhere except the sebaceous gland. In contrast estrogen receptor beta was highly expressed in epidermis, blood vessels, and dermal fibroblasts, whereas in the hair follicle it was localized to nuclei of the outer root sheath, epithelial matrix, and dermal papilla cells. Serial sections also showed strong nuclear expression of estrogen receptor beta in the cells of the bulge, whereas neither estrogen receptor alpha or androgen receptor was expressed. In the sebaceous gland, estrogen receptor beta was expressed in both basal and partially differentiated sebocytes in a similar pattern to estrogen receptor alpha. There was no obvious difference in the expression of either estrogen receptor in male or female nonbalding scalp skin. The results of this immunohistochemical study propose that estrogen receptor beta and not estrogen receptor alpha is the main mediator of estrogen action in human skin and the hair follicle. Further studies with androgen-dependent skin are required to determine whether estrogen receptor beta has a regulatory role on androgen receptor expression in the hair follicle in parallel with its role in other androgen-dependent tissues.
: ERA induces PGE2, but this study says ERB is the main receptor in hair follicles. What ever it is, it can be implied that both receptors are important in their own ways(their own downstream target genes) for hair growth in the balding scalp, as can be justified in:
estradiol binds equally well to both receptors[15]
Rage F1, Lee BJ, Ma YJ, Ojeda SR.
Author information
Abstract
Prostaglandin E2 (PGE2) mediates the stimulatory effect of norepinephrine (NE) on the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling reproductive function. In rodents, this facilitatory effect requires previous exposure to estradiol, suggesting that the steroid affects downstream components in the cascade that leads to PGE2-induced LHRH release. Because astroglia are the predominant cell type contacting LHRH-secreting nerve terminals, we investigated the involvement of hypothalamic astrocytes in the estradiol facilitation of PGE2-induced LHRH release. A subpopulation of LHRH neurons was found to express the mRNA encoding the PGE2 receptor subtype EP1-R, which is coupled to calcium mobilization. The LHRH-producing cell line GT1-1 also contains EP1-R mRNA and, to a lesser extent, the three alternatively spliced forms of EP3-R mRNA (alpha, beta, and gamma) that encode receptors linked to inhibition and stimulation of cAMP formation. Hypothalamic astrocytes treated with estradiol produced a conditioned medium that when applied to GT1-1 cells resulted in a selective upregulation of EP1-R and EP3gamma-R mRNAs. The conditioned medium also enhanced the LHRH response to EP1-R and EP3-R agonists and the cAMP response to EP3-R activation. Thus, one mechanism by which estradiol facilitates the effect of neurotransmitters acting via PGE2 to stimulate LHRH release is by enhancing the glial production of substances that upregulate PGE2 receptors on LHRH neurons. The existence of such a mechanism underscores the emerging importance of glial-neuronal communication in the control of brain neurosecretory activity.
: Estradiol, through binding to Estrogen receptor Alpha(not Estrogen receptor beta- the target of Estriol)- is the body's natural PGE2 inducer
Binding and functional selectivity[edit]
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.[13][14]
Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
- estradiol binds equally well to both receptors[15]
- estrone, and raloxifene bind preferentially to the alpha receptor[15]
- estriol, and genistein to the beta receptor[15]
Estrogen receptor Alpha is the gene that induces PGE2 production. This is not to say that Estrogen receptor Beta is not important, because:
The distribution of estrogen receptor beta is distinct to that of estrogen receptor alpha and the androgen receptor in human skin and the pilosebaceous unit.
Thornton MJ1, Taylor AH, Mulligan K, Al-Azzawi F, Lyon CC, O'Driscoll J, Messenger AG.
Author information
Abstract
Both estrogens and androgens play important parts in skin and hair physiology, although studies of estrogen action in human skin have been rather limited. Recently, a second estrogen receptor (beta) has been identified in many nonclassical target tissues, including androgen-dependent tissues. Therefore, we have revisited the role of estrogens in human skin and hair by comparing the pattern of expression by immunohistochemistry for both estrogen receptors (alpha and beta) and the androgen receptor. Immunolocalization of androgen receptors was only seen in hair follicle dermal papilla cells and the basal cells of the sebaceous gland. Little specific staining of estrogen receptor alpha was seen anywhere except the sebaceous gland. In contrast estrogen receptor beta was highly expressed in epidermis, blood vessels, and dermal fibroblasts, whereas in the hair follicle it was localized to nuclei of the outer root sheath, epithelial matrix, and dermal papilla cells. Serial sections also showed strong nuclear expression of estrogen receptor beta in the cells of the bulge, whereas neither estrogen receptor alpha or androgen receptor was expressed. In the sebaceous gland, estrogen receptor beta was expressed in both basal and partially differentiated sebocytes in a similar pattern to estrogen receptor alpha. There was no obvious difference in the expression of either estrogen receptor in male or female nonbalding scalp skin. The results of this immunohistochemical study propose that estrogen receptor beta and not estrogen receptor alpha is the main mediator of estrogen action in human skin and the hair follicle. Further studies with androgen-dependent skin are required to determine whether estrogen receptor beta has a regulatory role on androgen receptor expression in the hair follicle in parallel with its role in other androgen-dependent tissues.
: ERA induces PGE2, but this study says ERB is the main receptor in hair follicles. What ever it is, it can be implied that both receptors are important in their own ways(their own downstream target genes) for hair growth in the balding scalp, as can be justified in:
estradiol binds equally well to both receptors[15]
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20p11 lies inbetween Pax1 and FOXA2, so it affects PAX1 too, as can be seen in:
In this study, we confirmed that the susceptibility locus 20p11 for Androgenetic Alopecia in the Chinese Han population, which suggested the existence of common genetic factors shared for Androgenetic Alopecia in diverse ethnic populations. Because a gene contributing to the development of Androgenetic Alopecia would be expected to be expressed in the human scalp, Hillmer AM et al quantified the gene expression of the 20p11 locus and the expression of the closest paired box 1 (PAX1) gene [13]. The results showed that PAX1 was expressed at very high levels in the scalp skin.
PAX1 affects Hedgehog signalling, which in turn affects Noggin expression that in turn- affects BMP4 expression that keeps hair in telogen:
"When BMP4 is expressed ectopically, within transgenic mice the hair follicle outer root sheath (ORS) the proliferation of the cell matrix is inhibited. BMP4 also activates hair keratin gene expression noting that BMP4 is important in the differentiation of the hair shaft. Noggin, a known inhibitor of BMP4, is found within the matrix cells of the hair bulb. Other important factors to consider in the development of hair is the expression of Shh (sonic hedgehog), BMP7, BMP2, WNT, and β-catenin as these are required in early stage morphogenesis.[35]"
= Noggin is the jump-start activator of hair growth, while BMP4 keeps hair follicles in dormancy
20p11 Androgenetic Alopecia variant => PAX1 downregulation +FOXA2 downregulation => Cholesterol biosynthesis downregulation(not total deletion- just lesser) => Sonic Hedgehog downregulation + CYP27B1 downregulation(in Caucasians) => 3β-HSD1 downregulation + Aromatase downregulation / 5 Alpha redutase upregulation => Calcitriol downregulation(in Caucasians) / Progesterone downregulation + Estradiol downregulation / Testosterone + DHT upregulation(from whatever cholesterol biosynthesis that is left in the balding scalp tissue, which makes sense because testosterone have to come from cholesterol- so there must be some cholesterol biosynthesis in the balding scalp. Whatever it is, the balding scalp is preferentially utilising the already depleted intracellular cholesterol supply to make androgens at the expense of progesterone and estradiol) => Noggin downregulation + Insulin/IGF-1 upregulation => Adipocyte profileration downregulation +Sebocyte proliferation upregulation => PTGDS upregulation + PTGES downregulation => PGD2 upregulation + PGE2 downregulation => CRTh2 upregulation + EP2/EP4 downregulation => Hair loss
All steroids, including Vitamin D- have to be formed from cholesterol.
In this study, we confirmed that the susceptibility locus 20p11 for Androgenetic Alopecia in the Chinese Han population, which suggested the existence of common genetic factors shared for Androgenetic Alopecia in diverse ethnic populations. Because a gene contributing to the development of Androgenetic Alopecia would be expected to be expressed in the human scalp, Hillmer AM et al quantified the gene expression of the 20p11 locus and the expression of the closest paired box 1 (PAX1) gene [13]. The results showed that PAX1 was expressed at very high levels in the scalp skin.
PAX1 affects Hedgehog signalling, which in turn affects Noggin expression that in turn- affects BMP4 expression that keeps hair in telogen:
"When BMP4 is expressed ectopically, within transgenic mice the hair follicle outer root sheath (ORS) the proliferation of the cell matrix is inhibited. BMP4 also activates hair keratin gene expression noting that BMP4 is important in the differentiation of the hair shaft. Noggin, a known inhibitor of BMP4, is found within the matrix cells of the hair bulb. Other important factors to consider in the development of hair is the expression of Shh (sonic hedgehog), BMP7, BMP2, WNT, and β-catenin as these are required in early stage morphogenesis.[35]"
= Noggin is the jump-start activator of hair growth, while BMP4 keeps hair follicles in dormancy
20p11 Androgenetic Alopecia variant => PAX1 downregulation +FOXA2 downregulation => Cholesterol biosynthesis downregulation(not total deletion- just lesser) => Sonic Hedgehog downregulation + CYP27B1 downregulation(in Caucasians) => 3β-HSD1 downregulation + Aromatase downregulation / 5 Alpha redutase upregulation => Calcitriol downregulation(in Caucasians) / Progesterone downregulation + Estradiol downregulation / Testosterone + DHT upregulation(from whatever cholesterol biosynthesis that is left in the balding scalp tissue, which makes sense because testosterone have to come from cholesterol- so there must be some cholesterol biosynthesis in the balding scalp. Whatever it is, the balding scalp is preferentially utilising the already depleted intracellular cholesterol supply to make androgens at the expense of progesterone and estradiol) => Noggin downregulation + Insulin/IGF-1 upregulation => Adipocyte profileration downregulation +Sebocyte proliferation upregulation => PTGDS upregulation + PTGES downregulation => PGD2 upregulation + PGE2 downregulation => CRTh2 upregulation + EP2/EP4 downregulation => Hair loss
All steroids, including Vitamin D- have to be formed from cholesterol.
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Switzer
Established Member
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Interesting posts @sktboiboi
Pgd2 can also increase the conversion of androstenedione to testosterone through increased ROS formation in human keratinocytes. So there may be a positive feedback loop where higher testosterone levels leads to increased pgd2 synthesis and vice versa.
https://www.ncbi.nlm.nih.gov/pubmed/28941500
Quote from the full study:
"Here we show that PGD2-treated keratinocytes showed enhanced capacity to convert androstenedione, a weak androgen found to be elevated in Androgenetic Alopecia patients, to testosterone (Schmidt, 1994). Therefore, high PGD2 levels found in the bald scalp of Androgenetic Alopecia patients may indirectly lead to increased testosterone (which can be converted to dihydrotestosterone by 5a-reductases), a function that will further drive hair loss. Correlation between testosterone levels and the expression of the PGD2 synthase, LPGDS, has been shown in rats (Zhu et al., 2004). If such action has been preserved in human skin, a positive feedback loop may take place whereby increased testosterone levels drive LPGDS expression and PGD2 synthesis, which in turn further enhance testosterone synthesis from keratinocytes. Although we didn’t define the exact molecular mechanism by which PGD2 induced testosterone synthesis enhancement in keratinocytes, this effect was completely abolished in the presence of NAC, suggesting a ROS-driven function."
Pgd2 can also increase the conversion of androstenedione to testosterone through increased ROS formation in human keratinocytes. So there may be a positive feedback loop where higher testosterone levels leads to increased pgd2 synthesis and vice versa.
https://www.ncbi.nlm.nih.gov/pubmed/28941500
Quote from the full study:
"Here we show that PGD2-treated keratinocytes showed enhanced capacity to convert androstenedione, a weak androgen found to be elevated in Androgenetic Alopecia patients, to testosterone (Schmidt, 1994). Therefore, high PGD2 levels found in the bald scalp of Androgenetic Alopecia patients may indirectly lead to increased testosterone (which can be converted to dihydrotestosterone by 5a-reductases), a function that will further drive hair loss. Correlation between testosterone levels and the expression of the PGD2 synthase, LPGDS, has been shown in rats (Zhu et al., 2004). If such action has been preserved in human skin, a positive feedback loop may take place whereby increased testosterone levels drive LPGDS expression and PGD2 synthesis, which in turn further enhance testosterone synthesis from keratinocytes. Although we didn’t define the exact molecular mechanism by which PGD2 induced testosterone synthesis enhancement in keratinocytes, this effect was completely abolished in the presence of NAC, suggesting a ROS-driven function."
https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.15577
Study of gene expression alteration in male androgenetic alopecia: evidence of predominant molecular signalling pathways.
Michel L1,2, Reygagne P3, Benech P4,5, Jean-Louis F1,2, Scalvino S6, Ly Ka So S1, Hamidou Z3, Bianovici S3, Pouch J7, Ducos B7,8, Bonnet M1, Bensussan A1,2, Patatian A5, Lati E5,6, Wdzieczak-Bakala J9, Choulot JC10, Loing E11, Hocquaux M11.
Author information
Abstract
BACKGROUND:
Male androgenetic alopecia (Androgenetic Alopecia) is the most common form of hair loss in men. It is characterized by a distinct pattern of progressive hair loss starting from the frontal area and the vertex of the scalp. Although several genetic risk loci have been identified, relevant genes for Androgenetic Alopecia remain to be defined.
OBJECTIVES:
To identify biomarkers associated with Androgenetic Alopecia.
METHODS:
Molecular biomarkers associated with premature Androgenetic Alopecia were identified through gene expression analysis using cDNA generated from scalp vertex biopsies of hairless or bald men with premature Androgenetic Alopecia, and healthy volunteers.
RESULTS:
This monocentric study reveals that genes encoding mast cell granule enzymes, inflammatory mediators and immunoglobulin-associated immune mediators were significantly overexpressed in Androgenetic Alopecia. In contrast, underexpressed genes appear to be associated with the Wnt/β-catenin and bone morphogenic protein/transforming growth factor-β signalling pathways. Although involvement of these pathways in hair follicle regeneration is well described, functional interpretation of the transcriptomic data highlights different events that account for their inhibition. In particular, one of these events depends on the dysregulated expression of proopiomelanocortin, as confirmed by polymerase chain reaction and immunohistochemistry. In addition, lower expression of CYP27B1 in patients with Androgenetic Alopecia supports the notion that changes in vitamin D metabolism contributes to hair loss.
CONCLUSIONS:
This study provides compelling evidence for distinct molecular events contributing to alopecia that may pave the way for new therapeutic approaches.
= Calcitriol is downregulated in Caucasian balding scalps
"Vitamin D3‐related genes
CYP27B1 Androgenetic Alopecia scalps = 107 control scalps = 176"
CYP27B1 => https://en.wikipedia.org/wiki/25-Hydroxyvitamin_D3_1-alpha-hydroxylase
25-Hydroxyvitamin D3 1-alpha-hydroxylase (VD3 1A hydroxylase) also known as cytochrome p450 27B1(CYP27B1) or simply 1-alpha-hydroxylase is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene.[5][6][7]
VD3 1A hydroxylase is located in the proximal tubule of the kidney and a variety of other tissues, including skin (keratinocytes), immune cells,[8] and bone (osteoblasts).[9] The enzyme catalyzes the hydroxylation of Calcifediol to calcitriol (the bioactive form of Vitamin D):[10]
again, Calcitriol, just like other steroids(androgens, estrogens, progestogens)- ultimately stems from cholesterol. Less cholesterol available = less calcitriol(and estrogens and progestogens) at the benefit of more testosterone and hence, DHT.
Study of gene expression alteration in male androgenetic alopecia: evidence of predominant molecular signalling pathways.
Michel L1,2, Reygagne P3, Benech P4,5, Jean-Louis F1,2, Scalvino S6, Ly Ka So S1, Hamidou Z3, Bianovici S3, Pouch J7, Ducos B7,8, Bonnet M1, Bensussan A1,2, Patatian A5, Lati E5,6, Wdzieczak-Bakala J9, Choulot JC10, Loing E11, Hocquaux M11.
Author information
Abstract
BACKGROUND:
Male androgenetic alopecia (Androgenetic Alopecia) is the most common form of hair loss in men. It is characterized by a distinct pattern of progressive hair loss starting from the frontal area and the vertex of the scalp. Although several genetic risk loci have been identified, relevant genes for Androgenetic Alopecia remain to be defined.
OBJECTIVES:
To identify biomarkers associated with Androgenetic Alopecia.
METHODS:
Molecular biomarkers associated with premature Androgenetic Alopecia were identified through gene expression analysis using cDNA generated from scalp vertex biopsies of hairless or bald men with premature Androgenetic Alopecia, and healthy volunteers.
RESULTS:
This monocentric study reveals that genes encoding mast cell granule enzymes, inflammatory mediators and immunoglobulin-associated immune mediators were significantly overexpressed in Androgenetic Alopecia. In contrast, underexpressed genes appear to be associated with the Wnt/β-catenin and bone morphogenic protein/transforming growth factor-β signalling pathways. Although involvement of these pathways in hair follicle regeneration is well described, functional interpretation of the transcriptomic data highlights different events that account for their inhibition. In particular, one of these events depends on the dysregulated expression of proopiomelanocortin, as confirmed by polymerase chain reaction and immunohistochemistry. In addition, lower expression of CYP27B1 in patients with Androgenetic Alopecia supports the notion that changes in vitamin D metabolism contributes to hair loss.
CONCLUSIONS:
This study provides compelling evidence for distinct molecular events contributing to alopecia that may pave the way for new therapeutic approaches.
= Calcitriol is downregulated in Caucasian balding scalps
"Vitamin D3‐related genes
CYP27B1 Androgenetic Alopecia scalps = 107 control scalps = 176"
CYP27B1 => https://en.wikipedia.org/wiki/25-Hydroxyvitamin_D3_1-alpha-hydroxylase
25-Hydroxyvitamin D3 1-alpha-hydroxylase (VD3 1A hydroxylase) also known as cytochrome p450 27B1(CYP27B1) or simply 1-alpha-hydroxylase is a cytochrome P450 enzyme that in humans is encoded by the CYP27B1 gene.[5][6][7]
VD3 1A hydroxylase is located in the proximal tubule of the kidney and a variety of other tissues, including skin (keratinocytes), immune cells,[8] and bone (osteoblasts).[9] The enzyme catalyzes the hydroxylation of Calcifediol to calcitriol (the bioactive form of Vitamin D):[10]
again, Calcitriol, just like other steroids(androgens, estrogens, progestogens)- ultimately stems from cholesterol. Less cholesterol available = less calcitriol(and estrogens and progestogens) at the benefit of more testosterone and hence, DHT.
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Very complex....
the answer to your question is simple:
Just the Hedgehog signalling pathway, for being the most downregulated pathway in alopecic tissues.
Hedgehog signaling stimulates the conversion of cholesterol to steroids
Abstract
Cholesterol modification of Hedgehog (Hh) ligands is fundamental for the activity of Hh signaling, and cholesterol biosynthesis is also required for intracellular Hh signaling transduction. Here, we investigated the roles and underlying mechanism of Hh signaling in metabolism of cholesterol. The main components of the Hh pathway are abundantly expressed in both human cytotrophoblasts and trophoblast-like cells. Activation of Hh signaling induces the conversion of cholesterol to progesterone (P4) and estradiol (E2) through up-regulating the expression of steroidogenic enzymes including P450 cholesterol side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), and aromatase. Moreover, inhibition of Hh signaling attenuates not only Hh-induced expression of steroidogenic enzymes but also the conversion of cholesterol to P4 and E2. Whereas Gli3 is required for Hh-induced P450scc expression, Gli2 mediates the induction of 3β-HSD1 and aromatase. Finally, in ovariectomized nude mice, systemic inhibition of Hh signaling by cyclopamine suppresses circulating P4 and E2 levels derived from a trophoblast-like choricarcinoma xenograft, and attenuates uterine response to P4 and E2. Together these results uncover a hitherto uncharacterized role of Hh signaling in metabolism of cholesterol.
Gli2 is the effector gene of the Hedgehog pathway- meaning it's the most terminal, major downstream gene that finalises the execution of Hedgehog signalling.
The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity
ABSTRACT
Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation. Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca2+ flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFκB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity upon TCR ligation. These data are important for understanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli-activating ligands such as TGFβ are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments.
This means once hedgehog signalling is activated via Gli2, T cell activation is impaired(inflammation inhibition- allowing cell to profilerate instead of being attacked by T cells).
In other words, u automatically stop inflammation once Hedgehog signalling is activated.
Progesterone and Estradiol would be the solution- they are the end-products of activated Hegdehog signalling, as per above.
Throw in Calcitriol too if you're Caucasian(as per above also)
Progesterone in alopecic tissues will resolve Insulin/IGF-1(PGD2 comes from Insulin/IGF-1 activating mast cells in sebocytes),5 Alpha redutase and inflammation. Progesterone shifts cytokine profile to https://en.wikipedia.org/wiki/Regulatory_T_cell , is a tumor suppressor and is to keep hedgehog signalling in check. This is the reason why Progesterone up to 2% can be bought OTC in nutritional form, but not Estradiol. They reduce the size of prostates and prevent Breast tenderness.
A simple way of understanding the function of Treg cells is pregnancy. Think of the growing hair follicle as a 'fetus'.
The growting fetus in a mother's body is a 'foreign' object by nature. Treg cells prevents the mother's T cells from attacking the fetus
Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice.
Abstract
Mechanisms maintaining the growth of a "semi-foreign" fetus within the maternal uterus via immune tolerance remain unclear. CD4(+)CD25(+) regulatory T (Treg) cells have been implicated in the maintenance of maternal-fetal immune tolerance. Additionally, 17β-estradiol (E2) is able to initiate immune suppression through CD4(+)CD25(+) Treg cells during early pregnancy. Little is known, however, regarding the relationship between progesterone (P4) and immune tolerance during midterm pregnancy, an important period, characterized by higher levels of P4 but lower levels of E2 in the serum. Here, we examined the effects of P4 on the expansion and function of systemic and local uterine CD4(+)CD25(+) Treg cells during midterm pregnancy in mice. Using in vivo and in vitro models, we provide the first evidence that P4 not only increases the proportion of CD4(+)CD25(+) Treg cells and IL-10 expression but also enhances their suppressive function. Moreover, at physiological doses relevant to midterm pregnancy, P4, but not E2, converts CD4(+)CD25(-) T cells into CD4(+)CD25(+) Treg cells. This conversion was inhibited in vitro by the nuclear P4 receptors antagonist RU 486 and in vivo in P4-treated ovariectomized and pseudopregnant mice models, suggesting that P4 expands Treg populations via nuclear P4 receptors. Furthermore, RU 486 significantly reduced the quantity and function of Treg cells in the fetal-maternal interface before the onset of induced abortion. Interestingly, with decreasing Foxp3, proinflammatory factors increased. Together, the present results demonstrate that P4 is an important regulator of systemic and local CD4(+)CD25(+) Treg cells, which are involved in maintaining maternal-fetal immune tolerance during midterm pregnancy.
Estradiol itself in alopecic tissue provides PGE2(from PGE2's receptors EP2/EP4- comes WNT signalling), SHBG, is inflammatory in nature that it shifts ceullar cytokine balance towards Th17 away from Th2(which is dominant in PGD2). Hence if u use only Estradiol, u will still get inflammation. Estradiol is an oncogene itself- it cannot be bought OTC and goes by prescription only. Progesterone is to counter the oncogenic effects of Estradiol, Estrone and Androgens- allowing controlled cellular growth.
This is the reason why normal hair-bearing tissues secretes Progesterone(inhibitor of T cell Receptor signalling aka inflammation) and Estradiol(activator of cellular proliferation) together- they are the end-products of Hegdehog signalling and in the context of hair growth- the dual initiators and providers of maintanence.
In simple terms, Progesterone allows the hair follicle to grow without being attacked by providing a 'protective shield'(aka https://www.genecards.org/cgi-bin/carddisp.pl?gene=CD200 ) around the hair follicle, while Estradiol allows the growth of the hair follicle itself by inducing numerous growth factors.
If you inhibit production of Progesterone and Estradiol, Testosterone(and hence- DHT) is greatly boosted- because these 3 types of sex steroids are the major hormones in the Steroidogenic pathway.
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It is complex- hence i made it easy for people who are too lazy to dive into all these.
The simple solution is Progesterone and Estradiol(and some Calcitriol if you're Caucasian).
So become a woman
Progesterone and estradiol are both found in men.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854098/
The role of estradiol in male reproductive function
Michael Schulster,1 Aaron M Bernie,1 and Ranjith Ramasamy2
Author information ► Article notes ► Copyright and License information ► Disclaimer
See commentary "Estradiol exerts alterations in sexual function and fertility in human males" in volume 18 on page 441.
This article has been cited by other articles in PMC.
Go to:
Abstract
Traditionally, testosterone and estrogen have been considered to be male and female sex hormones, respectively. However, estradiol, the predominant form of estrogen, also plays a critical role in male sexual function. Estradiol in men is essential for modulating libido, erectile function, and spermatogenesis. Estrogen receptors, as well as aromatase, the enzyme that converts testosterone to estrogen, are abundant in brain, penis, and testis, organs important for sexual function. In the brain, estradiol synthesis is increased in areas related to sexual arousal. In addition, in the penis, estrogen receptors are found throughout the corpus cavernosum with high concentration around neurovascular bundles. Low testosterone and elevated estrogen increase the incidence of erectile dysfunction independently of one another. In the testes, spermatogenesis is modulated at every level by estrogen, starting with the hypothalamus-pituitary-gonadal axis, followed by the Leydig, Sertoli, and germ cells, and finishing with the ductal epithelium, epididymis, and mature sperm. Regulation of testicular cells by estradiol shows both an inhibitory and a stimulatory influence, indicating an intricate symphony of dose-dependent and temporally sensitive modulation. Our goal in this review is to elucidate the overall contribution of estradiol to male sexual function by looking at the hormone's effects on erectile function, spermatogenesis, and libido.
Keywords:
https://www.ncbi.nlm.nih.gov/pubmed/15669543
Progesterone: the forgotten hormone in men?
Oettel M, Mukhopadhyay AK.
Abstract
'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in birds and mammals that they are detectable. In the different species, they mediate manifold effects regarding the differentiation of target organ functions, mainly in the reproductive system. Surprisingly, we know little about the physiology, endocrinology, and pharmacology of progesterone and progestins in male gender or men respectively, despite the fact that, as to progesterone secretion and serum progesterone levels, there are no great quantitative differences between men and women (at least outside the luteal phase). In a prospective cohort study of 1026 men with and without cardiovascular disease, we were not able to demonstrate any age-dependent change in serum progesterone concentrations. Progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. Other progesterone effects in men include those on the central nervous system (CNS) (mainly mediated by 5alpha-reduced progesterone metabolites as so-called neurosteroids), including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate weight gain and appetite in men as well as in women. The detection of progesterone receptor isoforms would have a highly diagnostic value in prostate pathology (benign prostatic hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets is connected with a great pharmacodynamic variability. The reason for this is that, in men, some important effects of progesterone are mediated non-genomically through different molecular biological modes of action. Therefore, the precise therapeutic manipulation of progesterone actions in the male requires completely new endocrine-pharmacological approaches.
Not to mention that Progesterone is both anti-androgenic and anti-estrogenic.
it can be inferred that your mindset is narrow and closed in that Estrogens and Progesterone makes a men feminine.
Please comment in this thread only when u have something intelligent to say
Thanks.
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I am a caucasian, should I take vitamin d3? and why do Caucasians have a different solution?
Your question is a good question.
the study above were done on French men. there are photos in it u can go have a look at the link. Also, it makes sense since Caucasian skin pigmentation has got alot to do with Vit D metabolism. Naturally, Vit D would have something to do with it, as affirmed by the study that indicated the enzyme(CYP27B1) needed to produce the active form of Vit D, Calcitriol- is slightly lesser in alopecic scalps of French men, as can be seen in:
"Although the upstream mechanisms by which modulation of these genes is achieved in Androgenetic Alopecia remain to be determined, the increased SFRP2 expression might result in part from altered metabolism of vitamin D3. The underexpression of CYP27B1, leading to reduced production of calcitriol, known to inhibit DKK1 and SFRP2 expression, might contribute to reduce b-catenin activity.'"
Im not saying that reduced calcitriol levels occur in alopecic scalps of Caucasian men only- they might/might not also occur in men of other ancestry- specially those of fair-skin phenotypes.
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Simple enough to answer - get a blood test. My recent results have me wondering about my progesterone levels and whether I should consider supplementing and the potential effects on hair quality.
My results:
(ref)
Progesterone 0.2 ng/mL (0.0-0.5)
Estradiol 45.4 pg/mL (7.6-42.6)
Vit D, 25-Hydroxy 70.7 ng/mL (30.0-100.0)
Testosterone 935 ng/dL (264-916)
tested values are first number (ref) is reference or considered normal range.
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Interesting accumulation of studies here, I am at work so I can't dive in-depth into the literature at the moment.
In what you have posted, it appears that cholesterol is an agonist of the Hedgehog pathway, have you read any studies where a topical cholesterol agent was used and observed any effect? If the HMGCoA reductase enzyme is downregulated, can't we bypass this with direct administration of cholesterol for use by the cells?
Then they could self-regulate like a normal cell according to your hypothesis correct?
**EDIT**
Here is a study with hair growth defect that was corrected by simvastin, interesting study:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929004/
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your question is a good question.
the answer is no, because the cholesterol is not the 1 that grows hair. It's cholesterol's end-products that are growing hair- which is progesterone and estradiol(and calcitriol in some people)- for these are the terminal products of activated hedgehog signalling- which is immediately downstream of Gli2- the terminal effector of Hedgheog signalling.
i have tried topical cholesterol- it makes scalp itch and pain worst. IMO, it's very likely the cholesterol just gets metabolized into more androgens in the scalp.
It's the kind of cholesterol-derived product that we are looking at- not cholesterol itself
Sonic hedgehog-dependent activation of Gli2 is essential for embryonic hair follicle development.
Mill P1, Mo R, Fu H, Grachtchouk M, Kim PC, Dlugosz AA, Hui CC.
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Abstract
Sonic hedgehog (Shh) signaling plays a critical role in hair follicle development and skin cancer, but how it controls these processes remains unclear. Of the three Gli transcription factors involved in transducing Shh signals in vertebrates, we demonstrate here that Gli2 is the key mediator of Shh responses in skin. Similar to Shh(-/-) mice, Gli2(-/-) mutants exhibit an arrest in hair follicle development with reduced cell proliferation and Shh-responsive gene expression, but grossly normal epidermal differentiation. By transgenic rescue experiments, we show that epidermal Gli2 function alone is sufficient to restore hair follicle development in Gli2(-/-) skin. Furthermore, only a constitutively active form of Gli2, but not wild-type Gli2, can activate Shh-responsive gene expression and promote cell proliferation in Shh(-/-) skin. These observations indicate that Shh-dependent Gli2 activator function in the epidermis is essential for hair follicle development. Our data also reveal that Gli2 mediates the mitogenic effects of Shh by transcriptional activation of cyclin D1 and cyclin D2 in the developing hair follicles. Together, our results suggest that Shh-dependent Gli2 activation plays a critical role in epithelial homeostasis by promoting proliferation through the transcriptional control of cell cycle regulators.
GLI2 Is Expressed in Normal Human Epidermis and BCC and Induces GLI1 Expression by Binding to its Promoter
Author links open overlay panelMohammed S.Ikram*Graham W.Neill*GerhardRegl†ThomasEichberger†Anna-MariaFrischauf†FritzAberger†AnthonyQuinn*MikePhilpott*
https://doi.org/10.1111/j.0022-202X.2004.22612.xGet rights and content
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Sonic hedgehog (Shh) binds to its receptor patched (PTCH), leading to the activation and repression of target genes via the GLI family of zinc-finger transcription factors. Deregulation of the Shh pathway is associated with basal cell carcinoma (BCC) due to upregulation of GLI1 and GLI2. We recently demonstrated a positive feedback loop between GLI1 and GLI2, which revealed that GLI1 may be a direct target of GLI2. Using band shift and luciferase reporter assays, we now show that GLI2 binds the GLI-binding consensus sequence in the GLI1 promoter. These data suggest that GLI2 directly activates GLI1 and that retrovirally expressed GLI2 induces expression of endogenous GLI1 in human primary keratinocytes. Finally, using in situ hybridization, we show that GLI2 is expressed in the interfollicular epidermis and the outer root sheath of hair follicles in normal skin as well as in BCC tumor islands. These results suggest an important role for GLI2 in regulating epidermal proliferation and skin tumorigenesis.
I highly recommend you to peruse just this study- https://www.ncbi.nlm.nih.gov/pubmed/25582983.
Remember https://www.genecards.org/cgi-bin/carddisp.pl?gene=GLI2 is the 1 that grows hair
It is strongly implied Progesterone is defnitely missing in alopecic scalp. This list of pathways downregulated in alopecic scalp from the primero study in this thread implies it:
Hedgehog signaling pathway
Progesterone-mediated oocyte maturation
Oocyte meiosis SNARE interactions in vesicular transport
Phospholipase D signaling pathway
Maturity onset diabetes of the young
Description of the Progesterone-mediated oocyte maturation pathway:
http://www.genome.jp/kegg-bin/show_pathway?map=xla04914&show_description=show
"Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway [where ERK is an extracellular signal-related protein kinase, MEK is a MAPK/ERK kinase and Mos is a p42(MAPK) activator] and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP."
Coupled by the fact that Progesterone is coincidentally, indeed the product of activated Hedgheog signalling as discovered by another study(and it's a DHT-inhibitor as well) - all these strongly backs up the implication of progesterone as being the key hormone missing in alopecic scalp. In fact, u just have to read Progesterone's wiki entry to be able to see why it helps grow hair.
IGF-1/Insulin is not the missing gene in alopecic scalp- they are in fact, the causative pathways of Androgenetic Alopecia(go dig for numerous studies all indicating that IGF-1 is overexpressed in vertex scalp of balding men)
The 2nd study in this thread already indicated that the Insulin receptor is overexpressed in alopecic tissue. This means our balding scalps are highly sensitive to Insulin/Igf-1(igf-1 can bind to the Insulin receptor )- the fact that sebocytes are enlarged there highlights this phenomenon.
THis recent sutdy from feb 2018 again reinforces this observation:
Article Prostaglandin D2-Mediated DP2 and AKT Signal Regulate the Activation of Androgen Receptors in Human Dermal Papilla Cells
Abstract: Prostaglandin D2 (PGD2) and prostaglandin D2 receptor 2 (DP2)(aka CRTh2) is known to be an important factor in androgenetic alopecia (Androgenetic Alopecia). However, the effect of PGD2 in human dermal papilla cells (hDPCs) is not fully understood. The function of PGD2-induced expression of the androgen receptor (AR), DP2, and AKT (protein kinase B) signal were examined by using real time-PCR (qRT-PCR), western blot analysis, immunocytochemistry (ICC), and siRNA transfection system. PGD2 stimulated AR expression and AKT signaling through DP2. PGD2 stimulated AR related factors (transforming growth factor beta 1 (TGFβ1), Creb, lymphoid enhancer binding factor 1 (LEF1), and insulin-like growth factor 1, (IGF-1)) and AKT signaling (GSK3β and Creb) on the AR expression in hDPCs. However, these factors were down-regulated by DP2 antagonist (TM30089) and AKT inhibitor (LY294002)(and Setipiprant) as well as DP2 knockdown in hDPCs decreased AR expression and AKT signaling. Finally, we confirmed that PGD2 stimulates the expression of AR related target genes, and that AKT and its downstream substrates are involved in AR expression on hDPCs. Taken together, our data suggest that PGD2 promotes AR and AKT signal via DP2 in hDPCs, thus, PGD2 and DP2 signal plays a critical role in AR expression. These findings support the additional explanation for the development of Androgenetic Alopecia involving PGD2-DP2 in hDPCs.
IGF-1, which are related to the activity of AR and AKT signalling, was blocked by TM30089(same drug class as Setipiprant) (Figure 4D–G). In addition, protein levels of AR and phosphorylation of AKT/GSK3β was also reduced by the TM30089. (Figure 4H). PGD2-inhibited cell viability was significantly recovered by 30% upon treatment with TM30089 compared with the PGD2-treated group (Figure 4I). These results indicated that AR expression and hDPC viability were regulated by PGD2 through DP2. Figure 3. PGD2 regulates the AKT signal. The AKT phosphorylation was determined using western blot analysis. hDPCs were treated with PGD2 (200 nM) for the indicated times and harvested (A). hDPCs were pretreated with LY294002 for 1 h, and then PGD2 (200 nM) treatment for 5 h. The protein levels of AR, and AKT/GSK3β/Creb phosphorylation was measured using western blot analysis (B). The mRNA expression of AR, LEF1, Creb, and IGF-1 was measured using qRT-PCR (C). β-actin served as a loading control for protein normalization. GAPDH was used as an internal control for mRNA normalization. The results are expressed as the mean ± SD of three independent experiments. * p < 0.05, compared with the control (0 nM PGD2), # p < 0.05 compared with PGD2. 2.4. PGD2-Induced AR Expression and AKT Signalling Are Regulated by a DP2 Antagonist We confirmed that PGD2-DP2 affects AR expression via AKT and its involved factors (including LEF1, Creb, and IGF-1). We hypothesized that suppression of DP2 would inactivate AR expression by inhibiting AR-related factors and AKT signalling. Thus, we examined whether inhibition of DP2 could regulate the activity of AR and its related factors. TM30089 has been known as a highly potent antagonist on mouse CRTH2/DP2 [10]. PGD2-induced AR, DP2, and COX2 mRNA expression was reduced by TM30089 (Figure 4A–C). We also found that the mRNA expression of TGFβ1, Creb, LEF1, and IGF-1, which are related to the activity of AR and AKT signalling, was blocked by TM30089 (Figure 4D–G). In addition, protein levels of AR and phosphorylation of AKT/GSK3β was also reduced by the TM30089. (Figure 4H). PGD2-inhibited cell viability was significantly recovered by 30% upon treatment with TM30089 compared with the PGD2-treated group (Figure 4I). These results indicated that AR expression and hDPC viability were regulated by PGD2 through DP2.
= PGD2 ups IGF-1 via CRTh2
In fact, the man whose team discovered that PGD2 is upregulated inbalding scalps already clearly listed IGF-1 as being overexpressed- in balding scalp:
https://patents.google.com/patent/US20110021599A1/en Page 91, the 21st most upregulated gene in alopecic scalp.
IGF-1/insulin growths facial/body hair- but not scalp hair in balding men. It puts bullshit snake oil products like this http://www.jhgc.com.sg/theory/igf-1/index.html to shame.
IGF-1/Insulin grows scalp hair in balding scalps? Your call- though i say they defnitely grow muscles and beards(and an oily face)
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