Here is an update to the androgenetic alopecia pathway and information on important topics for hair growth. I will include information about products and a possible cure.
1)))Androgen receptors are the main key. The factors that act on them, such as DHT and other androgens kick starts the alopecia pathway.
GSK3-beta is involved in androgen receptor nuclear binding. It is also involved with stem cell differentiation (causes it), inhibits stem cell proliferation and the canonical wnt/beta catenin pathway. It has been shown in prostate cells that LITHIUM CHLORIDE a gsk3-b inhibitor, inhibits the nuclear binding of the androgen receptor even if it is bound to DHT. So, this means no transcription or translation of the androgen receptor= cessation of androgenetic alopecia.
Creating a topical gsk3-b is key. Lithium chloride, lithium succinate (used in seborrheic dermatitis), and lithium orotate are options. However, be careful as not all gsk3-b inhibitors have to same action on the androgen receptor.
2))) Androgen receptors create a cascade of growth inhibitors like TGF-beta to cause cell death and IL-6 expression in the hair follicle.
IL-6, Stem Cell factor (in follicle), and CD34+ progenitor cells(follicle) cause the differentiation of CD34 cells into mast cells. This is my theory as to what is happening to the CD34+ cells and why there is a depletion of them. Mast Cells are being produced and the types being produced are large, filled with ILs, chymase (involed with atherosclerosis/fibrosis), and histamine. This is important to understand the itching, tingling, burning, and inflammation on the scalp. The yeast on the scalp is reacting to the change of fatty acids produced by sebaceous gland hyperplasia (I will explain this later). This causes the allergen reaction, IgE activation of these mast cells, and the eventual cascade of microinflammation involving lymphocytes(th2), basophiles, and eosinophils. This will a create a vicious PGD2 cycle, miniaturization, and fibrosis.
3))) Mast cells and lymphocyte created PGD2. This is due to the DHT/androgen receptor IL-6 production. These cells also produce various ILs. IL-6 is one of them that cause the microinflammation around the follicle which leads to eventual miniaturization and possible death. Hematopoietic PGD2 is produced by these cells. H-PGD2 causes a gene called NRF2 to activate. NRF2 causes sebaceous gland hyperplasia and hair follicle regression via hyperkeratosis (why I believe the hair follicle miniaturizes and can, eventually, die). TGF-beta via androgen receptor/DHT causes NRF2 activation.
NRF2 is extremely important. It is an anti-inflammatory activator and its product is LIPOCALIN PGD2 SYNTHASE (L-PGD2s). Whenever nrf2 is exposed to any type of pgd2, it will keep producing L-PGD2S, hence the vicious PGD2 cycle. What happens when Prostaglandin H2 from COX2 is converted to L-PGD2? It eventually produces 15D-PGJ2.
15D-PGJ2 is a PPAR GAMMA receptor agonist. What does PPAR GAMMA do? It is for ANTI TUMOR protection. Interestingly it can cause anti inflammation or inflammation. PPAR GAMMA still needs to be studied more, however from research I found out that 15D-PGJ2 inhibits the proliferation of CD200.
CD200 is one the the two type of progenitor cells that are lacking in balding hairs. It is involved with self protection, causing production of IL10 and IL12 to down regulate inflammation against the host (hair). follicle) and involved with melanocytes (low cd200 positively correlated with graying hair). My theory is that PPAR gamma has anti tumor effects and that the hair follicle is being viewed as a tumor, hence the depletion of CD200 in order to removed the tumor(hair). PPAR gamma is needed in order to prevent scarring alopecia as it maintains functional stem cell compartment. Like I said, PPAR gamma in studies have been shown to causes inflammation or the opposite probably due to which ligand /receptor is activated and needs to be studied more.
Stem cell factor is decreased in androgenetic alopecia, so a decrease in all progenitor cells and loss of CD34 (mast cells) and CD200 (15D PGJ/ppar gamma)
Inflammation is not all bad. Certain types of inflammatory processes are needed for hair growth, but they need to be done in a certain time and manner which is not being allowed in androgenentic alopecia. This topical should be discussed further.
Here is some information of products used for hair loss:
Lithium: This should be the number one used topical for all hair loss suffers. It inhibits GSK3 beta, so it should totally inhibit the androgen receptor; EVEN IF DHT IS ATTACHED! It increases B-catenin and the wnt canonical pathway by inhibiting gsk3 beta, so it can increase anagen in hairs. It also inhibits TGF-beta which causes hair loss.
Minoxidil: It is a PGH1 synthase activator. This means more prostaglandins production. It will cause an onset of inflammation due PGE2 causing enhanced function of IgE on mast cells and increase IL-6 in those cells. Also, don’t forget PGD2 and other products from cox2 that cause inflammation. Hence, the initial shed using minoxidil and it can cause thinning of existing hair (inflammation,pgd2 increase). However, due to its ability to create capillaries in dermal papilla and E2 increase, it causes regrowth of hairs and minoxidil dependent growth of hair by being a canonical wnt pathway weak agonist.
Azelaic Acid: It decreases p53 and p21 causing a decrease in apoptosis. It decreases nf kappab which is overexpressed in hair loss but is needed for anagen. It also is an anti inflammatory by apparently activating ppar gamma which explains why it is used for skin lightening (decrease melanocyes due to a decrease of CD200). PPAR gamma plus p53 causes apoptosis, hence Azelaic acid is anti-apoptotic. Also, combined with high levels of vitamin b6, it decreases DHT production.
Retinoic Acid (tretinoin, all trans retinoic acid): It can possibly cause skin cancer and this is good for hair generation. Remember that hair is being targeted as a tumor/cancer even though it is not, so we need something that can reverse/balance that anti tumor effect and RA is that something. RA inhibits canonical wnt pathway(bad for hair anagen) via tcf2 but upregulated noncanonical wnt pathway. This is good for stem cell generation. RA also inhibits NRF2 (Decrease L-PGD2s and L-PGD2). RA also activates the ERK2 pathway which is different than the ERK1 pathway. ERK2 is involved with cell angiogenesis and ERK1 is involved with apoptosis.
[h=1]Fenugreek contains Trigonelline and it inhibits NRF2 to downregulated lipocalin pgd2s and l pgd2 and does not effect wnt pathway.[/h] Luetolin inhibits NRF2 but also inhibits the canonical wnt pathway.
Hypoxia causes NRF2 inhibition: Neogenic and ciclopirox
Some information about signaling:
The JAK STAT pathway is key in regulating hair loss. There is a report that a JAK STAT inhibitor was used on a patient with alopecia totalis and all his hair grew back. We know that Androgenetic Alopecia and Alopecia Areata/Totalis are different, but are similar in their pathways.
IL-6 is the problem with Androgentic Alopecia that causes inflammation, hair thinning, fibrosis, and a pathway that leads to NRF2/PGD2. IL-6 is involved with the jak stat pathway, particularly with stat3. If we can inhibit STAT3, we can solve the IL-6 problem. This should shut down the IL-6 mast cell instigation of microinflammation around the hair follicle. There are natural and synthetic JAK STAT inhibitors available. I found one topical that should contain a stat3 inhibitor, but I will not dicuss the product so that we can focus on other important matter written here and I don’t want to have to defend myself from being called a shill.
The possible cure:
We first need to realize that if the hair follicle is not there (dead) nothing will grow in its place except for transplanted hair. Second, we need to affirm that fibrosis of the hair follicle is most likely present and is the reason why hair regrowth will be difficult. This is why there needs to be in place a new wounding method. My idea is a non roller, but stamp like process that has needles about the fourth of the width of current dermarollers that go 3-4mm deep. Small width micro wounds that go deep enough to break up the fibrotic plaque, heal, and protect existing hair follicles as much as possible. I do not recommend doing this by yourself. Having a trained physician do this would be ideal.
From this article: http://www.nature.com/ncb/journal/v13/n7/full/ncb2267.html
What I understood from it is that stem cell regeneration is possible. The process involves tcf3 and gsk-3 inhibition. We already have a way to do both. Retinoic Acid (tretinoin) creates tcf3 and lithium OR Estradiol is a gsk-3 inhibitor. These two used together in theory should regenerated stem cells and cause the regrowth of hair. I could be completely right or wrong on this, PLEASE DISCUSS!!!!
About the Big 3:
Minoxidil from what I described above causes inflammation, exacerbates andogenetic alopecia (Increase various PGs), but has its own unique pathway to grow hair; which is why hairs become minoxidil dependent. Finasteride/Dutasteride inhibits 5 alpha reductase and reduce DHT, but our bodies are adaptive. Androgen receptors will become more sensitive/increase with time and DHT can be produced by other pathways such as hydroxysteroid dehydrogenase enzymes. Other androgens can cause DHT like effects, for example in prostate cancer; and I don’t see why this can’t be true for hair as well. As for ketoconazole, it is good to get rid of the inflammation that scalp yeast causes that can cause the onset of androgenetic alopecia. However once that cascade starts, it will not stop it (PGD2 vicious cycle). Also, it is a NRF2 (PGD2) agonist. This is why I believe some people notice hair becoming straw like/thin.
I am not against the Big 3. The reason all three work together well is because the pros outweigh the cons. However, in time it will fail.
Please discuss and add to this. There are too many references for me to put up.
1)))Androgen receptors are the main key. The factors that act on them, such as DHT and other androgens kick starts the alopecia pathway.
GSK3-beta is involved in androgen receptor nuclear binding. It is also involved with stem cell differentiation (causes it), inhibits stem cell proliferation and the canonical wnt/beta catenin pathway. It has been shown in prostate cells that LITHIUM CHLORIDE a gsk3-b inhibitor, inhibits the nuclear binding of the androgen receptor even if it is bound to DHT. So, this means no transcription or translation of the androgen receptor= cessation of androgenetic alopecia.
Creating a topical gsk3-b is key. Lithium chloride, lithium succinate (used in seborrheic dermatitis), and lithium orotate are options. However, be careful as not all gsk3-b inhibitors have to same action on the androgen receptor.
2))) Androgen receptors create a cascade of growth inhibitors like TGF-beta to cause cell death and IL-6 expression in the hair follicle.
IL-6, Stem Cell factor (in follicle), and CD34+ progenitor cells(follicle) cause the differentiation of CD34 cells into mast cells. This is my theory as to what is happening to the CD34+ cells and why there is a depletion of them. Mast Cells are being produced and the types being produced are large, filled with ILs, chymase (involed with atherosclerosis/fibrosis), and histamine. This is important to understand the itching, tingling, burning, and inflammation on the scalp. The yeast on the scalp is reacting to the change of fatty acids produced by sebaceous gland hyperplasia (I will explain this later). This causes the allergen reaction, IgE activation of these mast cells, and the eventual cascade of microinflammation involving lymphocytes(th2), basophiles, and eosinophils. This will a create a vicious PGD2 cycle, miniaturization, and fibrosis.
3))) Mast cells and lymphocyte created PGD2. This is due to the DHT/androgen receptor IL-6 production. These cells also produce various ILs. IL-6 is one of them that cause the microinflammation around the follicle which leads to eventual miniaturization and possible death. Hematopoietic PGD2 is produced by these cells. H-PGD2 causes a gene called NRF2 to activate. NRF2 causes sebaceous gland hyperplasia and hair follicle regression via hyperkeratosis (why I believe the hair follicle miniaturizes and can, eventually, die). TGF-beta via androgen receptor/DHT causes NRF2 activation.
NRF2 is extremely important. It is an anti-inflammatory activator and its product is LIPOCALIN PGD2 SYNTHASE (L-PGD2s). Whenever nrf2 is exposed to any type of pgd2, it will keep producing L-PGD2S, hence the vicious PGD2 cycle. What happens when Prostaglandin H2 from COX2 is converted to L-PGD2? It eventually produces 15D-PGJ2.
15D-PGJ2 is a PPAR GAMMA receptor agonist. What does PPAR GAMMA do? It is for ANTI TUMOR protection. Interestingly it can cause anti inflammation or inflammation. PPAR GAMMA still needs to be studied more, however from research I found out that 15D-PGJ2 inhibits the proliferation of CD200.
CD200 is one the the two type of progenitor cells that are lacking in balding hairs. It is involved with self protection, causing production of IL10 and IL12 to down regulate inflammation against the host (hair). follicle) and involved with melanocytes (low cd200 positively correlated with graying hair). My theory is that PPAR gamma has anti tumor effects and that the hair follicle is being viewed as a tumor, hence the depletion of CD200 in order to removed the tumor(hair). PPAR gamma is needed in order to prevent scarring alopecia as it maintains functional stem cell compartment. Like I said, PPAR gamma in studies have been shown to causes inflammation or the opposite probably due to which ligand /receptor is activated and needs to be studied more.
Stem cell factor is decreased in androgenetic alopecia, so a decrease in all progenitor cells and loss of CD34 (mast cells) and CD200 (15D PGJ/ppar gamma)
Inflammation is not all bad. Certain types of inflammatory processes are needed for hair growth, but they need to be done in a certain time and manner which is not being allowed in androgenentic alopecia. This topical should be discussed further.
Here is some information of products used for hair loss:
Lithium: This should be the number one used topical for all hair loss suffers. It inhibits GSK3 beta, so it should totally inhibit the androgen receptor; EVEN IF DHT IS ATTACHED! It increases B-catenin and the wnt canonical pathway by inhibiting gsk3 beta, so it can increase anagen in hairs. It also inhibits TGF-beta which causes hair loss.
Minoxidil: It is a PGH1 synthase activator. This means more prostaglandins production. It will cause an onset of inflammation due PGE2 causing enhanced function of IgE on mast cells and increase IL-6 in those cells. Also, don’t forget PGD2 and other products from cox2 that cause inflammation. Hence, the initial shed using minoxidil and it can cause thinning of existing hair (inflammation,pgd2 increase). However, due to its ability to create capillaries in dermal papilla and E2 increase, it causes regrowth of hairs and minoxidil dependent growth of hair by being a canonical wnt pathway weak agonist.
Azelaic Acid: It decreases p53 and p21 causing a decrease in apoptosis. It decreases nf kappab which is overexpressed in hair loss but is needed for anagen. It also is an anti inflammatory by apparently activating ppar gamma which explains why it is used for skin lightening (decrease melanocyes due to a decrease of CD200). PPAR gamma plus p53 causes apoptosis, hence Azelaic acid is anti-apoptotic. Also, combined with high levels of vitamin b6, it decreases DHT production.
Retinoic Acid (tretinoin, all trans retinoic acid): It can possibly cause skin cancer and this is good for hair generation. Remember that hair is being targeted as a tumor/cancer even though it is not, so we need something that can reverse/balance that anti tumor effect and RA is that something. RA inhibits canonical wnt pathway(bad for hair anagen) via tcf2 but upregulated noncanonical wnt pathway. This is good for stem cell generation. RA also inhibits NRF2 (Decrease L-PGD2s and L-PGD2). RA also activates the ERK2 pathway which is different than the ERK1 pathway. ERK2 is involved with cell angiogenesis and ERK1 is involved with apoptosis.
[h=1]Fenugreek contains Trigonelline and it inhibits NRF2 to downregulated lipocalin pgd2s and l pgd2 and does not effect wnt pathway.[/h] Luetolin inhibits NRF2 but also inhibits the canonical wnt pathway.
Hypoxia causes NRF2 inhibition: Neogenic and ciclopirox
Some information about signaling:
The JAK STAT pathway is key in regulating hair loss. There is a report that a JAK STAT inhibitor was used on a patient with alopecia totalis and all his hair grew back. We know that Androgenetic Alopecia and Alopecia Areata/Totalis are different, but are similar in their pathways.
IL-6 is the problem with Androgentic Alopecia that causes inflammation, hair thinning, fibrosis, and a pathway that leads to NRF2/PGD2. IL-6 is involved with the jak stat pathway, particularly with stat3. If we can inhibit STAT3, we can solve the IL-6 problem. This should shut down the IL-6 mast cell instigation of microinflammation around the hair follicle. There are natural and synthetic JAK STAT inhibitors available. I found one topical that should contain a stat3 inhibitor, but I will not dicuss the product so that we can focus on other important matter written here and I don’t want to have to defend myself from being called a shill.
The possible cure:
We first need to realize that if the hair follicle is not there (dead) nothing will grow in its place except for transplanted hair. Second, we need to affirm that fibrosis of the hair follicle is most likely present and is the reason why hair regrowth will be difficult. This is why there needs to be in place a new wounding method. My idea is a non roller, but stamp like process that has needles about the fourth of the width of current dermarollers that go 3-4mm deep. Small width micro wounds that go deep enough to break up the fibrotic plaque, heal, and protect existing hair follicles as much as possible. I do not recommend doing this by yourself. Having a trained physician do this would be ideal.
From this article: http://www.nature.com/ncb/journal/v13/n7/full/ncb2267.html
What I understood from it is that stem cell regeneration is possible. The process involves tcf3 and gsk-3 inhibition. We already have a way to do both. Retinoic Acid (tretinoin) creates tcf3 and lithium OR Estradiol is a gsk-3 inhibitor. These two used together in theory should regenerated stem cells and cause the regrowth of hair. I could be completely right or wrong on this, PLEASE DISCUSS!!!!
About the Big 3:
Minoxidil from what I described above causes inflammation, exacerbates andogenetic alopecia (Increase various PGs), but has its own unique pathway to grow hair; which is why hairs become minoxidil dependent. Finasteride/Dutasteride inhibits 5 alpha reductase and reduce DHT, but our bodies are adaptive. Androgen receptors will become more sensitive/increase with time and DHT can be produced by other pathways such as hydroxysteroid dehydrogenase enzymes. Other androgens can cause DHT like effects, for example in prostate cancer; and I don’t see why this can’t be true for hair as well. As for ketoconazole, it is good to get rid of the inflammation that scalp yeast causes that can cause the onset of androgenetic alopecia. However once that cascade starts, it will not stop it (PGD2 vicious cycle). Also, it is a NRF2 (PGD2) agonist. This is why I believe some people notice hair becoming straw like/thin.
I am not against the Big 3. The reason all three work together well is because the pros outweigh the cons. However, in time it will fail.
Please discuss and add to this. There are too many references for me to put up.
