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Evidence That Cortisol Really Does Cause Hair Loss
- Thread starter ecstatichamster
- Start date
L
lollipop
Guest
This so makes intuitive sense in my husband’s case.
here are some threads about hairloss and cortisol (adrenal up regulation)
THREAD 1: https://raypeatforum.com/community/threads/the-cause-of-baldness.20374/page-5#post-284345
Heres some references supporting the adrenal up regulation piece:
1) Hormonal parameters in androgenetic hair loss in the male. - PubMed - NCBI
"Significant differences in serum levels of androstenedione, cortisol, 17 beta-estradiol and luteinizing hormone were noted between hair loss patients and control subjects. Suprarenal stimulation as well as hypophyseal feedback mechanisms therefore seem to be involved in male pattern alopecia."
2) Hormone studies in females with androgenic hairloss. - PubMed - NCBI
"The results of the study show no significant elevation of androgens in females with androgenic hairloss, but a more complex condition with involvement of the glandula suprarenalis and the hypophyseal level"
(this was in women, the study also shows with up regulation of the HPA axis, the Thyroid is down regulated, this is evidenced by the increased TSH in the women.)
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
3) Hormonal profile of men with premature balding. - PubMed - NCBI
"The frequency of subnormal values in SHBG, FSH, testosterone and epitestosterone (but not in free androgen index) was significant in the balding men. A borderline significant trend was recorded with respect to increased levels in 17OH-P and prolactin."
4) 17-Hydroxyprogesterone in children, adolescents and adults. - PubMed - NCBI
"An inherited deficiency of 21-hydroxylase leads to greatly increased serum concentrations of 17-OHP, while the absence of cortisol synthesis causes an increase in adrenocorticotrophic hormone. The classical congenital adrenal hyperplasia (CAH) presents usually with virilisation of a girl at birth."
"A non-classical form of congenital adrenal hyperplasia (NC-CAH) presents later in life usually with androgen excess. Moderately raised or normal 17-OHP concentrations can be seen basally but, if normal and clinical suspicion is high, an ACTH stimulation test will show 17-OHP concentrations (typically >30 nmol/L) above the normal response."
#3 and #4 are together. #3 shows increase in hypophyseal activation with FSH test and epitest but also shows increased 170H-P and prolactin. As shown earlier Prolactin is indicative of tissue estrogen and serotonin (look at original post). Also, prolactin shows an increase In hypophyseal activation. The 17OH-P is often elevated in congenital adrenal hyperplasia as shown in #4 hence the grouping of these two together, which as shown above is also elevated in balding men. What do you know, babies with congenital adrenal hyperplasia also show virilisation at birth (increased body hairiness) which is similar to the hirsutism seen in balding men and also the hirsutism seen in cushings syndrome. I don' think these are coincidences. All of these disorders show adrenal up regulation clearly and all have similar side effects. Also, shows why PCOS and balding are related. They are the same diseases just in different genders. PCOS is adrenal up regulation in females leading to high androgens from DHEA. Also, PCOS presents with insulin resistance, and obesity which are side effects of excess cortisol, i.e. adrenal up regulation.
adrenal androgens PCOS:
The adrenal and polycystic ovary syndrome. - PubMed - NCBI
PCOS, IR, Obesity:
https://www.hindawi.com/journals/ijrmed/2014/719050/
adrenal gland volume in PCOS:
Adrenal gland volume assessed by magnetic resonance imaging in women with polycystic ovary syndrome - ScienceDirect
THREAD 2: Latest Hair Studies: Hairloss Is Caused By Immune Imbalance
T-regs are dependent on the colonic microfolora. From what I understand and my own experience with hair loss, intestinal inflammation is the main culprit of hairloss, I think on multiple fronts:
1) Intestinal inflammation upregulates in general way the adrenal gland leading to production of aldosterone, cortisol and DHEA. People on here have talked about bald men having hirsute properties, this is DHEA from the adrenal gland being converted in DHT and estrogen I think. The upregulation of cortisol leads to the expression of aromatas in the body causing DHEA to convert to estrogen and when it converts to DHT the tissue environment, I think, causes DHT to convert to estrogenic beta-diols. This combination of estrogen, mineralocorticoids, glucocorticoids and estrogenic DHT derivates is what leads to hairloss
2) this T-reg is a new component in the hairloss paradigm in a more direct way atleast. The T-reg, as the name suggest regulate inflammation (colonic dysbiosis upregulates inflammation upregulates the adrenals and downregulates T-regs. Lack of T-regs also allows inflammation to increase thus the cycle becomes self perpetuating). They are dependent on the colonic microflora. Without them you develop autoimmunity. I think all hairloss is a variation of these mechanisms. These studies now indicate its more direct than I thought in the sense that you need T-regs to regrow hair. This I think is the reason that you arent seeing bald men regrow hair; no one is addressing the underlying problem with thier colonic ecosystem, just taking ridiculous drugs that are very specific and have no context of the problem.
To summarize, colonic dysbiosis leads to inflammation directly and downregulation of T-regs, upregulates the adrenals leading to hairloss through cortisol, aldosterone and DHEA/ DHT/ estrogen derivatives and overactice immune response.
The cure is to address your intestinal issue I think; the ecosystem needs to be fixed.
"Foxp3+ regulatory T cells (Tregs) are key suppressive cell types that regulate autoimmune inflammation in the body (23). In the gut, Tregs accumulate under steady-state conditions where they play an important role in the regulation of inflammation against microbial stimuli."
"Tregs are critical for the prevention of spontaneous inflammation against commensal microbes (Fig. 1). In antibiotic-treated mice or GF mice, Tregs remain detectable, but their numbers are significantly decreased in the intestinal LP, suggesting that the microbiota promotes the differentiation and/or maintenance of Tregs (26, 27). Colonization of GF mice with 46 strains of Clostridium(26), or with a cocktail of 8 defined commensals, called altered Schaedler flora (ASF) is sufficient to induce Tregs in the gut (26, 27). "
"Treg development is largely dependent on the microbiota in the colon, but not in the small intestine."
Role of the Gut Microbiota in the Development and Function of Lymphoid Cells
----------------------------------------
@Travis
@haidut
Both have discussed hairloss as a function of general adrenal upregulation. Travis has discussed anti-glucocorticoids and mineralcorticoids to treat hair loss as well as topical cyclosporin and vit D ( @Such_Saturation also mentioned vit a; D and A go hand in hand). All of these things, I think are indications of the true cause. I dont think they are the cure tho, all of them have significant side effects and from what I undersrand need to be used continuously. Also, the inflammation is still going on elsewhere, now its just blocked locally at the scalp or from some endpoints in the pathways with the drugs; definetly not a cure.
this is travis (hope its ok I quote you, Your posts are great):
"I think it's multifactorial; a cross between three separate pathways:
➤ Cortisol is the big one. This is greatly increased in males and acts directly on the mineralcorticoid receptor shortening the anagen phase. This has been proven directly in vitro: with a hair follicle, some cortisol, and a clock. Mice with overexpressed mineralcorticoid receptor in their skin are nude throughout life, and mineralcorticoid-inhibitors (spironolactone, cyclosporin) cause spontaneous and hairgrowth in most cases. Hydrocortisone directly thins hair when applied topically.
➤ Vitamin D analogues have been shown to stimulate hair growth. Vitamin D receptor null mice are totally hairless, always. The use of a hat can lower vitamin D on the scalp.
➤ Something must be said about ischemic hair loss, or cardiovascular hair loss. The vessels near the crown of the head are the thinnest and the first to suffer restriction of blood flow. There is a strong correlation between cardiovascular disease and balding.
Dihyrotestosterone stimulates hair growth in certain areas only. The scalp does not appear to be DHT-responsive. Only the hairs that grow at puberty are DHT-responsive follicles. The entire androgen paradigm came from Hamilton in the 30s based on logic and epidemiological evidence alone. This would make total sense if it weren't for the fact that males also have higher cortisol, wear hats, and get more cardiovascular disease. Shortly after, dozens or hundreds of experiments have shown cortisol to be a powerful killer of hair follicles in rats, cats, dogs, and even...sheep."
"I wan't to say that the hirsutism is caused by androgens. I'm fairly certain that it's actually defined this way. Androgens stimulate the growth of facial hair, and the other hair characteristic of males.
But I think the cortisol and aldosterone causes the balding of the scalp.
Certain follicles respond differently than others to particular steroid hormones. This has been shown in vitro. Emotional shock is one well-known initiator of scalp hair loss in women, a phenomenon almost certainly caused by the stress hormone cortisol.
Maybe Cushing's Disease is just hypercorticolism? Imagine a nonspecific overstimulation of the adrenal glands: this might produce cortisol, aldosterone, and the androgens. All three of these are produced mainly by the adrenal glands. In such a scenario you might actually expect scalp balding from both aldosterone and cortisol, but also androgen-stimulated hair growth elsewhere—at places which have actually been shown responsive to DHT, like the beard:"
"
Spironolactone works some, and is a purported DHT receptor antagonist; this is what the DHT proponents will say. However, it actually was originally designed as mineralcorticoid receptor agonist.
Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology." Kidney international 57.4 (2000): 1408-1411.
†Wysocki, G. P., and T. D. Daley. "Hypertrichosis in patients receiving cyclosporine therapy." Clinical and experimental dermatology 12.3 (1987): 191-196."
Hered the thread where its discussed: Announcement - Regarding The Recent @gbolduev Threads
THREAD 1: https://raypeatforum.com/community/threads/the-cause-of-baldness.20374/page-5#post-284345
Heres some references supporting the adrenal up regulation piece:
1) Hormonal parameters in androgenetic hair loss in the male. - PubMed - NCBI
"Significant differences in serum levels of androstenedione, cortisol, 17 beta-estradiol and luteinizing hormone were noted between hair loss patients and control subjects. Suprarenal stimulation as well as hypophyseal feedback mechanisms therefore seem to be involved in male pattern alopecia."
2) Hormone studies in females with androgenic hairloss. - PubMed - NCBI
"The results of the study show no significant elevation of androgens in females with androgenic hairloss, but a more complex condition with involvement of the glandula suprarenalis and the hypophyseal level"
(this was in women, the study also shows with up regulation of the HPA axis, the Thyroid is down regulated, this is evidenced by the increased TSH in the women.)
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------
3) Hormonal profile of men with premature balding. - PubMed - NCBI
"The frequency of subnormal values in SHBG, FSH, testosterone and epitestosterone (but not in free androgen index) was significant in the balding men. A borderline significant trend was recorded with respect to increased levels in 17OH-P and prolactin."
4) 17-Hydroxyprogesterone in children, adolescents and adults. - PubMed - NCBI
"An inherited deficiency of 21-hydroxylase leads to greatly increased serum concentrations of 17-OHP, while the absence of cortisol synthesis causes an increase in adrenocorticotrophic hormone. The classical congenital adrenal hyperplasia (CAH) presents usually with virilisation of a girl at birth."
"A non-classical form of congenital adrenal hyperplasia (NC-CAH) presents later in life usually with androgen excess. Moderately raised or normal 17-OHP concentrations can be seen basally but, if normal and clinical suspicion is high, an ACTH stimulation test will show 17-OHP concentrations (typically >30 nmol/L) above the normal response."
#3 and #4 are together. #3 shows increase in hypophyseal activation with FSH test and epitest but also shows increased 170H-P and prolactin. As shown earlier Prolactin is indicative of tissue estrogen and serotonin (look at original post). Also, prolactin shows an increase In hypophyseal activation. The 17OH-P is often elevated in congenital adrenal hyperplasia as shown in #4 hence the grouping of these two together, which as shown above is also elevated in balding men. What do you know, babies with congenital adrenal hyperplasia also show virilisation at birth (increased body hairiness) which is similar to the hirsutism seen in balding men and also the hirsutism seen in cushings syndrome. I don' think these are coincidences. All of these disorders show adrenal up regulation clearly and all have similar side effects. Also, shows why PCOS and balding are related. They are the same diseases just in different genders. PCOS is adrenal up regulation in females leading to high androgens from DHEA. Also, PCOS presents with insulin resistance, and obesity which are side effects of excess cortisol, i.e. adrenal up regulation.
adrenal androgens PCOS:
The adrenal and polycystic ovary syndrome. - PubMed - NCBI
PCOS, IR, Obesity:
https://www.hindawi.com/journals/ijrmed/2014/719050/
adrenal gland volume in PCOS:
Adrenal gland volume assessed by magnetic resonance imaging in women with polycystic ovary syndrome - ScienceDirect
THREAD 2: Latest Hair Studies: Hairloss Is Caused By Immune Imbalance
T-regs are dependent on the colonic microfolora. From what I understand and my own experience with hair loss, intestinal inflammation is the main culprit of hairloss, I think on multiple fronts:
1) Intestinal inflammation upregulates in general way the adrenal gland leading to production of aldosterone, cortisol and DHEA. People on here have talked about bald men having hirsute properties, this is DHEA from the adrenal gland being converted in DHT and estrogen I think. The upregulation of cortisol leads to the expression of aromatas in the body causing DHEA to convert to estrogen and when it converts to DHT the tissue environment, I think, causes DHT to convert to estrogenic beta-diols. This combination of estrogen, mineralocorticoids, glucocorticoids and estrogenic DHT derivates is what leads to hairloss
2) this T-reg is a new component in the hairloss paradigm in a more direct way atleast. The T-reg, as the name suggest regulate inflammation (colonic dysbiosis upregulates inflammation upregulates the adrenals and downregulates T-regs. Lack of T-regs also allows inflammation to increase thus the cycle becomes self perpetuating). They are dependent on the colonic microflora. Without them you develop autoimmunity. I think all hairloss is a variation of these mechanisms. These studies now indicate its more direct than I thought in the sense that you need T-regs to regrow hair. This I think is the reason that you arent seeing bald men regrow hair; no one is addressing the underlying problem with thier colonic ecosystem, just taking ridiculous drugs that are very specific and have no context of the problem.
To summarize, colonic dysbiosis leads to inflammation directly and downregulation of T-regs, upregulates the adrenals leading to hairloss through cortisol, aldosterone and DHEA/ DHT/ estrogen derivatives and overactice immune response.
The cure is to address your intestinal issue I think; the ecosystem needs to be fixed.
"Foxp3+ regulatory T cells (Tregs) are key suppressive cell types that regulate autoimmune inflammation in the body (23). In the gut, Tregs accumulate under steady-state conditions where they play an important role in the regulation of inflammation against microbial stimuli."
"Tregs are critical for the prevention of spontaneous inflammation against commensal microbes (Fig. 1). In antibiotic-treated mice or GF mice, Tregs remain detectable, but their numbers are significantly decreased in the intestinal LP, suggesting that the microbiota promotes the differentiation and/or maintenance of Tregs (26, 27). Colonization of GF mice with 46 strains of Clostridium(26), or with a cocktail of 8 defined commensals, called altered Schaedler flora (ASF) is sufficient to induce Tregs in the gut (26, 27). "
"Treg development is largely dependent on the microbiota in the colon, but not in the small intestine."
Role of the Gut Microbiota in the Development and Function of Lymphoid Cells
----------------------------------------
@Travis
@haidut
Both have discussed hairloss as a function of general adrenal upregulation. Travis has discussed anti-glucocorticoids and mineralcorticoids to treat hair loss as well as topical cyclosporin and vit D ( @Such_Saturation also mentioned vit a; D and A go hand in hand). All of these things, I think are indications of the true cause. I dont think they are the cure tho, all of them have significant side effects and from what I undersrand need to be used continuously. Also, the inflammation is still going on elsewhere, now its just blocked locally at the scalp or from some endpoints in the pathways with the drugs; definetly not a cure.
this is travis (hope its ok I quote you, Your posts are great):
"I think it's multifactorial; a cross between three separate pathways:
➤ Cortisol is the big one. This is greatly increased in males and acts directly on the mineralcorticoid receptor shortening the anagen phase. This has been proven directly in vitro: with a hair follicle, some cortisol, and a clock. Mice with overexpressed mineralcorticoid receptor in their skin are nude throughout life, and mineralcorticoid-inhibitors (spironolactone, cyclosporin) cause spontaneous and hairgrowth in most cases. Hydrocortisone directly thins hair when applied topically.
➤ Vitamin D analogues have been shown to stimulate hair growth. Vitamin D receptor null mice are totally hairless, always. The use of a hat can lower vitamin D on the scalp.
➤ Something must be said about ischemic hair loss, or cardiovascular hair loss. The vessels near the crown of the head are the thinnest and the first to suffer restriction of blood flow. There is a strong correlation between cardiovascular disease and balding.
Dihyrotestosterone stimulates hair growth in certain areas only. The scalp does not appear to be DHT-responsive. Only the hairs that grow at puberty are DHT-responsive follicles. The entire androgen paradigm came from Hamilton in the 30s based on logic and epidemiological evidence alone. This would make total sense if it weren't for the fact that males also have higher cortisol, wear hats, and get more cardiovascular disease. Shortly after, dozens or hundreds of experiments have shown cortisol to be a powerful killer of hair follicles in rats, cats, dogs, and even...sheep."
"I wan't to say that the hirsutism is caused by androgens. I'm fairly certain that it's actually defined this way. Androgens stimulate the growth of facial hair, and the other hair characteristic of males.
But I think the cortisol and aldosterone causes the balding of the scalp.
Certain follicles respond differently than others to particular steroid hormones. This has been shown in vitro. Emotional shock is one well-known initiator of scalp hair loss in women, a phenomenon almost certainly caused by the stress hormone cortisol.
Maybe Cushing's Disease is just hypercorticolism? Imagine a nonspecific overstimulation of the adrenal glands: this might produce cortisol, aldosterone, and the androgens. All three of these are produced mainly by the adrenal glands. In such a scenario you might actually expect scalp balding from both aldosterone and cortisol, but also androgen-stimulated hair growth elsewhere—at places which have actually been shown responsive to DHT, like the beard:"
"
Spironolactone works some, and is a purported DHT receptor antagonist; this is what the DHT proponents will say. However, it actually was originally designed as mineralcorticoid receptor agonist.
Mineralocorticoid receptor antagonists: the evolution of utility and pharmacology." Kidney international 57.4 (2000): 1408-1411.
†Wysocki, G. P., and T. D. Daley. "Hypertrichosis in patients receiving cyclosporine therapy." Clinical and experimental dermatology 12.3 (1987): 191-196."
Hered the thread where its discussed: Announcement - Regarding The Recent @gbolduev Threads
raypeatclips
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Interesting, I am going to try this. How important do you think the MCT was to the mix?
T
tca300
Guest
@raypeatclips Very important. Vinegar alone can drop my dandruff for a few days, but the combo is powerful.
raypeatclips
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Thanks. Got both ordered, will report back.
raypeatclips
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@tca300 Do you dilute your apple cider vinegar at all, or is it straight ACV with the MCT oil added? I tried tonight for the first time and the ACV seems to have irritated my forehead and made it red.
I use to use and enjoy the acv rinsing after shampooing, and this was long before my shedding started. Im not sure how you used it but a 3-1 or 4-1 left things really nice and shiny. It irritated my skin as well, very briefly though. It helped with my slight seasonal dandruff too
raypeatclips
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I may dilute it next time but the following morning the redness was gone, all back to normal.
My update on the acv and MCT oil combination is inconclusive at the moment. It may have slightly reduced dandruff, it is hard to tell, or maybe it has done nothing at all. It definitely hasn't completely eliminated it after one wash in my experience. More testing needed.
T
tca300
Guest
Your skin must be extra sensitive. I have been doing vinegar for a while, so maybe Im use to it.
Did you wash the vinegar out with soap or shampoo?
In the beginning I would just barely rinse the vinegar with water so as to let it be in my hair afterwords to continue to kill the fungus. But if your sensitive, maybe dilute it 50:50 or so with water.
raypeatclips
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I washed it with soap as following your instructions. I was paranoid of smelling like vinegar so gave it a thorough wash and because of this probably washed more than I should have.
Next time I shall leave it a bit longer in the hair when I don't have people at work to disgust with my smell.
My forehead was fine and normal coloured when I woke the following morning.
T
tca300
Guest
Ya, for mild dandruff washing the vinegar out with soap is fine and effective, but If the dandruff is bad enough it might be best to not completely wash it out, and most find that once their hair dries, the vinegar smell goes away, until the hair gets wet again, then vinegar stink.
Interesting experiment you did. I've been suffering from flaking on my scalp. for a long time. It's worse than dandruff, as it seems to be a continuous healing process that never stops. It goes from being moist to being dry and flaky, however it is confined to specific recurring sites in my scalp. I read the article, and found that it was the oleic-acid contaminated sample that supported the Malassezia culture. Since oleic acid is 18-chain and is monounsaturated, could it be possible it's not so much the chain length that would be the differentiating factor? Is it possible that other derivations of coconut oil could be used other than mct oil (by the way, mct oil includes lauric acid), such as refined coconut oil (is being fully saturated is the differentiating factor)? Would virgin coconut oil also work because the short-chain saturated fatty acid portion of coconut oil prdominates (although yes, MCT oil is already proven - by you)? Maybe even fresh coconut milk could work as well as this is something used often in the Phili8ppines, although not specifcally to remove dandruff but more known to give hair body and shine (but I suppose if dandruff occurs I assume it would still be negative enough for it not to be touted for body and shine).
I could buy MCT oil just as well but I'll give the refined coconut oil a try first. On the ACV, I did some experimentation over a week applying something that is related to it - copper acetate (the acetate is how it's related). It didn't work, but I wonder now if it would have worked if I followed it up with the MCT (or functionally equivalent coconut oil derivative).
mayweatherking
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Yeah I notice when I get "scalp itch", my temperature has decreased during the "scalp itch" sensation. I mean, that's a pretty clear thing showing that adrenaline is high. Seems like the only true way to control cortisol is thyroid to stop the cortisol to get magnesium stores back up and having your vitamin D level good enough to keep parathyroid at bay.
(this is easier said than done)
(this is easier said than done)
T
tca300
Guest
Mct oil is liquid and lauric acid is solid at room temp. The MCT oil I use is a combo of C:8 and C:10.
Experimentation is good! You could always try those ideas and see if they work.
Yeah! I didn't think about the solid-liquid state to be a consideration. The tropical weather does that to me.
DaveFoster
Member
'Dem dere academic causality recognition skills.
Travis
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Let's not forget about aldosterone.
Cortisol can work through either the glucocorticoid receptor or the mineralcorticoid receptor; but mice overexpressing the glucocorticoid receptor have hair, while mice overexpressing the mineralcorticoid receptor are completely bald. This makes evolutionary sense, in a way, as this receptor is charged with the function of reducing sodium loss through the skin. I don't think that it would be too strange to think that it does so by reducing pore size, or had done so in the past.
Aquatic animals have the need for a mineralcorticoid receptor on the skin to control Na⁺ intake through skin. Otherwise, their blood pressure would be dependent on the whims of local salinity levels—not exactly safe for making the transition from ocean to rivers, or perhaps even traversing the Straight of Gilbraltar (the Mediterranean has higher salinity than the North Atlantic, which could otherwise be slightly-hypertensive for a fish.)
So the mineralcorticoid receptor is expressed on the skin, and actually predates the glucocorticoid receptor. Salt on the skin is not sensed directly, since the adrenals are needed to produce this signal. A further control mechanism has evolved called 11β-HSD₁, the enzyme which turns the nearly inactive cortisone into cortisol—despite it's somewhat contradictory name.
But it doesn't end there. Cortisol and aldosterone upregulate transcription of cytokine TGF-β₁ nearly threefold—a cytokine which has shown to disrupt the hair cycle just as powerfully as cortisol itself. This normally exists in low amounts through the hair cycle, but slowly rises and spikes right before the catagen stage is reached. This could actually be the prime intercellular signal for catagen induction; if you'd see the graphs and assays I think you'd agree.
The cytokine TGF-β₁ activates phospholipase A₂ on the cellular membrane. This causes a release in arachidonic acid—powerful prostaglandin precursor. The prostaglandins themselves have been shown to regulate the hair cycle, and prostaglandin J₂ initiates catagen just as well as TGF-β₁. Prostaglandin F₂α actually stimulates the induction of anagen with one very sharp spike—a growth impulse. The precursor for prostaglandin J₂ is prostaglandin D₂—an eicosanoid made by a separate enzyme, a bit downstream from COX-2.
I think it would be helpful to find-out why prostaglandin J₂ is produced: Also, what causes the growth-stimulatory prostaglandin F₂α spike which proceeds growth in a dormant follicle?
It seems to me that the main cortisol hairloss signal is transduced by TGF-β₁, to prostaglandin D₂/J₂, and then to cell nucleus. This signal travels from an endocrine hormone to a paracrine hormone(s) ⟶ and then to an autocrine hormone(s). If all roads lead to prostaglandin J₂/D₂, then this could explain why there are so many factors. A diet high in linoleic acid would certainly lead to more prostaglandins in general, but the main drug target could be the enzyme prostaglandin D₂ synthase. More investigation is needed.
So . . . a tentative pathway:
stress (or low salt) ⟶ cortisol (aldosterone) ⟶ TGF-β₁ ⟶ prostaglandin D₂ ⟶ prostaglandin J₂⟶ MPB
Which would predict that people who eat high linoleic acid would generally have increased hairloss, something that could have evolved as we migrated from the tropics towards high linoleate regions. Cold weather stimulates the production of unsaturated fatty acids, and now people eat quite a bit more than previous as a result of agriculture.
But there's also the Wnt/β-catenin pathway which seems involved as well. Vitamin D₃ has been shown to fit into this scheme on the transcriptional level, but it is actually also known as an inhibitor of the prostaglandin E₂ receptor. Also, vitamin A inhibits the enzyme prostaglandin D₂ synthase—binding it directly at it's catalytic domain. Nothing seems to bind stronger than cis-retinol. These two vitamins could exert much of the activity usually ascribed to them by antagonizing prostaglandin signalling. Conversely, prostaglandins might be expected to antagonize many of the functions attributed to these vitamins. It should be noted that vitamin A is a lipid, and the vitamin D₃ seco-steroidal ring has as much in common with prostaglandins as it does with steroids.
Prostaglandins aren't commonly measured in cell experiments. Most cell biologists analyze nucleic acids and proteins since they are easy to separate and characterize by gel electrophoresis, something which fits into their general paradigm and lab equiptment. While powerful techniques, the role of lipids is generally ignored by most. Even when studying cytokines, known to release arachidonic acid from the cell membrane, they usually just concentrate on protein phosphate groups and nucleic acids. Changes in protein phosphorylation are commonly measured with gel shift assays, but not the other side of the coin—the prostaglandins themselves—which are necessarily produced from phospholipase A₂ activation—a prerequisite for the Wnt/β-catenin pathway. They take phosphorylated proteins as primary; eicosanoids as secondary. Considering the powerful and undeniable hormonal activities that prostaglandins exhibit, the reverse is likely true.
And besides them perhaps being artefacts of prostaglandin release from phospholipids, the reaction mechanisms used to describe these phosphorylation events are unbelievable:
No mention of prostaglandins at all.. . . . . ..Now from Wikipedia:
So instead of explaining how one protein can phosphorylate another protein, they just sprinkle more fairy dust.
The beta-catenin destruction complex[edit source]
For GSK3 to be a highly effective kinase on a substrate, pre-phosphorylation is not enough. There is one additional requirement: Similar to the mitogen-activated protein kinases (MAPKs), substrates need to associate with this enzyme through high-affinity docking motifs. Beta-catenin contains no such motifs, but a special protein does: axin. What is more, its GSK3 docking motif is directly adjacent to a β-catenin binding motif.[23]This way, axin acts as a true scaffold protein, bringing an enzyme (GSK3) together with its substrate (β-catenin) into close physical proximity.
So axin becomes the real catalyst in this scheme—although never considered as such—in the sense that it lowers entropy and aligns the reactant and cofactor. GSK3 doesn't sound much like an enzyme now, does it? It needs a pre-phosphorylated substrate, something it apparently can't do itself despite being called a "kinase." (An imposter kinase: Perhaps impostkinase-3?) Perhaps we can just assume that this explanation is a slight misinterpretation, and that GSK3 and β-catenin are actually nativly bound in situ through a phosphodiester linkage like so many other biochemicals (i.e. ATP and DNA). After the complex is lysed and centrifuged, this labile phosphodiester bond could be broken—especially if high rotational speeds and/or acids are used. The elecrophoretic gel shift assays then would detect the phosphate groups on either GSK3 or β-catenin almost randomly, perhaps creating unicorns in the process.
So what is this scaffold? Do these sound like microtubule associated proteins to you? on the cytoskeleton? This is what they sound like to me. They are both phosphorylated (n) and immobilized on a cytosolic structure.
So it sounds like β-catenin is a microtubule support protein, which when disrupted can be found in the cell nucleus. This could be how the cell nucleus knows the state of it's microtubule framework.
The eicosanoids are another way in which the cell's nucleus can respond to changes, by sensing the lipids that are dislodged from the membrane. It should then be no surprise that the Wnt/β-catenin pathway and the eicosanoid pathway are both primarily characterized by inflammation.
The Wnt cytokines are actually neural growth factors; and β-catenin is a cytoskeletal support protein which has a dual role as a nuclear transcription factor.
Simple and straightforward. The phospholipase A₂ on the cell membrane releases arachidonic acid which diffuses through the cytosol and activates the nuclear PPARδ receptor—a process which had been known before the Wnt/β-catenin pathway had been first described. Phospholipase A₂ is a real enzyme and can do real things in vitro; I would love to see them try to get GSK3 to do the things in vitro that Wikipedia claims it can.
Makes sense. It's easy to see how phospholipase A₂ could release arachidonic acid from the cell membrane and activate PPARδ.
Notice how the protein levels of β-catenin did not even increase in the nucleus, yet TCF/LEF activity was increased. This is the classic way to measure β-catenin activity—a fluorescent signal that increases . . . not in response to the absolute amount of β-catenin protein, but in response to arachidonic acid binding to PPARδ. All three of these need to be present for TCF/LEF activity, and yet only arachidonic acid needs to be increased to increase the fluorescent signal. A naïve researcher might interpret this fluorescence as as an increase in "total β-catenin," and subsequently use this interpretation to create wild and ridiculous cellular pathways involving "destruction complexes," translocators, and proteins phosphorylating other proteins. This signal was not blocked by indometacin, indicating that PPARδ binds arachidonic acid itself.
You will find many of the same players in both the "Wnt/β-catenin pathway" and the eicosanoid pathway. The same cytokines are known to be step #1 of both pathways: Phospholipase A₂ in the obligatory second in both; prostaglandin receptors are coupled to the G-protein; both cis-retinol and all trans-retinoic acid bind the enzyme prostaglandin D₂ synthase more than anything; and there are really too many interactions to list. The "Wnt/β-catenin pathway" is the eicosanoid pathway when examined using the protein fraction while ignoring the lipid fraction—arachidonic acid and the eicosanoids—that important part that floated to the top of the centrifuge vial, but decanted. These molecular biologists found a way to explain the already well-characterized eicosanoid pathway by focusing only on proteins and nucleic acids—thinking they'd discovered something entirely novel but hadn't. The ridiculous mechanics invoked and whimsical names are further testament to this.
Using the "Wnt/β-catenin pathway" to explain cellular inflammation cascades is akin to commentating an entire soccer match by focusing exclusively on one team only.. . ..and then watching that team make an "own goal" while not telling the listeners what had just happened.
Though perhaps more glamorous than thin-layer chromatography and HPLC, polyacrylamide gel electrophoresis and DNA hybridization allows only the measurements of proteins and amino acids. The mechanisms which result from such experiments are necessarily incomplete for explaining signals whose origins begin with phospholipase A₂—the cytokine-induced liberator of arachidonic acid.
The nuclear transcription events correlate better with the eicosanoids than with the paradigmatic Wnt/β-catenin proteins, both in their phosphorylation status and absolute amounts.
I think that a study which explains inflammatory events in Wnt/β-catenin terms can be useful as long as one is cognizant of the assumptions being made, the existence of the microtubule cytoskeleton, and the prostaglandins present (but not emphasized.)
Is this pathway just one of the many tenable pathways that were available, but given precedence through selective funding by food industries wishing to explain inflammation in alternative ways? . . Ways not involving their product? Perhaps even created by one of their own, wheeled-up to the threshold of scientific literature and left there like a Trojanhorse unicorn—a device used to confuse and befuddle the next generation into thinking that inflammation can be explained by β-catenin alone (and that proteins can "walk.")
Cortisol can work through either the glucocorticoid receptor or the mineralcorticoid receptor; but mice overexpressing the glucocorticoid receptor have hair, while mice overexpressing the mineralcorticoid receptor are completely bald. This makes evolutionary sense, in a way, as this receptor is charged with the function of reducing sodium loss through the skin. I don't think that it would be too strange to think that it does so by reducing pore size, or had done so in the past.
Aquatic animals have the need for a mineralcorticoid receptor on the skin to control Na⁺ intake through skin. Otherwise, their blood pressure would be dependent on the whims of local salinity levels—not exactly safe for making the transition from ocean to rivers, or perhaps even traversing the Straight of Gilbraltar (the Mediterranean has higher salinity than the North Atlantic, which could otherwise be slightly-hypertensive for a fish.)
So the mineralcorticoid receptor is expressed on the skin, and actually predates the glucocorticoid receptor. Salt on the skin is not sensed directly, since the adrenals are needed to produce this signal. A further control mechanism has evolved called 11β-HSD₁, the enzyme which turns the nearly inactive cortisone into cortisol—despite it's somewhat contradictory name.
But it doesn't end there. Cortisol and aldosterone upregulate transcription of cytokine TGF-β₁ nearly threefold—a cytokine which has shown to disrupt the hair cycle just as powerfully as cortisol itself. This normally exists in low amounts through the hair cycle, but slowly rises and spikes right before the catagen stage is reached. This could actually be the prime intercellular signal for catagen induction; if you'd see the graphs and assays I think you'd agree.
The cytokine TGF-β₁ activates phospholipase A₂ on the cellular membrane. This causes a release in arachidonic acid—powerful prostaglandin precursor. The prostaglandins themselves have been shown to regulate the hair cycle, and prostaglandin J₂ initiates catagen just as well as TGF-β₁. Prostaglandin F₂α actually stimulates the induction of anagen with one very sharp spike—a growth impulse. The precursor for prostaglandin J₂ is prostaglandin D₂—an eicosanoid made by a separate enzyme, a bit downstream from COX-2.
I think it would be helpful to find-out why prostaglandin J₂ is produced: Also, what causes the growth-stimulatory prostaglandin F₂α spike which proceeds growth in a dormant follicle?
It seems to me that the main cortisol hairloss signal is transduced by TGF-β₁, to prostaglandin D₂/J₂, and then to cell nucleus. This signal travels from an endocrine hormone to a paracrine hormone(s) ⟶ and then to an autocrine hormone(s). If all roads lead to prostaglandin J₂/D₂, then this could explain why there are so many factors. A diet high in linoleic acid would certainly lead to more prostaglandins in general, but the main drug target could be the enzyme prostaglandin D₂ synthase. More investigation is needed.
So . . . a tentative pathway:
stress (or low salt) ⟶ cortisol (aldosterone) ⟶ TGF-β₁ ⟶ prostaglandin D₂ ⟶ prostaglandin J₂⟶ MPB
Which would predict that people who eat high linoleic acid would generally have increased hairloss, something that could have evolved as we migrated from the tropics towards high linoleate regions. Cold weather stimulates the production of unsaturated fatty acids, and now people eat quite a bit more than previous as a result of agriculture.
But there's also the Wnt/β-catenin pathway which seems involved as well. Vitamin D₃ has been shown to fit into this scheme on the transcriptional level, but it is actually also known as an inhibitor of the prostaglandin E₂ receptor. Also, vitamin A inhibits the enzyme prostaglandin D₂ synthase—binding it directly at it's catalytic domain. Nothing seems to bind stronger than cis-retinol. These two vitamins could exert much of the activity usually ascribed to them by antagonizing prostaglandin signalling. Conversely, prostaglandins might be expected to antagonize many of the functions attributed to these vitamins. It should be noted that vitamin A is a lipid, and the vitamin D₃ seco-steroidal ring has as much in common with prostaglandins as it does with steroids.
Prostaglandins aren't commonly measured in cell experiments. Most cell biologists analyze nucleic acids and proteins since they are easy to separate and characterize by gel electrophoresis, something which fits into their general paradigm and lab equiptment. While powerful techniques, the role of lipids is generally ignored by most. Even when studying cytokines, known to release arachidonic acid from the cell membrane, they usually just concentrate on protein phosphate groups and nucleic acids. Changes in protein phosphorylation are commonly measured with gel shift assays, but not the other side of the coin—the prostaglandins themselves—which are necessarily produced from phospholipase A₂ activation—a prerequisite for the Wnt/β-catenin pathway. They take phosphorylated proteins as primary; eicosanoids as secondary. Considering the powerful and undeniable hormonal activities that prostaglandins exhibit, the reverse is likely true.
And besides them perhaps being artefacts of prostaglandin release from phospholipids, the reaction mechanisms used to describe these phosphorylation events are unbelievable:
Wnt / β-Catenin Signaling Interactive Pathway
Pathway Description:
The conserved Wnt/β-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This developmental cascade integrates signals from other pathways, including retinoic acid, FGF, TGF-β, and BMP, within different cell types and tissues. The Wnt ligand is a secreted glycoprotein that binds to Frizzled receptors...
I know it's hard to take biologists seriously when they use whimsical and imprecise terminology such as "frizzled receptors"—and especially the proteins named "sonic hedgehog" and "mothers against decapentaplegic"—but some of these proteins, such as "hairless" and "dishevelled," are actually appropriately named in a way which calls attention to their role.Pathway Description:
The conserved Wnt/β-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This developmental cascade integrates signals from other pathways, including retinoic acid, FGF, TGF-β, and BMP, within different cell types and tissues. The Wnt ligand is a secreted glycoprotein that binds to Frizzled receptors...
...leading to the formation of a larger cell surface complex with LRP5/6. Frizzleds are ubiquitinated by ZNRF3 and RNF43, whose activity is inhibited by R-spondin binding to LGR5/6. In this manner R-spondins increase sensitivity of cells to the Wnt ligand. Activation of the Wnt receptor complex triggers displacement of the multifunctional kinase GSK-3β from a regulatory APC/Axin/GSK-3β-complex. In the absence of Wnt-signal (Off-state), β-catenin, an integral E-cadherin cell-cell adhesion adaptor protein and transcriptional co-regulator, is targeted by coordinated phosphorylation by CK1 and the APC/Axin/GSK-3β-complex leading to its ubiquitination and proteasomal degradation through the β-TrCP/Skp pathway. In the presence of Wnt ligand (On-state), the co-receptor LRP5/6 is brought in complex with Wnt-bound Frizzled. This leads to activation of Dishevelled (Dvl) by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK-3β from APC/Axin through an unclear mechanism that may involve substrate trapping and/ or endosome sequestration. Stablized β-catenin is translocated to the nucleus via Rac1 and other factors where it binds to LEF/TCF transcription factors, displacing co-repressors and recruiting additional co-activators to Wnt target genes. Additionally, β-catenin cooperates with several other transcription factors to regulate specific targets. Importantly, researchers have found β-catenin point mutations in human tumors that prevent GSK-3β phosphorylation and thus lead to its aberrant accumulation. E-cadherin, APC, R-spondin and Axin mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. Wnt signaling has also been shown to promote nuclear accumulation of other transcriptional regulator implicated in cancer, such as TAZ and Snail1. Furthermore, GSK-3β is involved in glycogen metabolism and other signaling pathways, which has made its inhibition relevant to diabetes and neurodegenerative disorders.
No mention of prostaglandins at all.. . . . . ..Now from Wikipedia:
Function[edit source]
Regulation of degradation through phosphorylation[edit source]
The cellular level of beta-catenin is mostly controlled by its ubiquitination and proteosomal degradation. The E3 ubiquitin ligase TrCP1 (also known as β-TrCP) can recognize β-catenin as its substrate through a short linear motif on the disordered N-terminus. However, this motif (Asp-Ser-Gly-Ile-His-Ser) of β-catenin needs to be phosphorylated on the two serines in order to be capable to bind β-TrCP. Phosphorylation of the motif is performed by Glycogen Synthase Kinase 3 alpha and beta (GSK3α and GSK3β). GSK3s are constitutively active enzymes implicated in several important regulatory processes. There is one requirement, though: substrates of GSK3 need to be pre-phosphorylated four amino acids downstream (C-terminally) of the actual target site. Thus it also requires a "priming kinase" for its activities. In the case of beta-catenin, the most important priming kinase is Casein Kinase I (CKI). Once a serine-threonine rich substrate has been "primed", GSK3 can "walk" across it from C-terminal to N-terminal direction, phosphorylating every 4th serine or threonine residues in a row.
Regulation of degradation through phosphorylation[edit source]
The cellular level of beta-catenin is mostly controlled by its ubiquitination and proteosomal degradation. The E3 ubiquitin ligase TrCP1 (also known as β-TrCP) can recognize β-catenin as its substrate through a short linear motif on the disordered N-terminus. However, this motif (Asp-Ser-Gly-Ile-His-Ser) of β-catenin needs to be phosphorylated on the two serines in order to be capable to bind β-TrCP. Phosphorylation of the motif is performed by Glycogen Synthase Kinase 3 alpha and beta (GSK3α and GSK3β). GSK3s are constitutively active enzymes implicated in several important regulatory processes. There is one requirement, though: substrates of GSK3 need to be pre-phosphorylated four amino acids downstream (C-terminally) of the actual target site. Thus it also requires a "priming kinase" for its activities. In the case of beta-catenin, the most important priming kinase is Casein Kinase I (CKI). Once a serine-threonine rich substrate has been "primed", GSK3 can "walk" across it from C-terminal to N-terminal direction, phosphorylating every 4th serine or threonine residues in a row.
So instead of explaining how one protein can phosphorylate another protein, they just sprinkle more fairy dust.
The beta-catenin destruction complex[edit source]
For GSK3 to be a highly effective kinase on a substrate, pre-phosphorylation is not enough. There is one additional requirement: Similar to the mitogen-activated protein kinases (MAPKs), substrates need to associate with this enzyme through high-affinity docking motifs. Beta-catenin contains no such motifs, but a special protein does: axin. What is more, its GSK3 docking motif is directly adjacent to a β-catenin binding motif.[23]This way, axin acts as a true scaffold protein, bringing an enzyme (GSK3) together with its substrate (β-catenin) into close physical proximity.
So axin becomes the real catalyst in this scheme—although never considered as such—in the sense that it lowers entropy and aligns the reactant and cofactor. GSK3 doesn't sound much like an enzyme now, does it? It needs a pre-phosphorylated substrate, something it apparently can't do itself despite being called a "kinase." (An imposter kinase: Perhaps impostkinase-3?) Perhaps we can just assume that this explanation is a slight misinterpretation, and that GSK3 and β-catenin are actually nativly bound in situ through a phosphodiester linkage like so many other biochemicals (i.e. ATP and DNA). After the complex is lysed and centrifuged, this labile phosphodiester bond could be broken—especially if high rotational speeds and/or acids are used. The elecrophoretic gel shift assays then would detect the phosphate groups on either GSK3 or β-catenin almost randomly, perhaps creating unicorns in the process.
So what is this scaffold? Do these sound like microtubule associated proteins to you? on the cytoskeleton? This is what they sound like to me. They are both phosphorylated (n) and immobilized on a cytosolic structure.
- Huang, P., T. Senga, and M. Hamaguchi. "A novel role of phospho-β-catenin in microtubule regrowth at centrosome." Oncogene 26.30 (2007)
β-Catenin is a biologically important molecule playing critical roles in both cell adhesion and transcriptional regulation in the Wnt pathway. Here, we show that phospho-β-catenin, which is reported to be degraded immediately after its phosphorylation, accumulated in the centrosome. Whereas phospho-mimicking mutant-β-catenin could localize to the centrosome, mutant-β-catenin that lacks the phosphorylation site lost its localization to the centrosome.
Depletion of β-catenin with small interfering RNA or inhibition of its phosphorylation by LiCl treatment caused disruption of radial microtubule (MT) array and retardation of the MT regrowth during the recovery from nocodazole treatment.
Depletion of β-catenin with small interfering RNA or inhibition of its phosphorylation by LiCl treatment caused disruption of radial microtubule (MT) array and retardation of the MT regrowth during the recovery from nocodazole treatment.
So it sounds like β-catenin is a microtubule support protein, which when disrupted can be found in the cell nucleus. This could be how the cell nucleus knows the state of it's microtubule framework.
The eicosanoids are another way in which the cell's nucleus can respond to changes, by sensing the lipids that are dislodged from the membrane. It should then be no surprise that the Wnt/β-catenin pathway and the eicosanoid pathway are both primarily characterized by inflammation.
- Han, Chang, et al. "Regulation of Wnt/β‐catenin pathway by cPLA2α and PPARδ." Journal of cellular biochemistry 105.2 (2008)
- Salinas, Patricia C. "Modulation of the microtubule cytoskeleton: a role for a divergent canonical Wnt pathway." Trends in cell biology (2007)
A low concentration of Wnt, specifically Wnt3a, provides similar Fz-mediated [frizzle receptor], positive guidance information to chick dorsal (but not ventral) retina ganglion cell (RGC) axons that project to the tectum. In addition, high concentrations of Wnt3a strongly inhibit dorsal, as well as ventral, RGC axon outgrowth.
- Han, Chang, et al. "Regulation of Wnt/β‐catenin pathway by cPLA2α and PPARδ." Journal of cellular biochemistry 105.2 (2008): 534-545.
Mammalian cells contain a large number of phospholipases that hydrolyze phospholipids in a structurally specific manner for production of a variety of biologically active products. Phospholipase A₂s are distinct families of enzymes that catalyze hydrolysis of the sn-2 ester bond of membrane glycerophospholipids, leading to the production of two classes of lipid mediators: fatty acid metabolites and lysophospholipid-related lipids [these have roles two, and are simply the phospholipid sans arachidonic acid]. Among the many types of mammalian PLA₂, cytosolic PLA₂ (cPLA₂) is the rate-limiting key enzyme for hormone, growth factor, and mitogen-induced eicosanoid synthesis, since the cPLA₂ selectively cleaves AA from substrate phospholipids and its enzyme activity is tightly controlled by several intracellular signaling events, including physiologically relevant concentrations of Ca²⁺ [prolactin does this by activating phospholipase C to cleave calcium-chelating inositol phosphates], enzyme phosphorylation [a unicorn, as far as I can tell], S-nitrosylation, G-proteins and induction of gene expression. The free AA cleaved by cPLA₂ is subsequently converted to prostaglandins (PGs) and leukotrienes (LTs), whereas the lysophospholipid is converted to platelet-activating factor (PAF), lysophosphatidic acid (LPA), and sphingosine-1-phosphate (S1P). These lipid products function as local hormones through binding to their cellular receptors in autocrine or paracrine fashions or serve as intracellular second messengers to mediate a myriad of physiological and pathophysiological functions such as inflammation, cell proliferation, and carcinogenesis.
Phospholipase knock-out mice have less damage in response to injury, and you would expect a low linoleic acid diet to do the same.
In particular, our data reveal that AA directly binds to PPARδ in vitro and that addition of AA to isolated nuclear extracts or recombinant PPARδ protein enhances PPARδ DNA binding ability. These observations suggest that the effect of cPLA₂ on PPARδ activation may be mediated at least in part through increased AA in the nuclei.
Simple and straightforward. The phospholipase A₂ on the cell membrane releases arachidonic acid which diffuses through the cytosol and activates the nuclear PPARδ receptor—a process which had been known before the Wnt/β-catenin pathway had been first described. Phospholipase A₂ is a real enzyme and can do real things in vitro; I would love to see them try to get GSK3 to do the things in vitro that Wikipedia claims it can.
In the absence of a Wnt signal, β-catenin exists within a cytoplasmic complex (β-catenin destruction complex) along with glycogen synthase kinase 3b (GSK3b), adenomatous polyposis coli (APC), and axin, where it is phosphorylated and targeted for degradation by the proteasome. Activation of Wnt signaling perturbs this destruction complex, leading to cytoplasmic accumulation of b-catenin and allowing its translocation into the cell nucleus.
I think he's essentially correct except that he's semantically confused like most people. Beta-catenin is also an extracellular adhesion protein and an intracellular microtubule support protein; it's not fair to call the scaffold it's on a "destruction complex." I don't see how considering the process of phosphorylation is "inactivation," since it needs these to be a structural protein. Obviously it can't help PPARδ transcribe DNA when acting out one of its other roles, as a structural protein. But stucture has function—pull one of the legs out from your computer desk and see how well it computes.
Given that PPARδ and β-catenin are nuclear transcription factors or cofactors, we sought to further determine whether these two molecules might interact with each other in cell nucleus to modulate gene expression. In this study, we provide experimental evidence for a direct binding between PPARδ and β-catenin in human cholangiocarcinoma cells and show that this interaction is important for TCF/LEF transcription activity. Our data further reveal that the interaction between PPARδ and b-catenin and their transcription activity is regulated by cPLA₂.
Makes sense. It's easy to see how phospholipase A₂ could release arachidonic acid from the cell membrane and activate PPARδ.
Since the protein levels of β-catenin and TCF/LEF were not altered by cPLA₂ overexpression, the effect is likely mediated through increased β-catenin binding affinity to TCF/LEF element. The involvement of cPLA₂ in b-catenin activation is further confirmed by the observations that inhibition of cPLA₂ by specific siRNA or chemical inhibitors significantly reduced the TCF/LEF reporter activity. Moreover, inactivation of cPLA₂ by site directed mutagenesis abolished TCF/LEF transcription activity, suggesting that cPLA₂ activity is likely required for β-catenin activation. In contrast, the cyclooxygenase inhibitor, indomethacin, or the COX-2 inhibitor, NS-398, exhibited no significant effect on TCF/LEF reporter activity under the same experimental conditions. These results suggest that cPLA₂ initiated signaling cascade facilitates β-catenin association to TCF/ LEF element and enhances transcription activity.
Notice how the protein levels of β-catenin did not even increase in the nucleus, yet TCF/LEF activity was increased. This is the classic way to measure β-catenin activity—a fluorescent signal that increases . . . not in response to the absolute amount of β-catenin protein, but in response to arachidonic acid binding to PPARδ. All three of these need to be present for TCF/LEF activity, and yet only arachidonic acid needs to be increased to increase the fluorescent signal. A naïve researcher might interpret this fluorescence as as an increase in "total β-catenin," and subsequently use this interpretation to create wild and ridiculous cellular pathways involving "destruction complexes," translocators, and proteins phosphorylating other proteins. This signal was not blocked by indometacin, indicating that PPARδ binds arachidonic acid itself.
this assertion is supported by the observations that AA directly bound to PPARδ in vitro and that addition of AA to isolated nuclear extracts or recombinant PPARδ protein enhanced the ability of PPARδ binding to its DNA response element, DRE (PPARδ response element). Given the key role of cPLA₂-derived AA in PPARδ activation as indicated above, in the current study we sought to further determine whether cPLA2a-mediated PPARδ activation is implicated in b-catenin activity. As shown in Figure 2b, overexpression of cPLA2a enhanced the association of PPARδ with the b-catenin-TCF/ LEF complex, whereas it did not alter PPARδ protein level. Furthermore, siRNA suppression of PPARδ inhibited the cPLA₂-induced increase of TCF/LEF reporter activity. These results suggest a potential role for PPARδ in cPLA₂-mediated b-catenin activation.
All of the previous assays which had measured β-catenin by these two methods are increased by arachidonic acid alone, and hence cannot then be considered to represent an absolute increase in β-catenin levels. All of the cellular signalling mechanisms based on β-catenin DNA binding assays and TCF/LEF activity which hadn't measured arachidonic acid are now suspect. The simple activation of cell membrane phospholipase A₂ will create enough arachidonic acid to give the naïve impression of "more β-catenin"—increasing the transciptional activity of the β-catenin/PPARδ complex without actually increasing β-catenin in number.
The degree of β-catenin binding induced by AA is comparable to that by GW501516. In contrast, oleic acid, which has no effect on PPARδ activation, failed to alter β-catenin binding to TCF/LEF response element. These findings further support the role of PPARd in β-catenin activation. [...] We show that activation of PPARδ by cPLA₂ results in the formation of PPARδ-β-catenin complex, thus leading to β-catenin activation. The cPLA₂-induced PPARδ activation is mediated by arachidonic acid rather than PGE2. [...] In summary, this study depicts a novel connection linking cPLA₂ PPARδ and Wnt/β-catenin signaling pathways in human cholangiocarcinoma cells. Given the documented involvement of these molecules in bile duct inflammation and cancer, it is conceivable that activation of β-catenin by cPLA₂ and PPARδ may represent an important mechanism by which inflammatory process drives carcinogenesis.
You will find many of the same players in both the "Wnt/β-catenin pathway" and the eicosanoid pathway. The same cytokines are known to be step #1 of both pathways: Phospholipase A₂ in the obligatory second in both; prostaglandin receptors are coupled to the G-protein; both cis-retinol and all trans-retinoic acid bind the enzyme prostaglandin D₂ synthase more than anything; and there are really too many interactions to list. The "Wnt/β-catenin pathway" is the eicosanoid pathway when examined using the protein fraction while ignoring the lipid fraction—arachidonic acid and the eicosanoids—that important part that floated to the top of the centrifuge vial, but decanted. These molecular biologists found a way to explain the already well-characterized eicosanoid pathway by focusing only on proteins and nucleic acids—thinking they'd discovered something entirely novel but hadn't. The ridiculous mechanics invoked and whimsical names are further testament to this.
Using the "Wnt/β-catenin pathway" to explain cellular inflammation cascades is akin to commentating an entire soccer match by focusing exclusively on one team only.. . ..and then watching that team make an "own goal" while not telling the listeners what had just happened.
Though perhaps more glamorous than thin-layer chromatography and HPLC, polyacrylamide gel electrophoresis and DNA hybridization allows only the measurements of proteins and amino acids. The mechanisms which result from such experiments are necessarily incomplete for explaining signals whose origins begin with phospholipase A₂—the cytokine-induced liberator of arachidonic acid.
The nuclear transcription events correlate better with the eicosanoids than with the paradigmatic Wnt/β-catenin proteins, both in their phosphorylation status and absolute amounts.
I think that a study which explains inflammatory events in Wnt/β-catenin terms can be useful as long as one is cognizant of the assumptions being made, the existence of the microtubule cytoskeleton, and the prostaglandins present (but not emphasized.)
Is this pathway just one of the many tenable pathways that were available, but given precedence through selective funding by food industries wishing to explain inflammation in alternative ways? . . Ways not involving their product? Perhaps even created by one of their own, wheeled-up to the threshold of scientific literature and left there like a Trojan
Last edited:
sladerunner69
Member
Interesting find there, hamster.
One thing that has always confused me about pattern baldness is the "pattern" aspect that much more commonly affects males. If stress was the primary culprit responsible for hair follicles to shut down or shed or go into "sleep" phase, then why so broadly does it exhibit the classic pattern of receding hairline and bald spot on the crown? Of course many people, and commonly women as well, can experience "diffuse" thinning, and even lose their hair in random spots and patches uniformly around the scalp. The mainstream knowledge says that this form of baldness is responsible to "stress" where as the former is due to androgens. Hence why women commonly don't experience the former, although that is not to say it doesn't happen. For example I know female bodybuilders and athletes who commonly experience male pattern baldness, especially when taking androgens for athletic performance. I also personally knew a girl who had issues with a slightly receding hairlines and acne which worried her as a teenager, so her doctor said she had high androgens (for a female) and prescribed her estrogen supplement. Of course I begged her to quit taking it and showed her progesterone instead.
sladerunner69
Member
Interesting find there, hamster.
One thing that has always confused me about pattern baldness is the "pattern" aspect that much more commonly affects males. If stress was the primary culprit responsible for hair follicles to shut down or shed or go into "sleep" phase, then why so broadly does it exhibit the classic pattern of receding hairline and bald spot on the crown? Of course many people, and commonly women as well, can experience "diffuse" thinning, and even lose their hair in random spots and patches uniformly around the scalp. The mainstream knowledge says that this form of baldness is responsible to "stress" where as the former is due to androgens. Hence why women commonly don't experience the former, although that is not to say it doesn't happen. For example I know female bodybuilders and athletes who commonly experience male pattern baldness, especially when taking androgens for athletic performance. I also personally knew a girl who had issues with a slightly receding hairlines and acne which worried her as a teenager, so her doctor said she had high androgens (for a female) and prescribed her estrogen supplement. Of course I begged her to quit taking it and showed her progesterone instead.
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