NLRP3 Inflammasome Cause Of Male Pattern Baldness theory

Pigeon

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Interesting theory and discussion going on at raypeat.com


So far I haven't really seen any profound regrowth stories on this forum (eg returning to dense nw1).

I think Danny and Ray are correct, though I wonder if someone who has a better understanding of biochemistry than i do could possibly integrate this guys theory into our bioenergetic view:

(i imagine its the subtle piece of the puzzle that allows some of us to revert multiple norwoods. maybe not idrk lol)

here's a really interesting comment on a Danny Roddy video:

1:
Mark Panbecker:
"It only took me 17 years and and about 50K pubmed abstracts to find out the SAME mechanism that causes gout ALSO is the same mechanism that causes male pattern baldness. Castration prevents both gout and male pattern baldness. The mechanism or VERY close is: NLRP3 inflammasome activation which involves casp1 activation(which is higher in male pattern baldness scalp). Problem with too much casp1 is that it cleaves(chews up) the glucocorticoid receptor. Inflammation and autoimmunity are well known with NLRP3 activation. Without glucorticoid receptor function(I believe) you get AR upreg stepping in as a surrogate for a dysfunctional GC receptor. Glucocorticoid resistance is THEE major problem in hair loss. Autophagy prevents the NLRP3 cascade. That's why you see also babies sometimes born like a male pattern baldness shape even in girls because sometimes the mother has high GC levels in late term."

- I saw in a Peat facebook group a woman claiming her husband growing his hairline back after fasting

- casp1 in Androgenetic Alopecia scalps study Caspase-1 level is higher in the scalp in androgenetic alopecia - PubMed

- this may explain some of the finasteride/ mtf transition successful regrowth

- its been mentioned on this forum that a finasteride user kept great hair but aged poorly in other ways

- could this mean there is a very specific type of inflammation cascade occuring in the scalps of balding men?

- some hypothyroid people maintain really great hair. Some people recover their stress/thyroid health to ideal / hyper yet struggle to gain significant regrowth

- in other words, could this make sense of how some unhealthy people can keep great hair?

2:
"Mark Panbecker4 years ago
Read this link about lyme disease(activates NLRP3) and male pattern baldness initiation. https://www.nczonline.net/blog/2014/04/02/i-have-lyme-disease/ Also immortal hair has some college guys suddenly develop male pattern baldness in their mold filled apartment. NLRP3 activated by microbes, cholesterol crystals, low PH, numerous things."


- a possible connection with Danny - genetically some have stress physiology that is susceptible to this "NLRP3 cascade"

- btw im not suggesting castration as a solution lmao, maybe there is some peaty method that should be doubled down on in particular to allow sufficient / youth like autophagy of "NLRP3 inflammasome" (?)

3:
"Mark Panbecker3 years ago
I never said GOUT was the cause of male pattern baldness. NLRP3 is the key pathway to look at for gout and male pattern baldness.Castration cures both. Autophagy (lack of it) it the real problem because dht downregulates it thru microRNA 221. Autophagy stops the nlrp3 from firing. Look at all drugs that cause hair growth just "happen" to increase autophagy."

possibly related forum thread?: Hair Regrowth After Glucocorticoids - Any Ideas Why?

dafaq?
Autophagy is essential for maintaining the growth of a human (mini-)organ: Evidence from scalp hair follicle organ culture
Autophagy is essential for maintaining the growth of a human (mini-)organ: Evidence from scalp hair follicle organ culture


link to the Danny Roddy video where you can find the discussion towards the bottom of the comment section:


(sorry if my writing is scattered)

surely we can solve male pattern baldness completely and for good. (Btw i like to imagine that if the Ray Peat / pro metabolic community can legitimately surpass the mainstream big 3 'treatments' - itd lead to a huge awakening in the masses view of mainstream pharmaceuticals/thyroid/scientism)

id love to hear what you folks think of this.
 
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There was some discussion last year on autophagy and this study.

Alpha ketoglutarate was one that was mentioned that induced autophagy in the skin (along with Metformin, Rapamycin).

Contrast showers are thought to induce autophagy. So maybe experiment with sticking your head under cold water for a couple minutes, then transfer to hot water, and repeat.
 

hairDespair

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I understand about zero of that, but is the talk about inflammation what could be responsible for that annoying itch. Some people say there's no connection, but it's always been in spots where I recede
 

pegasus2

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I understand about zero of that, but is the talk about inflammation what could be responsible for that annoying itch. Some people say there's no connection, but it's always been in spots where I recede
That itch is from oxidative stress, and it is indeed connected.
 

OtyMac

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I think the post on raypeat discusses glucocorticoid resistance. One way to overcome glucocorticoid resistance is by MORE GC's. Dexamethasone given to this patient rapidly reversed his frontal balding. He also had other problems, so this is hardly and open and shut case but tends to support the GC resistance hypothesis.

PDF file on researchgate:
Coexistence of Glucocorticoid Resistance and Pseudohypoparathyroidism
R Krysiak, A Kędzia, B Okopień


"
Although insulin resistance is commonly found in clinical practice (1), resistance to other hormone
occurs much less frequently and the prevalence may be higher than described in the literature.
The underestimation of these clinical entities partially results from physicians' inadequate knowledge about
their existence.

Glucocorticoid resistance is characterized by an inability of glucocorticoids to produce their
biological effects at the level of target tissues (2, 3). This results in a compensatory increase in the
secretion of adrenocorticotrophic hormone (ACTH) and cortisol, which in some patients may protect
against the signs of adrenal cortex insufficiency (4, 5). Increased plasma ACTH levels also stimulate
mineralocorticoid and androgen productions, leading to increased renal sodium absorption and to
androgen excess. Therefore, patients with diagnosed glucocorticoid resistance are often characterized
by arterial hypertension and hyperandrogenism coexisting with symptoms of glucocorticoid deficiency

At the age of 23 years, he developed arterial hypertension and therefore was treated by a general practitioner with -
receptor antagonists and calcium channel blockers. Because this treatment resulted in only a moderate
reduction in blood pressure, the patient was admitted to clinic with a suspicion of secondary
hypertension. On admission, he complained of asthenia, adynamia, muscular cramps and weakness,
paresthesias as well as frontal baldness.


The patients was diagnosed with glucocorticoid resistance and prescribed with dexamethasone (at the initial daily dose of 1 mg) which
had to be increased to 2 mg daily to induce a rapid disappearance of tiredness, hair regrowth and a
normalization of blood pressure. The resultant clinical improvement was associated with a
normalization of urinary free cortisol (85 g/day), plasma aldosterone levels and plasma renin activity."
 
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I understand about zero of that, but is the talk about inflammation what could be responsible for that annoying itch. Some people say there's no connection, but it's always been in spots where I recede

Anyone who says there's no connection between inflammation and Androgenetic Alopecia should be ridiculed like flathearthers and moon landing deniers. That being said androgens are absolutely the trigger.
 

Squeegee 2.0

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Interesting find Pigeon!

Overactivation of the NLRP3 inflammasome triggers the abundant secretion of IL-1β and IL-18, induces pyroptosis, and promotes the release of a swathe of proinflammatory proteins, all of which contribute to fibrogenic processes in multiple organs..

 

Squeegee 2.0

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Vitamin B regulates the activation of NLRP3 inflammasome​

 

Squeegee 2.0

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Collectively, these findings reveal novel anti-inflammatory activities for vitamin B6 and suggest its potential for preventing inflammatory diseases driven by the NLRP3 inflammasome.

Vitamin B6 Prevents IL-1β Protein Production by Inhibiting NLRP3 Inflammasome Activation​


 
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I think the post on raypeat discusses glucocorticoid resistance. One way to overcome glucocorticoid resistance is by MORE GC's. Dexamethasone given to this patient rapidly reversed his frontal balding. He also had other problems, so this is hardly and open and shut case but tends to support the GC resistance hypothesis.

PDF file on researchgate:
Coexistence of Glucocorticoid Resistance and Pseudohypoparathyroidism
R Krysiak, A Kędzia, B Okopień


"
Although insulin resistance is commonly found in clinical practice (1), resistance to other hormone
occurs much less frequently and the prevalence may be higher than described in the literature.
The underestimation of these clinical entities partially results from physicians' inadequate knowledge about
their existence.

Glucocorticoid resistance is characterized by an inability of glucocorticoids to produce their
biological effects at the level of target tissues (2, 3). This results in a compensatory increase in the
secretion of adrenocorticotrophic hormone (ACTH) and cortisol, which in some patients may protect
against the signs of adrenal cortex insufficiency (4, 5). Increased plasma ACTH levels also stimulate
mineralocorticoid and androgen productions, leading to increased renal sodium absorption and to
androgen excess. Therefore, patients with diagnosed glucocorticoid resistance are often characterized
by arterial hypertension and hyperandrogenism coexisting with symptoms of glucocorticoid deficiency

At the age of 23 years, he developed arterial hypertension and therefore was treated by a general practitioner with -
receptor antagonists and calcium channel blockers. Because this treatment resulted in only a moderate
reduction in blood pressure, the patient was admitted to clinic with a suspicion of secondary
hypertension. On admission, he complained of asthenia, adynamia, muscular cramps and weakness,
paresthesias as well as frontal baldness.


The patients was diagnosed with glucocorticoid resistance and prescribed with dexamethasone (at the initial daily dose of 1 mg) which
had to be increased to 2 mg daily to induce a rapid disappearance of tiredness, hair regrowth and a
normalization of blood pressure. The resultant clinical improvement was associated with a
normalization of urinary free cortisol (85 g/day), plasma aldosterone levels and plasma renin activity."

Adding strong topical corticosteroids to my standard anti androgen regimen is pretty much the only thing that helps me. Problem is you can't use them more than couple of weeks so it's pretty useless for fighting Androgenetic Alopecia.
 

Squeegee 2.0

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Pharmacological Inhibitors of the NLRP3 Inflammasome​


Table 1​

Potential inhibitors of NLRP3 inflammasome and their targets.
Agent
Target(s)
Potential mechanism
References
Glyburide​
NLRP3 (indirectly)​
Inhibits ATP-sensitive K+ channels; downstream of P2X7 resulting in inhibition of ASC aggregation​
(48, 54)​
16673-34-0​
NLRP3 (indirectly)​
Induces NLRP3 conformational changes secondary to its activation or binding to ASC​
(55, 56)​
JC124​
NLRP3?​
Blocks the expression of NLRP3, ASC, caspase-1, pro-IL-1β, TNFα and iNOS​
(57)​
FC11A-2​
NLRP3 (indirectly)​
Interferes with proximity induced autocleavage of pro-caspase-1, suppresses IL-1β/18 release​
(58)​
Parthenolide​
NLRP1, NLRP3 inflammasome, Caspase-1, NF-κB, IKKβ kinase activity​
Alkylates cysteine residues in caspase-1 and in ATPase domain of NLRP3, inhibits NLRP3 ATPase activity​
(59, 60)​
VX-740​
Caspase-1​
Covalent modification of the catalytic cysteine residue in the active site of caspase-1 resulting in caspase-1 blocking and resultant cleavage of pro-IL-1β/18​
(61, 62)​
VX-765​
Caspase-1​
Covalent modification of the catalytic cysteine residue in the active site of caspase-1 resulting in caspase-1 blocking and resultant cleavage of pro-IL-1β/18​
(61, 63)​
Bay 11-7082​
NLRP3, IKK, E2/3 enzymes, PTPs​
Alkylates the cysteines in the ATPase domain of NLRP3, inhibits NLRP3 ATPase activity​
(59, 6466)​
BHB​
NLRP3 (Indirectly)​
Inhibits K+ efflux resulting in reduced oligomerization of ASC and IL-1β/18 release​
(49)​
MCC950​
NLRP3​
Blocks the ATPase domain of NLRP3 resulting in inhibition of canonical and non-canonical NLRP3 inflammasome activation​
(67, 68)​
MNS​
NLRP3​
Inhibits NLRP3 ATPase activity by cysteine modification, blocks NLRP3 inflammasome activation​
(53)​
CY-09​
NLRP3​
Inhibits NLRP3 ATPase activity, blocks NLRP3 inflammasome activation​
(69)​
Tranilast​
NLRP3​
Binds to NLRP3 NACHT domain to block NLRP3-NLRP3 and NLRP3-ASC interaction​
(52)​
OLT1177​
NLRP3​
Inhibits NLRP3 ATPase activity, blocks NLRP3 inflammasome activation​
(70)​
Oridonin​
NLRP3​
Binds to cysteine 279 of NLRP3 to abolish NLRP3-NEK7 interaction, blocks NLRP3 inflammasome activation​
(71)​


 

Squeegee 2.0

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Anti-NLRP3 Inflammasome Natural Compounds: An Update​


 

StayPositive

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zaman

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Tranilast too, already comes in a gel formulation with betamethasone
 

OtyMac

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Predictable outcome from estradiol, I guess.


Estradiol inhibits NLRP3 inflammasome in fibroblast-like synoviocytes activated by lipopolysaccharide and adenosine triphosphate​



Conclusion​


These results suggested the increased LPS and ATP in joint-space may promote knee OA by NLRP3 inflammasome and E2 may exert a protective effect by inhibiting the activation of NLRP3 inflammasome in FLS.

________________

My other interest is in LPS as to whether they cause or contribute to balding. Mybiohack and selfhacked and Haidut on raypeat have some excellent articles about LPS. I found out too that LPS(lipo) has an affinity for sebum.

By the way, LPS works on skin immunity.


Since the LPS molecule contains a lipid that has an affinity for sebum, it penetrates the sebum-containing stratum corneum.

However, as described earlier, the granular layer beneath the stratum corneum contains “tight junction” that prevent most substances from passing through.

LPS is believed to be no exception and cannot penetrate the tight junction.

However, LPS receptors are present in keratinocytes, found most commonly in the epidermis; Langerhans cells, whose dendrites extend to the stratum corneum; and regulatory T (Treg) cells, which mediate inflammation in a suppressive manner. Therefore, all these cell types respond to LPS. Thus, even if LPS does not penetrate the “tight junction”, it can work on the skin immune system.
 
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OtyMac

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NLRP3 pathway activation shows hair loss in mice.​

NLRP3 Inflammasome Plays an Important Role in the Pathogenesis of Collagen-Induced Arthritis​



There was no mortality in CIA and Normal mice during the experiment. 16 mice in CIA group developed CIA. The mice in Normal group showed increased weight gain, active, shiny hair, and easy movement. The mice in CIA group showed various degrees of redness and swelling in the hind limbs, dull hair and hair loss, fatigue, weariness, and slower or even declined weight gain at 3-4 weeks after immunization.
 
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