RENIN-ANGIOTENSIN-ALDOSTERONE SYSYTEM And HAIR LOSS PROCESS

[md_a]

so topical licorice/liquorice is an option?

Although in some studies it seems to be an interesting substance, it could help to grow hair on the head or remove hair from the body, however, I do not understand exactly how it works and could produce some pretty serious side effects, and from this reason, I am reluctant to test it.


Common side effects of licorice include:

Absence of a menstrual period

Congestive heart failure

Decreased sexual interest (libido)

Erectile dysfunction

Excess fluid in the lungs (pulmonary edema)

Fluid and sodium retention

Headache

High blood pressure (hypertension)

Hypertensive encephalopathy

Hypokalemic myopathy

Lethargy

Low potassium levels (hypokalemia)

Mineralocorticoid effects

Muscle wasting

Myoglobinuria

Occasionally brain damage in otherwise healthy people

Paralysis (quadriplegia)

Swelling (edema)

Tiredness

Weakness

Licorice: Side Effects, Dosages, Treatment, Interactions, Warnings

Licorice abuse: time to send a warning message


Man dies after eating bags of black licorice every day

Man dies after eating bags of black licorice every day | Live Science

 

[johnwester130]

Although in some studies it seems to be an interesting substance, it could help to grow hair on the head or remove hair from the body, however, I do not understand exactly how it works and could produce some pretty serious side effects, and from this reason, I am reluctant to test it.


Common side effects of licorice include:

Absence of a menstrual period

Congestive heart failure

Decreased sexual interest (libido)

Erectile dysfunction

Excess fluid in the lungs (pulmonary edema)

Fluid and sodium retention

Headache

High blood pressure (hypertension)

Hypertensive encephalopathy

Hypokalemic myopathy

Lethargy

Low potassium levels (hypokalemia)

Mineralocorticoid effects

Muscle wasting

Myoglobinuria

Occasionally brain damage in otherwise healthy people

Paralysis (quadriplegia)

Swelling (edema)

Tiredness

Weakness

Licorice: Side Effects, Dosages, Treatment, Interactions, Warnings

Licorice abuse: time to send a warning message


Man dies after eating bags of black licorice every day

Man dies after eating bags of black licorice every day | Live Science

I think travis said it should only be used topically, not eaten

 

[johnwester130]

Mineralocorticoid Receptor Antagonists Stimulate Human Hair Growth Ex Vivo
Abstract

Whilst topical steroids represent one of the most frequently administered treatments for skin and hair diseases, predominantly based on their glucocorticoid receptor-mediated anti-inflammatory effects, the mineralocorticoid effects of topical steroids have received surprisingly little attention. However, the role of mineralocorticoid receptor (MR) signaling is now known to extend beyond the kidney, with human skin, including the hair follicle (HF), expressing the MR. Using microdissected female HFs treated ex vivo with MR agonists and antagonists, we sought to determine the effects of MR-mediated signaling in the cutaneous context. Indeed, not only did the skin and HF epithelium express the MR at both the gene and protein level, but its expression was hair cycle dependent. Moreover, the selective MR antagonist eplerenone promoted hair shaft elongation and hair matrix keratinocyte proliferation whilst delaying catagen (HF regression). These novel observations suggest that the female human HF is sensitive to the inhibition of MR signaling and provide the first evidence that sustained MR signaling may even be required to maintain the growth phase (anagen) of human scalp HFs. Indeed, these data encourage the systematic evaluation of MR agonists and antagonists in human hair growth control so as to identify much-needed, novel anti-hirsutism and/or hair growth-promoting agents, respectively.

Mineralocorticoid Receptor Antagonists Stimulate Human Hair Growth Ex Vivo - PubMed

...
Eplerenone, sold under the brand name Inspra, is a steroidal antimineralocorticoid of the spirolactone group that is used as an adjunct in the management of chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevated aldosterone. Classed as a selective aldosterone receptor antagonist (SARA),[5] it is similar to the diuretic spironolactone, though it is much more selective for the mineralocorticoid receptor in comparison (i.e., does not possess any antiandrogen, progestogen, glucocorticoid, or estrogenic effects), and is specifically marketed for reducing cardiovascular risk in patients following myocardial infarction. Eplerenone is a potassium-sparing diuretic, meaning that it helps the body get rid of water but still keep potassium.

It was patented in 1983 and approved for medical use in the United States in 2002.[6][7] Eplerenone is currently approved for sale in Canada, the US, EU, Netherlands and Japan.[7] Eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension.[8]

Eplerenone may have a lower incidence than spironolactone of sexual side effects such as feminization, gynecomastia, impotence, low sex drive and reduction of size of male genitalia.[8] This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes.[3] When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone.[3]

Eplerenone - Wikipedia

...

Eplerenone: A Selective Aldosterone Receptor Antagonist (SARA)

ABSTRACT
Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensinconverting enzyme (ACE) inhibitors and angiotensin type 1 (AT1) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels — a phenomenon termed “aldosterone synthesis escape.” Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone — the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs) — is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

CONCLUSION
Eplerenone will be the first drug in a new class of SARAs. The ability to effectively block the MR while avoiding limiting side effects promises to be an important advancement in the chronic treatment of life-threatening cardiovascular disorders. Ongoing phase III trials in hypertension and heart failure will soon reveal if the promising preclinical and phase II clinical data can be extended to large patient populations and are likely to uncover additional benefits of this unique agent.

Error - Cookies Turned Off

would you think topical eplerenone would be a good idea?

this contains enoxolone and Glycyrrhetinic acid that Travis mentioned

Akilwinter CHILBLAIN Frostbite Inflammation Warming Cream Cold Weather 75ml | eBay

 

[md_a]

would you think topical eplerenone would be a good idea?

this contains enoxolone and Glycyrrhetinic acid that Travis mentioned

Akilwinter CHILBLAIN Frostbite Inflammation Warming Cream Cold Weather 75ml | eBay

From studies it seems an interesting substance, but I have not tested it and I can not be sure if it is effective and without side effects.

 

[johnwester130]

From studies it seems an interesting substance, but I have not tested it and I can not be sure if it is effective and without side effects.

okay thanks

this says topical spironoalctone does not go systemic and cites 4 sources

https://www.maapgh.com/assets/files/TOPICAL_SPIRO.pdf


Final question - why not just take

ANGIOTENSIN blockers ?

 

[md_a]

okay thanks

this says topical spironoalctone does not go systemic and cites 4 sources

https://www.maapgh.com/assets/files/TOPICAL_SPIRO.pdf


Final question - why not just take

ANGIOTENSIN blockers ?

Studies show that AT1 inhibitors have an anti-inflammatory and beneficial effect on hair. AT1 inhibitors are ARB-I, and ACE-I stimulates the inflammatory process through bradykinin and harms hair. Because they are drugs, they are supposed to have side effects. In my experience, stopping hair loss can be done quickly and efficiently by stimulating CO2 production, if necessary, by breathing in the bag, at least 1 hour a day for good effect, breath control ... The difficult part involves regenerating hair once fallen, and I think as certain lotions applied topically at the scalp level is necessary, but because it is a long process must be experienced until the most suitable solution is found, and I am thinking of emodin, urea, carbonic anhydrase inhibitors, certain essential oils, FO-TI. As internal supplements, I think that vitamins B1, B2, B3 are important (to reduce lactic acid and help the liver to work effectively in eliminating toxins), magnesium, and the diet should focus on Folate, Zinc, Copper, B6, a lot of sugar, adequate protein, little fat, more calcium than phosphate, enough magnesium, sun, light treatment, without excess Vitamin A :).

…

The finding of the vitamin D hormone as a negative endocrine regulator of the RAS has important physiological and clinical significance. It suggests that the vitamin D endocrine system may maintain the homeostasis of the cardiovascular system through suppressing the RAS, and vitamin D-deficiency or insufficiency may lead to activation of the RAS, thus increasing the risk of cardiovascular disease. Vitamin D analogs as novel renin inhibitors have great therapeutic potentials for cardiovascular disease. Combination therapy with vitamin D analogs and RAS inhibitors can enhance the therapeutic efficacy in the treatment of cardiovascular disease.

MOLECULAR MECHANISM OF VITAMIN D IN THE CARDIOVASCULAR SYSTEM

…

Conclusions

The present review indicates that AT1R antagonists or vitamin D or a combination may be useful in treating the lung complication of COVID-19. Appropriately designed clinical studies are needed to establish the benefit of the combination of AT1R antagonists with vitamin D.

Can a Combination of AT1R Antagonist and Vitamin D Treat the Lung Complication of COVID-19?

…

Serum ACE levels have been found to be significantly elevated in AIDS patients, patients in the intermediate stage of HIV infection, and patients with Pneumocystis carinii pneumonia.

Thiamine attenuates hypertension and metabolic abnormalities in spontaneously hypertensive rats (SHRs). Thiamine repletion downregulates the expression of angiotensinogen (−80%), ACE (−77%), and angiotensin type 1 receptor (−72%) mRNAs in SHRs.34 These observations suggest that thiamine affects ACE activity in HIV-infected patients.

The role of thiamine in HIV infection - ScienceDirect

…

The role of RAAS in the hair loss process should be considered as highly possible due to reports linking to the intake of ACE-I to hair loss. Interestingly, discontinuation of ACE-I (ACE inhibitor) treatment or switching patients from ACE-I (ACE inhibitor) to ARB (Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) has resulted in hair regrowth.

JPP No 3/2019 article 01

...

Hypoxia causes cells to produce more AT-1 which leads to edema.

Old people have a decreased expression of ACE2 (Angiotensin-converting enzyme 2), and increased expression of AT-1 receptors compared to the young.

Cancer, hypertension, diabetes, chronic obstructive pulmonary disease…. are all conditions that are associated with higher levels of the AT-1 receptor (Angiotensin II receptor type 1), with greater age or severity related to higher levels.

In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.

ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage by way of the Angiotensin II receptor type 1 which is called the AT1, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production.

In some pathological conditions, overactivation of AT1 may lead to damaging events like fibrosis in different organs such as liver and lungs, perhaps through increasing TGFβ expression.

Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.

ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.

…

TGF-β plays important roles in the induction of catagen during the hair cycle. We examined whether TGF-β2 could activate a caspase in human hair follicles. Using active caspase-9 and -3 specific antibodies, we found that TGF-β2 activated these caspases in two regions, the lower part of the hair bulb and the outer layer of the outer root sheath. In addition, we searched for a plant extract that can effectively suppress TGF-β action. We found that an extract of Hydrangea macrophylla reduced synthesis of a TGDβ-inducible protein. We confirmed that the extract has a potential to promote hair elongation in the organ culture system. Furthermore, it delayed in vivo progression of catagen in a mouse model. Our results suggest that the induction of catagen by TGF-β is mediated via activation of caspases and that a suppressor of TGF-β could be effective in preventing male pattern baldness.

A Potential Suppressor of TGF-β Delays Catagen Progression in Hair Follicles - ScienceDirect

…

Our data demonstrated the expression of 11β-HSD1 in human DPCs and revealed that inhibition of 11β-HSD1 activity can partially prevent the negative effect of glucocorticoids on DPCs, suggesting the possible application of 11β-HSD1 inhibitors for stress-related hair loss.

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Attenuates the Adverse Effects of Glucocorticoids on Dermal Papilla Cells

…

Angiotensin II is also well known in inducing reactive oxygen species and promoting inflammatory phenotype switch via its type 1 receptor. In clinic, Angiotensin II type 1 (AT1) receptor blocker like candesartan has been widely applied as an antihypertensive medication.

It was found that pre-treat with candesartan significantly suppressed transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) expression after incubation with TNF-α.

Candesartan inhibits inflammation through an angiotensin II type 1 receptor independent way in human embryonic kidney epithelial cells

…

Lisinopril-Induced Alopecia: A Case Report

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines consider angiotensin-converting enzyme (ACE) inhibitors as one of the mainstay therapies in the management of heart failure. The widespread use of ACE inhibitors has been associated with several notable adverse effects such as hyperkalemia and an increased serum creatinine. There are no previous reports of alopecia associated with lisinopril use; however, a few previous cases of alopecia associated with other ACE inhibitors exist. This report discusses a case of lisinopril-induced alopecia of a 53-year-old male presenting to our outpatient heart failure clinic with a chief complaint of a new onset of alopecia. Upon evaluation, it was suspected that the patient’s alopecia was likely medication induced by lisinopril; therefore, lisinopril was discontinued and switched to an angiotensin receptor blocker (ARB), losartan potassium. Alopecia resolved in 4 weeks after the therapeutic intervention.

SAGE Journals: Your gateway to world-class research journals

…

The beneficial effect of Ang-(1-7) in alopecia can be attributed to their vasodilation action on blood vessels (Santos et al., 2000). The vasodilation of arterioles present in the dermis improves irrigation of the hair follicles, increasing the supply of nutrients and oxygen. Thus, the cells of the hair follicle increase their proliferation, accelerating hair growth

https://patents.google.com/patent/US20150313829A1/en

…

The RAS is a coordinated complex hormonal cascade that is composed of angiotensinogen, angiotensin-converting enzyme (ACE) and its homolog angiotensin converting enzyme 2 (ACE2), and angiotensin II (Ang II) type 1 and type 2 receptors (AT1, AT2). ACE cleaves the decapeptide Ang I into the octapeptide Ang II, while ACE2 cleaves a single residue from Ang II to generate Ang 1-7, which in turn blocks Ang II and inhibits ACE.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729230/

…

ACE converts Angiotensin I to Angiotensin II and also inactivates bradykinin.

ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin.

ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation). Increased bradykinin levels are also responsible for the most common side effect of ACE inhibitor treatment; a dry cough.

KKS (kallikrein-kinin system) activation and liberation of bradykinin increases endothelial cell permeability.

Bradykinin induces vasodilation by stimulating production of nitric oxide, the arachidonic acid metabolites prostacyclin (PGI-2) and PGE-2, and endothelium-derived hyperpolarizing factor.

During inflammation, it is released locally from mast cells and basophils during tissue damage.

Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.

Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks. Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.

Beside the classical mediators, such as catecholamines, histamine, serotonin, and bradykinin, increasing attention has recently focused on metabolites of arachidonic acid, cytokines, and products from circulating or resident inflammatory cells. Of all these humoral and cellular alterations, the activation and liberation of proteinases seems to play an essential role with regard to loss of capillary barrier function and interstitial edema formation.

…

The theory connects many of the disparate symptoms of COVID-19, from a loss of sense of smell and taste, to a gel-like substance forming in the lungs, and abnormal coagulation. It posits that SARS-CoV-2 disrupts both the renin-angiotensin system (RAS) and the kinin-kallikrein pathways, sending bradykinin -- a peptide that dilates blood vessels and makes them leaky -- out of whack. The process impedes the transfer of oxygen from the lung to the blood and subsequently to all other tissues, a common abnormality in COVID-19 patients.

When the virus interacts with ACE2, it triggers an abnormal response in the bradykinin pathway, Jacobson said. At the same time, levels of angiotensin-converting enzyme, which is involved in the breakdown of bradykinin, were lower in COVID-19 patients than in controls.

The Bradykinin molecular structure over a computer rendering of the coronavirus

In the last week, questions have been raised about whether cytokine storm is indeed a culprit in severe COVID-19, while a paper from a government lab has made an intriguing and much-discussed case for a new mechanism, bradykinin storm.

While the concepts are not necessarily mutually exclusive, scientists trying to understand how COVID-19 wreaks its damage on the human body have been buzzing about the new possibilities.

The theory connects many of the disparate symptoms of COVID-19, from a loss of sense of smell and taste, to a gel-like substance forming in the lungs, and abnormal coagulation. It posits that SARS-CoV-2 disrupts both the renin-angiotensin system (RAS) and the kinin-kallikrein pathways, sending bradykinin -- a peptide that dilates blood vessels and makes them leaky -- out of whack. The process impedes the transfer of oxygen from the lung to the blood and subsequently to all other tissues, a common abnormality in COVID-19 patients.

Jacobson and co-authors used a supercomputer to compare gene expression in lung cells from nine infected and 40 uninfected individuals.

They found the COVID-19 cases had extremely high levels (increased nearly 200-fold) of angiotensin-converting enzyme 2 (ACE2), the surface protein used by the coronavirus to enter the cell.

When the virus interacts with ACE2, it triggers an abnormal response in the bradykinin pathway, Jacobson said. At the same time, levels of angiotensin-converting enzyme, which is involved in the breakdown of bradykinin, were lower in COVID-19 patients than in controls.

"This is the perfect storm, where all the things that could go wrong will lead the system to really go out of control," Jacobson told MedPage Today. "When that happens, you're going to get hyper-permeable blood vessel fluid pouring out of these infected areas and into the lungs."

Compared with controls, patients with COVID-19 also had upregulated genes responsible for synthesizing hyaluronic acid -- a polymer that can absorb more than 1,000 times its weight in water -- and downregulated genes responsible for degrading it, Jacobson said.

In effect, the bradykinin dysregulation will cause blood vessels to leak, and the hyaluronic acid dysregulation will pour massive quantities of a gel-like substance into the alveoli. This aligns with autopsy reports that detail the lungs of patients with COVID-19 feeling "like a water balloon that is filled with Jell-O," Jacobson said.

"That explains why ventilation has been so difficult," he noted. "At some point when you have enough of this hyaluronic acid in your lungs, with all the water you've captured, it kind of doesn't matter how much oxygen you're pumping into the lungs -- it can't get through to do gas exchange in the capillaries and alveoli."

Excess bradykinin can also shift important electrolyte levels, like potassium, which in turn can cause angioedema, sudden cardiac death, diarrhea, and reduced cognitive function, Jacobson and co-authors noted. ACE inhibition has also been linked with a loss of taste or smell.


The bradykinin storm is not mutually exclusive from the cytokine storm described in severe COVID-19 in the early stages of the pandemic. While cytokines are involved in the virus's attack, Jacobson said they did not see the same out-of-control, cascading effect represented by the cytokine storm hypothesis.

https://www.medpagetoday.com/infectiousdisease/covid19/88560

...

Conclusions

The invasiveness and immunosuppression of many cancers appears dependent on inflammation and the upregulation of AT1. Two mechanisms for upregulation of AT1 are discussed: 1) evolutionary changes to take advantage of this pro-inflammatory control mechanism, 2) AT1 expression induced by an alternating environment of hypoxia and oxidative stress. Immunosuppression as a common protection mechanism of solid tumours against immune responses has been verified from current literature and experimental procedures, as has the implication of cytokines and chemokines in tumour growth and metastasis. Given the involvement of AT1 in the immunosuppression and inflammatory processes, as well as in the expression of the pro-inflammatory cytokines and chemokines, it becomes evident that the AT1 receptor is essential for tumour protection and progression. A combination therapy consisting of AT1 receptor antagonists, NSAID for further control of the inflammation and immune therapy in the form of tumour vaccines should provide a novel and successful treatment for solid tumours.


In the renin-angiotensin system, the angiotensin II receptors AT1 and AT2 seem to have opposing functions. The actions of AT1 being principally pro-inflammatory whilst AT2 provides protection against hypoxia, draws inflammatory action to a close and promotes healing. The various direct and indirect mechanisms for feedback between the receptors, their induced products and the external hormonal system in the control of inflammation and healing are summarised in a highly simplified model which none the less can be used to explain how many key promoters and inhibitors of disease exert their effects.


From a review of the current disease literature, it has been demonstrated that the role of AT1 and AT2 in inflammation is not limited to cancer-associated inflammation, but is generally consistent and system wide. Potential therapy by manipulation of these receptors, although at an early stage, has been demonstrated for some of these diseases and it is proposed that this approach will provide an effective basis for the treatment of autoimmune, inflammatory and neurodegenerative disorders using existing drugs. AT1 receptor blockade should, in addition, provide a treatment to alleviate the damage caused by bacterial and viral infections, where their destructive action is through chronic inflammation. Given the importance of the immune suppressant effect of inflammation in cancer, it is anticipated that AT1 blockade should also serve to elicit a more effective immune response to other invaders that seek to corrupt the wound recovery process.


Manipulation of the AT1 and AT2 receptors has profound and exciting implications in the control of disease.

https://journal-inflammation.biomed...vPkIEcKQU24at749wzqLNFX1cMYgDeshptNPsyUER02Qs

 

[md_a]

Carboxytherapy Found to Be Effective As Alopecia Treatment
Summary
Background
Management of alopecia areata (AA) and androgenetic alopecia (AGA) is often challenging. The use of carboxytherapy may be a novel therapeutic option for such cases.

Objective
To evaluate the clinical efficacy and safety of carboxytherapy in alopecia areata and androgenetic alopecia.

Patients and methods
This study was conducted on 80 patients with alopecia divided into two groups; Group I included 40 AA patients (Group IA received carboxytherapy and Group IB control received placebo), and Group II included 40 AGA patients (Group IIA received carboxytherapy and Group IIB control received placebo), and followed up monthly for 3 months. They were evaluated clinically (by assessment of Severity of Alopecia Tool (SALT) score in group I, and Sinclair scale and Norwood‐Hamilton scale in group II), by dermoscopy and digital dermoscopy at each visit.

Results
Group IA patients showed significant clinical improvement in SALT score and dermoscopic improvement after carboxytherapy and at the end of follow‐up period with significant reduction in dystrophic hair, black dots, yellow dots, and tapered hair coinciding with significant emergence of regrowing hair. Group IIA patients showed significant clinical and dermoscopic improvement after carboxytherapy with significant increase in hair density measured by digital dermoscopy. However, regression of these results was observed during the follow‐up period but was still significantly better than before treatment. There were statistically significant improvements in clinical score, global assessments, dermoscopic, and digital dermoscopic findings in both group IA and group IIA received carboxytherapy in comparison with group IB and group IIB received placebo injections, respectively.

Conclusion
Carboxytherapy seems to be a promising therapeutic option for patchy AA and could be helpful as an adjuvant therapy of AGA but more than 6 sessions are required and adjuvants are recommended for maintenance of the results.

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...

How does Carboxytherapy for hair loss work?
Carboxytherapy works by triggering a process of oxygenation and improving circulation in the area that is injected. It does this by making the red bloods cells release oxygen and pick up the C02 so it can be eliminated from the body. This process effectively breaths new life into the hair follicle, which stimulates hair growth.

Carboxytherapy for Hair Loss London | Dr SW Clinics

...

Effective combination therapy with high concentration of Minoxidil and Carboxygas in resistant Androgenetic alopecia: Report of nine cases

Abstract

Background: Androgenetic alopecia (AGA) is widely characterized as the main reason of hair loss which most of the time it has been reported in adults regarding dermatological consultation. Also, it is broadly believed that the progressive miniaturization of hair follicles could be usually different at the age of onset.

Aims: Over the last decade, detecting and understanding newer genetic basis in AGA lead to provide better therapeutic approaches. We have highlighted on an evidence-based method to treat AGA whose incidence is increasing significantly in our country.

Patients/methods: In this study, 9 adults with AGA including 5 women and 4 men, age range of 25-55 years, were treated with a combination of minoxidil (20%) by micro-needling and carboxytherapy mediated by needling. All cases had a normal physical development. Hair numbers (density) and diameter were calculated using trichograms before and after treatment. Hair growth was assessed by the pull test as well.

Results: Our results showed that combination of high concentration of minoxidil and carboxygas extremely can increase the level of hair growth.

Conclusion: Our treatment effects on the terminal follicles using needling make sticky follicles become progressively smaller as a result of mechanical forces.
Effective combination therapy with high concentration of Minoxidil and Carboxygas in resistant Androgenetic alopecia: Report of nine cases - PubMed

 

[JDreamer]

so topical licorice/liquorice is an option?

Interestingly enough this site says licorice "also contains glycyrrhizin, an acid that plays a role in increasing steroid hormones that naturally occur in skin."

Licorice Extract and Skin Care

So does mean we would need a de-glycyrrhizin licorice creme? If so, I see some can be ordered online.

 

[GorillaHead]

Multiple studies point to retinoic acid build up in the scalp.

and its responsible for the immune response in hairloss

vitamin a antagonizes D.

Retinoids Regulate Survival and Antigen Presentation by Immature Dendritic Cells


renin system more likely causes temporary hairloss rather than male pattern baldness

 

[GorillaHead]

I think our focus should be heavy on the d and A

 

[johnwester130]

Studies show that AT1 inhibitors have an anti-inflammatory and beneficial effect on hair. AT1 inhibitors are ARB-I, and ACE-I stimulates the inflammatory process through bradykinin and harms hair. Because they are drugs, they are supposed to have side effects. In my experience, stopping hair loss can be done quickly and efficiently by stimulating CO2 production, if necessary, by breathing in the bag, at least 1 hour a day for good effect, breath control ... The difficult part involves regenerating hair once fallen, and I think as certain lotions applied topically at the scalp level is necessary, but because it is a long process must be experienced until the most suitable solution is found, and I am thinking of emodin, urea, carbonic anhydrase inhibitors, certain essential oils, FO-TI. As internal supplements, I think that vitamins B1, B2, B3 are important (to reduce lactic acid and help the liver to work effectively in eliminating toxins), magnesium, and the diet should focus on Folate, Zinc, Copper, B6, a lot of sugar, adequate protein, little fat, more calcium than phosphate, enough magnesium, sun, light treatment, without excess Vitamin A :).

…

The finding of the vitamin D hormone as a negative endocrine regulator of the RAS has important physiological and clinical significance. It suggests that the vitamin D endocrine system may maintain the homeostasis of the cardiovascular system through suppressing the RAS, and vitamin D-deficiency or insufficiency may lead to activation of the RAS, thus increasing the risk of cardiovascular disease. Vitamin D analogs as novel renin inhibitors have great therapeutic potentials for cardiovascular disease. Combination therapy with vitamin D analogs and RAS inhibitors can enhance the therapeutic efficacy in the treatment of cardiovascular disease.

MOLECULAR MECHANISM OF VITAMIN D IN THE CARDIOVASCULAR SYSTEM

…

Conclusions

The present review indicates that AT1R antagonists or vitamin D or a combination may be useful in treating the lung complication of COVID-19. Appropriately designed clinical studies are needed to establish the benefit of the combination of AT1R antagonists with vitamin D.

Can a Combination of AT1R Antagonist and Vitamin D Treat the Lung Complication of COVID-19?

…

Serum ACE levels have been found to be significantly elevated in AIDS patients, patients in the intermediate stage of HIV infection, and patients with Pneumocystis carinii pneumonia.

Thiamine attenuates hypertension and metabolic abnormalities in spontaneously hypertensive rats (SHRs). Thiamine repletion downregulates the expression of angiotensinogen (−80%), ACE (−77%), and angiotensin type 1 receptor (−72%) mRNAs in SHRs.34 These observations suggest that thiamine affects ACE activity in HIV-infected patients.

The role of thiamine in HIV infection - ScienceDirect

…

The role of RAAS in the hair loss process should be considered as highly possible due to reports linking to the intake of ACE-I to hair loss. Interestingly, discontinuation of ACE-I (ACE inhibitor) treatment or switching patients from ACE-I (ACE inhibitor) to ARB (Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) has resulted in hair regrowth.

JPP No 3/2019 article 01

...

Hypoxia causes cells to produce more AT-1 which leads to edema.

Old people have a decreased expression of ACE2 (Angiotensin-converting enzyme 2), and increased expression of AT-1 receptors compared to the young.

Cancer, hypertension, diabetes, chronic obstructive pulmonary disease…. are all conditions that are associated with higher levels of the AT-1 receptor (Angiotensin II receptor type 1), with greater age or severity related to higher levels.

In patients with low ACE2 by age, sickness or virus binding to ACE2 means that it leaves the ACE1 which produces angiotensin.

ACE2 is capable in inactivating angiotensin breaking down to the first seven amino acids, they call it angiotensin 1-7, and this is a defensive anti-inflammatory peptide, so if your ACE2 is knocked out, angiotensin has a free range to cause damage by way of the Angiotensin II receptor type 1 which is called the AT1, with stimulation of the larger population of AT-1 receptors within the local tissue eliciting further edema, leading to hypoxia witch upregulates the expression and function of AT1 receptor, with a whole range of destructive processes, nitric oxide production.

In some pathological conditions, overactivation of AT1 may lead to damaging events like fibrosis in different organs such as liver and lungs, perhaps through increasing TGFβ expression.

Endotoxin (LPS) induced an increase in the AT1 subtype of the angiotensin II receptors.

ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.

…

TGF-β plays important roles in the induction of catagen during the hair cycle. We examined whether TGF-β2 could activate a caspase in human hair follicles. Using active caspase-9 and -3 specific antibodies, we found that TGF-β2 activated these caspases in two regions, the lower part of the hair bulb and the outer layer of the outer root sheath. In addition, we searched for a plant extract that can effectively suppress TGF-β action. We found that an extract of Hydrangea macrophylla reduced synthesis of a TGDβ-inducible protein. We confirmed that the extract has a potential to promote hair elongation in the organ culture system. Furthermore, it delayed in vivo progression of catagen in a mouse model. Our results suggest that the induction of catagen by TGF-β is mediated via activation of caspases and that a suppressor of TGF-β could be effective in preventing male pattern baldness.

A Potential Suppressor of TGF-β Delays Catagen Progression in Hair Follicles - ScienceDirect

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Our data demonstrated the expression of 11β-HSD1 in human DPCs and revealed that inhibition of 11β-HSD1 activity can partially prevent the negative effect of glucocorticoids on DPCs, suggesting the possible application of 11β-HSD1 inhibitors for stress-related hair loss.

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Attenuates the Adverse Effects of Glucocorticoids on Dermal Papilla Cells

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Angiotensin II is also well known in inducing reactive oxygen species and promoting inflammatory phenotype switch via its type 1 receptor. In clinic, Angiotensin II type 1 (AT1) receptor blocker like candesartan has been widely applied as an antihypertensive medication.

It was found that pre-treat with candesartan significantly suppressed transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) expression after incubation with TNF-α.

Candesartan inhibits inflammation through an angiotensin II type 1 receptor independent way in human embryonic kidney epithelial cells

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Lisinopril-Induced Alopecia: A Case Report

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines consider angiotensin-converting enzyme (ACE) inhibitors as one of the mainstay therapies in the management of heart failure. The widespread use of ACE inhibitors has been associated with several notable adverse effects such as hyperkalemia and an increased serum creatinine. There are no previous reports of alopecia associated with lisinopril use; however, a few previous cases of alopecia associated with other ACE inhibitors exist. This report discusses a case of lisinopril-induced alopecia of a 53-year-old male presenting to our outpatient heart failure clinic with a chief complaint of a new onset of alopecia. Upon evaluation, it was suspected that the patient’s alopecia was likely medication induced by lisinopril; therefore, lisinopril was discontinued and switched to an angiotensin receptor blocker (ARB), losartan potassium. Alopecia resolved in 4 weeks after the therapeutic intervention.

SAGE Journals: Your gateway to world-class research journals

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The beneficial effect of Ang-(1-7) in alopecia can be attributed to their vasodilation action on blood vessels (Santos et al., 2000). The vasodilation of arterioles present in the dermis improves irrigation of the hair follicles, increasing the supply of nutrients and oxygen. Thus, the cells of the hair follicle increase their proliferation, accelerating hair growth

https://patents.google.com/patent/US20150313829A1/en

…

The RAS is a coordinated complex hormonal cascade that is composed of angiotensinogen, angiotensin-converting enzyme (ACE) and its homolog angiotensin converting enzyme 2 (ACE2), and angiotensin II (Ang II) type 1 and type 2 receptors (AT1, AT2). ACE cleaves the decapeptide Ang I into the octapeptide Ang II, while ACE2 cleaves a single residue from Ang II to generate Ang 1-7, which in turn blocks Ang II and inhibits ACE.

Recombinant human ACE2: acing out angiotensin II in ARDS therapy

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ACE converts Angiotensin I to Angiotensin II and also inactivates bradykinin.

ACE inhibitors inhibit ACE competitively. That results in the decreased formation of angiotensin II and decreased metabolism of bradykinin.

ACE inhibitors block the breakdown of bradykinin, causing levels of this protein to rise and blood vessels to widen (vasodilation). Increased bradykinin levels are also responsible for the most common side effect of ACE inhibitor treatment; a dry cough.

KKS (kallikrein-kinin system) activation and liberation of bradykinin increases endothelial cell permeability.

Bradykinin induces vasodilation by stimulating production of nitric oxide, the arachidonic acid metabolites prostacyclin (PGI-2) and PGE-2, and endothelium-derived hyperpolarizing factor.

During inflammation, it is released locally from mast cells and basophils during tissue damage.

Overactivation of bradykinin is thought to play a role in a rare disease called hereditary angioedema, formerly known as hereditary angio-neurotic edema.

Bradykinins have been implicated in a number of cancer progression processes. Increased levels of bradykinins resulting from ACE inhibitor use have been associated with increased lung cancer risks. Bradykinins have been implicated in cell proliferation and migration in gastric cancers, and bradykinin antagonists have been investigated as anti-cancer agents.

Beside the classical mediators, such as catecholamines, histamine, serotonin, and bradykinin, increasing attention has recently focused on metabolites of arachidonic acid, cytokines, and products from circulating or resident inflammatory cells. Of all these humoral and cellular alterations, the activation and liberation of proteinases seems to play an essential role with regard to loss of capillary barrier function and interstitial edema formation.

…

The theory connects many of the disparate symptoms of COVID-19, from a loss of sense of smell and taste, to a gel-like substance forming in the lungs, and abnormal coagulation. It posits that SARS-CoV-2 disrupts both the renin-angiotensin system (RAS) and the kinin-kallikrein pathways, sending bradykinin -- a peptide that dilates blood vessels and makes them leaky -- out of whack. The process impedes the transfer of oxygen from the lung to the blood and subsequently to all other tissues, a common abnormality in COVID-19 patients.

When the virus interacts with ACE2, it triggers an abnormal response in the bradykinin pathway, Jacobson said. At the same time, levels of angiotensin-converting enzyme, which is involved in the breakdown of bradykinin, were lower in COVID-19 patients than in controls.

The Bradykinin molecular structure over a computer rendering of the coronavirus

In the last week, questions have been raised about whether cytokine storm is indeed a culprit in severe COVID-19, while a paper from a government lab has made an intriguing and much-discussed case for a new mechanism, bradykinin storm.

While the concepts are not necessarily mutually exclusive, scientists trying to understand how COVID-19 wreaks its damage on the human body have been buzzing about the new possibilities.

The theory connects many of the disparate symptoms of COVID-19, from a loss of sense of smell and taste, to a gel-like substance forming in the lungs, and abnormal coagulation. It posits that SARS-CoV-2 disrupts both the renin-angiotensin system (RAS) and the kinin-kallikrein pathways, sending bradykinin -- a peptide that dilates blood vessels and makes them leaky -- out of whack. The process impedes the transfer of oxygen from the lung to the blood and subsequently to all other tissues, a common abnormality in COVID-19 patients.

Jacobson and co-authors used a supercomputer to compare gene expression in lung cells from nine infected and 40 uninfected individuals.

They found the COVID-19 cases had extremely high levels (increased nearly 200-fold) of angiotensin-converting enzyme 2 (ACE2), the surface protein used by the coronavirus to enter the cell.

When the virus interacts with ACE2, it triggers an abnormal response in the bradykinin pathway, Jacobson said. At the same time, levels of angiotensin-converting enzyme, which is involved in the breakdown of bradykinin, were lower in COVID-19 patients than in controls.

"This is the perfect storm, where all the things that could go wrong will lead the system to really go out of control," Jacobson told MedPage Today. "When that happens, you're going to get hyper-permeable blood vessel fluid pouring out of these infected areas and into the lungs."

Compared with controls, patients with COVID-19 also had upregulated genes responsible for synthesizing hyaluronic acid -- a polymer that can absorb more than 1,000 times its weight in water -- and downregulated genes responsible for degrading it, Jacobson said.

In effect, the bradykinin dysregulation will cause blood vessels to leak, and the hyaluronic acid dysregulation will pour massive quantities of a gel-like substance into the alveoli. This aligns with autopsy reports that detail the lungs of patients with COVID-19 feeling "like a water balloon that is filled with Jell-O," Jacobson said.

"That explains why ventilation has been so difficult," he noted. "At some point when you have enough of this hyaluronic acid in your lungs, with all the water you've captured, it kind of doesn't matter how much oxygen you're pumping into the lungs -- it can't get through to do gas exchange in the capillaries and alveoli."

Excess bradykinin can also shift important electrolyte levels, like potassium, which in turn can cause angioedema, sudden cardiac death, diarrhea, and reduced cognitive function, Jacobson and co-authors noted. ACE inhibition has also been linked with a loss of taste or smell.


The bradykinin storm is not mutually exclusive from the cytokine storm described in severe COVID-19 in the early stages of the pandemic. While cytokines are involved in the virus's attack, Jacobson said they did not see the same out-of-control, cascading effect represented by the cytokine storm hypothesis.

COVID-19 Storms: Bradykinin In, Cytokine Out?

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Conclusions

The invasiveness and immunosuppression of many cancers appears dependent on inflammation and the upregulation of AT1. Two mechanisms for upregulation of AT1 are discussed: 1) evolutionary changes to take advantage of this pro-inflammatory control mechanism, 2) AT1 expression induced by an alternating environment of hypoxia and oxidative stress. Immunosuppression as a common protection mechanism of solid tumours against immune responses has been verified from current literature and experimental procedures, as has the implication of cytokines and chemokines in tumour growth and metastasis. Given the involvement of AT1 in the immunosuppression and inflammatory processes, as well as in the expression of the pro-inflammatory cytokines and chemokines, it becomes evident that the AT1 receptor is essential for tumour protection and progression. A combination therapy consisting of AT1 receptor antagonists, NSAID for further control of the inflammation and immune therapy in the form of tumour vaccines should provide a novel and successful treatment for solid tumours.


In the renin-angiotensin system, the angiotensin II receptors AT1 and AT2 seem to have opposing functions. The actions of AT1 being principally pro-inflammatory whilst AT2 provides protection against hypoxia, draws inflammatory action to a close and promotes healing. The various direct and indirect mechanisms for feedback between the receptors, their induced products and the external hormonal system in the control of inflammation and healing are summarised in a highly simplified model which none the less can be used to explain how many key promoters and inhibitors of disease exert their effects.


From a review of the current disease literature, it has been demonstrated that the role of AT1 and AT2 in inflammation is not limited to cancer-associated inflammation, but is generally consistent and system wide. Potential therapy by manipulation of these receptors, although at an early stage, has been demonstrated for some of these diseases and it is proposed that this approach will provide an effective basis for the treatment of autoimmune, inflammatory and neurodegenerative disorders using existing drugs. AT1 receptor blockade should, in addition, provide a treatment to alleviate the damage caused by bacterial and viral infections, where their destructive action is through chronic inflammation. Given the importance of the immune suppressant effect of inflammation in cancer, it is anticipated that AT1 blockade should also serve to elicit a more effective immune response to other invaders that seek to corrupt the wound recovery process.


Manipulation of the AT1 and AT2 receptors has profound and exciting implications in the control of disease.

Cancer, inflammation and the AT1 and AT2 receptors

this entire thread is extraordinary

one more final question

do you think blood pressure medications can be used for baldness, and is there any overlap between spironolactone and the renin-angiostenin system?

 

[md_a]

this entire thread is extraordinary

one more final question

do you think blood pressure medications can be used for baldness, and is there any overlap between spironolactone and the renin-angiostenin system?

Studies show that AT1 inhibitors have an anti-inflammatory and beneficial effect on hair. AT1 inhibitors are ARB-I and helps regenerate hair, and ACE-I stimulates the inflammatory process through bradykinin and harms hair. Because they are drugs, they are supposed to have side effects.

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Aldosterone Antagonists

Spironolactone and eplerenone competitively antagonize aldosterone by binding to its receptor on the late distal tubule and the collecting duct to increase sodium, calcium, and water excretion and decrease potassium loss. Spironolactone is most efficacious in hyperaldosteronism, and this defines its main clinical applications in liver and heart failure, usually in combination with a more efficient loop diuretic.1,2,4 Spironolactone also seems to have a positive effect on myocardial remodeling and reduction of cardiac fibrosis.14 It is commonly combined with other diuretics to reduce their potassium-wasting effects. Recent studies have reported that spironolactone is safe and well tolerated as an adjunctive therapy in dogs with CHF, but there have been contradictory findings with regard to the impact on outcome.15-17

Spironolactone - an overview | ScienceDirect Topics

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Aldosterone increases plasminogen activator inhibitor-1

Plasminogen activator inhibitor-1 (PAI-1) is an anti-thrombolytic factor that also promotes tissue fibrosis. Under certain conditions, exposure to aldosterone can result in cardiac fibrosis by an unknown mechanism. In the current study, we tested the hypothesis that PAI-1 is a mediator of aldosterone's fibrotic effects. Aldosterone increased levels of PAI-1 mRNA and protein in the H9c2 rat cardiac cell line, responses that could be blocked by the mineralocorticoid receptor (MR) antagonist spironolactone.

Aldosterone increases plasminogen activator inhibitor-1 synthesis in rat cardiomyocytes - PubMed

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Background/Aims: Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists have beneficial effects on impaired fibrinolytic activity of hypertensive patients. The aim of the study was to evaluate the effect of antialdosterone treatment on impaired fibrinolysis of hypertensive patients. Methods: Fourteen hypertensive outpatients and 14 normotensive healthy volunteers participated in this study. Blood samples for plasminogen activator inhibitor-1 (PAI-1) antigen and tissue plasminogen activator (t-PA) antigen were obtained at baseline in all patients and control subjects. Then all hypertensive patients used spironolactone 50 mg/day for a week. Blood samples were again obtained after a week of spironolactone treatment. Results: The mean basal plasma level of PAI-1 of hypertensive patients was higher than those of the normotensive control group (60.98 ± 4.2 vs. 24.09 ± 1.61 ng/ml, p < 0.01) The mean basal t-PA level was similar in the hypertensive and control subjects (7.49 ± 0.65 vs. 8.78 ± 0.92 ng/ml, p > 0.05). The mean PAI-1 level decreased after a week of spironolactone treatment (60.98 ± 4.2 vs. 42.99 ± 7.98 ng/ml, p < 0.05). The mean plasma t-PA level of hypertensive patients increased after spironolactone treatment (7.49 ± 0.65 vs. 11.09 ± 1.33 ng/ml, p < 0.05). Conclusion: This study shows that spironolactone improves impaired fibrinolysis in systemic hypertension. It provides evidence for a direct link between aldosterone and the fibrinolytic system in humans.

Effect of Spironolactone on Impaired Fibrinolysis of Hypertensive Patients

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Hair Loss Study to Investigate PAI-1 Protein in Follicles

Scalp biopsy required

Researchers will explore the protein PAI-1 and the extent to which it is expressed in test subjects both with and without non-scarring forms of hair loss, including male and female pattern hair loss (androgenetic alopecia), telogen effluvium and the autoimmune condition alopecia areata.

Eleven of the selected participants will have a scalp biopsy using a 4 mm punch, similar to those used in FUE hair transplants. This will allow PAI-1 levels in the scalp’s skin tissue to be determined through immunohistochemical staining.

Following each biopsy the sample skin will be formalin-fixed overnight at room temperature, processed and embedded with paraffin. Sections measuring six microns in depth will be prepared and stored at room temperature.

The amount of active PAI-1 in each total tissue area will be measured using imaging software. After this, the levels of PAI-1 found in scalp tissues both with and without hair loss will be recorded and the results compared.

What is PAI-1?

The protein known as PAI-1, or Plasminogen Activator Inhibitor-1, is a serine protease inhibitor (serpin) which is mostly produced in the cells lining the blood vessels. It is critical to the fibrinolytic system and plays an important role in preventing blood clots.

Elevated levels of PAI-1 are found in people who are obese or who have a number of diseases, including various forms of cancer. It has also been linked to patients with these conditions developing thrombosis.

Potential implications

The study’s resulting findings could help to not only further understanding of the behaviour of hair follicles, but also aid development of the next generation of hair loss treatments for various conditions.



For instance, should researchers discover higher levels of PAI-1 expression in the follicles of people with hair loss, this could open up a new avenue in the development of future treatments. It will also be interesting to discover if there are significant differences in PAI-1 levels between each of the hair loss conditions – so whether, for example, people with Alopecia Areata have a higher, lower or no meaningful difference in PAI-1 levels when compared to those with genetic hair loss.

The Belgravia Centre

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The present disclosures provides surprising insight into new technologies for treatment and/or prevention of certain types of hair loss (also known as alopecia), including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia. Among other things, the present disclosure provides surprising insight that plasminogen activator inhibitor -1 (PAI-1) inhibitors may be surprisingly effective and/or useful in the treatment and/or prevention of certain types of hair loss, including androgenetic alopecia, alopecia areata, frontal fibrosing alopecia, and senescent alopecia. Furthermore, the present disclosure provides insight that provided new technologies may not be particularly effective and/or useful in the treatment and/or prevention of other types of alopecia such as radiation-induced alopecia, chemotherapy-induced alopecia, and alopecia due to chronic discoid lupus erythematosus.

WO2020056191 USES OF PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) INHIBITORS

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By directly inhibiting t-PA, PAI-1 stabilizes fibrin and thus promotes the formation of lysis-resistant cross-linked fibrin clot.5 Generation of PAI1–deficient mice by Carmeliet et al6

in 1993 and identification of Amish cohort with PAI-1 deficiency because of a premature stop codon in the PAI-1 gene by Fay et al7,8 have been pivotal in advancing our understanding of the biological roles of PAI-1. To further explore the consequence of elevated levels of PAI-1 in organismal biology, our laboratory generated the transgenic PAI-1 stab mice line overexpressing human PAI-1 in 20029 (Figure 1). We observed that transgenic mice overexpressing PAI-1 developed age-dependent coronary arterial thromobosis, alopecia areata, and systemic amyloidosis.9,10 In addition to our transgenic mice, 3 other PAI-1 transgenic mice lines have been developed and described. These include followings: (1) transgenic mice that overexpress native human PAI-1 and develop transient venous thrombosis, abnormal hair growth, and epidermal morphology similar to the phenotypes of PAI1-stab mice11; and (2) stable mouse PAI-112,13 and native mouse PAI-114 transgenics with different phenotypes and viability because of usage of different promoters, developmental stage– specific and ubiquitous expression of PAI-1. Thus, it has been difficult to reconcile the phenotypic differences developed in these different lines of transgenic mice. Yamamoto et al15 reported that the levels of PAI-1 increase with age in different tissues and correlate with an increased incidence of stress-induced thrombosis in aged mice.

Evidence from numerous studies during the past 3 decades illustrates that PAI-1, beyond its role in fibrinolysis, also regulates numerous pathophysiological processes. These include metabolic syndrome,16 chronic kidney disease,17 multiorgan fibrosis,18 and aging.19

Recently, elevated PAI-1 activity has been implicated in the pathogenesis of major depressive disorders (MDD). MDD is an endemic disease that affects 1 in 20 people. Furthermore, it is well established that depression is tightly linked with cardiovascular diseases.20 Interestingly, examination of 258 serum markers in patients with MDD revealed that circulating PAI-1 is significantly altered with depression.20 The levels of PAI-1, along with thrombomodulin and fibrinogen, were also significantly elevated in diabetic patients with depression compared with nondepressive patients and controls.21 In addition, Savoy et al22 recently measured elevated PAI-1 levels in patients with MDD. It is interesting to contemplate why elevated levels of PAI-1 consistently correlate with the prevalence of depression….

PAI-1 Is a Bonafide Marker of Cellular

Senescence

In 1991, Murano et al29 reported that dermal fibroblasts isolated from patients with Werner syndrome (characterized by accelerated aging phenotypes, including premature hair loss, diabetes mellitus, and osteoporosis) exhibit premature senescence and elevated PAI-1 levels….

Conclusion and Future Directions

In this perspective, we summarized the science linking PAI-1 with cellular senescence. Furthermore, we discussed recent studies illustrating the role of PAI-1 as an important senescence mediator as genetic deficiency or pharmacological inhibition of PAI-1 is sufficient to forestall cellular replicative senescence and prevent age-related pathology and morbidity in mammals. Therefore, the development of novel small molecule-based therapies targeting normalization/inhibition of elevated PAI-1 provides a novel and rational approach to control cellular senescence and age-associated pathologies, including thrombosis, arteriosclerosis, obesity, diabetes mellitus, organ fibrogenesis, emphysema, and MDD. There is broad acceptance among investigators that PAI-1 comprises an important component of the molecular signature of senescence.

Beyond that, recent studies from our own and other laboratories indicate that PAI-1 is not a merely a marker of cellular senescence but also a key mediator of senescence at the cellular level and is also a major contributor to physiological aging. We are currently investigating the role of PAI-1 in aging and age-associated pathologies, including insulin resistance, chronic kidney diseases, and cardiac fibrosis, and testing the effects of novel pharmacological inhibitors of PAI-1 in reversal of PAI-1–associated pathologies in animals and humans. We anticipate that ongoing and future investigations will further establish PAI-1 as a central mediator of organismal aging and provide additional rationale for prospective trials designed to determine the role of specific PAI-1 inhibitors in delaying aging-related morbidity and mortality in humans.

https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.117.309451

...

TGF-β suppression activity of plant extracts

Dermal papilla (DP) cells were isolated according to the method ofItami et al (1990) and used within 4 passages. DP cells were incubated with plant extracts in the presence of TGF-β2 (1 ng/ml) for 24 h. TGF-β suppression was assessed by monitoring the amount of plasminogen activator inhibitor 1 (PAI-1), a TGF-β-responsive gene product, in culture medium using TintElize PAI-1 (Biopool, CA). Cytotoxicity of every extract was tested using AlamarBlue (Biopool) according to the manufacturer's instructions.



Hydrangea macrophylla, a potential TGF-β2 antagonist, caused elongation of hair follicles

Suppression of TGF-β was hypothesized to prevent apoptosis and to delay catagen entry. Therefore, we sought a natural inhibitor of TGF-β action. We developed a screening method for TGF-β suppression by monitoring changes in PAI-1, a TGF-β responsive gene product. (Zhang et al, 1998). Over 400 plant extracts were screened. Among these, the extract from Hydrangea macrophylla (tea of Heaven) was most effective in suppressing PAI-1 synthesis (Figure 2a). Using the organ culture system, the effect of the H. macrophylla extract on hair follicle elongation was tested. Human hair follicles were cultured in the presence of the extract for 7 d. The resulting follicles showed significant elongation (Figure 2b). Treated follicles showed an average of 2.25 mm elongation, compared to an average of 2.0 mm for the controls. The difference is significant to a p-value of <0.05 as assessed by the one-way ANOVA and Dunnett's posthoc procedure.

A Potential Suppressor of TGF-β Delays Catagen Progression in Hair Follicles

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PCOS: the role of aldosterone

PCOS is the most common endocrine disease of reproductive-aged women, with a prevalence of about 15%. The main characteristics of the syndrome are oligo-amenorrhea, clinical and/or biochemical symptoms of hyperandrogenism, and polycystic ovaries on the ultrasound examination. Following the criteria of Rotterdam consensus, the diagnosis is done upon two of these three characteristics, after having excluded other causes of hyperandrogenism [7]. PCOS patients frequently have obesity, insulin resistance, and an increased risk of developing dyslipidemia, hypertension, type 2 diabetes, metabolic syndrome, and cardiovascular disease [8]. Insulin resistance affects about 70% of patients independently of body mass index (BMI) and is considered the most important factor involved in the pathogenesis and progression of the disease [9].



Women with PCOS have frequently a hyperaldosteronism (30% of the cases). In a previous study, we found that both the aldosterone to renin ratio and blood pressure values are normal in PCOS but significantly higher compared with healthy controls, comparable in age and BMI [10]. Moreover, PCOS is characterized by an increased prevalence of different pathological conditions associated with hyperaldosteronism and/or increased aldosterone activity, like hypertension, Hashimoto’s thyroiditis, diabetes, obesity, and preeclampsia, particularly after menopause.



Actually aldosterone is considered the main inducer of inflammation, heart hypertrophy, and atherosclerosis. In previous studies, we have characterized mineralocorticoid receptors (MR) in mononuclear leukocytes (MNL) [11], and later, we demonstrated that the incubation of MNL with aldosterone regulates the intracellular content of electrolytes and increases the expression of two oxidative stress-related proteins, PAI-1 and p22(phox) [12]. All these effects were blocked by coincubation of MNL with canrenone, the main metabolite of SP. These results suggest that MNL would drive MR in the site of inflammation, allowing aldosterone to promote inflammation and atherosclerosis. The studies of Pitt et al. on the prevention of cardiovascular risk are important in this regard, SP being also able to decrease or block the relapse of new cerebral or cardiac events in patients with previous cerebral or cardiac ischemia [13].

https://www.tandfonline.com/doi/full/10.1080/14656566.2016.1215430

 

[md_a]

A possible mechanism for improving the quality of hair by taurine is inhibition of the renin angiotensin aldosterone system, regulation of intracellular calcium, prevention of excess collagen, anti-fibrotic and anti-stress (adrenal hyperactivity).

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The site of taurine uptake, i.e. the hair bulb, is an area where a highly active cellular proliferation takes place, one of the most active in the whole body and from which all different follicular compartments originate [36]. This compartment is structurally and functionally surprisingly stable, since, when grown in a totally defined medium, isolated hair follicle keeps producing a normal hair fibre [18, 37]. Moreover, survival rate in vitro is increased when isolated human hair follicles are grown in the presence of taurine. These findings strongly suggest that taurine could be involved in the maintenance of human hair bulb either as an osmolyte [4, 13, 14, 38] or a regulator of cysteine and/or calcium metabolism [35].

Alternatively, it is now well established that during the development of androgenetic alopecia and the progressive transformation of terminal into vellus‐like follicles, inflammatory events occur that precede perifollicular fibrosis and ultimately sclerosis of collagenous streamers [15-17]. In this respect, taurine was described as a protective agent against age‐related progressive renal fibrosis in rats [39]. As one of the master switches of the fibrotic program is TGF‐β1, a growth factor known to inhibit hair growth in vitro [19], and since taurine can inhibit collagen synthesis [9], a down‐stream response to TGF‐β1 [40], we further investigated a possible protective role of taurine against TGF‐β1‐induced alterations. Interestingly, the most conspicuous effect of TGF‐β1 treatment was the curvature of hair follicle bulb, accompanied by a thickening of the dermal sheath as demonstrated by collagen staining. In fact, this phenomenon likely resulted from combined dermal sheath myofibroblast activation [41] and inhibition of matrix keratinocyte proliferation [19, 42, 43]. Taurine treatment dramatically counteracted this effect through a biological mechanism which remains to be explained.

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Simulative evaluation of taurine against alopecia caused by stress in Caenorhabditis elegans​

Abstract​

Hair loss or alopecia has been portrayed as a modern malady which is aggravated by stressful conditions. Major cases of alopecia were found among individuals of 40s-50s, nowadays, even among the 20s-30s. This study characterized taurine's potential against alopecia caused by chemical stress agents based on the comparison with other commercially available anti-alopecia agents using Caenorhabditis elegans. The criteria used are their effects on the expression of stress markers and measurements of vital signs: lifespan comparison, progeny number, and mobility. C. elegans showed the typical stress symptoms under treatment with tunicamycin, endoplasmic reticulum stress agent. Hsp-70 protein expression increased, while worm's lifespan and per capita progeny number significantly decreased along with an unusually retarded movement. A positive response was shown when worms were treated with taurine along with astressin-B and finasteride. Between the treatments, finasteride showed better outcomes in terms of stress-reducing effects. Taurine helped worms recover more effectively from adverse influence of stress. In conclusion, there is strong evidence that taurine has a great potential as anti-alopecia effect especially against the one caused by the chemical stress. The present study implies that taurine might strongly work against hair loss when used in combination with other commercially available -anti-alopecia agents.

Simulative evaluation of taurine against alopecia caused by stress in Caenorhabditis elegans - PubMed

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The mechanisms of taurine mediated protection against cell damage induced by hypoxia and reoxygenation

Abstract

Taurine administered during hypoxia markedly reduced the cell damage due to O2 deficiency and reoxygenation. Different mechanisms are responsible for the improved survival of the renal cell cultures. Taurine markedly reduces the osmoregulatory deterioration during hypoxia and reoxygenation. Calcium homeostasis was markedly improved. Ca2+ efflux during hypoxia as well as Ca2+ overload during reoxygenation was significantly reduced by the amino acid. The effect of taurine was partly comparable to the effect induced by Ca2+ channel blockers. One of the effects mainly responsible for cellular protection seems to be the taurine-induced acceleration of cellular growth processes in spite of hypoxia and reoxygenation. The spectrum of cytoprotective effects of taurine predisposes this substance to be a physiological protective agent responsible for cellular homeostasis or enantiostasis.

The mechanisms of taurine mediated protection against cell damage induced by hypoxia and reoxygenation - PubMed

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Interaction between the actions of taurine and angiotensin II

Abstract

The amino acid, taurine, is an important nutrient found in very high concentration in excitable tissue. Cellular depletion of taurine has been linked to developmental defects, retinal damage, immunodeficiency, impaired cellular growth and the development of a cardiomyopathy. These findings have encouraged the use of taurine in infant formula, nutritional supplements and energy promoting drinks. Nonetheless, the use of taurine as a drug to treat specific diseases has been limited. One disease that responds favorably to taurine therapy is congestive heart failure. In this review, we discuss three mechanisms that might underlie the beneficial effect of taurine in heart failure. First, taurine promotes natriuresis and diuresis, presumably through its osmoregulatory activity in the kidney, its modulation of atrial natriuretic factor secretion and its putative regulation of vasopressin release. However, it remains to be determined whether taurine treatment promotes salt and water excretion in humans with heart failure. Second, taurine mediates a modest positive inotropic effect by regulating [Na+]i and Na+/Ca2+ exchanger flux. Although this effect of taurine has not been examined in human tissue, it is significant that it bypasses the major calcium transport defects found in the failing human heart. Third, taurine attenuates the actions of angiotensin II on Ca2+ transport, protein synthesis and angiotensin II signaling. Through this mechanism taurine would be expected to minimize many of the adverse actions of angiotensin II, including the induction of cardiac hypertrophy, volume overload and myocardial remodeling. Since the ACE inhibitors are the mainstay in the treatment of congestive heart failure, this action of taurine is probably very important.

Interaction between the actions of taurine and angiotensin II - PubMed


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Effects of Taurine on ACE, ACE2 and HSP70 Expression of Hypothalamic-Pituitary-Adrenal Axis in Stress-Induced Hypertensive Rats​

Abstract​

The experiment was to elucidate protective mechanism of taurine against stress-induced hypertension. Thirty two male Wistar rats were randomly divided into four groups. Normal control group and stress control group were intragastrically administered saline; β-alanine stress group were fed with β-alanine (200 mg/kg/day) and taurine stress group with taurine (200 mg/kg/day). The hypertensive model was established by giving rats stress for 3 weeks.Results showed that significant expression levels of angiotensin converting enzyme (ACE) in the hypothalamus, pituitary and adrenal were observed in β-alanine stress group and stress control group (P < 0.05), but significant mRNA expression levels of angiotensin-converting enzyme 2 (ACE2) in taurine stress group and normal control group (P < 0.05). All the groups showed no significant differences in HSP70 mRNA expression levels in hypothalamus (P > 0.05), while taurine stress group exhibited the highest HSP70 mRNA expression levels both in pituitary and in adrenal (P < 0.05). It was also found that β-alanine stress group and stress control group had significantly higher protein expression levels of ACE in hypothalamus, pituitary and adrenal (P < 0.05), but significantly lower protein expression of ACE2 compared to taurine stress group and control groups (P < 0.05). The results indicated that taurine regulated the hypothalamus pituitary adrenal (HPA) axis of the renin-angiotensin-aldosterone system (RAAS) by inhibiting ACE gene and protein expressions and promoting ACE2 and HSP70 protein expressions, thereby contributing to the prevention of stress-induced hypertension.

Effects of Taurine on ACE, ACE2 and HSP70 Expression of Hypothalamic-Pituitary-Adrenal Axis in Stress-Induced Hypertensive Rats - PubMed

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Effects of Taurine on Blood Index of Hypothalamic Pituitary Adrenal (HPA) Axis of Stress-Induced Hypertensive Rat​

Abstract​

To elucidate the protective mechanism of taurine against stress induced hypertension, 32 male Wistar rats were randomly divided into four groups: normal control group; stress control group; β–alanine stress group and taurine stress group. Rats of the two control groups were administered physiological saline while the β–alanine treated group was administered β–alanine (200 mg/kg/day) and the taurine treated group was administered taurine (200 mg/kg/day). The hypertensive model was produced by stressing the rats for 3 weeks. Serum levels of angiotensin converting enzyme (ACE), angiotensin II (AngII), glucocorticoid hormone (CRH), adrenocorticotropic hormone (ACTH), Glucocorticoid (GC), epinephrine (EPI), norepinephrine (NA) in the β–alanine stress group was significantly higher than those of the other groups (P < 0.05). However, serum of the taurine stress group contained more angiotensin converting enzyme 2 (ACE2) than those of the other groups (P < 0.05). These data indicate that taurine regulates the hypothalamus pituitary adrenal (HPA) axis of the renin-angiotensin-aldosterone system (RAAS), thereby contributing to the prevention of stress-induced hypertension.

Effects of Taurine on Blood Index of Hypothalamic Pituitary Adrenal (HPA) Axis of Stress-Induced Hypertensive Rat

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Effect of taurine on alteration in adrenal functions induced by stress

Abstract

When rats were exposed to immobilized cold stress, adrenaline content in the adrenal gland as well as noradrenaline content in the brain stem were reduced drastically, while noradrenaline content in the atria was not altered by the application of stress. Oral administrations of taurine (4-7 g/kg/day, for 3 days) prevented the stress-induced decline of adrenaline in the adrenal gland and this preventive effect could not be duplicated by the administration of L-isoleucine or DL-methionine. In hypophysectomized rats, the stress also induced a significant fall in adrenaline content of the adrenal gland, however taurine administration did not show significant preventive effects on the decline in adrenal catecholamines. The immobilized cold stress induced a significant increase in blood sugar and this increase was antagonized by pretreatment with taurine. Taurine had no significant effects on the stress-induced increase in the activity of adrenal tyrosine hydroxylase and the turnover rate of adrenaline in the adrenal gland measured by the rate of decline of this amine following alpha-methyl-tyrosine administration. The administration of taurine, in both in vivo and in vitro, inhibited the release of adrenaline from adrenal medullary granules, but that of dopamine-beta-hydroxylase was not significantly affected. The stress-induced elevation of the blood level of corticosterone was not affected by taurine administration. These findings indicate that taurine antagonizes the stress-induced elevation of blood sugar by reducing adrenaline output from the adrenal gland. The regulatory mechanism most likly involves the inhibition of adrenaline release from adrenal medullary granules, possibly by stabilizing the membrane of the granules.

Effect of taurine on alteration in adrenal functions induced by stress - PubMed

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The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease​

Abstract​

Taurine is a non-protein amino acid that is expressed in the majority of animal tissues. With its unique sulfonic acid makeup, taurine influences cellular functions, including osmoregulation, antioxidation, ion movement modulation, and conjugation of bile acids. Taurine exerts anti-inflammatory effects that improve diabetes and has shown benefits to the cardiovascular system, possibly by inhibition of the renin angiotensin system. The beneficial effects of taurine are reviewed.

The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease - PubMed

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Role of taurine in regulation of intracellular calcium level and neuroprotective function in cultured neurons​

Abstract​

Glutamate-induced excitotoxicity has been implicated as an important mechanism underlying a variety of brain injuries and neurodegenerative diseases. Previously we have shown that taurine has protective effects against glutamate-induced neuronal injury in cultured neurons. Here we propose that the primary underlying mechanism of the neuroprotective function of taurine is due to its action in preventing or reducing glutamate-induced elevation of intracellular free calcium, [Ca(2+)](i). This hypothesis is supported by the following findings. First, taurine transport inhibitors, e.g., guanidinoethyl sulfonate and beta-alanine, have no effect on taurine's neuroprotective function, suggesting that taurine protects against glutamate-induced neuronal damage through its action on the extracellular membranes. Second, glutamate-induced elevation of [Ca(2+)](i) is reduced to the basal level upon addition of taurine. Third, pretreatment of cultured neurons with taurine prevents or greatly suppresses the elevation of [Ca(2+)](i) induced by glutamate. Furthermore, taurine was found to inhibit the influx but not the efflux of (45)Ca(2+) in cultured neurons. Taurine has little effect on the binding of [(3)H]glutamate to the agonist binding site and of [(3)H]MDL 105,519 to the glycine binding site of the N-methyl-D-aspartic acid receptors, suggesting that taurine inhibits (45)Ca(2+) influx through other mechanisms, including its inhibitory effect on the reverse mode of the Na(+)/Ca(2+) exchangers (Wu et al. [2000] In: Taurine 4: taurine and excitable tissues. New York: Kluwer Academic/Plenum Publishers. p 35-44) rather than serving as an antagonist to the N-methyl-D-aspartic acid receptors.

Role of taurine in regulation of intracellular calcium level and neuroprotective function in cultured neurons - PubMed

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Taurine increases mitochondrial buffering of calcium: role in neuroprotection

Abstract

We have determined the role of mitochondria in the sequestration of calcium after stimulation of cerebellar granule cells with glutamate. In addition we have evaluated the neuroprotective role of taurine in excitotoxic cell death. Mitochondrial inhibitors were used to determine the calcium buffering capacity of mitochondria, as well as how taurine regulates the ability of mitochondria to buffer intracellular calcium during glutamate depolarization and excitotoxicity. We report here that pre-treatment of cerebellar granule cells with taurine (1 mM, 24 h) significantly counteracted glutamate excitotoxicity. The neuroprotective role of taurine was mediated through regulation of cytoplasmic free calcium ([Ca(2+)]( i )), and intra-mitochondrial calcium homeostasis, as determined by fluo-3 and (45)Ca(2+)-uptake. Furthermore, the overall mitochondrial function was increased in the presence of taurine, as assessed by rhodamine accumulation into mitochondria and total cellular ATP levels. We specifically tested the hypothesis that taurine reduces glutamate excitotoxicity through both the enhancement of mitochondrial function and the regulation of intracellular (cytoplasmic and intra-mitochondrial) calcium homeostasis. The role of taurine in modulating mitochondrial calcium homeostasis could be of particular importance under pathological conditions that are characterized by excessive calcium overloads. Taurine may serve as an endogenous neuroprotective molecule against brain insults.

Taurine increases mitochondrial buffering of calcium: role in neuroprotection - PubMed

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Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus​

Abstract​

Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus.

Background: Knowledge about biological functions of podocytes in the glomerulus is limited because of its unique anatomical location. Here we introduce a new method for measuring the intracellular calcium activity ([Ca2+]i) in the podocyte in the intact glomerulus.

Methods: With the help of fluorescence high-resolution digital imaging and a recently developed ultraviolet laser-scanning microscope, [Ca2+]i was measured in fura-2-loaded glomeruli and single podocytes of intact microdissected rat glomeruli.

Results: Angiotensin II (Ang II) increased [Ca2+]i reversibly in a biphasic and concentration-dependent manner. In contrast to Ang II, bradykinin, thrombin, arginine vasopressin, and serotonin did not change [Ca2+]i in the glomerulus. At reduced extracellular Ca2+ activity, Ang II released [Ca2+]i from intracellular stores, but the second phase, corresponding to a Ca2+ influx from the extracellular space, was absent. The L-type Ca2+ channel blocker nicardipine did not influence the Ang II-mediated [Ca2+]i increase, and an increase of the extracellular K+ concentration did not change [Ca2+]i in the glomerulus. The angrotensin II type I (AT1) receptor antagonist losartan inhibited the Ang II-mediated [Ca2+]i increase. Confocal [Ca2+]i measurements using fura-2 or fluo-3 or fluo-4 on the single cell level show that some of the Ang II-mediated [Ca2+]i response originated from podocytes. Costaining with calcein allowed the identification of podocytes because of the characteristic morphology and location in relationship to the capillary network.

Conclusions: These data suggest that podocytes in the intact glomerulus respond to Ang II with an increase of [Ca2+]i via an AT1 receptor.

Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus - PubMed

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Androgenetic alopecia in males: a histopathological and ultrastructural study.

Background Androgenetic alopecia is a common cosmetic hair disorder, resulting from interplay of genetic, endocrine, and aging factors leading to a patterned follicular miniaturization. Microinflammation seems to be a potential active player in this process. Aims To study the histopathological and ultrastructural changes occurring in male androgenetic alopecia (AGA). Patients/methods Fifty-five subjects were included in this study (40 with AGA and 15 as normal age-matched controls). Skin biopsies from frontal bald area and occipital hairy area were subjected to histopathological examination, immunohistochemical staining for collagen I and ultrastructural study. Results The frontal bald area of patients showed highly significant increase in telogen hairs and decrease in anagen/telogen ratio and terminal/vellus hair ratio (P < 0.001). Perifollicular inflammation was almost a constant feature in early cases and showed a significant correlation with perifollicular fibrosis (P = 0.048), which was more marked with thickening of the follicular sheath in advanced cases. Conclusion Follicular microinflammation plays an integral role in the pathogenesis of AGA in early cases. Over time, thickening of perifollicular sheath takes place due to increased deposition of collagen, resulting in marked perifollicular fibrosis, and sometimes ends by complete destruction of the affected follicles in advanced cases.

Androgenetic alopecia in males: a histopathological and ultrastructural study - PubMed

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Taurine-induced diuresis and natriuresis in cirrhotic patients with ascites​

Abstract​

Taurine is a non-protein sulfur aminoacid widely distributed in mammalian tissues, with poorly understood functions. Taurine administration has a variety of hemodynamic effects, including improvement of cardiac function and suppression of sympathetic activity. Increased urinary volume and sodium excretion have been reported in taurine-fed hamsters. Since patients with ascitic liver cirrhosis have severe hemodynamic and renal abnormalities potentially sensitive to taurine feeding, we evaluated the effects of the i.v. infusion of taurine on urinary flow and sodium excretion and on the hormones involved in the control of hydrosaline homeostatis. Eight cirrhotic patients with tense ascites were given an i.v. bolus of taurine (16 μmoles in 40 ml of saline). The next day patients were given saline only, as a control. Diuresis, urinary sodium and plasma renin activity, aldosterone, atrial natriuretic peptide and arginin vasopressine were measured for the following 6 hrs. Plasma taurine increased ten fold after infusion, then decreased exponentially. No side effects were recorded. After taurine, but not after saline, there was a prompt and significant increase in both urinary volume and sodium excretion. Diuresis increased from 340±43 to 817±116 μl/min (p<0.01); urinary sodium from 13.8±3 to 26.3±4 μmoles/min (p<0.05). Both values returned to normal after 2–3 hrs. Taurine infusion caused a concomitant significant decrease in plasma renin activity (from 7.7±2.2 to 4.3±1.9 ng/ml/hr, p<0.05) and aldosterone (from 588±47 to 348±89 pg/ml, p<0.05), but no changes in atrial natriuretic peptide and arginin vasopressine. We conclude that i.v. taurine infusion in ascitic cirrhosis promotes a transient diuresis and natriuresis, apparently through the inhibition of the renin-aldosterone axis.

Taurine-induced diuresis and natriuresis in cirrhotic patients with ascites

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Taurine prevents fructose-diet induced collagen abnormalities in rat skin​

Abstract​

Objective: The aim of the study is to investigate the effect of taurine administration on the content and characteristics of skin collagen in high-fructose-fed rats.
Research design and methods: Adult male Wistar rats were divided into four groups of six each: a control group (CON) and a taurine-supplemented control group (CON+TAU), a high fructose diet-fed group (FRU), and a taurine supplemented fructose diet-fed group (FRU+TAU). After 30 days, collagen was isolated from the skin, and its physicochemical properties were studied.
Results: Fructose administration caused an accumulation of collagen and extensive cross-linking. This was evidenced by increases in glycation, fluorescence, and peroxidation in collagen samples. The physicochemical properties of collagen, like shrinkage temperature, aldehyde content, solubility pattern, and susceptibility to denaturing agents, were altered in the fructose-fed rats. The sodium dodecyl sulphate-polyacrylamide gel electrophoretic (SDS-PAGE) pattern of collagen from fructose-fed rats showed and elevated beta component of Type I collagen. Simultaneous administration of taurine alleviated these changes.
Conclusion: The positive influence of taurine on both collagen content and its properties suggests a potential mechanism for the ability of taurine to delay diabetic complications.

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Effect of taurine on wound healing​

Summary​

Taurine which has antioxidant effects is also known to have effects on cell proliferation, inflammation and collagenogenesis. The aim of this study was to investigate the effect of taurine on incisional skin wounds.
The mice incised on the dorsal area were divided into control and experimental groups. Saline was injected intraperitoneally to half of the animals in the control group and locally applied to the other half. Fifty mM taurine solution was given intraperitoneally to the first half of the experimental animals and locally to the second half of the experimental group.
After four days of treatment, malondialdehyde (MDA) and histamine levels as well as the tensile strength of the wound tissue were measured. Structural alterations in epidermis and dermis were histologically evaluated.
The locally administreated taurine significantly increased wound tensile strength by decreasing the MDA and histamine levels and prevented the degranulation of the mast cells. These observations suggest that taurine may be useful on wound healing.

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A cell-based system for screening hair growth-promoting agents.

Androgen-inducible transforming growth factor beta (TGF-beta1) derived from dermal papilla cells (DPCs) is a catagen inducer that mediates hair growth suppression in androgenetic alopecia (AGA). In this study, a cell-based assay system was developed to monitor TGF-beta1 promoter activity and then used to evaluate the effects of activated TGF-beta1 promoter in human epidermal keratinocytes (HaCaT). To accomplish this, a pMetLuc-TGF-beta1 promoter plasmid that expresses the luciferase reporter gene in response to TGF-beta1 promoter activity was constructed. Treatment of HaCaT with dihydrotestosterone, which is known to be a primary factor of AGA, resulted in a concentration-dependent increase in TGF-beta1 promoter activity. However, treatment of HaCaT with the TGF-beta1 inhibitor, curcumin, resulted in a concentration-dependant decrease in TGF-beta1 expression. Subsequent use of this assay system to screen TGF-beta1 revealed that HaCaT that were treated with apigenin showed decreased levels of TGF-beta1 expression. In addition, treatment with apigenin also significantly increased the proliferation of both SV40T-DPCs (human DPCs) and HaCaT cells. Furthermore, apigenin stimulated the elongation of hair follicles in a rat vibrissa hair follicle organ culture. Taken together, these findings suggest that apigenin, which is known to have antioxidant, anti-inflammatory, and anti-tumor properties, stimulates hair growth through downregulation of the TGF-beta1 gene. In addition, these results suggest that this assay system could be used to quantitatively measure TGF-beta1 promoter activity in HaCaT, thereby facilitating the screening of agents promoting hair growth.

A cell-based system for screening hair growth-promoting agents - PubMed

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[PeskyPeater]

Hoi, just want to add, for inhibiting cortisol topically you can use derivative from licorice : dipotassium glycyrrhizate

edit
and, to inhibit TGF Beta you can just use caffeine which is also a carbonic anhydrase inhibitor, that is already available in hair tonics together with niacinamide, and has been shown to be effective to help hair grow.
-link

 

[Shackles]

Thanks!
I started implementing the information from Ray Peat in 2009, I went from a state of extreme hypothyroidism to a state of hyper with the help of the thyroid Cynomel / Cynoplus in just a few days because I took a large amount of thyroid, I reached 37.1 Celsius from 35.8 C with a lot of positive effects, this made me realize how important it is to keep my temperature at 37 and pulse 80-90 beats per minute, which is not easy to obtain in my case only with food without thyroid when it is cold and with the toxic environment in the city. When my temperature drops below 36.8, my extremities get cold and I don't feel ok. I think, those who do not respond to the thyroid is probably the thyroid product is not good or do not get enough. From the age of 14 I started to have hair problems and a few times my hair fell out in proportion of 80%, and so I tested various methods to recover it but with some side effects. Now I am 41 years old. Since 2009 I managed to keep my hair only with info from Ray Peat but without regenerating my areas where I had visible gaps, and in moments of stress, lack of good food and thyroid, my hair was starting to fall out massive and I quickly stopped it with the help of breathing in the bag about 2 hours a day, so in my case, CO2 helps me to stop hair loss, but for regrowth, I think that in addition to the internal part related to nutrition, light, we must emphasize on external stimulation. Recently I started reading about Covid-19 and how inflammation generally acts through the angiotensin 2 and so I noticed that it has also an important role in hair loss related to inflammation, cytokines, fibrosis...

With the new information I started to test scalp massage with different combinations to see if I can regenerate from fallen hair. In the front part of my head, there are small hairless places and it seems that it is the first time I notice that hairs have started to develop in that area, which I find quite interesting. I don't know exactly what effect it had because I tested massage with salt in a little aloe for emodin plus a few drops of thyme oil, oregano, and cloves. I think that in the last 2 months I have massaged only 8 times without following a rigorous program for it. In time I will observe if I will have some success with this, I am still accumulating information.

So, I think could help hair regeneration a massage 2 or 3 times a week that includes Kosher salt, a little coconut oil, essential oil for hair stimulation and TGF-β₁ inhibitor, carbonic anhydrase inhibitor, maybe urea.

11b-HSD1 inhibitors: coffee, emodin, niacinamide, retinol (vitamin A), zinc, glycine, theanine, taurine, magnesium, thyroid, vitamin E, vitamin B6, vitamin B1, aspirin..

“Eucalyptus oil, containing cineole or eucalyptol, is a traditional remedy for asthma, that inhibits the products of unsaturated fatty acid metabolism and the cytokines most associated with asthma symptoms.” RP

I looked at some essential oils recognized as antiviral and I observed that they have a role of cellular protection, antioxidant, blocking lipid peroxidation and iron chelation. Ray Peat mentioned eucalyptus oil as being good for asthma because it chelates iron and prevents lipid peroxidation, and so I became curious to find out more.

Assessment of Antioxidative, Chelating, and DNA-Protective Effects of Selected Essential Oil Components (Eugenol, Carvacrol, Thymol, Borneol, Eucalyptol) of Plants and Intact Rosmarinus officinalis Oil

ABSTRACT: Selected components of plant essential oils and intact Rosmarinus officinalis oil (RO) were investigated for their antioxidant, iron-chelating, and DNA-protective effects. Antioxidant activities were assessed using four different techniques.

DNA-protective effects on human hepatoma HepG2 cells and plasmid DNA were evaluated with the help of the comet assay and the DNA topology test, respectively. It was observed that whereas eugenol, carvacrol, and thymol showed high antioxidative effectiveness in all assays used, RO manifested only antiradical effect and borneol and eucalyptol did not express antioxidant activity at all. DNA-protective ability against hydrogen peroxide (H2O2)-induced DNA lesions was manifested by two antioxidants (carvacrol and thymol) and two compounds that do not show antioxidant effects (RO and borneol). Borneol was able to preserve not only DNA of HepG2 cells but also plasmid DNA against Fe2+-induced damage. This paper evaluates the results in the light of experiences of other scientists.

https://sci-hub.tw/https://pubs.acs.org/doi/10.1021/jf501006y

https://pubs.acs.org/doi/10.1021/jf...IC73s6Zv5qr4Ey0_HxtE-sHNiqJ1-IgKsudY9QV3xzGgI


„Carboxytherapy is an injection of C02 gas below the skin with the use of a 30.5 gauge mesotherapy needle. Carboxytherapy is used for the treatment of hair regrowth or hair loss. It improves circulation at the injection site by forcing red bloods cells to release oxygen and pick up C02 which is then eliminated by the body. This process of oxygenating the area of concern allows for improved healing and nourishing of the hair follicles. For hair rejuvenation, the injection of C02 has a vasodilation effect which allows for the increased nourishment of vitamins and nutrients to the scalp for increased hair growth and stabilization of hair loss. It is considered a natural hair loss treatment and works well in combination with laser therapy.”



„Measuring the amount of thyroid in the blood isn't a good way to evaluate adequacy of thyroid function, since the response of tissues to the hormone can be suppressed (for example, by unsaturated fats). In the 1930's accurate diagnosis was made by evaluating a variety of indications, including basal oxygen consumption, serum cholesterol level, pulse rate, temperature, carotenemia, bowel function, and quality of hair and skin. A good estimate can be made using only the temperature and pulse rate.”RP

“If your thyroid is working efficiently, your pituitary doesn’t have much to do and you’re not likely to get a pituitary tumor, your adrenals don’t have much to do, and your ovaries don’t get over stimulated. The other glands have an easy job when your thyroid is working right. If your thyroid gets interfered with, you have to rev up your adrenals and your pituitary becomes commander in chief and tells everyone what to do.”RP

“The process of inflammation and fibrosis is initiated in response to anything that blocks the adequate production of energy” Ray Peat

“Between its formation and its exhalation, C02 participates in many essential processes, including the stabilization of the energy producing system. When there isn't enough C02, the conversion of glucose to lactate increases, as an inefficient alternative source of energy, and then to supplement the rapidly consumed glucose, the use of the amino acid glutamine for energy increases, with ammonia as a byproduct. Both lactate and ammonia stimulate breathing, which can be lifesaving if a simple lack of oxygen was the reason for the lack of C02; however, if the lungs have a normal supply of oxygen, increased ventilation resulting from ammonia and lactate will cause a further decrease of C02.

Since C02 relaxes smooth muscle, cells that are working and consuming oxygen and glucose (producing C02 in proportion to their activity) cause nearby blood vessels to relax and expand, delivering more oxygen and glucose in proportion to the increased need. When C02 is decreased, blood vessels constrict, limiting the supply of glucose and oxygen. With restricted blood supply, cells have to resort to locally stored glycogen for glucose, and to the breakdown of internal proteins for glutamine.

In hypothyroidism, with lowered oxidative metabolism, the organism is never far from stress and hyperventilation, with the chronic production of lactate and ammonia. The inefficient metabolism of diabetes has similar effects. Diabetes and hypothyroidism are very closely related, since the use of glucose is required for the activation of the thyroid hormone, which is required for the efficient use of glucose. Besides ammonia and lactate, other stress related substances can also increase the drive to breathe more, depleting the essential C02-endotoxin, acetylcholine, serotonin, hydrogen sulfide, nitric oxide, carbon monoxide, angiotensin, and estrogen, for example.

The hypoxia inducible factor increases many enzymes that promote the reductive state-aromatase (Samarajeewa, et al., 2013), prostaglandin synthase/cyclooxygenase (Xing, et al., 2015), the enzymes of glycolysis (MarinHemandez, et al., 2009), glutaminolysis (Kappler, et al., 2017), and glutamatergic excitation (Hsieh, et al., 2017), for example. Two of the enzymes that it activates, angiotensin converting enzyme (ACE) and carbonic anhydrase, have fundamental roles in shaping metabolism. Angiotensin II, the peptide produced by ACE, increases blood pressure and water retention and activates the pituitary and adrenal stress hormones, especially aldosterone. Both angiotensin and aldosterone activate carbonic anhydrase. It seems that any chemical that causes contraction of blood vessels also activates carbonic anhydrase (Puscas, et al., 2001 ). When the carbonic anhydrase in the wall of the blood vessel is activated, it converts the acid C02 to bicarbonate, raising the pH of the cell, increasing its excitability. The alkaline shift in pH (the shift that becomes chronic in cancer cells) increases the excitation and energy expenditure of any type of cell. These shifts toward pseudo hypoxia, alkalinity, excitation, water retention, and inefficient energy production can be seen, either locally or systemically, in all of the chronic and degenerative conditions that are now known to involve inflammation. Stress modifies our breathing, causing a vicious cycle, in which the lactate and ammonia produced when stimulation exceeds our oxidative capacity stimulate more intense breathing, causing more carbon dioxide to be lost, reducing oxidative efficiency and increasing the formation of ammonia and lactate.

Considering the crucial role of C02 in preserving the integrity of cells, there should be more attention to using it therapeutically-bag breathing (rebreathing expired air until the oxygen in the bag is uncomfortably depleted), bathing in it (using a bag or tub of pure C02), using carbogen (5% C02 in oxygen) in hospitals and for emergency resuscitation, and using carbonic anhydrase inhibitors such as acetazolamide in more situations, including psychiatric. Direct use of carbon dioxide is likely to be helpful in all the situations that are known to be benefitted by acetazolamide, without the risk of allergy to that drug-traumatic brain edema, mountain sickness, osteoporosis, epilepsy, glaucoma, hyperactivity (ADHD), inflammation, polyps of the intestine, and arthritis. Diabetes, cardiomyopathy (Torella, et al., 2014), obesity (Arechederra, et al., 2013), cancer, dementia and psychosis are also likely to benefit…

Other things that should be taken into account in any therapy are the light environment and the intestinal flora ( endotoxin activates HIF), the cycles of sleep and activity, and the quality of environmental stimulation. Among the common inhibitors of carbonic anhydrase are the mildly oxidizing flavonoids such as apigenin and fisetin, some polyphenols, vitamin Bl, vitamin D (Mras, et al., 2012), progesterone (partly by blocking the activation by estrogen and aldosterone ), and emodin.” Ray Peat

...

There are some studies indicating the potential role of aldosterone and mineralocorticoid receptors in hair loss. Clinical studies have shown that both male and female patients with androgenic alopecia have higher aldosterone serum levels. The mechanism underlying this process may be associated with the skin microinflammation found in those patients.

...

„It has been known for many years that decreasing sodium intake causes the body to respond adaptively, increasing the renin-angiotensin-aldosterone system (RAAS). The activation of this system is recognized as a factor in hypertension, kidney disease, heart failure, fibrosis of the heart, and other problems. Sodium restriction also increases serotonin, activity of the sympathetic nervous system, and plasminogen activator inhibitor type-1 (PAI-1), which contributes to the accumulation of clots and is associated with breast and prostate cancer. The sympathetic nervous system becomes hyperactive in preeclampsia (Metsaars, et al., 2006).” Ray Peat

...

„The ratio of estrogen to progesterone--regardless of age or gender-is an important factor in regulating minerals and water, cell energy metabolism, and blood pressure. The ratios of many other regulatory substances (including serotonin/dopamine, glucagon/insulin, and aldosteronelcortiso1+progesterone) vary according to the quality of the individual's level of adaptation. to the environment. Improving the environment can shift the ratio in the direction of restoration rather than mere survival.

While stress typically causes the adrenal glands to produce cortisol, extreme stress, as described by Hans Selye, damages the adrenal cortex, and can cause the cells to die, leading to the death of the animal. There is evidence that it is the breakdown of unsaturated fatty acids that causes damage to the adrenal cortex in extreme stress. Although many factors influence the production of the adrenal steroids, arachidonic acid, even without being converted to prostaglandins, is an important activator of aldosterone synthesis. Adrenalin, produced in response to a lack of glucose, liberates :free fatty acids from the tissues, so when the tissues contain large amounts of the polyunsaturated fatty acids, the production of aldosterone will be greater than it would be otherwise. The continuing accumulation of polyunsaturated fats in the tissues is undoubtedly important in the changing relationship between the pancreas and the adrenal glands in aging. Aspirin, which is antilipolytic, decreasing the release of free fatty acids, as well as inhibiting their conversion to prostaglandins, lowers the production of stress induced aldosterone, and belps to lower blood pressure, if it's taken in the evening, to prevent the increase of free fatty acids during the night. Aspirin increases insulin sensitivity. A low salt diet increases the free fatty acids, leading to insulin resistance, and contributing to atherosclerosis (Prada, et al., 2000; Mroka, et aI., 2000; Catanozi, et al., 2003; Garg, et al., 2011).

The same factors that support or interfere with cellular renewal in the pancreas and adrenal glands have similar effects in the bones, skin, skeletal and heart muscle, nervous system, liver, and other organs. In every case, the local circulation of blood is influenced by both local and systemic factors. The loss of control over the water in the body is the result of energy failure, and hypertension is one of the adaptations that helps to preserve or restore energy production. Lowering inflammation and the associated excess of free fatty acids in the blood, and improving the ability to oxidize glucose, will lower blood pressure while improving tissue renewal, but lowering blood pressure without improving energy production and use will create new problems or intensify existing problems...”

Ray Peat - When energy fails: Edema, hypertension, heart failure sarcopenia, cramps, etc.

...

„Most of the known biochemistry of lithium happens to overlap the actions of progesterone, e.g. , aldosterone antagonism. However, while lithium has an anti-thyroid action, progesterone supports secretion of thyroxine. And apparently inhibits the formation of reverse T3 that chemical blocks the action of thyroid hormone. I have seen several women substitute progesterone for lithium, and several of these have then gone on to rely on nutrition and light.” RP

...


Angiotensin is a protein hormone that causes blood vessels to become narrower. It helps to maintain blood pressure and fluid balance in the body.

What is angiotensin?

The liver creates and releases a protein called angiotensinogen. This is then broken up by renin, an enzyme produced in the kidney, to form angiotensin I. This form of the hormone is not known to have any particular biological function in itself but, is an important precursor for angiotensin II. As it passes in the bloodstream through the lungs and kidneys, it is further metabolised to produce angiotensin II by the action of angiotensin-converting enzyme.


The overall effect of angiotensin II is to increase blood pressure, body water and sodium content. Angiotensin II has effects on:

Blood vessels – it increases blood pressure by causing constriction (narrowing) of the blood vessels

Nerves: it increases the sensation of thirst, the desire for salt, encourages the release of other hormones that are involved in fluid retention.

Adrenal glands: it stimulates production of the hormone aldosterone, resulting in the body retaining sodium and losing potassium from the kidneys

The kidneys: it increases sodium retention and alters the way the kidneys filter blood. This increases water reabsorption in the kidney to increase blood volume and blood pressure.

How is angiotensin controlled?

An increase in renin production occurs if there is a decrease in sodium levels and a decrease in blood pressure, which is sensed by the kidneys. In addition, low blood pressure can stimulate the sympathetic nervous system to increase renin production, which results in increased conversion of angiotensinogen to angiotensin I, and so the cycle continues.

The renin–angiotensin system is also activated by other hormones, including corticosteroids, oestrogen and thyroid hormones. On the other hand, natriuretic peptides (produced in the heart and central nervous system) can impede the renin–angiotensin system in order to increase sodium loss in the urine.

What happens if I have too much angiotensin?

Too much angiotensin II is a common problem resulting in excess fluid being retained by the body and, ultimately, raised blood pressure. This often occurs in heart failure where angiotensin is also thought to contribute to growth in the size of the heart. To combat these adverse effects, drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are used in the clinic, although these do have side effects and can lead to excessive retention of potassium (hyperkalaemia).

What happens if I have too little angiotensin?

Control of plasma sodium and potassium concentrations, and the regulation of blood volume and pressure, are all hormonal mechanisms that are impaired by low angiotensin levels. Absence of angiotensin can be associated with retention of potassium, loss of sodium, decreased fluid retention (increased urine output) and low blood pressure.

Angiotensin | You and Your Hormones from the Society for Endocrinology

...

Follicular hyperkeratosis also known as keratosis pilaris (KP), is a skin condition characterized by excessive development of keratin in hair follicles, resulting in rough, cone-shaped, elevated papules. The openings are often closed with a white plug of encrusted sebum. When called phrynoderma the condition is associated with nutritional deficiency or malnourishment….

It can be treated with urea-containing creams, which dissolve the intercellular matrix of the cells of the stratum corneum, promoting desquamation of scaly skin, eventually resulting in softening of hyperkeratotic areas.

Urea is an emollient (a skin softening agent). Urea enhances penetration kinetics of vitamin A into the various layers of human skin. Urea may also help to soften thick scalp plaques. Urea is also a source of nitrogen for hair growth.

...

Inhibit the enzyme carbonic anhydrase

Carbonic anhydrase is an enzyme which converts CO2 to bicarbonate. Inhibiting this enzyme will increase the amount of CO2 in the blood. Carbonic anhydrase inhibitors are anti-glaucoma, diuretic, anti-epileptic, and are also used to treat mountain sickness, intracranial hypertension, duodenal ulcers, neurological disorders, and even osteoporosis. (R)


Safe natural carbonic anhydrase inhibitors include thiamine (24), biotin, coffee, nicotine, pomegranate (1 oz of juice) (25), courmarin (found in cinnamon and citrus), capsaicin (chillies), ferulic acid (bamboo shoots and coffee), gallic acid (garlic), syringic acid (red wine and vinegar), salicylic acid (aspirin) (26), apigenin (dried parsley, guava), eriocitrin (lemons) (27) and testosterone (28).


Histamine (29), serotonin (30), and estrogen (31) are carbonic anhydrase activators, therefore their antagonism will increase CO2 production.

8 best ways to increase CO2 and gain its benefits » MenElite

...


HD: It’s interesting you say that; I read the article just a couple of days ago actually it was from the Drudge Report. It was that the increasing hairiness of females is actually becoming recognized. And I think there was a poll done in 2004 and I think 95% of females shaved. They did a recent poll here and I think it was down to 78% and they were saying that essentially that ‘au natural’ was becoming more ‘normal’ whether or not they are talking about hair on a male’s head or hair from a baldness perspective or not, I don’t know caller, but Dr Peat what do you think?

RP: I think the hair on the head actually has the function of preserving heat, helping to keep the brain warm. Wearing a wool hat will substitute somewhat for not having enough hair on the head. And the other hair (armpits and pubic), I think that has the function of helping to somewhat distribute pheromones. The facial hair and arm hair has probably that pheromone distributing function. But I think that the body hair that is tending to appear more often in women is a sign of stress. That it’s probably related to that pheromone system shifting to an exaggerated steroid production in the skin.


HD: So Dr Peat just to carry on with testosterone a little bit, it’s a bit of a divergent question but - in terms of men being able to maximize their testosterone production without thinking that they have to go to a gym and get aerobic and pump huge amounts of weights to build muscle - what would you say would be a good program for a male who wanted to increase lean muscle mass in order to be exposed to more testosterone? Because it’s the muscle itself that actually promotes a testosterone surge in the body; and by its own mechanism will directly relate back to testosterone itself.

RP: Yeah muscle contraction activates the synthesis, locally in the muscle, of testosterone, and decreases the cortisol activity; so good physical work is probably the central thing to keeping your testosterone up. It shouldn’t be episodic, intense, stressful work; that is known to lower your testosterone and increase cortisol. And at the same time keeping your metabolic rate up so that you can do more intense activity without it being stressful. Having your liver very healthy is essential for keeping your testosterone up, because otherwise the episodes of falling blood sugar activate cortisol, oestrogen and all of the other stress hormones.

Ray Peat, Endocrinology Part 3, KMUD, 2017

...

From forum:

I wrote Dr. Peat and he was kind to reply to a few questions. Well, actually, he didn't really answer each of my questions directly, but he did offer a lot of great information. I asked him if it was ok to share his answer on the forum, and he said he didn't mind. My words are in black; Ray's is in dark blue and the references he gave are in light blue.

Hello Dr. Peat,

My name is Brandon. I recieved this email address in the forum when requesting a way to contact you. If you don't mind, I'd like to get your perspective on the following questions concerning the pattern of common baldness in adult males:

1. What is the basis for the onset of common pattern baldness in adult males, starting at the temples and vertex and developing into the virtually symmetrical horseshoe shape?

2. Is the development of this precise pattern a sign of a systemic problem?

3. How do you make sense of the association between pattern baldness and elevated prolactin and cortisol if women also experience elevations in these hormones, but don't show this pattern of baldness?

I listened to the KMUD episode on hair loss and inflammation you were on, where you mentioned that prolactin and cortisol are elevated in people with baldness (I'm assuming you were referring to the common pattern baldness), but I didn't hear an explanation about how this elevation is related to the actual pattern of baldness seen in males.


RP: Women are more strongly protected than men by progesterone against the stress hormones. Prostaglandins, which are one of the products of estrogen-related mast cells, are increased by the accumulation of polyunsaturated fats with aging, and correspond roughly to the health problems, such as the “metabolic syndrome,” that are associated in men with baldness. Testosterone has some of the protective effects of progesterone, except that with the gradual accumulation of the PUFA, it tends to be turned into estrogen, activating cortisol, prostaglandins, mast cells, and prolactin.


J Am Anim Hosp Assoc. 2015 Mar-Apr;51(2):136-42.

Canine alopecia secondary to human topical hormone replacement therapy in six

dogs.

Berger DJ(1), Lewis TP, Schick AE, Miller RI, Loeffler DG.

(1)From the Iowa State University College of Veterinary Medicine, Ames, IA

(D.B.); Dermatology for Animals (T.L., A.S., R.M.); and DVM Pathology Associates

(D.L.).


Dermatologica Sinica Volume 34, Issue 1, March 2016, Pages 10–13

Assessment of semen quality in patients with androgenetic alopecia in an infertility clinic

Emre Sinan Güngör, Şule Güngör, , , Ali Galip Zebitay. . . .

Redirecting


Urolithiasis. 2016 Oct;44(5):409-13.

Relation of urinary stone disease with androgenetic alopecia and serum

testosterone levels.

Polat EC(1), Ozcan L(2), Otunctemur A(3), Ozbek E(3).

(1)Department of Urology, Okmeydani Training and Research Hospital, Sisli, 34384,

Istanbul, Turkey. [email protected]. (2)Department of Urology, Derince

Training and Research Hospital, Kocaeli, İzmit, Turkey. (3)Department of Urology,

Okmeydani Training and Research Hospital, Sisli, 34384, Istanbul, Turkey.


Am J Phys Anthropol. 1992 May;88(1):59-67.

Relations between sex hormone level and characters of hair and skin in healthy

young men.

Knussmann R(1), Christiansen K, Kannmacher J.

(1)Institut für Humanbiologie, University of Hamburg, Germany.


Singapore Med J. 2010 Dec;51(12):931-6.

The association of insulin resistance and metabolic syndrome in early

androgenetic alopecia.

Acibucu F(1), Kayatas M, Candan F.

(1)Department of Endocrinology and Metabolism, Faculty of Medicine, Cumhuriyet

University, Sivas 58140, Turkey. [email protected]


J Drugs Dermatol. 2016 Aug 1;15(8):1001-4.

Stress and the Hair Growth Cycle: Cortisol-Induced Hair Growth Disruption.

Thom E.


J Cutan Pathol. 1975;2(2):58-70.

Male pattern alopecia a histopathologic and histochemical study.

Lattanand A, Johnson WC.


J Cutan Pathol. 2014 Apr;41(4):364-9.

A prostaglandin D-synthase-positive mast cell gradient characterizes scalp

patterning.

Larson AR(1), Zhan Q, Johnson E, Fragoso AC, Wan M, Murphy GF.


Thank you so much for your reply. Do you have a sense of why the pattern of baldness is the way it is (horseshoe)?


RP: I think the pattern is just an expression of the interacting gradients that shape all development. In the skin, pheromones and electrical fields are among the factors that affect sweat, oil, hair, fibroblasts, inflammatory, and pigment cells. Each type of cell responds to changing gradients in its own way.


RP: I think a lot of experimenting is needed, for example with topical use of carbonic anhydrase inhibitors.


I asked him if there are any over the counter products that are carbonic anhydride inhibitors.

RP: Vitamin B1, curcumin and silymarin.


I asked Dr Peat about references for the concept of "gradients."

RP: The background is Charles M. Child’s work in embryological gradients, Joseph Needham’s Chemical Embryology, Tracy Sonneborn’s work, and Gershom Zajicek’s streaming organism


Then I asked him how pattern baldness may be reversed and if there is a point where's it's too late.

RP: As long as there are stem cells in the organism, and energy, I think the patterns of aging can be reversed. Cell respiration, and the resulting CO, are basic factors


...


Drugs similar to acetazolamide, sulfonamides that inhibit carbonic anhydrase have recently been discovered to stop the growth of a wide variety of tumors. -Ray Peat, PhD


Lactic acid and carbon dioxide oppose each other. Cancer patients have a deficiency of carbon dioxide because of the respiratory defect where lactic acid is formed from glucose despite the presence of oxygen (Warburg effect/aerobic glycolysis). Carbonic anhydrase inhibitors cause the body to retain carbon dioxide. Those living at high altitude retain more carbon dioxide (Haldane-Bohr Effect) and have less susceptibility to degenerative disease, including cancer. High altitude itself acts naturally like carbonic anhydrase inhibitor therapy.

Carbonic Anhydrase Inhibitors as Cancer Therapy – Functional Performance Systems (FPS)

Pre-Treatment with Ten-Minute Carbon Dioxide Inhalation Prevents Lipopolysaccharide-Induced Lung Injury in Mice via Down-Regulation of Toll-Like Receptor 4 Expression

Various animal studies have shown beneficial effects of hypercapnia in lung injury. However, in patients with acute respiratory distress syndrome (ARDS), there is controversial information regarding the effect of hypercapnia on outcomes. The duration ...

www.ncbi.nlm.nih.gov

 

[johnwester130]

I think excess cortisol-aldosterone- mineralocorticoid activation trough angiotensin system are main players in balding by cytokine activation and progressing to fibrosis. Focusing on TGF-β₁, which shuts off the anagen phase of the hair cycle, and 11β-HSD₁ expression should fix to the problem. Angiotensin 2 receptor (AT-1) is involved in the inflammation pathway.

Angiotensin - Aldosterone has been shown to upregulate TGF-β₁. DHT upregulates 11β-HSD₁ expression.

Cortisol synthesis depends on the enzyme 11β-HSD1 and it converts the inactive cortisone into the active cortisol.


RENIN-ANGIOTENSIN-ALDOSTERONE SYSYTEM AND HAIR LOSS PROCESS

Although hair follicles express almost a full set of RAAS-associated receptors, the role of this system in the regulation of hair growth has not yet been described.


The data describing serum ACE activity in patients with alopecia areata are not consistent; however, both of the studies performed to date have exploited relatively small groups (102, 103). Moreover, one study has shown that in patients with mild or moderate alopecia areata, ACE tissue activity is decreased in the epidermis, as well as in follicular epithelium and endothelium.


The role of RAAS in the hair loss process should be considered as highly possible due to reports linking to the intake of ACE-I to hair loss. Interestingly, discontinuation of ACE-I treatment or switching patients from ACE-I to ARB has resulted in hair regrowth. However, the mechanism of ACE-I-induced alopecia is unknown.


There are some studies indicating the potential role of aldosterone and MR in hair loss. Postnatal MR overexpression in keratinocytes in mice has resulted in delayed alopecia, hair follicle dystrophy, and abnormalities of the hair cycle, without alternation of the interfollicular epidermis. Moreover, clinical studies have shown that both male and female patients with androgenic alopecia have higher aldosterone serum levels. The mechanism underlying this process may be associated with the skin microinflammation found in those patients. Despite the potential role of aldosterone, there is only one study evaluating the influence of MR blockade on hair. This showed that spironolactone treatment reduced hair shaft size and weight resulting in softer, finer hair and a slower growth rate in patients with hirsutism. In this study, the action of spironolactone was mainly associated with its antiandrogenic activity. Nevertheless, the potential role of MR blockade cannot be excluded.

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Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor. To prevent over-stimulation of the mineralocorticoid receptor by cortisol, 11β-HSD converts the biologically active cortisol to the inactive cortisone, which can no longer bind the mineralocorticoid receptor. 11β-HSD co-localizes with intracellular adrenal steroid receptors. Licorice, which contains glycyrrhizinic acid and enoxolone, can inhibit 11β-HSD and lead to a mineralocorticoid excess syndrome. Cortisol levels consequently rise, and cortisol binding to the mineralocorticoid receptor produces clinical signs and symptoms of hypokalemia, alkalosis and hypertension (i.e. mineralocorticoid excess).

11β-hydroxysteroid dehydrogenase is expressed in the central nervous system of aged individuals. It is essential in Hypothalamo-Pituitary-Adrenal Axis function. 11β-hydroxysteroid dehydrogenase also partakes involvement in the decline of conscious intellectual activity due to ageing.

11β-HSD1 is responsible for activating glucocorticoids while 11β-HSD2 is responsible for deactivating them.

https://en.wikipedia.org/wiki/11β-Hydroxysteroid_dehydrogenase


Mineralocorticoid overexpression is expressed in hyper-keratinization. Mineralocorticoid excess is due to cortisol. Elevated mineralocorticoid is the consequence of defective cortisol metabolism, thus implicating impaired 11β-HSD2 activity.

A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. - PubMed - NCBI


The local renin-angiotensin-aldosterone system (RAAS) is fully expressed in the human skin at the mRNA and protein level. Local RAAS is known to play a regulatory function in epidermal proliferation, wound healing, scarring, cutaneous heating adaptation, and aging. There are also some indications of its role in the regulation of hair growth and sebum secretion. Impaired wound healing, skin diseases associated with diabetes, cancer development, psoriasis, and scleroderma may be related to changes in skin RAAS activity. Extensive research has shown that RAAS-modulating drugs can affect the skin when applied orally or topically, creating new therapeutic approaches against dermatological diseases.

The mineralocorticoid receptor as a novel player in skin biology: beyond the renal horizon? | Request PDF


Linoleic acid - Arachidonic acid – Iron (heavy metals) are involved in inflammation – lipid peroxidation – hair loss.

Our data suggest that iron overload increases both lipid peroxidation and TGF-beta1 expression, which together could promote hepatic injury and fibrogenesis.

Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis. - PubMed - NCBI

Arachidonic acid is synthesized from α-linolenic acid derived from linoleic acid, an essential fatty acid, by the enzyme Δ6-desaturase. ... Cyclooxygenase is an enzyme that transforms arachidonic acid into endoperoxides which are used to synthesize prostaglandins, prostacyclin, or thromboxanes.

Arachidonic Acid - an overview | ScienceDirect Topics



Oxidative Stress in Ageing of Hair

Ageing of hair manifests as decrease of melanocyte function or graying, and decrease in hair production or alopecia. There is circumstantial evidence that oxidative stress may be a pivotal mechanism contributing to hair graying and hair loss.

Oxidative Stress in Ageing of Hair \


A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors

AGA is the result of chronic GA-transmitted scalp tension mediated by pubertal and post-pubertal skull bone growth and/or the overdevelopment and chronic contraction of muscles connected to the GA. This tension induces a pro-inflammatory cascade (increased ROS, COX-2 signaling, IL-1, TNF-α, etc.) which induces TGF-β1 alongside increased androgen activity (5-αR2, DHT, and AR), which furthers TGF-β1 expression in already-inflamed AGA-prone tissues. The concomitant presence of DHT and TGF-β1 mediates perifollicular fibrosis, dermal sheath thickening, and calcification of the capillary networks supporting AGA-prone hair follicles. These chronic, progressive conditions are the rate-limiting factors in AGA recovery. They restrict follicle growth space and decrease oxygen and nutrient supply to AGA-prone tissues – leading to tissue degradation, hair follicle miniaturization, and eventually pattern baldness.

A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox and rate-limiting recovery factors - ScienceDirect


Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells

The progression of androgenetic alopecia is closely related to androgen-inducible transforming growth factor (TGF)-β1 secretion by hair follicle dermal papilla cells (DPCs) in bald scalp. Physiological levels of androgen exposure were reported to increase reactive oxygen species (ROS) generation. In this study, rat vibrissae dermal papilla cells (DP-6) transfected with androgen receptor showed increased ROS production following androgen treatment. We confirmed that TGF-β1 secretion is increased by androgen treatment in DP-6, whereas androgen inducible TGF-β1 was significantly suppressed by the ROS scavenger, N-acetyl cysteine. Therefore, we suggest that induction of TGF-β1 by androgen is mediated by ROS in hair follicle DPCs.

Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells


Clove oil (eugenol) inhibited 97.3% lipid peroxidation and decreases TGF‐β1 expression

Expression of TGF‐β1 was increased significantly in the diabetic control group. However, eugenol treatment decreases this increased expression.

Results suggest that treatment with eugenol involved amelioration of diabetic nephropathy by decreasing TGF‐β1 expression.

Error - Cookies Turned Off


Clove oil inhibited 97.3% lipid peroxidation of linoleic acid emulsion at 15 μg/mL concentration. However, under the same conditions, the standard antioxidant compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α-tocopherol and trolox demonstrated inhibition of 95.4, 99.7, 84.6 and 95.6% on peroxidation of linoleic acid emulsion at 45 μg/mL concentration, respectively. In addition, clove oil had an effective DPPH scavenging, ABTS+ scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, ferric ions (Fe3+) reducing power and ferrous ions (Fe2+) chelating activities.

Antioxidant activity of clove oil – A powerful antioxidant source



Multiple nutritional, environmental and lifestyle factors can directly affect hair follicles, to weaken and make them sensitive to the action of androgens. Hair loss can be corrected and hair growth can be improved by addressing these non-androgenic factors. Patients having hair fall, thinning, loss of volume and poor growth can be precursors to androgenetic alopecia. Recent research has shown that androgens inhibit hair growth through release of Transforming Growth Factor (TGF) ß1. Further study of this mechanism reveals that generation of Reactive Oxygen Species (ROS) induced by androgens leads to release of TGF ß1 and use of ROS scavengers can block the release of TGF ß1, explaining beneficial role of antioxidants in hair growth. The binding of ROS to intracellular proteins also causes hair loss by altering the protein structure, changing their immune recognition and converting them to new antigens targeted by inflammatory and immune systems. Calorie restriction and individual micronutrient deficiencies lead to a new process of intracellular destruction or autophagy before cell apoptosis, which could explain cessation of hair growth. Telogen is not a resting phase but now defined as active conservation of follicles under unfavorable conditions. Thus any stress, trauma, metabolic change or insult causes telogen. Micronutrients zinc, copper, selenium maintains immunity, control inflammation and preserve antioxidant activity of the cells. Vitamins A, C, D have a role in phagocytosis and antibodies maintaining resistance. Vitamin D3 modulates the hair-inductive capacity of dermal papilla cells. Vitamin and micronutrient deficiencies are prevalent among all the population of the world. Nutritive value of the foods has reduced over the years by 30%. Endocrine Disrupting chemicals are creating further damage to the hormonal balance of the body. All these can be countered by use of antioxidants and a well-planned nutritional program which will ensure strengthening and regrowth of hair follicles, without the use of Finasteride. (PDF) Role of Non Androgenic Factors in Hair loss and Hair Regrowth Review Article


Lisinopril-Induced Alopecia: A Case Report

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines consider angiotensin-converting enzyme (ACE) inhibitors as one of the mainstay therapies in the management of heart failure. The widespread use of ACE inhibitors has been associated with several notable adverse effects such as hyperkalemia and an increased serum creatinine. There are no previous reports of alopecia associated with lisinopril use; however, a few previous cases of alopecia associated with other ACE inhibitors exist. This report discusses a case of lisinopril-induced alopecia of a 53-year-old male presenting to our outpatient heart failure clinic with a chief complaint of a new onset of alopecia. Upon evaluation, it was suspected that the patient’s alopecia was likely medication induced by lisinopril; therefore, lisinopril was discontinued and switched to an angiotensin receptor blocker (ARB), losartan potassium. Alopecia resolved in 4 weeks after the therapeutic intervention.

https://journals.sagepub.com/doi/abs/10.1177/0897190016652554


The beneficial effect of Ang-(1-7) in alopecia can be attributed to their vasodilation action on blood vessels (Santos et al., 2000). The vasodilation of arterioles present in the dermis improves irrigation of the hair follicles, increasing the supply of nutrients and oxygen. Thus, the cells of the hair follicle increase their proliferation, accelerating hair growth

https://patents.google.com/patent/US20150313829A1/en


TGF-β plays important roles in the induction of catagen during the hair cycle. We examined whether TGF-β2 could activate a caspase in human hair follicles. Using active caspase-9 and -3 specific antibodies, we found that TGF-β2 activated these caspases in two regions, the lower part of the hair bulb and the outer layer of the outer root sheath. In addition, we searched for a plant extract that can effectively suppress TGF-β action. We found that an extract of Hydrangea macrophylla reduced synthesis of a TGDβ-inducible protein. We confirmed that the extract has a potential to promote hair elongation in the organ culture system. Furthermore, it delayed in vivo progression of catagen in a mouse model. Our results suggest that the induction of catagen by TGF-β is mediated via activation of caspases and that a suppressor of TGF-β could be effective in preventing male pattern baldness.

A Potential Suppressor of TGF-β Delays Catagen Progression in Hair Follicles



Angiotensin II is also well known in inducing reactive oxygen species and promoting inflammatory phenotype switch via its type 1 receptor. In clinic, Angiotensin II type 1 (AT1) receptor blocker like candesartan has been widely applied as an antihypertensive medication.

It was found that pre-treat with candesartan significantly suppressed transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) expression after incubation with TNF-α.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652019000300701


Related to stress


Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats.


Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

https://www.ncbi.nlm.nih.gov/pubmed/16574788

Have you read this study?

Vascular calcification--is aldosterone a culprit? - PubMed

In chronic kidney disease (CKD), increased plasma phosphate concentrations cause vascular calcification which substantially contribute to cardiovascular events and increased mortality of CKD patients. Similar to CKD patients, klotho-hypomorphic mice (kl/kl) also suffer from excessive vascular...

pubmed.ncbi.nlm.nih.gov

 

[md_a]

Have you read this study?

Vascular calcification--is aldosterone a culprit? - PubMed

In chronic kidney disease (CKD), increased plasma phosphate concentrations cause vascular calcification which substantially contribute to cardiovascular events and increased mortality of CKD patients. Similar to CKD patients, klotho-hypomorphic mice (kl/kl) also suffer from excessive vascular...

pubmed.ncbi.nlm.nih.gov

Thanks for the study.

There is a close link between PTH and aldosterone. Khloto protein appears to play an important role in preventing calcification, and in its absence 1.25 (OH) 2D3 is increased.

In chronic infectious diseases, low 25(OH)D is often found with elevated levels of the more active metabolite 1,25 dihydroxyvitamin D (1,25D).

1,25 (OH)2D is influenced by PTH and chronic infections, pathogens and aging.

Granulomatous disorders (e.g., sarcoidosis): due to increased 1α-hydroxylase activation in epithelioid macrophages → increased 1,25-dihydroxyvitamin D synthesis

……..

"The aging suppressing gene discovered in 1997, named after the Greek life-promoting goddess Klotho, suppresses the reabsorption of phosphate by the kidney (which is also a function of the parathyroid hormone), and inhibits the formation of the activated form of vitamin D, opposing the effect of the parathyroid hormone. In the absence of the gene, serum phosphate is high, and the animal ages and dies prematurely. In humans, in recent years a very close association has been has been documented between increased phosphate levels, within the normal range, and increased risk of cardiovascular disease. Serum phosphate is increased in people with osteoporosis (Gallagher, et al., 1980), and various treatments that lower serum phosphate improve bone mineralization, with the retention of calcium phosphate (Ma and Fu, 2010; Batista, et al., 2010; Kelly, et al., 1967; Parfitt, 1965; Kim, et al., 2003)."Ray Peat



Klotho production is affected by many physiological and non-physiological conditions. Angiotensin II downregulates renal Klotho protein expression (23), and AT1R blockade increases circulating Klotho. Conversely, oxidative stress downregulates Klotho production (23).

Serum Klotho Levels in Trained Athletes

……..

The Interplay Between the Renin-Angiotensin-Aldosterone System and Parathyroid Hormone

The renin-angiotensin-aldosterone system (RAAS) is the regulatory system by which renin induces aldosterone production. Angiotensin II (Ang II) is the main effector substance of the RAAS. The RAAS regulates blood pressure and electrolyte balance by controlling blood volume and peripheral resistance. Excessive activation of the RAAS is an important factor in the onset of cardiovascular disease and the deterioration of this disease. The most common RAAS abnormality is primary aldosteronism (PA). Parathyroid hormone (PTH) is a peptide secreted by the main cells of the parathyroid gland, which promotes elevated blood calcium (Ca2+) levels and decreased blood phosphorus (Pi) levels. Excessive secretion of PTH can cause primary hyperparathyroidism (PHPT). Parathyroidism is highly prevalent in postmenopausal women and is often associated with secondary osteoporosis. PA and PHPT are common endocrine system diseases. However, studies have shown a link between the RAAS and PTH, indicating a positive relationship between them. In this review, we explore the complex bidirectional relationship between the RAAS and PTH. We also point out possible future treatment options for related diseases based on this relationship.

The Interplay Between the Renin-Angiotensin-Aldosterone System and Parathyroid Hormone

...

Medial vascular calcification, a major pathophysiological process associated with cardiovascular disease and mortality, involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). In chronic kidney disease (CKD), osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification is mainly driven by hyperphosphatemia, resulting from impaired elimination of phosphate by the diseased kidneys. Hyperphosphatemia with subsequent vascular calcification is a hallmark of klotho-hypomorphic mice, which are characterized by rapid development of multiple age-related disorders and early death. In those animals, hyperphosphatemia results from unrestrained formation of 1,25(OH)2D3 with subsequent retention of calcium and phosphate. Analysis of klotho-hypomorphic mice and mice with vitamin D3 overload uncovered several pathophysiological mechanisms participating in the orchestration of vascular calcification and several therapeutic opportunities to delay or even halt vascular calcification. The present brief review addresses the beneficial effects of bicarbonate, carbonic anhydrase inhibition, magnesium supplementation, mineralocorticoid receptor (MR) blockage, and ammonium salts. The case is made that bicarbonate is mainly effective by decreasing intestinal phosphate absorption, and that carbonic anhydrase inhibition leads to metabolic acidosis, which counteracts calcium-phosphate precipitation and VSMC transdifferentiation. Magnesium supplementation, MR blockage and ammonium salts are mainly effective by interference with osteo-/chondrogenic signaling in VSMCs. It should be pointed out that the, by far, most efficient substances are ammonium salts, which may virtually prevent vascular calcification. Future research will probably uncover further therapeutic options and, most importantly, reveal whether these observations in mice can be translated into treatment of patients suffering from vascular calcification, such as patients with CKD.

Therapeutic Interference With Vascular Calcification—Lessons From Klotho-Hypomorphic Mice and Beyond

 

[johnwester130]

Thanks for the study.

There is a close link between PTH and aldosterone. Khloto protein appears to play an important role in preventing calcification, and in its absence 1.25 (OH) 2D3 is increased.

In chronic infectious diseases, low 25(OH)D is often found with elevated levels of the more active metabolite 1,25 dihydroxyvitamin D (1,25D).

1,25 (OH)2D is influenced by PTH and chronic infections, pathogens and aging.

Granulomatous disorders (e.g., sarcoidosis): due to increased 1α-hydroxylase activation in epithelioid macrophages → increased 1,25-dihydroxyvitamin D synthesis

……..

"The aging suppressing gene discovered in 1997, named after the Greek life-promoting goddess Klotho, suppresses the reabsorption of phosphate by the kidney (which is also a function of the parathyroid hormone), and inhibits the formation of the activated form of vitamin D, opposing the effect of the parathyroid hormone. In the absence of the gene, serum phosphate is high, and the animal ages and dies prematurely. In humans, in recent years a very close association has been has been documented between increased phosphate levels, within the normal range, and increased risk of cardiovascular disease. Serum phosphate is increased in people with osteoporosis (Gallagher, et al., 1980), and various treatments that lower serum phosphate improve bone mineralization, with the retention of calcium phosphate (Ma and Fu, 2010; Batista, et al., 2010; Kelly, et al., 1967; Parfitt, 1965; Kim, et al., 2003)."Ray Peat



Klotho production is affected by many physiological and non-physiological conditions. Angiotensin II downregulates renal Klotho protein expression (23), and AT1R blockade increases circulating Klotho. Conversely, oxidative stress downregulates Klotho production (23).

Serum Klotho Levels in Trained Athletes

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The Interplay Between the Renin-Angiotensin-Aldosterone System and Parathyroid Hormone

The renin-angiotensin-aldosterone system (RAAS) is the regulatory system by which renin induces aldosterone production. Angiotensin II (Ang II) is the main effector substance of the RAAS. The RAAS regulates blood pressure and electrolyte balance by controlling blood volume and peripheral resistance. Excessive activation of the RAAS is an important factor in the onset of cardiovascular disease and the deterioration of this disease. The most common RAAS abnormality is primary aldosteronism (PA). Parathyroid hormone (PTH) is a peptide secreted by the main cells of the parathyroid gland, which promotes elevated blood calcium (Ca2+) levels and decreased blood phosphorus (Pi) levels. Excessive secretion of PTH can cause primary hyperparathyroidism (PHPT). Parathyroidism is highly prevalent in postmenopausal women and is often associated with secondary osteoporosis. PA and PHPT are common endocrine system diseases. However, studies have shown a link between the RAAS and PTH, indicating a positive relationship between them. In this review, we explore the complex bidirectional relationship between the RAAS and PTH. We also point out possible future treatment options for related diseases based on this relationship.

The Interplay Between the Renin-Angiotensin-Aldosterone System and Parathyroid Hormone

...

Medial vascular calcification, a major pathophysiological process associated with cardiovascular disease and mortality, involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). In chronic kidney disease (CKD), osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification is mainly driven by hyperphosphatemia, resulting from impaired elimination of phosphate by the diseased kidneys. Hyperphosphatemia with subsequent vascular calcification is a hallmark of klotho-hypomorphic mice, which are characterized by rapid development of multiple age-related disorders and early death. In those animals, hyperphosphatemia results from unrestrained formation of 1,25(OH)2D3 with subsequent retention of calcium and phosphate. Analysis of klotho-hypomorphic mice and mice with vitamin D3 overload uncovered several pathophysiological mechanisms participating in the orchestration of vascular calcification and several therapeutic opportunities to delay or even halt vascular calcification. The present brief review addresses the beneficial effects of bicarbonate, carbonic anhydrase inhibition, magnesium supplementation, mineralocorticoid receptor (MR) blockage, and ammonium salts. The case is made that bicarbonate is mainly effective by decreasing intestinal phosphate absorption, and that carbonic anhydrase inhibition leads to metabolic acidosis, which counteracts calcium-phosphate precipitation and VSMC transdifferentiation. Magnesium supplementation, MR blockage and ammonium salts are mainly effective by interference with osteo-/chondrogenic signaling in VSMCs. It should be pointed out that the, by far, most efficient substances are ammonium salts, which may virtually prevent vascular calcification. Future research will probably uncover further therapeutic options and, most importantly, reveal whether these observations in mice can be translated into treatment of patients suffering from vascular calcification, such as patients with CKD.

Therapeutic Interference With Vascular Calcification—Lessons From Klotho-Hypomorphic Mice and Beyond

Do you know anything about using enoxolone? Travis mentioned it in connection to cortisol

 

[BrianF]

Enocolone is a by product of the liquorice plant

 

[md_a]

Do you know anything about using enoxolone? Travis mentioned it in connection to cortisol

I think it's risky.

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Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor. To prevent over-stimulation of the mineralocorticoid receptor by cortisol, 11β-HSD converts the biologically active cortisol to the inactive cortisone, which can no longer bind the mineralocorticoid receptor. 11β-HSD co-localizes with intracellular adrenal steroid receptors. Licorice, which contains glycyrrhizinic acid and enoxolone, can inhibit 11β-HSD and lead to a mineralocorticoid excess syndrome. Cortisol levels consequently rise, and cortisol binding to the mineralocorticoid receptor produces clinical signs and symptoms of hypokalemia, alkalosis and hypertension (i.e. mineralocorticoid excess).

11β-Hydroxysteroid dehydrogenase - Wikipedia
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Travis said: ↑

Enoxolone in any amount would be expected to inhibit the cortisone cortisol ⟶ conversion. It's safe, and doesn't appear to have much affinity for anything other than 11β-HSD₁.


The 2% can also be found on Ebay.


I would think that 2% would be effective. It is used in cosmetics for this very reason, to inhibit cortisol production on the skin.


There are prostaglandin and cytokine signalling events downstream of cortisol which seems to transduce the signal. Cortisol upregualtes prostaglandin D₂ synthase through the glucocorticoid receptor and TGF-β₁ through to nuclear mineralcorticoid receptor. The enzyme prostaglandin D₂ synthase produces the only prostaglandin shown to inhibit hair growth, a prostaglandin found greatly elevated in bald parts of the head—compared to haired regions of the same person. The mRNA for this enzyme was also found upregulated, showing that this is a transcriptional event. Cortisol is both the main glucocorticoid and nuclear mineralcorticoid—it does not activate the mineralcorticoid receptor on the cell membrane, aldosterone is the only endogenous molecule that can do that.


The cytokine TGF-β₁, also upregulated by cortisol, activates phospholipase A₂ which releases arachidonic acid. This later can become either prostaglandin E₂, prostaglandin F₂, or prostaglandin D₂ (and their derivatives). Oddly, prostaglandins E₂ and F₂ slightly stimulate hair growth while prostaglandin D₂ powerfully inhibits it. The effect of prostaglandin D₂ is unambiguous.


As the only ligand of both the glucocorticoid receptor and n-mineralcorticoid receptor, cortisol is the only thing that can powerfully upregulate both prostaglandin D₂ synthase and TGF-β₁. Cortisol also exists in much higher concentrations than aldosterone, especially in places like the skin where 11β-HSD₁ is powerfully unidirectional. This is where enoxolone can help, by inhibiting the cortisol ⟶ conversion; but unfortunately, it can do nothing about the cortisol produced in other places and transported to the skin. It might not be complete in itself, and could take oleuropein to inhibit the downstream prostaglandin signalling events.


And cyclosporine works on a different level. I think that it must bond to an extracellular receptor, like that for TGF-β₁, or inhibit soluble prostaglandin D₂ synthase—a unique enzyme which exists in the plasma, lymph, CSF, and extracellular space and carries vitamin A in addition to being the only thing capable of transforming prostaglandin E₂ to prostaglandin D₂ through it's catalytic thiol domain inside its β-barrel structure. Mice lacking this enzyme appear normal, but exhibit better wound healing and hair growth.


Since COX-2 inhibitors also promote hair growth, at times, you would think that simply limiting the amount of linoleic acid would lessen the amount of drugs needed to inhibit excessive prostaglandin D₂ formation and upstream cortisol production and/or binding.

Haidut:

I beg to disagree a bit. Enoxolone is actually an indiscriminate inhibitor of 11b-HSD - i.e. it inhibits both type I and II. This leads to increase in cortisol levels due to decreased degradation, even though new synthesis is also inhibited. This is why enoxolone leads to high blood pressure in humans and it not used more often clinically. I considered it as a supplement years ago but its indiscriminate 11b-HSD activity convinced me not to do it. I have tried it myself and it does lead to excess mineralocorticoid symptoms including water retention and weight gain around the midsection.

Enoxolone - Wikipedia

"...The structure of glycyrrhetinic acid is similar to that of cortisone. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory action.[citation needed] 3-β-D-(Monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of 'active' cortisol to 'inactive' cortisone in the kidneys.[6] This occurs via inhibition of the enzyme by inhibiting the enzyme 11-β-hydroxysteroid dehydrogenase.[citation needed] As a result, cortisol levels are high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like aldosterone and increases sodium reabsorption) that work on ENaC channels in the collecting duct.[citation needed]Hypertension develops due to this mechanism of sodium retention. People often have high blood pressure with a low renin and low aldosterone blood level.[citation needed] The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, high blood pressure and inhibition of the renin-angiotensin-aldosterone system. Therefore, licorice should not be given to patients with a known history of hypertension in doses sufficient to inhibit 11-β-hydroxysteroid dehydrogenase.[7]"

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Travis:

What is implied is that it should be quite safe topically. The kidneys of course have the 11β-HSD₂ working in the opposite direction, so taking enoxolone—or its all natural glycone found in licorice—certain can cause extreme mineralocorticoid effects due to excessive cortisol. I am even fairly certain that this has killed people, as has other natural mineralocorticoid-active molecules like digoxin, oubain, and solanine.


But topically, I think you could expect local inhibition of cortisol synthesis. There are better drugs out there, that work in a more direct way, but this has been tested topically on rats and they all had survived and the all had increased hair growth—proving that cortisol was being inhibited and had not increased, as would occur if the skin were to contained 11β-HSD₂ and not 11β-HSD₁. Although spironolactone would be a more direct approach, topically, it is more expensive and difficult to acquire.

Haidut:

Concur. What about RU486 or even progesterone, both of which block GR? Maybe even combine exonolone and one of these two? What about topical emodin, which is a selective 11b-HSD1 inhibitor?

Travis:

Emodin is nice, cheap, unpatented, prevalent, and it works, but if you look at the binding affinities I think you'd note that enoxolone binds far stronger than anything else. As far as I can tell, enoxolone and its parent compound are the only 11β-HSD₁∶₂ inhibitors that bind so well as to be dangerous.