Posts made by haidut

As many of my readers know, the medical industry has been quietly increasing its interest in and clinical trials with so-called “neurosteroids”, most of them members of the pregnane family. I think the term “neurosteroid” as used by mainstream medicine is a misnomer as it is used selectively for only a few of all the known steroids, despite the fact that virtually all of them have been demonstrated to have a central (brain) effect. For example, currently the label “neurosteroid” is applied almost exclusively to steroids such as pregnenolone, progesterone, allopregnanolone and various of their synthetic derivatives, though steroid families such as estrogens, androgens, mineralo/gluco-corticoids, and even thyroid hormones have all been demonstrated to have potent and rapid central effects as well, with indisputable influence on mood, cognition, various neurological conditions, traumas (e.g. TBI) and even cancer.

Recently, the FDA approved the progesterone derivative allopregnanolone (3α, 5α-tetrahydroprogesterone), commonly known as Allo or AlloP, as a treatment for post-partum depression. In addition, multiple companies are running clinical trials with that steroid for wide range of other conditions including dementia (e.g. Alzheimer Disease), anxiety disorders, autism, psychotic states (e.g. schizophrenia), post-traumatic stress disorder (PTSD), and even direct brain damage states such as traumatic brain injury (TBI) as well as its chronic form known as chronic traumatic encephalopathy (CTE). As of now, the only condition for which AlloP has been approved is postpartum depression with expectations that the steroid will soon be also approved for depression of any origin. The currently approved formulation is through IV infusion, but some of the new formulations currently being tested are meant for oral use, and use a preparation very close to the ideas of Dr. Peat for using long-chain fats and vitamin E to circumvent first-pass metabolism of any steroid and ensure most of the steroid gets absorbed through the lymphatic system. As such, selling AlloP has become very legally risky.

Interestingly enough, the first commercial antidepressant of the SSRI class known as fluoxetine (Prozac) was found to increase the activity and expression of an enzyme called 3α-hydroxysteroid dehydrogenase (3α-HSD), which is one of the major steps in synthesizing allopregnanolone from progesterone.

https://www.ucsf.edu/news/1999/11/97489/scientists-identify-new-pathway-antidepressant-action

https://www.pnas.org/doi/10.1073/pnas.96.23.13512

Since levels of allopregnanolone have been consistently found to increase after fluoxetine administration, and allopregnanolone levels were found to be universally low in people with depression (as well as many other brain/mood conditions) the hypothesis was that it was allopregnanolone that was the true antidepressant, with fluoxetine functioning only as a trigger for the synthesis of that “neurosteroid”.

https://pubmed.ncbi.nlm.nih.gov/37746458/

However, this hypothesis is incomplete since fluoxetine was found to increase activity and expression of mostly 3α-HSD, and while this MAY results in higher allopregnanolone levels it does not guarantee it, since the cascade has to also pass through the enzyme 5α-reductase (5-AR) in order to synthesize allopregnanolone. In fact, the steps of allopregnanolone synthesis are as follows: progesterone -> 5α-dihydroprogesterone (5-AR activity) -> allopregnanolone (3α-reductase activity). If fluoxetine selectively increases the activity of only 3α-HSD, then the only thing that can be said for sure is that fluoxetine would increase the levels of a steroid that takes progesterone as input and produces a 3α-reduced steroid, which is a steroid with a hydroxyl group (OH) on position C-3, in the alpha configuration. Once progesterone goes through 3α-HSD, and produces a C-3-ol steroid, the reaction terminates there, since that output steroid cannot undergo processing by 5-AR, as the latter can only accept as input steroids with a keto group on C-3 (progesterone, testosterone, cortisol, etc). However, since the enzyme 3α-HSD is bi-directional (oxido-reductase), the end steroid output may get converted back to progesterone. The output of the progesterone being processed by 3α-HSD is the steroid 3α-Dihydroprogesterone (3α-DHP), and if fluoxetine works primarily by increasing 3α-HSD activity and levels, then a more appropriate hypothesis would be that the anti-depressant and anti-anxiety effects of fluoxetine may be due more to the increased levels of 3α-DHP, and not so much on the increased levels of allopregnanolone.

https://en.wikipedia.org/wiki/3%CE%B1-Dihydroprogesterone

Interestingly enough, 3α-DHP has been found to have the same affinity and strength as a GABA agonist as allopregnanolone, and the latter is known as the most potent endogenous GABA agonist agent. As such, multiple studies have demonstrated that 3α-DHP has similar anxiolytic, sedative and analgesic effects as allopregnanolone. In addition, levels of 3α-DHP have been found to be low in many conditions where allopregnanolone levels have also been found to be low.

“…3α-Dihydroprogesterone (3α-DHP), also known as 3α-hydroxyprogesterone, as well as pregn-4-en-3α-ol-20-one, is an endogenous neurosteroid.[1] It is biosynthesized by 3α-hydroxysteroid dehydrogenase from progesterone.[1] 3α-DHP has been found to act as a positive allosteric modulator of the GABAA receptor and is described as being as active as allopregnanolone in regard to this action.[1] In accordance, it has anxiolytic effects in animals.[2] 3α-DHP has also been found to inhibit the secretion of follicle-stimulating hormone (FSH) from the rat pituitary gland, demonstrating possible antigonadotropic properties.[1] Unlike the case of most other inhibitory neurosteroids, 3α-DHP production is not blocked by 5α-reductase inhibitors like finasteride.[1] No data were available on the progestogenic activity of 3α-DHP as of 1977.[3] Levels of 5α-DHP have been quantified.[4]”

Strong GABA agonists are known to have a cortisol-lowering effects and there are several published case reports showing successful treatment of Cushing disease/syndrome in some people using the anti-anxiety benzodiazepine drugs (also GABA agonists, but more selective). Being the strongest endogenous GABA agonist, allopregnanolone has also been demonstrated to have cortisol-lowering effects in humans.

https://pubmed.ncbi.nlm.nih.gov/20158297

https://pubmed.ncbi.nlm.nih.gov/8946427/

https://pubmed.ncbi.nlm.nih.gov/36139100

Cortisol is a proven causal factor in depression, confirmed by multiple studies demonstrating rapid antidepressant effects of glucocorticoid antagonists (e.g. Mifepristone/RU486) in both animals and humans, as well as by rapid depressive effects caused by synthetic (e.g. dexamethasone) and natural (e.g. cortisol) glucocorticoid agonists. Since allopregnanolone has been shown to lower cortisol in humans that may explain most of its anti-depressant effects, as well as its anxiolytic effects.

https://www.newscientist.com/article/dn9516-abortion-drug-could-rapidly-treat-depression/

https://med.stanford.edu/news/all-news/2002/08/stanford-researchers-study-controversial-drug-as-treatment-for-psychotic-major-depression.html

https://doi.org/10.1016/j.steroids.2022.109058

https://link.springer.com/article/10.1134/S2079059717010142

https://pubmed.ncbi.nlm.nih.gov/34071053

As the Wiki article above states, 3α-DHP is as effective as allopregnanolone in terms of GABA activity, and likely has the same mental/physiological effects. Also, unlike allopregnanolone, 3α-DHP is not affected by administration of 5-AR inhibitor drugs such as finasteride, and is not currently regulated by medical authorities (e.g. FDA) in the US or other any other of the 30+ countries I was able to check.

https://pubmed.ncbi.nlm.nih.gov/7914815/

“…The effects of the centrally produced allylic neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on the responses of male mice to an aversive, anxiety-inducing, predator (cat) odor were examined in an odor preference test. Control untreated mice displayed an anxiogenic response to the cat odor, spending a minimal amount of time in a Y-maze in the vicinity of the cat odor. Intracerebroventricular (i.c.v.) administrations of 3 alpha HP had an anxiolytic action, resulting in significant dose-related (0.01-1.0 micrograms) increases in the amount of time spent in the proximity of the cat odor. These anxiolytic effects of 3 alpha HP were stereospecific, with the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3 beta HP) having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the response to cat odor indicating that the anxiolytic actions of 3 alpha HP were unlikely to be related to any analgesic effects. The effects of 3 alpha HP were significantly reduced by peripheral administrations of the GABAA antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results indicate that the allylic neurosteroid 3 alpha HP has anxiolytic actions involving interactions with the GABAA receptor.”

https://pubmed.ncbi.nlm.nih.gov/9870343/

“…Here we show that brief exposure of male mice to an ELF magnetic field (30 min, 60 Hz, 141 microT peak) significantly reduces the analgesic effects arising from intracerebroventricular (i.c.v.) administration of the centrally produced allylic neuroactive steroid, 3alpha-hydroxy-4-pregnen-20-one (3alphaHP) and that the dihydropyridine (DHP) calcium channel antagonists, diltiazem and nifedipine, block the inhibitory effects of the 60 Hz ELF on 3alphaHP-induced analgesia. These results indicate that exposure to 60 Hz ELF affects the analgesic effects of neuroactive steroids such as 3alphaHP through alterations in calcium channel function. These findings raise the possibility that ELF magnetic fields may, in part, exert their actions through effects on diverse neuroactive steroid modulated processes.”

https://pubmed.ncbi.nlm.nih.gov/3147122/

“…This allylic steroid elicited significant, dose-dependent (0.001-1.0 micrograms) analgesic responses for 90-150 min after injection. These analgesic effects of 3A4P were stereospecific, the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3B4P) failing to affect the nociceptive responses. The analgesic effects of 3A4P were blocked by peripheral administrations of the GABA antagonists, bicuculline and picrotoxin, and reduced by the benzodiazepine antagonist, Ro 15-1788. The exogenous opiate antagonist, naloxone, and the putative endogenous opioid antagonist, Tyr-MIF-1 (Pro-Leu-Gly-amide), also reduced 3A4P-induced analgesia, while i.c.v. administration of 3A4P (0.001 and 0.01 micrograms) itself attenuated the analgesic effects arising from peripheral administrations of opiate receptor agonist, morphine. In addition, the calcium channel antagonists, nifedipine and verapamil, enhanced 3A4P-induced analgesia but had no evident effects on the actions of 3B4P. These results suggest that the central analgesic effects of the FSH-suppressing steroid, 3A4P, arise via benzodiazepine–GABA–opiate mechanisms and calcium channels.”

The interesting properties of 3α-DHP are not exhausted by its close mimicry/overlap with allopregnanolone. The studies below suggest that it has a number of other interesting effects, at least in animals, include unique anti-cancer effects NOT shared by allopregnanolone. Since one of the tumor cell lines used in many of those cancer studies was the estrogen-sensitive (ER+) line known as MCF-7, a reasonable conclusion may be that 3α-DHP has anti-estrogenic effects, not shared by its cousin allopregnanolone, as other estrogen antagonists have also showed anti-cancer effects in MCF-7 models. For the record, 3α-DHP also demonstrated inhibitory effects on tumor growth from estrogen- and progesterone-negative cell likes, which suggests its effects are generic/systemic and not only focused on a specific steroid pathway.

https://pubmed.ncbi.nlm.nih.gov/25927181/

“…Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.”

https://pubmed.ncbi.nlm.nih.gov/19931389/

“…The studies were conducted on tumorigenic (MCF-7, MDA-MB-231, T47D) and non-tumorigenic (MCF-10A) human breast cell lines, employing several methods to assess the effects of the hormones on cell proliferation, mitosis, apoptosis and expression of Bcl-2, Bax and p21. In all four cell lines, 5alphaP increased, whereas 3alphaHP decreased cell numbers, [(3)H]thymidine uptake and mitotic index. Apoptosis was stimulated by 3alphaHP and suppressed by 5alphaP. 5alphaP resulted in increases in Bcl-2/Bax ratio, indicating decreased apoptosis; 3alphaHP resulted in decreases in Bcl-2/Bax ratio, indicating increased apoptosis. The effects of either 3alphaHP or 5alphaP on cell numbers, [(3)H]thymidine uptake, mitosis, apoptosis, and Bcl-2/Bax ratio, were abrogated when cells were treated simultaneously with both hormones. The expression of p21 was increased by 3alphaHP, and was unaffected by 5alphaP. The results provide the first evidence that 5alphaP stimulates mitosis and suppresses apoptosis, whereas 3alphaHP inhibits mitosis and stimulates apoptosis. The opposing effects of 5alphaP and 3alphaHP were observed in all four breast cell lines examined and the data suggest that all breast cancers (estrogen-responsive and unresponsive) might be suppressed by blocking 5alphaP formation and/or increasing 3alphaHP. ”

https://pubmed.ncbi.nlm.nih.gov/15212687

“…Recent evidence suggests that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that tumorous tissues have higher 5α-reductase (5αR) and lower 3α-hydroxysteroid oxidoreductase (3α-HSO) and 20α-HSO activities. The resulting higher levels of 5α-reduced progesterone metabolites such as 5α-pregnane-3,20-dione (5αP) in tumorous tissue promote cell proliferation and detachment, whereas the 4-pregnene metabolites, 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αDHP), more prominent in normal tissue, have the opposite (anti-cancer-like) effects. The aim of this study was to determine if the differences in enzyme activities between tumorous and nontumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression.”

“…The study shows changes in progesterone metabolizing enzyme gene expression in human breast carcinoma. Expression of SRD5A1 (5αR1) and SRD5A2 (5αR2) is elevated, and expression of AKR1C1 (20α-HSO), AKR1C2 (3α-HSO3) and AKR1C3 (3α-HSO2) is reduced in tumorous as compared to normal breast tissue. The changes in progesterone metabolizing enzyme expression levels help to explain the increases in mitogen/metastasis inducing 5αP and decreases in mitogen/metastasis inhibiting 3αHP progesterone metabolites found in breast tumor tissues. Understanding what causes these changes in expression could help in designing protocols to prevent or reverse the changes in progesterone metabolism associated with breast cancer.”

Furthermore, another study demonstrated striking spermatogenic effects of 3α-DHP, which were much stronger than the spermatogenic effects of testosterone. However, unlike testosterone, DHT and other related steroids, 3α-DHP did not display androgenic effects. Assuming allopregnanolone has similar effects, I would not be surprised if we soon see clinical trials for allopregnanolone (and/or, God forbid, 3α-DHP) as treatments for infertility, especially considering the skyrocketing rates of this issue in most Western/developed countries.

https://pubmed.ncbi.nlm.nih.gov/2502196/

“…The effect of 3 alpha-hydroxy-4-pregnen-3-one (3HP), a Sertoli cell steroid, on spermatogenesis was examined in normal and gonadotropin-suppressed rats, through s.c. as well as direct intratesticular injections. Early experiments employing normal prepubertal male rats indicated that 3HP, when administered at 65 micrograms/100 g BW daily for 15 days, was capable of stimulating pachytene spermatocyte number to 149% of untreated control numbers. It was of interest to determine if this effect could be amplified in gonadotropin-suppressed animals. Neonatally estrogenized rats (500 micrograms estradiol benzoate in 0.1 ml oil at 2 days) were treated on alternate days with 3HP (100 micrograms/100 g BW) for 3 wk, starting at 7 days of age. This treatment significantly increased the number of spermatocytes per tubule cross section from 17.3 +/- 1.9 (in estradiol benzoate-only animals) to 47.1 +/- 7.9 (p less than 0.01). In a similar study, 100 micrograms/100 g BW of testosterone propionate could stimulate spermatocyte number to only 15.1 +/- 2.2 cells per tubule cross section versus estradiol benzoate-only numbers. A single intratesticular injection of 3HP (2 ng in 2.0 microliters oil) in Methallibure-treated rats resulted in a significant increase in late pachytene spermatocyte numbers from 0.77 +/- 0.12 in Methallibure-only-treated rats to 1.70 +/- 0.10 (p less than 0.001) cells per tubule cross section in 28-day-old rats. However, in this study, no other progesterone metabolite or androgenic steroid (testosterone, 5 alpha-dihydrotestosterone, or 5 alpha-androstan-3 alpha, 17 beta-diol) tested was capable of this level of germ cell stimulation. In conclusion, 3HP appears to have a direct effect on germ cell development within the testis at levels much lower than those shown to be effective for androgens. It does not appear that this effect is mediated through the conversion of 3HP to any C21 or C19 steroids, and appears to be the first report of a Sertoli cell steroid with a possible role in the process of mammalian spermatogenesis.”

https://pubmed.ncbi.nlm.nih.gov/3106016/

“…Treatment of young (15-day-old) intact males with either 3-HP or 17 beta-hydroxy-5 alpha-androstan-3-one (DHT) for 14 days showed that DHT resulted in significant increases in prostate and seminal vesicle weights, while 3-HP showed no apparent androgenic activity. ”

Finally, 3α-DHP seems to have pro-sexual effects (at least in males) as it increased the preference of treated males for the odor of estrous females. While the study discusses GABA agonism by 3α-DHP as the main mechanism in achieving this pro-sexual effects, I suspect there is more at play since the administered GABA abtagonists did not completely block the effect. In my opinion, given the similar structure between 3α-DHP and allopregnanolone, the pro-dopamine and anti-serotonin (5-HT3 blocker) effects of the latter are likely to both be present in the former, and both of those pathways have a known pro-libido and performance enhancing effects.

https://pubmed.ncbi.nlm.nih.gov/8055331/

“…The effects of the centrally produced allylic neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on the responses of male mice to the odors of estrous female mice were examined in an odor preference test. Control untreated mice displayed a significant preference for the odors of an estrous female, spending more time in a Y-maze in the vicinity of the odors of an estrous than a non-estrous female. Intracerebroventricular (i.c.v.) administrations of 3 alpha HP enhanced male preference for the odors of estrous females, causing a significant dose-related (0.01-1.0 microgram) increase in the amount of time spent in the proximity of the odors of the estrous female, while having no significant effect on the responses to the non-estrous female odors. These effects of 3 alpha HP were stereospecific, with the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3 beta HP), having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the responses to female odors suggesting that the enhanced preference for estrous female odors were unlikely to be directly due to any analgesic effects of 3 alpha HP. The effects of 3 alpha HP were significantly reduced by peripheral administrations of the GABAA antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results suggest that the neurosteroid 3 alpha HP has facilitatory effects on olfactory mediated male sexual interest or motivation that involve interactions with the GABAA receptor.”

All in all, quite an interesting substance, and given its non-regulated nature we decided to release it as a product to the general public.

The units listed on the label are just for measurement purposes. They do not indicate or suggest optimal dose. Please note that similar to the liquid products sold by companies like Sigma Aldrich, Spectrum Chemical, Alfa Aesar, etc, this product if for lab/research use only.

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3α-DHP is a liquid (very viscous) product containing a bioidentical endogenous neurosteroid known as 3α-dihydroprogesterone (3α-DHP). While that steroid has not been as extensively studied as the closely-related neurosteroid allopregnanolone, 3α-DHP can perhaps be best described as an allopregnanolone mimetic, with similar (though not identical) pharmacological profile and strength (especially on the GABA system). Some of the more unique and interesting properties of 3α-DHP include its anti-cancer effects demonstrated in animal studies, with the notable finding that those anti-cancer effects are NOT shared by neither allopregnanolone nor its precursor neurosteroid 5α-dihydroprogesterone (5α-DHP). In addition, 3α-DHP has demonstrated potent spermatogenic and pro-sexual effects in some animal studies, with the former fax exceeding the effects of any other known and tested steroid (e.g. androgens).

Drops per container: about 250
Each drop contains the following ingredients:

3α-dihydroprogesterone (CAS 25680-68-6): 1mg

Other ingredients: add product to shopping cart to see info
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REFERENCES:

https://pubmed.ncbi.nlm.nih.gov/11606426/

https://pubmed.ncbi.nlm.nih.gov/9295205/

https://pubmed.ncbi.nlm.nih.gov/8199276/

https://pubmed.ncbi.nlm.nih.gov/8275952/

https://pubmed.ncbi.nlm.nih.gov/1331405/

https://pubmed.ncbi.nlm.nih.gov/2031864/

https://pubmed.ncbi.nlm.nih.gov/2500330/

Via: http://haidut.me/?p=2691

Yet another study that will surely earn me even more hate from the vitamin A antagonist crowd:-) Yet, the findings of the study below are quite clear. Namely, retinoic acid receptor (RAR) agonists, of which retinoic acid is the primary endogenous one, may both prevent and treat a number of progressive and often lethal neurological conditions against which there is currently not only no cure, but there is also no effective “symptom management therapy” either. Perhaps the most dreaded example is amyotrophic lateral sclerosis (ALS), which is not only invariably lethal within 3-5 years of diagnosis but has seen its rates climb sharply in the last several decades. The study used the so-called “superagonist” of RAR known as ellorarxine, but as the study states all the findings apply equally well to vitamin A, but probably at higher than physiological doses. The mechanism of action of the drug was opined to be related to its ability to decrease systemic inflammation, as ascertained by biomarkers such as interleukins, TNF-a, NF-kB, etc. Interestingly, the patent on the drug (link above) also states that the pharma company developing the drug thinks it would be effective for psychiatric conditions as well, including schizophrenia. Btw, one notable study finding was that despite using a “superagonist” of RAR on mice and rats, the study did not observe any toxicity. So, if a super-potent vitamin A analog did not cause toxicity, maybe vitamin A is not quite the villain some people have presented it to be.

https://doi.org/10.3389/fnins.2024.1422294

https://medicalxpress.com/news/2024-09-super-vitamin-motor-neuron-disease.html

“…New research from the University of Aberdeen published today in Frontiers in Neuroscience, found, for the first time, that drugs that target the specific receptors necessary to activate vitamin A may be therapeutic for diseases that lead to deterioration of the brain. Specifically, when disease conditions were simulated in the laboratory, the team found that super-activation of the vitamin A signaling system helped protect against the type of damage that can occur in diseases such as MND. Professor Peter McCaffery, Chair in Medical Sciences at the University of Aberdeen, who led the study, explains, “We discovered that these drugs bind and turn on the ‘retinoic acid receptor,’ a key protein involved in activation of vitamin A in the body.” Azita Kouchmeshky, neuroscientist at the University of California, San Francisco, and first author, said, “We tested these drugs in a series of studies on neurons grown in a dish. Chemicals were added to the neurons that caused harm similar to the changes that occur in diseases such as MND or ALS. “Usually, these chemicals will cause the neurons to die. However, the application of the drugs that bind to the retinoic acid receptor significantly reduced the number of cells that died off. “The same drugs were also tested in mice and were found to induce changes that suggest they may also be effective in the body.”

Via: http://haidut.me/?p=2689

As my readers know from prior posts, Big Pharma has spared no resource in its quest to convince the public that taking aspirin is at least as dangerous as playing a Russian roulette. One of the most commonly cited (and fear-inducing) reasons doctors give to patients against using aspirin regular is the bleeding risk that allegedly aspirin increases. Multiple studies have come out in the last 10-15 years showing that the alleged risk has been dramatically overblown and does not correspond to the available data. In addition, several studied demonstrates that aspirin can reduce the risk of dying from a major bleeding event in the GI tract or brain. Those bleeding risks in GI tract and brain are even listed on aspirin products as official warnings by the FDA. The study below is perhaps the first to show that aspirin not only reduces risk of dying from a bleeding event, but actually reduces the risk of bleeding itself. At least when it comes to the brain, that is, which also happens to be the more feared bleeding risk type given the difficulty of controlling a bleeding event in the brain (as opposed to the GI tract). In addition, the hospitalized (cancer) patients taking aspirin had (juts like in the prior aspirin studies mentioned above) lower mortality, lower rate of strokes, shorter hospital stays and were easier to stabilize/treat. It looks like the study came dangerously close to showing that aspirin may cure the cancer of those patients as well, but given the low dosage such an outcome was not expected.

I would not be surprised if soon we see studies, which found that aspirin reduces risk of GI bleeding as well, and does not cause GI ulcerations, as currently claimed. But it looks like such studies may not be needed, as another recent study found that a majority of people over 50 take aspirin regularly despite their doctor’s advice (actually, orders would be a more appropriate word). As the former editor of the esteemed BMJ said – until serious evidence to the contrary is available, one should assume every public health warning/policy is fraudulent, as it is likely based on openly fraudulent research. The story of aspirin’s fear-porn  is perhaps one of the best examples of that.

https://www.mdedge.com/hematology-oncology/article/270699/all/could-aspirin-avert-bad-outcomes-leukemia

“…A new analysis hints that there may be a benefit from aspirin for hospitalized patients with leukemia. In a preliminary study, researchers found that aspirin users had much lower odds of intracranial bleeding, deep vein thrombosis, in-hospital mortality, and septic stroke. Aspirin users also spent less time in the hospital and had less costly care.  No one is suggesting that clinicians give aspirin to hospitalized patients with leukemia when the drug is not otherwise indicated. However, the findings, released at the Society of Hematologic Oncology (SOHO 2024) meeting in Houston, do indicate that more research is warranted, study lead author Jayalekshmi Jayakumar, MD, of the Brooklyn Hospital Center in New York City, said in a presentation.”

Via: http://haidut.me/?p=2687

A very interesting study, which is bound to be labelled as “controversial” and my post about it will probably get censored on Twitter/X and other social media if/when it gets shared there. Given that the mechanism of action reported by the study (dopamine enhancement) is so generic, the findings of the study possibly apply to other respiratory viral infections (URTI) too, which should not only make P5 a candidate for treating influenza, cold, and the rest of the viruses responsible for URTI, but may obviate the need for vaccines against those viruses if P5 intake is regular (as it is for most people who use it). Years ago, I posted about studies showing that cholesterol and progesterone also have protective effects in severe influenza infections, which suggests that one of the reasons for ever-increasing magnitude and severity of viral pandemics may be due to the widespread use of statins, as well as hormonal birth control in women. The reason I mention birth control is that despite most hormonal contraceptives containing synthetic progestins , most of those progestins have been found to behave nothing like bioidentical progesterone (which is very rarely used clinically) and (many/most) are in fact potent agonists of the estrogen receptor(s).

https://pubmed.ncbi.nlm.nih.gov/39201608

“…n the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug–target network and dynamic network-based drug-repurposing analysis, ubiquitin–carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.”

“…Many candidate drugs have been proposed as repurposable drugs against SARS-CoV-2 infection, such as a group of kinase inhibitors [26,52], estrogen receptor modulators [53], microtubule-regulating agents [54], HCV inhibitors [55], and H1 antihistamines [27]. Notably, several drugs active in the CNS have been identified as repurposable for COVID-19, following SAveRUNNER analysis, such as dopaminergics and dopamine antagonists [56]. Herein, we proposed a series of dopamine-related drugs as potential drugs for COVID-19 treatment, especially pregnenolone and BRD-K87426499. Pregnenolone, as a dopamine release enhancer, is closely linked to the role of UCHL1 in regulating the dopamine system. UCHL1 may affect the function of dopaminergic neurons by participating in the processing of alpha-synuclein and reducing its accumulation, thereby inhibiting the production of alpha-synuclein aggregates in PD. Concurrently, it promotes dopamine release in the SCNS, which can alleviate local and systemic damage to the dopamine system and slow the progression of AD. This drug’s MOA in AD and PD suggests that pregnenolone and BRD-K87426499 may have a similar therapeutic effect in treating COVID-19.”

Via: http://haidut.me/?p=2685

One of the biggest failures of medicine to date is prevention and treatment of AD. As I posted a decade ago, 99%+ of all AD clinical trials over the last 20+ years have miserably failed. All those failed drugs have targeted one or both of the purported main causes of AD – the beta-amyloid and tau proteins, accumulating in the brains of AD patients.

https://www.bbc.com/news/health-28125265

Worse, the situation with preventing/treating AD has deteriorated so much more over those last 10 years that the latest AD drug (also targeting beta-amyloid/tau accumulation) approved by the FDA triggered the resignation of three (3) members of the drug approval board who thought that the drug is utterly ineffective and only getting approved as a “cash cow” for the pharma company running the trials with it.

https://www.npr.org/2021/06/11/1005567149/3-experts-have-resigned-from-an-fda-committee-over-alzheimers-drug-approval

In other words, ALL attempts to prevent or treat AD by targeting the beta-amyloid and/or tau plaques in the brains of AD patients have completely failed. As a result, a reasonable person would/should conclude that those plaques may not the main driver of AD, and may even be a protective mechanism the brain develops against another factor that actually causes the disease. Also a decade ago, I stumbled across the apparently well-known effects of the beta-amyloid protein (one of the two major proteins in AD plaques) as a powerful, brain-specific anti-oxidant, and an anti-microbial. Considering that the main role of anti-oxidants is protection against lipid peroxidation and reactive oxygen species (ROS), both of which promote each other, as well as the known compromised gut barrier in AD patients (i.e. increased systemic endotoxin) I made the (perhaps simplistic) suggestion in a podcast that the plaques seen in AD are nothing but a (possibly suboptimal) attempt of the brain to protect itself from PUFA and endotoxin/LPS.

https://pubmed.ncbi.nlm.nih.gov/19320465

https://pubmed.ncbi.nlm.nih.gov/12077180

https://pubmed.ncbi.nlm.nih.gov/25415602

https://en.wikipedia.org/wiki/Amyloid_beta

“…The normal function of Aβ is not yet known.[9] Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function,[10][11] several potential activities have been discovered for Aβ, including activation of kinase enzymes,[12][13] protection against oxidative stress,[14][15] regulation of cholesterol transport,[16][17] functioning as a transcription factor,[18][19] and anti-microbial activity.”

Now, in a healthy person eating diverse foods, including organ meats, this protective role would be performed by vitamin E. However, vitamin E intake has significantly dropped in “developed” countries and nowadays medicine even warns against taking vitamin E supplements due to this vitamin being linked to several cancers. Of course, those are just shameless lies, and autopsies on humans who died from AD demonstrate drastically reduced levels of vitamin E in the brains of such people. Furthermore, there are multiple animal studies demonstrating preventative and therapeutic effects of vitamin E in AD. So, preventing/treating AD may be as simple as taking vitamin E as a supplement or eating foods rich in that vitamin. Coincidentally, excessive fatty acid oxidation (FAO), lipid peroxidation, and high ROS are hallmarks of other conditions, especially diabetes (as well as cancer). In that context, one could consider AD as a brain-specific form of diabetes type II, and amenable to the same metabolic treatments. Several recent studies have made the same connection and have called on the FDA to reclassify AD as “diabetes of the brain” and allow drugs for diabetes II to be used for AD.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8910482/

https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-minute-is-alzheimers-type-3-diabetes/

While that is a great step in the right direction, the main first-line of therapy for diabetes II is the drug metformin, which happens to be a potent inhibitor of complex I of the electron transport chain (ETC) and as such is likely to drastically increase ROS levels as well as lipid (PUFA) peroxidation. Luckily, the pro-dopamine and anti-serotonin drug bromocriptine has also been approved by the FDA for diabetes II treatment and is a much better choice for both diabetes and AD.

https://en.wikipedia.org/wiki/Bromocriptine

Despite FDA claiming that the mechanism of action for bromocriptine’s benefit in diabetes is unknown, multiple human and animal studies have demonstrated that bromocriptine lowers the levels of free fatty acids in the blood (anti-lipolysis), as well as FAO. With that in mind, niacinamide, thiamine, biotin, aspirin, progesterone, testosterone, DHT, etc all become possible candidates for AD drugs given their effects of inhibiting excessive lipolysis and FAO, promoting the oxidation of glucose, lowering PUFA peroxidation, and opposing both the effects of endotoxin/LPS, as well as its absorption from the gut.

Well, I digressed quite a bit, but I think it is worth it since the digression not only builds the case for AD being a metabolic, lipid/PUFA-driven disease, but also demonstrates that medicine has once again gotten things exactly backwards. The study below not only demonstrated protective effects of the tau protein against ROS, but also demonstrated that its lack can cause serious neurodegenerative changes. Administering a simple anti-oxidant (in this case NAC, which is risky and quite inferior to vitamin E) was able to protect against the ROS in a manner very similar to the tau protein, confirming the role of tau is indeed protective and related to lipid peroxidation, Speaking of lipids, the study opined that the ROS seen in AD can be caused by excessive lipid accumulation (like diabetes), and such accumulation (even when localized by the brain) can itself easily be caused by a low-carb/high-fat diet. Yet another reason to keep the fat intake at bay.

https://www.nature.com/articles/s41593-024-01740-1

https://www.texaschildrens.org/content/research/new-role-discovered-for-tau-protecting-brain-from-oxidative-stress

“…Excess reactive oxygen species or free radicals (ROS) are a common feature of neurodegenerative diseases like Alzheimer’s disease. A recent study by postdoctoral associate Dr. Lindsey Goodman and Dr. Hugo Bellen, a distinguished service professor in Molecular Biology and Genetics at Baylor College of Medicine, who also holds a Chair in Neurogenetics at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, have discovered an important role for the disease-associated protein, Tau, in mitigating damage to the brain caused by excessive ROS and in promoting healthy aging. The study was recently published in Nature Neuroscience.”

“…There is mounting evidence supporting the notion that our brains have developed multiple neuroprotective strategies to combat ROS-induced oxidative damage. Studies in the past decade by the Bellen Lab and others have found a new neuroprotective mechanism by which glia (non-neuron brain cells) help to protect neurons from these toxic peroxidated lipids. In 2015, the Bellen team discovered that these toxic lipids are exported to neighboring glial cells and sequestered into lipid droplets (LDs) for storage and future energy production. Lipid droplets are evolutionarily conserved organelles employed by many cell types including glia to stockpile lipids and this can be triggered under conditions of cellular stress such as a high-fat diet, inflammation, altered oxygen levels, etc…Lipid droplets play important roles during development, aging, and in neuropathologies. Recent studies have found a growing number of Alzheimer’s disease-risk-associated genes are associated with the formation and function of lipid droplets in the glia, suggesting that defects in this pathway contribute to disease progression.”

“…While previous research has highlighted Tau’s critical functions in neurons, the Bellen team found that endogenous Tau protein is also important in glia. Flies lacking Tau in glia showed signs of degeneration such as progressive motor defects and decreased lifespans. Interestingly, these flies build up peroxidated lipids in their brains and treating them with an antioxidant, N-acetylcysteine amide, can prevent the motor defects caused by Tau loss in glia. “We also found that endogenous Tau in flies is required for glial lipid droplet formation and for protecting against neuronal ROS. Similarly, Tau was required in glial cells obtained from rats and humans to form lipid droplets,” said Dr. Goodman.”

Via: http://haidut.me/?p=2683

As many of my readers know, the current “standard of care” for treating conditions such as schizophrenia are anti-psychotic drugs, most of which are potent dopamine antagonists. One of the main side effects of taking such drugs is elevated prolactin (dopamine and prolactin oppose each other), which is another way of saying that dopamine antagonists are estrogenic. One of the symptoms of excess estrogen is repetitive, uncontrollable movements clinically known as chorea, as well as parkinsonism (due to the dopamine antagonism of the drugs). The family of chorea-like symptoms are ubiquitous in people taking anti-psychotic drugs. Mainstream medicine claims that such side effects not only cannot be addressed effectively, but are often permanent and irreversible. The study below demonstrates striking reductions (80%+) of those chorea-like symptoms in a patient using anti-psychotic drugs after 3 weeks of taking 400 IU vitamin E daily, and after that patient failed to respond to all other therapies. This is yet another confirmation of the anti-estrogenic effects of vitamin E, which were well-known and publicized up until the 1950s when mass estrogenic therapy was embraced by medicine and all natural anti-estrogenic substances were quickly “cancelled” from both the medical literature and clinical practice. Nowadays, if vitamin E is mentioned at all, it is always as an anti-oxidant and never as an endocrine modulator (e.g. progestogenic and anti-estrogenic).

https://www.cureus.com/articles/291429-effectiveness-of-vitamin-e-in-treatment-of-antipsychotic-induced-tardive-dyskinesia-and-extrapyramidal-symptoms-a-case-report#!/

“…Antipsychotic medications, while crucial in managing severe psychiatric disorders such as schizophrenia and bipolar disorder, are frequently associated with extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). TD, characterized by repetitive, involuntary movements, especially of the face and limbs, poses a substantial clinical challenge due to its often irreversible nature. Conventional management strategies, including dose reduction and switching to atypical antipsychotics, frequently offer limited success, prompting exploration of alternative therapies. This case report highlights the effectiveness of vitamin E, a potent antioxidant, in treating a 28-year-old male with severe antipsychotic-induced EPS and TD, unresponsive to traditional therapies. The patient, who had been receiving paliperidone injections as part of his psychotic disorder treatment regimen, developed marked EPS, including muscle rigidity, a parkinsonian gait, significant motor disturbances as well as tardive dyskinesia. Despite discontinuation of paliperidone and initiation of procyclidine, propranolol, clonazepam, and omega-3 supplements, his symptoms persisted. Introduction of oral vitamin E at 400 IU daily led to a dramatic improvement, with an 80% reduction in EPS and TD symptoms within weeks.”

Via: http://haidut.me/?p=2681

A few years ago, I did a post on the strikingly positive effects in-vivo of the dopamine agonist and (partial) serotonin antagonist bromocriptine (a member of the ergot class) in breast cancer. Using both native tumors and human tumors transplanted into rodents, bromocriptine achieved ~50%+ cure rates – i.e. primary tumor and metastases completely regressed and did not recur. My though at the time was that this was solid evidence that breast cancer is caused (and promoted) by estrogen, and since anti-prolactin drugs are de-facto anti-estrogenic, the effects of bromocriptine are hardly surprising.

https://pubmed.ncbi.nlm.nih.gov/327183/

http://www.ncbi.nlm.nih.gov/pubmed/6416848

At the time I had a few exchanges with doctors about that post, some of whom were oncologists. Their take was that since bromocriptine is a “dirty drug” (has multiple mechanisms of action) one cannot claim that it was bromocriptine’s anti-estrogenic effects that are solely responsible. And guess what? They were right…but for the wrong reasons! Since then, I discovered a multitude of studies demonstrating serotonin (5-HT) is both a cause and promoter of cancer, and that dopamine can activate the progesterone receptors. In other words, bromocriptine works by antagonizing estrogen and serotonin and promoting progesterone signalling, with the final conclusion being that estrogen/serotonin cause and promote cancer, while progesterone/dopamine are therapeutic. The study below corroborates this hypothesis by demonstrating that another drug, with much more selective pro-dopamine effects, is also therapeutic for breast cancer. And unlike the studies above, which used only estrogen-sensitive cancers, the study below found that the dopaminergic drug was effective against all types of breast cancer, including the dreaded triple-negative type (TNBC). The drug of note is our old friend selegiline (Deprenyl), which has acquired notoriety worldwide as being the anti-aging drug of choice of the elite for decades…and the only one so far proven to work in humans for anti-aging purposes. Selegiline’s sole known mechanism of action is being a monoamine oxidase B (MAO-B) inhibitor. Considering getting access to this drug is hard (and bound to become even harder considering its therapeutic potential), it would be helpful if one could use another MAO-B inhibitor not subject to the same notoriety/restrictions. Luckily, naphthoquinones such as vitamin K and the the main constituent of clove oil known as eugenol are also potent and selective MAO-B inhibitors.

https://pubmed.ncbi.nlm.nih.gov/22071524/

“…Herein we show that MAO-B was inhibited competitively by 1,4-NQ (K(i)=1.4 μM) whereas MAO-A was inhibited by non-competitive mechanism (K(i)=7.7 μM). Contrasting with TMN and 1,4-NQ, menadione (vitamin K3) exhibited a 60-fold selectivity for MAO-B (K(i)=0.4 μM) in comparison with MAO-A (K(i)=26 μM), which makes it as selective as rasagiline.”

https://onlinelibrary.wiley.com/doi/abs/10.1111/jfbc.13571

“…The phytoconstituents were investigated for their MAO-B inhibitory activity by an in vitro fluorimetric assay. The phytoconstituents were tested to inhibit the MAO-B enzyme at two different concentrations, 10μM and 40μM. It was observed that eugenol showed the maximum inhibition of 21.48± 0.059% and 63.11± 2.95% at 10μM and 40μM concentration, respectively. Whereas piperine showed inhibition of 13.32± 3.91% and 37.19± 12.21% at 10μM and 40μM concentration, respectively. The reference drug selegiline, which is a known inhibitor of MAO-B, showed 84.63****± 4.32% and 85.30± 2.92% inhibition at 10μM and 40 μM concentration, respectively (Figure 3a).”

All in all, the evidence continues to accumulate that pro-metabolic, anti-estrogenic, anti-serotonin, progestogenic and dopaminergic pathways are highly beneficial not only for a large number of very serious degenerative conditions, but they make one slim, happy, frisky (due to the antiprolactin effects) and long-living. And since estrogenic (PUFA, birth control, endocrine disruptors, etc) and serotonergic (SSRI) substances functionally approximately opposite to selegiline, you can imagine what their effects are.

https://pib.gov.in/PressReleasePage.aspx?PRID=2050881

“…This research group has shown that Selegiline (L-deprenyl), an antidepressant drug from a class of drugs called monoamine oxidase (MAO) inhibitors, might be applied as anticancer therapeutics for breast cancer. The integrated network pharmacological studies found that selegiline interacts with ten genes intricately linked to various types of cancer, with a significant number of nodes. The study conducted a preliminary comparative evaluation of the efficacy of selegiline on six cancer cell lines. Selegiline was found effective in killing estrogen and progesterone-positive (ER+ & PR+) as well as triple-negative breast cancer (TNBC).”

Via: http://haidut.me/?p=2679

Another study causally linking PUFA with a chronic, debilitating disease. Namely, it appears that PUFA is capable of causing autism in both humans and animals, which suggests that the detrimental effects of PUFA is generic and likely applies not only to other species, but to other diseases as well. More specifically, the study below demonstrated that a dihydroxy-metabolite of the PUFA arachidonic acid (itself highly inflammatory even when intact) can reliably cause autism symptoms in animals and is causally linked to autism development and severity in humans. While the study implicated only one PUFA metabolite so far, there are other studies demonstrating that arachidonic acid, and even its precursor linoleic acid, are also linked to autism development. As such, the best option is to avoid dietary PUFA altogether instead of trying to modulate/block its downstream metabolites (which is what the study below is suggesting as therapy), of which undoubtedly there are many yet to be discovered. Finally, considering that inflammation has already been confirmed to be a major component in both autism and virtually all other chronic disease, I think it would not be far-fetched to conclude that PUFA is a major causal factor for all chronic diseases known to medicine so far, so its avoidance becomes that much more important.

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(20)30292-9/fulltext

https://onlinelibrary.wiley.com/doi/10.1002/aur.2365

http://dx.doi.org/10.1111/pcn.13710

https://www.sciencedaily.com/releases/2024/07/240729104241.htm

“…Although the exact causes of ASD are unclear, currently available evidence points to neuroinflammation as a major factor. Several studies in mouse models of ASD have hinted at the importance of polyunsaturated fatty acids (PUFA) and their metabolites during pregnancy in playing a key role in ASD development. PUFA metabolites regulated by the cytochrome P450 (CYP) affect fetal development in mice causing impairments closely linked to ASD symptoms. However, it is still unclear if the same is true for humans and needs further investigation.”

“…After careful statistical analyses of the results, the researchers identified one compound in cord blood that may have strong implications for ASD severity, namely 11,12- dihydroxyeicosatrienoic acids (diHETrE), a dihydroxy fatty acid derived from arachidonic acid. “The levels of diHETrE, an arachidonic acid-derived diol, in cord blood at birth significantly impacted subsequent ASD symptoms in children and were also associated with impaired adaptive functioning. These findings suggest that the dynamics of diHETrE during the fetal period is important in the developmental trajectory of children after birth,” highlights Prof. Matsuzaki.”

“…”The effectiveness of early intervention for children with ASD is well established and detecting it at birth could enhance intervention and support for children with ASD,” muses Prof. Matsuzaki. He also adds that inhibiting diHETrE metabolism during pregnancy might be a promising avenue for preventing ASD traits in children, although more research will be needed in this regard.”

Via: http://haidut.me/?p=2677

Just a few days ago I posted about a study showing that serotonin (5-HT) plays a role in driving the growth of a rare but lethal pediatric cancer. The authors of that study opined that the growth-promoting effects of 5-HT are generic enough that they may apply to all cancers. The studies below corroborate that view with evidence that 5-HT forms a positive feedback cycle for its production (just like cortisol, which also drives cancer growth) by increasing both the expression and activity of the enzyme tryptophan hydroxylase (TPH) – i.e. the 5-HT producing enzyme. Apparently, 5-HT also activates aerobic glycolysis, known as the Warburg Effect (WE). The WE was considered up until very recently a benign symptom of cancer, but not oncogenic. Recent studies have completely disproved that view and it is now known that the WE is a required factor for growth of ALL cancer types studied so far. In light of these effects, it is little wonder that the studies below found 5-HT to be a robust promoter of the growth of breast, colon and pancreatic cancers, the first two of which combined are responsible for the majority of cancer cases and cancer-related deaths. In further corroboration, one of the studies identified 5-HT as a diagnostic biomarker in breast cancer that not only reliably predicts whether a specific tissue/organ is cancerous, but also predicts the severity/aggressiveness of the tumor. Namely, serotonin levels were found to be highest in the most aggressive and difficult to treat triple-negative breast cancer. Conversely, the studies describe therapeutic effects of 5-HT antagonists in the studied cancers, which has already been corroborated by a recent peer-reviewed human case study demonstrating complete disappearance of terminal, metastatic liver cancer by monotherapy with the non-selective 5-HT antagonist cyproheptadine.

The evidence for the oncogenic role of 5-HT is, in fact, so strong that one of the studies stated that 5-HT is required for (breast) cancer survival, meaning without 5-HT the tumor disappears or, better, does not even form in the first place. So, now we can add cancer to the CVD that 5-HT is also implicated in causing, and those two maladies just happen to be the top two causes of death in all developed countries. In light of this evidence, one would be forgiven to conclude that SSRI drugs (widely prescribed to cancer patients to “prevent” or “treat” their depression/PTSD from the cancer diagnosis) are likely a major causative factor for the skyrocketing rates of those conditions, as well as the deaths they cause. In corroboration, one of the studies below mentions extensive evidence for SSRI both promoting cancer formation, as well as increasing the mortality rates of already diagnosed cancer patients.

https://www.nature.com/articles/s41388-022-02584-4

“…Serotonin (5-hydroxytryptamine, 5-HT) is synthesized from the essential amino acid tryptophan and mediates motility in the gastrointestinal tract and is a vasoactive agent in the blood. As a monoamine neurotransmitter, it also acts in the central nervous system. It regulates epithelial homeostasis in the breast. Serotonin is believed to impact immune signaling and stimulate growth of breast cancer cells [57,58,59,60,61]. Olfati et al. showed that in samples from breast cancer patients, 5HTR2A and 5HTR3A genes are more expressed in tumoral tissues than marginal tissues [62]. Serotonin also initiates angiogenesis by the proliferation, invasion, and migration of endothelial cells [63]. Sonier et al. found that serotonin promotes the growth and division of breast cancer cells, specifically MCF-7 cells, in part through the 5-HT2A receptor. Proliferation and invasion is also facilitated by the 5-HT7 receptor in MDA-MB-231 cells. In these cells, 5-HT is essential to enhance the expression of TPH1 (tryptophan hydroxylase 1) and VEGF, supporting the mitogenic and oncogenic impact of 5-HT on breast cancer.”

“…If lowering serotonin activity reduces breast cancer recurrence, then a logical question is the impact of medications that raise serotonin levels. Evidence has been conflicting on this long-standing question. Two decades ago, researchers reported that use of tricyclic medications was associated with significantly increased breast cancer risk [66, 67] and that use of selective serotonin reuptake inhibitor (SSRI) drugs may also pose a breast cancer risk [68, 69]. The SSRI fluoxetine may increase the number of breast cancer brain metastases at least in part due to inflammatory changes in the brain [70]. Supporting these contentions, this year researchers in Israel reported based on an analysis of 7000 patients that use of SSRIs in the years prior to breast cancer diagnosis, or in the years following diagnosis, was associated with substantially increased mortality [71].”

https://pubmed.ncbi.nlm.nih.gov/32758183/

“…The data presented herein strongly suggests that structurally unrelated selective 5-HT5A antagonists reduce the frequency of tumorsphere initiating cells by affecting the activity of 5-HT5A. The latter is supported by our pharmacological data demonstrating that the IC50 of the guanidine-type 5-HT5A antagonists in sphere forming assays directly correlated with their binding affinity for 5-HT5A [24, 36]. Moreover, CRISPR-Cas9 mediated mutagenesis of HTR5A reduced the frequency of tumorsphere initiating cells and that of BTIC using in vitro and ex vivo assays, thus mimicking the effect of SB-699551. Hence both pharmacological and genetic means of reducing 5-HT5A activity resulted in the same phenotypic consequences in breast tumor cell lines, suggesting that 5-HT5A is indeed required for BITC survival. We also found that SB-699551 reduces the growth rate of human breast tumor xenografts in NOD/SCID mice when administered alone and shrinks the xenografts in combination with docetaxel. Histological examination and TUNEL assays revealed an increase in the frequency of apoptotic tumor cells in the xenografts of mice treated with a combination of both agents. ”

https://doi.org/10.1158/1541-7786.MCR-23-0513

“…A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in colorectal cancer tumor tissues, which was further identified as a strong risk factor for colorectal cancer prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of colorectal cancer cell, as well as the epithelial–mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via the Akt/mTOR pathway, which triggered cAMP-responsive element-binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for ZEB1 transcription after binding to CREB1 half-site (GTCA) at ZEB1 promoter. As a key regulator of EMT, ZEB1, therefore, enhances migration and EMT process in colorectal cancer cells. We also found that HTR2B-specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process in both HCT116 cell tail-vein–injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models.”

https://doi.org/10.2147/IJGM.S310591

“…Our results suggested that both human breast cancer cells and human breast epithelial cell line could synthesize serotonin and melatonin. Unlike melatonin, serotonin levels varied significantly between human breast cancer and breast epithelial cell line (p< 0.01). In addition, serotonin N-acetyltransferase (NAT) and acetylserotonin methyltransferase (ASMT), the key enzymes in the pathway of melatonin synthesis from serotonin, were also detectable. In agreement with these findings of human breast cancer cell and human breast epithelial cell line, serotonin expression was also much higher in triple-negative (PR−, ER−, HER-2−) breast cancer (TNBC) and triple-positive breast cancer (TPBC) compared to para-carcinoma tissues (PCTs). Here, we provided evidence that the human breast cancer cell (MCF-7, Bcap-37) and human breast epithelial cell (MCF-10A) could synthesize intrinsic serotonin and melatonin, and serotonin expression was higher in the breast cancer tissue compared with PCT. The findings suggested that serotonin might be used as a predictive marker for breast cancer patients.”

https://doi.org/10.1053/j.gastro.2017.03.008

“…In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels of 5-HT to be increased in human PDAC tissues compared with non-tumor pancreatic tissues, and PDAC cell lines compared with non-transformed pancreatic cells. Incubation of PDAC cell lines with 5-HT increased proliferation and prevented apoptosis. Agonists of HTR2B, but not other 5-HT receptors, promoted proliferation and prevented apoptosis of PDAC cells. Knockdown of HTR2B in PDAC cells, or incubation of cells with HTR2B inhibitors, reduced their growth as xenograft tumors in mice. We observed a correlation between 5-HT and glycolytic flux in PDAC cells; levels of metabolic enzymes involved in glycolysis, the phosphate pentose pathway, and hexosamine biosynthesis pathway increased significantly in PDAC cells following 5-HT stimulation. 5-HT stimulation led to formation of the HTR2B–LYN–p85 complex, which increased PI3K–Akt–mTOR signaling and the Warburg effect by increasing protein levels of MYC and HIF1A. Administration of SB204741 to KPC mice slowed growth and metabolism of established pancreatic tumors and prolonged survival of the mice. Human PDACs have increased levels of 5-HT, and PDAC cells increase expression of its receptor, HTR2B. These increases allow for tumor glycolysis under metabolic stress and promote growth of pancreatic tumors and PDAC xenograft tumors in mice.”

Via: http://haidut.me/?p=2675

The inflammatory interleukins IL-1 and IL-6 are among the most studied biomarkers/pathways. Their role in “autoimmune” conditions is undisputed and some of the top-selling drugs for such conditions are IL-1 and/or IL-6 blockers. There is also plenty of evidence that those interleukins play a role in other serious conditions, including cancer and various neurological disorders. Another mediator with systemically inflammatory effects is NF-kB, and its role in autoimmune conditions and atherosclerosis is also undisputed. Drugs that block NF-kB are currently being tested for virtually all chronic conditions, including ones where inflammation is not thought to play a direct role (diabetes, Parkinson’s, infertility, etc). The study below demonstrated that 5-HT robustly increased levels (and mRNA expression) of IL-6 and NF-kB, and as such likely plays a key role in cardiovascular disease (CVD)  – the current top cause of death in developed countries (soon to be overtaken by cancer, where IL-6 and NF-kB also play a key role). Needless to say, the administration of SSRI has the same effects as 5-HT, and their widespread use may explain the ever-rising CVD/cancer rates even in children (for who SSRI drugs are approved for use). Conversely, the study demonstrated that serotonin antagonists were able to block the inflammatory effects of serotonin, which would make them desirable candidates for preventing and treating CVD, cancer, autoimmune conditions, neurodegenerative diseases, diabetes, etc.

https://doi.org/10.1161/01.CIR.102.20.2522

“…IL-6 levels in the culture medium of VSMCs were determined by ELISA. IL-6 mRNA accumulation was determined by use of a Quantikine mRNA colorimetric quantification kit. NF-κB activation was tested by gel retardation assay. 5-HT induced IL-6 production by VSMCs in a time- and dose-dependent manner, with increased IL-6 mRNA accumulation and nuclear factor-κB activation. The effect of 5-HT on IL-6 production was significantly inhibited by the 5-HT2 receptor antagonist ketanserin and the selective 5-HT2A receptor antagonist sarpogrelate. Conversely, the 5-HT2 receptor agonist α-methyl-5-HT increased IL-6 production. The protein kinase C (PKC) inhibitor calphostin C, but not the protein kinase A inhibitor KT5720, suppressed 5-HT–induced IL-6 production. The effect of 5-HT was also abolished in PKC-depleted VSMCs after pretreatment with phorbol 12-myristate 13-acetate for 24 hours. 5-HT acts on 5-HT2A receptors and increases IL-6 synthesis in human VSMCs at least partially through a PKC-dependent pathway. These results suggested that 5-HT may contribute to inflammatory activation of the vessels during atherogenesis.”

Via: http://haidut.me/?p=2673

Over the last several years I have received hundreds of emails from males in regards to POIS. The number of publications about POIS in the scientific literature, as well as articles in the popular press have been steadily rising. While some medications such as finasteride and SSRI are known to cause POIS symptoms, the fact that the reports/rates of POIS have been steadily increasing suggest something else is also at play in this condition. Some people report relief after thyroid or testosterone therapy, suggesting the conditions is energetic in origin. The case study below is perhaps the most direct evidence that POIS is energetic in origin, considering its successful and sustained resolution with niacinamide therapy, at a daily dose of 500mg, taken for 5 months.

https://pubmed.ncbi.nlm.nih.gov/38952608/

“…Post-orgasmic illness syndrome (POIS) is a rare condition characterized by debilitating symptoms following ejaculation. We present a case of a 25-year-old male with flu-like symptoms post-ejaculation since age 17. Despite minimal relief from conventional treatments, a comprehensive evaluation led to the diagnosis of POIS and successful management with niacinamide therapy. The presentation of flu-like symptoms following ejaculation in this case raises several questions regarding the underlying pathophysiology. While the exact cause of his symptoms remains elusive, the resolution achieved with niacinamide therapy underscores the importance of considering alternative treatment modalities in complex cases. The role of varicocele in symptom manifestation, if any, also warrants consideration, as varicocele has been associated with male infertility and testicular dysfunction.”

“…Following the comprehensive evaluation, the patient was initiated on niacinamide therapy (500 mg per day, taken orally in the form of a tablet) for five months. Niacinamide, a form of vitamin B3, is known for its role in cellular energy production and overall metabolic function. Its mechanism of action in alleviating the post-ejaculation symptoms in this case remains an area of interest and warrants further exploration.”

Via: http://haidut.me/?p=2671

Mainstream medicine claims that once cardiovascular disease (CVD) is established, there is no way to reverse it. All one can do is try to inhibit further plaque formation in the hope of delaying the inevitable (vessel blockage/rupture, followed by heart attack and/or stroke). I have already found studies demonstrating that aspirin, in doses of 800mg+ daily can reduce already established atheroma (plaque) and prevent future CVD event. The study below found that vitamin E, in a human-equivalent dose of  about 5mg/kg daily, also reduces atherogenesis and improves cardiac function, without displaying antioxidant effects. The role of vitamin E as PUFA antagonist is probably the main mechanism of action, together with its role as an inhibitor of the inflammation producing enzyme COX/LOX, and its inhibitory effects on the release of other inflammatory mediators such as TNF-a, IL-1 and IL-6.

https://pubmed.ncbi.nlm.nih.gov/38717284/

“…The impact of α-tocopherol on atherosclerosis is unclear and controversial. While some studies suggest potential benefits, such as antioxidant properties that may reduce oxidative stress, other studies indicate no significant preventive effects. The intricate interplay of various factors, including dosage, individual differences, and study methodologies, contributes to the ongoing uncertainty surrounding α-tocopherol’s role in atherosclerosis. Further research is needed to clarify its impact and establish clearer guidelines. Therefore, we aimed to evaluate the impact of α-tocopherol on atherogenesis in ApoE−/− fibrillin (Fbn)1C1039G/+ mice, which is a unique mouse model of advanced atherosclerosis with typical features, such as large necrotic cores, high levels of inflammation, and intraplaque neovascularization, that resemble the unstable phenotype of human plaques. ApoE−/− Fbn1C1039G+/− mice were fed a western-type diet (WD) supplemented with a high dose of α-tocopherol (500 mg/kg diet), while control mice were fed a WD containing a low dose of α-tocopherol (50 mg/kg diet). The high dose of α-tocopherol reduced plaque thickness and necrotic core area in the right common carotid artery (RCCA) after 24 weeks WD. Moreover, α-tocopherol decreased plaque formation and intraplaque neovascularization in the RCCA. In addition to its antiatherogenic effect, chronic supplementation of α-tocopherol improved cardiac function in ApoE−/− Fbn1C1039G/+ mice. However, chronic supplementation of α-tocopherol did not decrease lipid peroxidation. On the contrary, α-tocopherol acted as a prooxidant by increasing plasma levels of oxidized LDL and plaque malondialdehyde, an end product of lipid peroxidation. Our data indicate that α-tocopherol inhibits atherogenesis and improves cardiac function independent of its antioxidant properties.”

Via: http://haidut.me/?p=2669

It looks like we can add vitamin E to the list of remedies against endotoxin/LPS, at least when it comes to muscle health/strength. Endotoxin/LPS is well-known to induce systemic inflammation and one of the core symptoms of systemic inflammation is muscle weakness, which eventually progresses into muscle loss (sarcopenia) if the endotoxin assault continues sufficiently long. There are virtually no known remedies for inflammation induced weakness, aside from aspirin and anabolic steroids, the latter of which has significant side effects. The study below demonstrates that vitamin E (alpha-tocopherol specifically) may be one of the main endogenous protective factors against systemic inflammation induced by endotoxin and the resulting myopathies. The benefits of vitamin E in this case cannot be explained with its antioxidant effects, which suggests that its role as a COX/LOX inhibitor is probably the main mechanism of action.

https://pubmed.ncbi.nlm.nih.gov/38141774/

“…αT concentrations in the liver, heart, and adipose tissue of WT mice were higher than Ttpa-/- mice. Although αT was detected in the brain, muscle, and serum of WT mice, it was undetectable in these tissues of Ttpa-/- mice. Cerebellar and serum concentrations of IL-6 were increased in LPS-treated groups but were not significantly affected by genotype. Grip strength was reduced in LPS-treated groups, an effect that was more pronounced in Ttpa-/- mice. Systemic LPS administration caused an acute inflammatory response with a concomitant decline in grip strength, especially in Ttpa-/- mice. αT depletion appears to exacerbate reductions in grip strength brought on by systemic inflammation.”

Via: http://haidut.me/?p=2667

Evil serotonin (5-HT) strikes again. This time by being exposed as a potent tumor growth promoter. Cortisol is another one, contrary to what medicine says and practices in regards to cortisol, and considering cortisol and serotonin promote each other’s synthesis it is little surprise to see evidence of serotonin promoting tumor growth. While the study focused on only one tumor type, the authors explain that the mechanism of serotonylation is very generic and seen in most other tumor types, so the findings likely apply to all  cancers. In corroboration, there have been quite a few recent publications demonstrating beneficial effects of the serotonin antagonist cyproheptadine in a wide variety of both solid and hematological malignancies. There is even a case study of terminal metastatic liver cancer in a human patient being completely cured by cyproheptadine in just 2 weeks. All in all, a damning verdict for serotonin and its promoters in Big Pharma, medical organizations, and public health agencies.

https://www.nature.com/articles/s41586-024-07751-z

https://d.newswise.com/articles/serotonin-uptake-regulates-ependymoma-tumor-growth

“…Do neurons play a role in brain tumor growth and development? Scientists at St. Jude Children’s Research Hospital and Baylor College of Medicine have evidence showing that, for childhood ependymomas, they do. There are no targeted therapies available to treat ependymoma due in large part to a lack of understanding of the tumor microenvironment. By leveraging a recently developed murine model, scientists explored the interaction between ependymoma cells and surrounding neurons. They found that hyperactivation of a specific subset of neurons has different effects on tumor cell proliferation. Increased serotonin production in the tumor microenvironment drives tumor growth. The findings were published today in Nature.”

“…This is notably relevant for difficult to treat cancers, such as ependymoma, the third most common type of brain tumor in children. The present study offers fundamental insights into how ependymoma regulation is impacted by the surrounding neuronal environment. Ependymoma is associated with poor survival and neurocognitive outcomes due to a lack of available targeted therapies. A newly developed mouse model successfully mimics an aggressive form of the cancer caused by a gene fusion between ZFTA and RELA, which creates a rogue transcription factor that drives tumor growth. The model has allowed researchers, including Mack, to finally gain insight into the biology of the disease, the lack of which has stymied drug discovery efforts from the outset.”

“…The researchers found that in ependymoma, pathways involved in neuronal function and neurotransmission were enriched, implying not just a tumor neuronal interaction but a dependency. Further analysis of this link steered them towards serotonergic neurons, those responsible for producing the neurotransmitter serotonin. Enrichment of serotonin transporters within tumor cells implied that the tumor cells were foraging serotonin from their environment, but it was not clear why. “We found that serotonin added to histone proteins is a modification critical for ependymoma tumor growth,” added first author Hsiao-Chi Chen, Baylor College of Medicine.”

“…The researchers also demonstrated that the tumor cells can “talk back” to the neurons. “We’ve dissected some of the gene regulatory mechanisms in these tumors and seen how tumor cells secrete factors that modulate normal activity,” Mack said. “You lose control of factors you would normally release to inhibit hyperactivity. It’s a vicious loop where these cells are communicating with each other to drive tumor cell proliferation.” Identifying such a fundamental link between tumor neuronal communication and tumor proliferation may impact cancers beyond ependymoma. “Finding that histone serotonylation regulates tumorigenesis and that it’s being driven by neurons in the microenvironment is remarkable,” said Mack. “It could apply to other tumor types too.”

Via: http://haidut.me/?p=2664

I posted about a study a few months ago demonstrating that reduced steroidogenesis, and especially androgen synthesis, is a major cause behind so-called dry-eye disease, and restoring steroidogenesis by administering niacinamide (thus raising NAD+) reversed most of the pathology. The study below suggests that vitamin D may be able to achieve the same, and the mechanism of action is probably largely the same considering that vitamin D is crucial for steroidogenesis, and especially progesterone and androgen synthesis. It gets even better – vitamin D, being a (seco)steroid itself is known to be able to bind and activate several steroid receptors directly and thus may work even in the context of severe/irreversible steroid deficiency. More specifically, vitamin D has been shown to bind and activate the progesterone, androgen and thyroid receptors, all of which have demonstrated benefit for ocular health and dry-eye disease in particular.

https://doi.org/10.1016/j.clae.2024.102169

https://medicaldialogues.in/ophthalmology/news/vitamin-d-supplementation-might-effectively-reduce-symptoms-of-dry-eye-disease-suggests-study-132727

“…A new study published in the recent issue of Contact Lens and Anterior Eye journal found that supplementing with vitamin D (VD) may be a useful adjuvant therapy to reduce the symptoms and indicators of dry eye. DED is a prevalent ocular illness that affects 5 to 50% of people globally, according to estimates. Common ocular discomfort symptoms in DED include dryness, redness, a feeling of a foreign body, heaviness, light sensitivity, pain, discharge, itching, and eye strain. Also, the vitamin that has immunomodulatory and anti-inflammatory properties is vitamin D which was demonstrated by numerous studies to have a correlation between VD insufficiency and both the incidence and severity of dry eye disease (DED). In this meta-analysis, Zeying Chen and colleagues examined the symptoms and indicators of DED patients both before and after using VD supplements. The effectiveness of VD supplement in patients with DED published up to January 2023 was searched using four clinical trials registry websites (ISRCTN, ICTRP, CT, GCP, ICH) and ten databases (Cochrane, PubMed, Web of science, Embase, Ovid, CNKI, Scopus, CSTJ, SinomedWanfang). There were 8 investigations in all, comprising a total of 439 patients. In order to determine standard mean differences (SMD) for the Schirmer’s test (SH test), corneal fluorescein staining scores (CFSS, Oxford Scale, 0–5), tear film break-up time (TBUT), ocular surface disease index (OSDI), lid hyperemia, and visual analogue pain scale (VAS), two reviewers independently evaluated the quality of the literature and extracted data. The key finding of this study was that VD supplementation was found to be effective in reducing lid hyperemia (SMD −0.71, 95% CI −1.09, −0.32, p = 0.000), OSDI (SMD −1.10, 95% CI −1.45, −0.74, p = 0.000), and tear production (SMD 1.43, 95% CI 0.81, 2.05, p = 0.000) as well as tear film stability (SMD 1.19, 95% CI 0.83, 1.55, p = 0.000). Overall, this meta-analysis suggests that VD supplementation is an effective way to reduce several of the symptoms of DED, including lid hyperemia, TBUT, and SH test. Additionally, the subjective DED symptom score, OSDI, also improved. The subgroup analysis revealed that the oral version significantly improved when compared to the buccal spray and intramuscular injection”

Via: http://haidut.me/?p=2662

A stunning discovery, which flies in the face of everything that medicine claims to know about dopamine. Official medical dogma views dopamine as largely a nuisance, and even danger to human health. High dopamine levels are thought to be responsible for serious conditions such as schizophrenia, as well as virtually all types of addiction (substance, gambling, sexual, etc). As such, there is a large number of dopamine antagonist drugs and a much smaller set of dopamine agonists. Now, dopamine is known to have a pro-cognitive effect and this has resulted in the development of amphetamine-based chemicals such as Adderall, Ritalin, Provigil, etc that are now abused on a mass scale by virtually every white-collar profession in a quest to enhance cognitive function and outcompete peers intellectually in a corporate setting. Unbeknownst to most, serotonin has also been (very, very quietly) suspected as a cause of AD and there have even been several clinical trials with suboptimal serotonin antagonists as treatment for AD. The study below demonstrates that dopamine has a plaque-dissolving effect and suggests that this is the main mechanism of action through which dopamine may treat AD. However, 99% of all AD trials based on drugs targeting the beta or tau amyloid plaques have been utter failures, which suggests that the plaque-busting effects of dopamine are not the real explanation. Also unbeknownst to most, dopamine (and dopamine agonists) are potent inhibitors of the enzyme tryptophan hydroxylase (TPH), which is the rate-limiting step for producing serotonin inside the body. If serotonin is indeed a major cause of AD, then the serotonin-reducing properties of dopamine (and dopamine agonists) are probably the true mechanism of action behind the beneficial effects seen in the study below.

https://doi.org/10.1126/scisignal.adk1822

Melting Away Alzheimer’s: How Dopamine Dissolves Harmful Brain Plaques

“…A new way to combat Alzheimer’s disease has been discovered by Takaomi Saido and his team at the RIKEN Center for Brain Science (CBS) in Japan. Using mice with the disease, the researchers found that treatment with dopamine could alleviate physical symptoms in the brain as well as improve memory. Published today (August 6) in the scientific journal Science Signaling, the study examines dopamine’s role in promoting the production of neprilysin, an enzyme that can break down the harmful plaques in the brain that are the hallmark of Alzheimer’s disease. If similar results are found in human clinical trials, it could lead to a fundamentally new way to treat the disease.”

“…Now the serious experiments began. Using a DREADD system, they inserted tiny designer receptors into the dopamine-producing neurons of the mouse ventral tegmental area. By adding a matching designer drug to the mice’s food, the researchers were able to continuously activate those neurons, and only those neurons, in the mouse brains. As in the dish, activation led to increased neprilysin and decreased levels of free-floating beta-amyloid, but only in the front part of the mouse brain. But could the treatment remove plaques? Yes. The researchers repeated the experiment using a special mouse model of Alzheimer’s disease in which the mice develop beta-amyloid plaques. Eight weeks of chronic treatment resulted in significantly fewer plaques in the prefrontal cortex of these mice.”

“…The DREADD system is an incredible system for precise manipulation of specific neurons. However, it is not very useful for human clinical settings. The final experiments tested the effects of L-DOPA treatment. L-DOPA is a dopamine precursor molecule often used to treat Parkinson’s disease because it can enter the brain from the blood, where it is then converted into dopamine. Treating the model mice with L-DOPA led to increased neprilysin and decreased beta-amyloid plaques in both frontal and posterior parts of the brain. Model mice treated with L-DOPA for 3 months also performed better on memory tests than untreated model mice. Tests showed that neprilysin levels naturally decreased with age in normal mice, particularly in the frontal part of the brain, perhaps making it a good biomarker for preclinical or at-risk Alzheimer’s disease diagnoses. How dopamine causes neprilysin levels to increase remains unknown, and is the next research topic for Saido’s group.”

Via: http://haidut.me/?p=2660

The topic of vitamin C and enhanced resistance against (as well as accelerated recovery from) infections (especially viral) is highly controversial. Modern medicine dismisses vitamin C as being good for only preventing/treating scurvy. However, a number of high-profile scientists, including Nobel laureate Linus Pauling believed (and repeatedly demonstrated in studies) that vitamin C has a broad immunostimulating effect and may be effective at both preventing and treating variety of infections, especially viral ones such as influenza and cold (COVID-19 anyone?), and even cancer! The study below seems to vindicate Mr. Pauling and demonstrates that the beneficial effects of vitamin C are not limited to just viral infections, but also extend to bacterial, fungal and even multi-cellular (parasitic) infections. The exact mechanism of action of vitamin C is not known, however given its structural similarity to sugar and usage of the same pathways of active transport into the cell (the GLUT channels/receptors), I suspect that vitamin C may serve as a glucose mimetic in situations when the cell is under stress and glucose availability is limited. Glucose availability has already been demonstrated to be crucial for resistance to all types of infection, and lowering serum glucose is known to increase lethality from both pathogens and allergens.

https://doi.org/10.3390/nu9040339

The Surprising Link Between Vitamin C and Fighting Off Infections, According to Science

“…The notion that vitamin C could help ward off infections is not new. As early as the 1930s, physicians like Dr. Casimir Funk pioneered the use of vitamin C to combat infectious diseases. However, the advent of antibiotics in the mid-20th century largely overshadowed research into vitamin C’s antimicrobial potential [1]. “Our review aimed to dust off a century’s worth of accumulated evidence on vitamin C and infections,” explained Dr. Samantha Patel, lead author of the study and a researcher at the University of Helsinki. “What we found was a wealth of data suggesting that this humble vitamin could be a valuable addition to our anti-infection toolkit.”

“…Dr. Patel’s team began by analyzing over 148 animal studies that investigated vitamin C’s impact on infectious conditions. Remarkably, they found that vitamin C demonstrated protective effects against a variety of pathogens, including bacteria, viruses, fungi like Candida albicans, and even parasitic protozoa [1]. “Across diverse animal models, vitamin C consistently helped prevent, shorten, and alleviate infectious diseases,” noted Dr. Patel. “While the human implications remain to be fully elucidated, these findings strongly suggest that vitamin C has untapped potential as a broad-spectrum antimicrobial agent.”

Via: http://haidut.me/?p=2658

Yet another win for aspirin, and this time in regards to something medicine considers next to impossible to treat – i.e. ionizing radiation-induced skin wounds. Aside from the known genotoxic effects of radiation, the latter can also cause severe skin burns that are very slow to heal and often become chronic, unhealing wounds subject to infection that can easily become life-threatening. The study below demonstrates that a simple mix of aspirin and glycopeptides (which can probably be closely approximated with a water solution of gelatin and sugar) significantly accelerated the healing of radiation-induced wounds. The same mix/solution would probably be a great remedy for preventing/treating sunburns, which are mostly triggered by the UV radiaion in sunlight, so they are a milder version of the radiation-induced wounds used in the study.

http://dx.doi.org/10.1021/acsbiomaterials.4c00698

https://www.sciencedaily.com/releases/2024/08/240812123241.htm

“…Glycopeptide-based hydrogels are especially promising: In laboratory and animal studies, the nanofiber structures have promoted cellular growth and regulated cell adhesion and migration. A research team led by Jiamin Zhang, Wei Wang, Yumin Zhang and Jianfeng Liu proposed loading aspirin, a common anti-inflammatory drug, into a glycopeptide-based hydrogel to create a multifunctional wound dressing for radiation-induced skin injuries. In lab tests with cultured cells, the researchers found that the aspirin-contained hydrogel scavenged reactive oxygen species, repaired DNA double-strand breaks and inhibited inflammation caused by radiation exposure without affecting cellular growth. In mouse models of radiation-induced skin injury, the researchers found that dressing wounds for three weeks with the salve reduced acute injuries and accelerated healing — results that the team says point to its potential as an easy-to-administer, on-demand treatment option for reducing radiation damage and promoting healing in humans.”

Via: http://haidut.me/?p=2655

An animal study with nicotinamide mononucleotide (NMN). Unfortunately, NMN has been declared as a “novel drug” by the FDA and pulled from the OTC market. Luckily, several human studies have demonstrated that NMN is non-superior to plain niacinamide in terms of raising NAD+ levels, and it is precisely this elevation of NAD+ that the study thinks is behind the lifespan and healthspan extending effects. The dosage was on the high side, with the human-equivalent dose being 2g-3g daily. However, multiple human studies with up to 3g daily have shown that there are no side effects with such treatment, so it should not be too risky to try and replicate the study, especially in elderly individuals whose NAD+ levels are greatly decreased and they can use the extra “juice” found in higher niacinamide doses. In corroboration to the higher NAD+ levels being responsible for the lifespan/healthspan increase, NMN was found to increase metabolism and higher metabolic rate is now starting to become recognized as a booster of longevity, not an impediment.

https://pubmed.ncbi.nlm.nih.gov/38979132/

https://www.biorxiv.org/content/10.1101/2024.06.21.599604v1.full

“…This is the first study to explore the effect of long-term NMN treatment on frailty and lifespan in mice. NMN treatment delayed frailty and increased both median and maximum lifespan in female but not male mice. Although we did not observe a lifespan extension in male mice, NMN was well tolerated, and the male mice showed delayed frailty and improved metabolic health. Additionally, in both sexes NMN-treatment led to a sustained increase in the gut microbiome of A. colihominis, a possible contributor to the beneficial health effects of NMN. Our detailed exploration of NMN metabolism in both sexes, suggests possible sex differences in the Preiss-Handler metabolic pathway, which may contribute to the sex differences in health outcomes. The mechanism of lifespan extension in female mice with NMN remains unclear and future studies will explore the effect of NMN on other tissues, especially brain and kidney to uncover potential mechanisms of sex-specific effects. Overall, this work adds to the promising preclinical evidence for NMN as a therapeutic to increase health in aging, and highlights the importance of exploring sex differences in aging studies.”

NMN Increases Lifespan in Female Mice

“…“The beneficial effects of NMN on metabolism and its ability to delay frailty in mice were expected,” David Sinclair said to Lifespan.io, “but we didn’t expect to see apparently positive changes to the microbiome or sex differences in lifespan. We hope the work is useful in guiding the design of future clinical trials testing the effects of NMN and other NAD boosters in humans.””

Via: http://haidut.me/?p=2653

The role of vitamin K in bone health is well-established, as is its role as a “coagulation” vitamin (hence its name “K”). However, the role of vitamin K in muscle homeostasis is not well-studied. It is known that vitamin K both stimulates the synthesis of osteocalcin as well as its carboxylation/activation. It is also well-known that osteocalcin has beneficial effects on muscle mass, likely through the stimulation of androgen synthesis in both male and female gonads. However, a direct link between vitamin K and muscle mass/strength has not yet been established. The study below is perhaps the first to establish such link, at least in males. Btw, vitamin K has a known synergistic effect with vitamin D for bone mass/strength, as well as improving insulin sensitivity, and even treating cancer. As such, I would expect the effects of combining vitamin K with vitamin D to be synergistic for muscle mass/strength as well. And last but not least, handgrip strength is one of the most reliable kinetic biomarkers of overall health, as well as a great predictor of longevity and healthspan. This suggests that vitamin K, especially when combined with vitamin D (already proven lifespan and healthspan booster) may be a great supplement to take for warding off the effects of aging and preventing future chronic disease.

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1378853/abstract

“…Results: Dietary vitamin K intake was positively associated with skeletal muscle mass in males (β=0.05747, P=0.0204) but not in females. We also revealed a positive association between dietary vitamin K intake and handgrip strength within the range of 0-59.871 µg/d (Pnonlinear=0.049). However, beyond this threshold, increasing vitamin K intake did not cause additional handgrip strength improvements. Conclusions: We provided evidence for a positive relationship between dietary vitamin K intake and skeletal muscle mass in males. Moreover, our study revealed a nonlinear relationship between dietary vitamin K intake and handgrip strength, highlighting an optimal intake range.”

Via: http://haidut.me/?p=2651