Posts made by haidut

The duplicity of public health agencies (and mainstream media) knows no bounds. The chemical 2,4-dinitrophenol (DNP) is one of the oldest (and most successful) weight loss drugs. It works by not only increasing respiration but also by uncoupling the reactions in the electron transport chain from ATP generation, so that a higher proportion of the energy we get from food is released as heat. In other words, DNP drastically increases thermogenesis (and metabolic rate/speed), which allows a significant portion of food to be “wasted” as heat instead of stored in the body (mostly as fat). Thus, DNP can not only prevent the weight gain from an obesogenic diet, but also induce weight loss in an already obese person. These effects made DNP a very popular remedy for weight loss in the first half of the 20th century. However, due to a few deaths as a result of heat strokes caused by overdosing DNP, the FDA stepped in and banned the sales and personal use of DNP in the US. To this day, people get aggressively prosecuted if they attempt to sell DNP online or give it to friends/family. Interestingly, the FDA does not seem to be as strict when it comes to pharma companies toying with such “poison”. Despite the ongoing fearmongering that DNP is “deadly”, behind the scenes multiple pharma companies are running clinical trials with DNP for quite a few serious and truly deadly conditions. In order to limit the fallout with the public due to the double-standard, DNP is no longer called DNP in clinical trials since it has now been patented (another abomination, as generic compounds should be unpatentable), as the pro-mitochondrial drug MP-101 (and its close analog MP-201). A quick look at the list of trials with MP-101 shows that pharma companies are banking on MP-101 treating a wide variety of serious chronic issues including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington Diasease (HD), Alzheimer Disease (AD), mental illness, obesity, diabetes, immunodeficiency, congenital disorders, etc (see first two links below). In other words, pretty much all major chronic conditions known to medicine. I guess the good news in this entire charade is that if FDA and pharma companies believe DNP….errr..I mean MP-101….can treat all of these conditions then this is an open admission by those entities that all such diseases are metabolic in origin, since DNP…errr…I mean MP-101…has no known mechanism of action other than its uncoupling/pro-metabolic effects. The bad news is that perhaps millions of people worldwide will get poisoned by the newest pharma fad for weight loss known as GLP-1 agonists (Ozempic, anyone?) before the public wisens up to the fact that there are safer, and truly beneficial pharmacological alternative (e.g. uncouplers) for losing weight. Now, since DNP usage does have risks due to its potency as a thermogenic compound, and it is highly illegal to use therapeutically (unless you are a pharma company, rubbing shoulders with the FDA), one could approximate its effects with other uncouplers such as aspirin, caffeine, progesterone, salt, flavones/flavanones, etc.

https://adisinsight.springer.com/drugs/800050437

https://synapse.patsnap.com/drug/7efa6f9581334bb3b18623859ad7835d

https://www.streetinsider.com/Business+Wire/European+Medicines+Agency+%28EMA%29+Greenlights+Mitochon+Pharmaceuticals+to+Initiate+Phase+IIIa+Biomarker+Study+in+Neurodegenerative+Diseases/22612238.html

EU agency OKs study of therapy to improve mitochondrial function

“…Mitochon Pharmaceuticals is launching a pilot clinical trial to evaluate MP101, its treatment candidate for improving mitochondrial function, in people with multiple sclerosis (MS) and other neurodegenerative diseases. The announcement follows the trial’s clearance by the European Medicines Agency (EMA), which enables Mitochon to begin enrolling patients with neurodegenerative conditions in the biomarker study. The Phase 1/2a trial will enroll people with MS, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Huntington’s disease, each of whom will receive the experimental therapy for 14 days. The goal is to demonstrate whether the therapy is safe in these populations and induces relevant changes in disease-related biomarkers. “We are delighted for the opportunity to explore [the] provocative idea that most, if not all neurodegenerative diseases are rooted in mitochondrial dysfunction,” John G. Geisler, PhD, Mitochon’s co-founder and chief scientific officer, said in a company press release.”

“…Mitochondria are small cellular structures that produce most of the energy cells need to function — including the energy required for nerve cells to transmit electrical signals to other cells. They’re also involved in other essential cell functions. However, research has shown that these cellular organelles are dysfunctional, or don’t work properly, in most neurodegenerative conditions, including in multiple sclerosis. Thus, impaired mitochondrial function is thought to play an important role in neuronal damage and disease progression. MP101 is an investigational, brain-penetrant oral therapy that works as a mitochondrial stimulator, improving the function of these organelles across cells in the brain and spinal cord. This increases the amount of energy produced by cells and also induces the production of neuroprotective factors, which help protect cells from neurodegenerative disease processes.”

“…In preclinical studies, researchers showed that MP101 was able to protect nerve cells from the demyelination that occurs in people with MS. It also reduced disease severity and improved mobility in animal models of the disease. Similar results were obtained with MP201, a similar candidate molecule. The upcoming trial is expected to confirm the benefits of MP101 in neurodegenerative conditions. If positive, these findings are expected to support Phase 2b studies in people with primary progressive MS and secondary progressive MS, as well as ALS, Huntington’s, and Alzheimer’s. “We predict that chronic treatment with this unique platform, at micro-doses, will resolve mitochondrial issues and change important disease specific biomarkers in all four indications similarly,” Geisler said.”

Via: http://haidut.me/?p=2502

Just a few minutes ago I did a post on the causative role of estrogen and its metabolites in both rheumatoid (RA) and osteo arthritis (OA). The study below presents evidence that a C-16 hydroxylated metabolites of estrogen is a causative factor in the progressive and invariably lethal condition known as PAH. Now, there is already strong evidence implicating serotonin (5-HT) as one of the causative factors in PAH and due to the accumulation of such evidence Pfizer is running clinical trials with a 5-HT antagonist known as terguride for treating PAH (and also heart failure). Considering estrogen and serotonin go hand in hand (both promote each other’s synthesis), the study below should not come as a surprise to anybody, and it actually suggests an additional pathway to target for patients with PAH who do not respond to a treatment with a 5-HT blocker – i.e. inhibiting estrogen synthesis and its activity at the receptor level, and improving mitochondrial function. Why the latter? Well, because the study found that the estrogenic metabolite drives PAH pathology by inhibiting mitochondrial function. This anti-mitochondrial finding in regards to estrogen is just (if not more) damning as the findings discussed previously that estrogen is genotoxic, mutagenic carcinogen. Thus, in addition to the obvious anti-estrogenic remedies such as vitamin E, progesterone, androgens, aspirin, and so on one can also add niacinamide, methylene blue, vitamin K, thyroid, and other substances which have a pro-metabolic/pro-mitochondrial effect(s).

https://doi.org/10.1161/CIRCULATIONAHA.115.016133

“…MicroRNA array profiling of human lung tissue found elevation of microRNAs associated with energy metabolism, including the miR-29 family, among HPAH patients. miR-29 expression was 2-fold higher in Bmpr2 mutant mice lungs at baseline compared with controls and 4 to 8-fold higher in Bmpr2 mice exposed to 16α-hydroxyestrone (16αOHE) 1.25 μg/h for 4 weeks. Blot analyses of Bmpr2 mouse lung protein showed significant reductions in peroxisome proliferator–activated receptor-γ and CD36 in those mice exposed to 16αOHE and protein derived from HPAH lungs compared with controls. Bmpr2 mice treated with anti–miR-29 (20-mg/kg injections for 6 weeks) had improvements in hemodynamic profile, histology, and markers of dysregulated energy metabolism compared with controls. Pulmonary artery smooth muscle cells derived from Bmpr2 murine lungs demonstrated mitochondrial abnormalities, which improved with anti–miR-29 transfection in vitro; endothelial-like cells derived from HPAH patient induced pluripotent stem cell lines were similar and improved with anti–miR-29 treatment.”

“…16αOHE promotes the development of HPAH via upregulation of miR-29, which alters molecular and functional indexes of energy metabolism. Antagonism of miR-29 improves in vivo and in vitro features of HPAH and reveals a possible novel therapeutic target.”

Via: http://haidut.me/?p=2499

Once again, estrogen rears its ugly head. The evidence on a link between estrogen and RA, as well as all “autoimmune” conditions, goes back decades, yet it is still considered “controversial (read: true), and medicine now pushes for reintroduction of estrogen therapy in females. Be that as it may, there is not much information in regards to a link between estrogen and “structural” conditions such as OA. The studies below present evidence that estrogen is a causative agent in both RA and OA, and one reason estrogen has not been officially implicated so far in either condition may be that it is not estrogens such as estrone and estradiol (the major circulating estrogens measured by doctors on blood tests) that are the causative agents, but their metabolites (also highly estrogenic). Namely, hydroxylated metabolites on position C-16 of both estrone and estradiol. To my knowledge, blood tests for these metabolites are not even commercially available through major labs such as LabCorp/Quest, which makes the task of implicating conclusively estrogens in those conditions that much more difficult. However, since multiple studies have demonstrated that blood levels of estrone sulfate (E1S) are highly predictive of total body estrogenic reserves, I suspect a test for E1S can be predictive and diagnostic for these conditions. And since E1S is also not easy to order as a blood test, another good surrogate for “estrogenicity” is prolactin, which is available as a test in virtually all labs. Coincidentally, elevated prolactin has already been linked to most “autoimmune” conditions, which corroborates both the suitability of prolactin for measuring estrogenicity of an organism, as well as the role of estrogens in “autoimmune” conditions. Interestingly enough, some of the studies below suggest that it is the ability of the estrogenic metabolites to generate reactive oxygen species (ROS) that drives the immunogenicity in tissues where the ROS are generated, and thus create/drive an “autoimmune” reaction. As such, vitamin E may be the perfect substance for “autoimmune” conditions, because not only is it the major endogenous anti-oxidant, but it is also a direct estrogen receptor antagonist and an aromatase inhibitor. Adding other anti-estrogenic chemicals such as progesterone, androgens, pregnenolone, flavones/flavanones, etc would probably synergize with vitamin E for such conditions and, again “coincidentally”, multiple studies have already demonstrated benefits of progesterone, testosterone, DHEA, DHT, etc in both RA and OA, as well as many other “autoimmune” conditions such as multiple sclerosis (MS), psoriasis, inflammatory bowel diseases, etc. Another major pathway through which estrogen may cause “autoimmune” conditions is apparently by activating the synthesis of prostaglandins and leukotrienes (PUFA metabolites) and the study authors suggest synthesis inhibitors of such metabolites as viable treatments for RA/OA. Aspirin, anyone? Oh, and last but not least – the studies below openly discuss the genotoxic and mutagenic properties of estrogen, as a mechanism behind estrogen’s immunogenicity. So, the next time some guru tries to make an argument that estrogen is “beneficial” and has no link to cancer (as it happened after one of my podcasts with Dr. Mercola), please remind that person that in the scientific literature estrogen is an established genotoxic, mutagenic carcinogen.

https://www.intechopen.com/chapters/39615

“…Remarkable progress have been made in understanding the role of estrogen in the etiology of RA but the role of catechol-estrogens (CE) in RA is lacking. Catechol metabolites are known to play an important role in RA but the exact patho-aetiology remain elusive. The evidence concerning the possibility of CEs in the development of RA is very limited and preliminary. It has been observed that oxidative reactions, often catalyzed by isoforms of the cytochrome P-450, can result in the formation of CEs from parent estrogen and subsequently, semiquinones and quinones derived from CEs, are capable of forming either stable or depurinating DNA adducts. Oxidation of CEs also leads to high amount of ROS that can generate extensive DNA damage**. This would probably alter its immunogenicity leading to the induction and elevated levels of RA autoantibodies** (Figure 4). Therefore, it is possible that the CE-modified bases of DNA might be one of the contributing factors towards production of SLE autoantibodies. In addition, estrogen not only induces DNA damage but also modulate immune response and immune mediated disease. Estrogen was found to increase IgG and IgM from PBMC, which let to elevated level of polyclonal IgG including IgG anti-ds DNA by enhancing B cell activity via IL-10. These autoantibodies could be strongly bound to DNA and serve as an immunological marker for the diagnosis of diseases. Estrogen is thought to play both pro- and anti-inflammatory role in chronic inflammatory diseases that were found to be related to low and high concentration. Increased estrogen to androgen ratio have been observed in RA patients SF, perhaps due to increase aromatase expression by inflammatory macrophages infiltrating synovial tissues. The discovery of high concentration in SF from RA patients of both sexes can also be explain by the fact that inflammatory cytokines (i.e. TNFα, IL-1, IL-6) are increased in RA cynovitis and can markedly stimulate aromatase activity in peripheral tissue. But renal excretion studies showed that enhanced estrogen metabolism observed in RA resulted in elevation of pro-inflammatory metabolites derived from estrone and estradiol such as 16-OHE1 (or 4-OHE2, 4-OHE1) which exert mitogenic effect on different synovial fibroblast. In contrast, RA SF have reduced amount of anti-inflammatory estrogen metabolites such as 2-hydroxyestrogen that inhibit the growth-promoting effect of estradiol. An unwanted shift from 2- to 4-hydroxyestrogen might be an additional pro-inflammatory signal because these 4-hydroxylated metabolites can be converted to 3,4-quinone, which lead to depurination and mutation in DNA. In conclusion, an increase in 16-OHE1 relative to the sum of all 2- and 4-hydroxylated estrogens must be considered as pro-inflammatory signal which is particularly evident in RA [60].”

https://www.nature.com/articles/ncprheum0308

“…Women with an increased urinary 2-hydroxyestrone:16α-hydroxyestrone ratio were more likely to develop incident knee OA, an association that persisted after controlling for confounding variables. Sowers et al. speculate that high concentrations of 2-hydroxyestrone in urine could reflect levels of leukotriene synthesis and modulation of lipoxygenases in the arachidonic acid pathway (which is associated with pain and inflammation), rather than estrogen-receptor-mediated effects. They suggest that the arachidonic acid pathway could provide therapeutic targets for intervention in OA.”

https://doi.org/10.1002/art.22005

“…Women who developed knee OA were more likely to have a ratio of 16α-hydroxyestrone to 2-hydroxyestrone in the highest tertile (>0.86; OR 1.86, 95% CI 1.01–3.44 compared with women with ratios in the 0.54–0.86 range), after adjustment for other covariates.”

Via: http://haidut.me/?p=2497

The actual molecule used was nicotinamide mononucleotide (NMN). However, not only is NMN very expensive, but the FDA recently classified it as a drug so it can no longer be obtained freely by people interested in experimenting. The good news is that plain niacinamide (NAM) has almost identical physiological effects compared to NMN and prior studies have also shown hair-growth promoting effects of NAM, though mostly in auto-immune conditions such as alopecia areata. Anyways, the stud below used a simple solution with 1% concentration of NMN in saline water and applied that solution topically on the hairless skin once daily for 2 weeks. The results were accelerated hair growth comparable to minoxidil in magnitude and speed of regrowth, and there was no toxicity or side effects related to the NMN treatment (both in-vitro and in-vivo). The findings of the study match the reports we get from clients in regards to our product SolBan (contains niacinamide), which they say strongly stimulated regrowth of hair in even advanced cases of androgenic alopecia (hair loss).

https://pubmed.ncbi.nlm.nih.gov/38398550/

“…The double-blind experiment revealed that mice exposed to hair removal exhibited a cessation in hair growth. However, the administration of NMN at a specific concentration in the NMN groups stimulated hair growth during the growth phase, similar to the effects observed in the control and blank groups. The effects of NMN were comparable to those of minoxidil. In the in vitro HDPCs experiment, a concentration of 2.5 mg/mL of NMN significantly increased VEGF secretion from HDPCs by 65.19% in comparison to the control groups. Additionally, the IL-6 content notably decreased with an inhibition rate of 13.60%. NMN was observed to downregulate the expression of DKK-1 and AR genes by 75.16% and 41.78%, respectively. Furthermore, there was a significant upregulation of β-catenin expression at a rate of 125.71%. These findings demonstrate that at this concentration, NMN inhibits IL-6 secretion while promoting the upregulation of VEGF and β-catenin gene expression, and simultaneously downregulating the expression of DKK-1 and AR genes. This mechanism contributes to the anti-hair loss effect of NMN, thereby achieving the desired preventative effect. Moreover, the cytotoxicity MTT test revealed that the administered experimental concentration of NMN did not induce any cellular toxicity.”

Via: http://haidut.me/?p=2493

The role of estrogen in developing various addictions is well-known in animal research, with a lot of work already performed to demonstrate the crucial role of estrogen in developing opioid addiction. Estrogen itself is an activator of the mu-opioid receptor, so it has direct opioid-like effects, but it has also been shown to accelerate the development of physical addiction to opioids, increase drug seeking and worsen withdrawal symptoms. The new study below demonstrates that estrogen is required for the development of “addiction” to psychologically-addictive drugs such as cocaine. Non-aromatizable androgens such as DHT did not promote “addiction” development and pure estrogen antagonists completely prevented the “addiction” development. These findings suggest that progesterone and/or aspirin, vitamin E/D/A/K, non-aromatizable androgens, caffeine, etc could be viable options for preventing cocaine “addiction”, and based on other research the study cites those remedies may even reverse already developed “addiction”.

https://pubmed.ncbi.nlm.nih.gov/38370714/

“…It must be emphasized that pharmacokinetics studies are complex, and multiple factors, such as age, dose, individual differences in metabolism among others can affect the results obtained. One factor that has received more attention is the role of gonadal steroids in mediating these different behavioral responses. For example, in females estradiol enhances cocaine-induced sensitization (Segarra et al., 2014; Souza et al., 2014), conditioned place preference (Segarra et al., 2014) cocaine self-administration (Hu and Becker, 2008; Lynch et al., 2002; Perry et al., 2013; Ramôa et al., 2013) and the motivation to seek drugs.”

“…We had previously demonstrated that gonadectomy increased the acute locomotor response to cocaine but prevented the progressive increase in locomotion over time observed after repeated injections, i.e. cocaine-induced behavioral sensitization (Menéndez-Delmestre and Segarra, 2011). We had also reported that testosterone administration to GDX rats restored sensitization in male rats and decreased the acute locomotor response to cocaine (Menéndez-Delmestre and Segarra, 2011). The present study extends these findings and reports that estradiol, but not DHT, enhances the locomotor response to repeated cocaine administration. These results suggest that in male rats, androgen receptors do not participate in mediating neuroadaptations resulting from long-term drug administration. Furthermore, we report that intracellular ERs mediate the enhancement of cocaine-induced locomotor activity over time. This study found that blocking central ERs eliminates cocaine-induced behavioral sensitization. To our knowledge, this is the first study that illustrates the pivotal role of ERs in cocaine sensitization in males, suggesting that estrogen receptors play a key role in cocaine-induced neuroadaptations. Moreover, this study indicates that estrogen signaling participates in mediating drug-related behaviors in males and is also a key signal of cocaine-induced neuroplasticity in the rodent brain.’

Via: http://haidut.me/?p=2491

My presence at social gatherings and parties is somewhat dreaded by the hosts (even if friends) due to the “scary stories” I tend to tell. One of the scariest stories I have been telling for the last couple of years is that there are no young people any more. Of course, what I mean by that is in terms of biological age. Over the last 5-8 years numerous studies have demonstrated that people in their 20s and 30s have rates of serious chronic diseases rivaling those of people in their 50s and 60s. Cancer, and especially colon cancer, is perhaps the most striking example since its rates have grown almost exclusively in the under-40 crowd over the last 10 years while the rates have been declining in the over-50 crowd. This is the exact opposite situation of what was experimentally observed up until 10-15 years ago, which is why the official guidelines for conducting a colonoscopy were to do the first one at age 50. Add to that the rising rates of strokes and heart attacks in the under-40 crowd, the close to 50% infertility, close to 50% mental illness in young women, the ~70% decline of male testosterone levels since the 1970s, the highest suicide rate (and rising) ever recorded in the young, diminishing physical strength, etc and it becomes scarily obvious just how much the quality of human life has declined in just 1-2 decades. Speaking of physical strength, frailty has always been associated with poor physical and mental health, however direct studies tying physical condition to biological age are rare partly due to the difficulty of coming up with a measure of general frailty. The study below shows that a simple measurement of hand grip strength is a very reliable biomarker of a person’s biological age, and given its simplicity and ease of measurement, it may become one of the most widely used biomarkers of health in the years to come. So, to ruin the party once again, grip strength in young people (both men and women) has been steadily declining over the last 30-40 years and currently sits at an all-time (since record keeping began) low. This not only corroborates the favorite millennial phrases that “40 is the new 20” and “50 is the new 30”, but…it makes the reverse also true – i.e. twenty is indeed the new forty and thirty is fifty, and not in a good way.

https://doi.org/10.1002/jcsm.13110

https://www.medicalnewstoday.com/articles/lack-of-grip-strength-may-indicate-premature-aging

“…Chronological age is different from biological age since it encompasses the amount of time that has passed between birth and a given date. Biological age refers to the rate at which your body is actually aging, which may depend on a host of variables, including genetics, behavior, the environment in which you live, and your demographic identity. Rather than focusing on age in terms of how many years have passed since birth, experts are investigating aging biomarkers that can help assess more accurately how an individual is aging. The goal is to gain clearer insights to help people, where possible, proactively manage their current or imminent health issues and predict longevity. A new study from researchers at the University of Michigan’s Michigan Medicine in Ann Arbor, MI, provides new evidence that grip strength in a person’s hands is one such biomarker of biological age. The study found an association between low grip strength weakness and accelerated DNA aging.”

“…The researchers analyzed data from 1,275 individuals participating in the longitudinal Health and Retirement Study(HRS). Participants were 50 and over in 2006 and 2008 when data collection began, followed for 8–10 years by the HRS. Interview transcripts, grip strength data, and biological measurements were available for all of them. Methylation values were collected from 4,018 of these participants in the 2016 Health and Retirement Venous Blood Study. The analysis revealed that decreasing grip strength aligned strongly with all three of the clocks (PhenoAge, GrimAge, DunedinPoAm), although there were differences between men and women**.** “The association between muscle strength and epigenetic aging is likely related to the mechanisms regulating general health,” Dr. Sillanpää said. Dr. Peterson noted: “We have recently also demonstrated that muscle weakness and testosterone deficiency were highly correlated and independently associated with multi-morbidity in young and older men.”

Via: http://haidut.me/?p=2489

Over the last couple of years I posted several times about studies demonstrating that stress from surgery, chemotherapy or radiation (aka “cut, poison, burn” therapy) has a promoting effect on cancer growth. Unfortunately, all those studies have been either completely ignored by mainstream medicine or dismissed as only applicable to certain aggressive types of cancer (e.g. triple negative breast cancer), which grow/spread fast anyways and thus the contribution of the iatrogenic stress is very minor in comparison. Putting iatrogenic stress from medical procedures aside, chronic stress of general environmental origin has long been suspected as playing a role in cancer development, but the connection has always been dismissed by oncology as being, at best, a facilitator after tumor appearance, and definitely not a cause. The study below begs to disagree and demonstrates that chronic stress (even when mild) not only initiates the cancerization process and makes a healthy tissue begin to exhibit the structural and metabolic markers of cancer, but directly enables and drives the metastatic process as well. All of these effects of chronic stress were directly mediated by cortisol. Thus, removing the glucocorticoid receptor (GR) made the animals completely resistant to metastases after primary tumors has already formed in their bodies, and also prevented the cancerization process initiated by cortisol in healthy tissue. So, there we have it in plain view – chronic stress kills by causing cancer and fueling its spread. Also, one of the most widely prescribed classes of drugs worldwide – bioidentical/synthetic glucocorticoids – are non-mutagenic carcinogens! Since glucocorticoids are prescribed in virtually all forms of cancer (to “tame inflammation”, which is ironic considering that cortisol actually promoted inflammation) it is probably not far-fetched to say that most cancer deaths are iatrogenic. In addition, most newly diagnosed cancer cases are not only completely preventable but can probably also be classified as iatrogenic given the mantra espoused by most doctors that regular endurance exercise (which reliably ups baseline cortisol levels) is the best thing for our health ever discovered.

Now, since removing the GR completely is obviously not something feasible (or even desirable) in humans, the main focus on cancer prevention should be limiting chronic stress exposure. In fact, the study authors themselves say in the popular press article below that stress reduction should be practiced for both preventing and treating cancer. And since in this day and age stress avoidance is next to impossible, other remedies with anti-cortisol effects must be considered. The drug RU486 is the drug of choice clinically for blocking the GR. However, it is prescription-only, expensive and largely unavailable due to the politicization of its role as the “abortion pill”. Natural substances with anti-cortisol effects include aspirin, progesterone, DHEA, pregnenolone, emodin, vitamin A/D, gelatin/glycine, moderate doses niacinamide, etc.

https://doi.org/10.1016/j.ccell.2024.01.013

“…Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients, yet the reasons are unclear. We show that chronic stress increases lung metastasis from disseminated cancer cells 2- to 4-fold in mice. Chronic stress significantly alters the lung microenvironment, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis. Chronic stress shifts normal circadian rhythm of neutrophils and causes increased neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Furthermore, digesting NETs with DNase I prevents chronic stress-induced metastasis. Together, our data show that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, NETs could be targets for preventing metastatic recurrence in cancer patients, many of whom will experience chronic stress due to their disease.”

Chronic stress spreads cancer … here’s how

“…Now, He and Egeblad may have reached a breakthrough in understanding exactly that. Working with CSHL Professor Linda Van Aelst, they discovered that stress causes certain white blood cells called neutrophils to form sticky web-like structures that make body tissues more susceptible to metastasis. The finding could point to new treatment strategies that stop cancer’s spread before it starts. The team arrived at their discovery by mimicking chronic stress in mice with cancer. They first removed tumors that had been growing in mice’s breasts and spreading cancer cells to their lungs. Next, they exposed the mice to stress. What He observed was shocking. Egeblad recalls: “She saw this scary increase in metastatic lesions in these animals. It was up to a fourfold increase in metastasis.” The team found that stress hormones called glucocorticoids acted on the neutrophils. These “stressed” neutrophils formed spider-web-like structures called NETs (neutrophil extracellular traps). NETs form when neutrophils expel DNA. Normally, they can defend us against invading microorganisms. However, in cancer, NETs create a metastasis-friendly environment.”

“…To confirm that stress triggers NET formation, leading to increased metastasis, He performed three tests. First, she removed neutrophils from the mice using antibodies. Next, she injected a NET-destroying drug into the animals. Lastly, she used mice whose neutrophils couldn’t respond to glucocorticoids. Each test achieved similar results. “The stressed mice no longer developed more metastasis,” He says. Notably, the team found that chronic stress caused NET formation to modify lung tissue even in mice without cancer. “It’s almost preparing your tissue for getting cancer,” Egeblad explains. To Van Aelst, the implication, though startling, is clear. “Reducing stress should be a component of cancer treatment and prevention,” she says. The team also speculates that future drugs preventing NET formation could benefit patients whose cancer hasn’t yet metastasized. Such new treatments could slow or stop cancer’s spread, offering much-needed relief.”

Via: http://haidut.me/?p=2486

It is hard to believe that the humble sunshine “vitamin” is also a powerful antibiotic, but that’s what the study below describes. Some of the effects were due to vitamin D activating the eponymous receptor (VDR), which increases T-cell activity. However, the study also demonstrates that vitamin D stimulates the release of antibacterial peptides by the gastric mucosa, as well as having direct antibiotic effects through some of its metabolites. The article does not mention doses, but other in-vivo studies I have seen on vitamin D for bacterial infections suggest that doses in the 5,000 IU – 10,000 IU range daily for 5-7 days may be sufficient to cure a bacterial infection.

https://www.dovepress.com/recent-advances-in-vitamin-d3-intervention-to-eradicate-helicobacter-p-peer-reviewed-fulltext-article-JMDH

“…In summary, the role of Vit D3 in the eradication of HP is certain and includes its classical pathway of binding to VDR to regulate the body’s immune defense and increase the secretion of AMPs, while the nonclassical pathway is a novel signaling pathway that initiates activation of the PDIA3-STAT3-MCOLN3-Ca2+ axis to reactivate the acidification and degradation of lysosomes and the collapse of the membrane structure of HP cells via degradation products. VitD3 represents a novel approach and a new option for the eradication of HP, but there are still some pathways or mechanisms that remain unclear and need further in-depth research and development.”

Via: http://haidut.me/?p=2484

A few months ago I did a post on a pair of studies showing that while cortisol has a negative feedback mechanism centrally, the peripheral feedback mechanism is positive. In other words, a person can have normal or even low blood levels of cortisol and very high cortisol levels in tissues, due to the ability of cortisol to increase the expression of the enzyme 11β-HSD1, which is the rate-limiting step in synthesizing cortisol and is expressed in most organs/tissues. So, the more cortisol one produces (due to stress, fasting carb-restriction, etc) the more one increases the ability to produce even more cortisol. This discrepancy between the peripheral and central feedback mechanism of cortisol is probably a major reason why most endocrinologists still do not want to admit the primary causative role cortisol plays in conditions such as diabetes II – i.e. the blood levels of cortisol in such people are often normal, or even low. However, multiple studies have demonstrated that tissue expressions of 11β-HSD1 are not only predictive of developing obesity/diabetes in the future, but are also predictive of the course of already established diabetes. As a result of this tacit admission that elevated cortisol is pathological for health (especially for metabolic conditions), a number of pharma companies are running clinical trials with 11β-HSD1 inhibitors as treatments for obesity, diabetes, dementia, sarcopenia, and even Cushing syndrome/disease. One of the criticisms I have heard from endocrinologists in regards to the positive feedback mechanism of cortisol peripherally is that most of the evidence so far is from in-vitro experiments. The in-vivo study below may be able to address that criticism by demonstrating that running daily for a few weeks doubled 11β-HSD1 expression in tissues, confirming once again that even “beneficial” stress such as “endurance” exercise is sufficient to cause peripheral state of high cortisol, which probably persists even after the stress/exercise stops since the increased expression of 11β-HSD1 is not known to downregulate on its own. In fact, a number of studies have suggested that once such peripheral hyper-cortisol state is established through increased expression of 11β-HSD1 (specifically through fasting and/or exercise), the only way to reset it back to the original (lower) levels is by using pharmacological interventions such as RU486. However, that is a prescription drug, which is currently out of stock in most suppliers due to political infighting in regards to its abortifacient use. It is also an “estrane” steroids, which means potential for causing unforseen estrogenic effects in specific organs/tissues. Thankfully, aspirin, emodin, and progesterone are also known to downregulate the expression of 11β-HSD1 and in the case of emodin and progesterone, they inhibit the actual activity of 11β-HSD1, and also increase activity of the cortisol-deactivating enzyme 11β-HSD2.

https://doi.org/10.1152/japplphysiol.00652.2016

“…In summary, we report that 6 wk of treadmill training leads to a significant increase in pulmonary corticosterone levels in ob/ob mice, which is in parallel with the favorable effects of exercise on obesity-associated pulmonary inflammation. We demonstrate for the first time that exercise training increases pulmonary 11β-HSD1 expression but has no significant effect on pulmonary 11β-HSD2 expression in both lean and ob/ob mice.”

Via: http://haidut.me/?p=2482

This is study that has very wide applicability since the immune system plays a role not only in acute issues such as COVID-19, but also in chronic conditions such as HIV/AIDS, and even cancer. So far, the decline in immune function seen in aging had been explain with the simplistic “wear and tear” concept, and when immunodeficiency occurs in younger people it is ascribed either to genetic vulnerability or lifestyle choices such as alcohol/drug consumption. In other words, to this day medicine does not seem to have a good grip on why immune function fails in aging and disease, and what (if anything) can be done to prevent that. The study below demonstrates that the direct cause of immune decline is rather simple – decline in mitochondrial function (OXPHOS). When T-cells (immune cells produced by the thymus) have dysfunctional mitochondria, they have to rely exclusively on glycolysis for energy production. Glycolytic production of energy is insufficient to support proper T-cell differentiation and activity, and in fact can lead to T-cell damage or even death due to the high amount of reactive oxygen species (ROS) produced when glycolysis is the main mode of energy production. The study also demonstrated that such mitochondrial dysfunction is a necessary and sufficient condition for immune decline to occur (aka T-cell “exhaustion”) and that the decline was reversible when mitochondrial function was restored pharmacologically. A corollary of such findings is that anything that suppresses oxidative metabolism directly causes immune decline (and ultimately failure). Chronic stress is one such example of a “metabolic inhibitor” and the well-known, but not-fully-explained, role of cortisol as immunosuppressant is now elucidated considering cortisol is a potent suppressor of mitochondrial biogenesis and function. In terms of remedies, aspirin, niacinamide, vitamin D, thyroid, progesterone, quinones, etc would probably be the most directly accessible and helpful remedies for restoring/improving mitochondrial function.

https://dx.doi.org/10.1038/s41467-023-42634-3

https://medicalxpress.com/news/2023-11-dysfunction-mitochondria-exhaustion-cells.html

“…In the immune system, chronic infections and the defense against tumors often lead to the phenomenon of T cell exhaustion: In this process, the T lymphocytes gradually lose their function, which impairs their responses against cancer and infections. The molecular mechanisms that control this loss of function have not been fully unraveled. This research has now shown that the exhaustion process is significantly influenced by the “powerhouses of the cells,” the mitochondria. When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells, a process that drives their functional exhaustion. But this “burnout” of the T cells can be counteracted—pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.”

“…”It was commonly assumed that the observed alterations in the mitochondrial (energy) metabolism were a consequence of T-cell exhaustion,” says Vaeth. To demonstrate that mitochondrial dysfunction is the actual cause of T cell exhaustion, his research group developed a new genetic model. It switches off the mitochondrial phosphate transporter (Slc25A3) and paralyses mitochondrial respiration in T cells. As a result, the T cells are forced to switch to alternative metabolic pathways, mainly aerobic glycolysis, to meet their bioenergetic demand in the form of adenosine triphosphate. However, this metabolic adaptation causes an increased production of reactive oxygen species in the T cells. Elevated levels of oxygen radicals prevent the degradation of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). The accumulation of HIF-1α protein causes a genetic and metabolic reprogramming of the T cells, accelerating their exhaustion. “This HIF-1α-dependent control of T-cell exhaustion was previously unknown. It represents a critical regulatory circuit between mitochondrial respiration and T cell function, serving as a ‘metabolic checkpoint’ in the process of T-cell exhaustion,” explains Vaeth.”

Via: http://haidut.me/?p=2480

This is yet another study that calls into serious doubt the main dogma of diabetic pathology provided by allopathic medicine. Namely, mainstream medicine claims that the well-known kidney damage occurring in majority of advanced cases of diabetes II is caused by the elevated blood glucose in such patients. However, the study below discovered that inside kidney cells, the picture was quite different. The degree of cellular dysfunction and damage was proportional to the decrease in glucose metabolism and, consequently, increase in fatty acid oxidation (e.g. Randle Cycle). Administering glycine in the diet was able to reverse that metabolic pattern, which not only results in normalization of blood glucose, but also reversal of the advanced kidney damage. Once again, we see that the truth is about 180 degrees from what the official medical version is, and that even advanced and serious chronic conditions can often be easily reversed with simple dietary methods. I cannot get access to the study since it is brand new, so I don’t know the dosage of glycine that achieved such great results, but other studies have shown that eating 6g-8g glycine (achievable with 15g-20g gelatin) daily restores the anabolic response of protein in older people. Since the downregulation of anabolism in older people being driven mostly by insulin resistance and inflammation, which matches the context of diabetes II, this dose can be tried for diabetic kidney damage too. Also, since gelatin is largely non-toxic, higher doses (up to 50%-60% of daily protein intake) can be taken if the person feels higher doses work better.

https://doi.org/10.1007/s00125-023-06078-0

https://medicaldialogues.in/nephrology/news/canagliflozin-improves-diabetic-kidney-disease-by-inducing-fasting-like-and-aestivation-like-metabolic-patterns-study-124801

“…Canagliflozin (CANA) regulates metabolic reprogramming in diabetic kidney disease (DKD) by inducing fasting-like and aestivation-like metabolic patterns, a recent study published in Diabetologia has shown.The study found that canagliflozin ameliorates diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and glycine beneficial effects were probably due to the activation of the AMP-activated protein kinase (AMPK)/mammalian target of the rapamycin (mTOR) pathway. Sodium–glucose co-transporter 2 (SGLT2) inhibitors are antihyperglycaemic drugs that protect the kidney of patients with type 2 diabetes (T2D). However, there is no clear understanding of the underlying mechanisms mediating the renal benefits of SGLT2 inhibitors. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, Yanyan Zhao, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China, and colleagues hypothesized that SGLT2 inhibitors induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease. For this purpose, the research team performed untargeted and targeted metabolomics on plasma samples from participants with T2D and kidney disease (n=35, 11 women) receiving 100 mg/day canagliflozin at baseline and 12 weeks follow-up. Next, using db/db mice, the researchers obtained a systematic snapshot of the effect of CANA on the key metabolites and pathways in the kidney. Moreover, they studied the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells. The study led to the following findings:· Treatment of DKD patients with CANA for 12 weeks significantly reduced HbA1c from a median of 49.0 mmol/mol to 42.2 mmol/mol, and reduced urinary albumin/creatinine ratio from 67.8 mg/mmol to 47.0 mg/mmol.· The untargeted metabolomics assay showed downregulated glycolysis and upregulated fatty acid oxidation.· The targeted metabolomics assay revealed significant upregulation of glycine.· The kidneys of db/db mice undergo significant metabolic reprogramming, with changes in sugar, lipid and amino acid metabolism; CANA regulated the metabolic reprogramming in the kidneys of db/db mice.· The pathways for glycine, serine and threonine metabolism, as well as the metabolite of glycine, were significantly upregulated in CANA-treated kidneys.· Glycine supplementation ameliorated renal lesions in db/db mice by inhibiting food intake, improving insulin sensitivity and reducing blood glucose levels.· Glycine supplementation improved apoptosis of human proximal tubule cells via the AMP-activated protein kinase/mammalian target of the rapamycin pathway.\”Our findings showed that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns, \” the researchers wrote. \”Furthermore, diabetic kidney disease was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway.”

Via: http://haidut.me/?p=2472

A human study, which makes it that much more important. While the findings are not very surprising, what is important to take from the study is that 1) elevated blood glucose is likely a good biomarker of poor mitochondrial function, 2) exposure to just 15min of red light daily can lower blood glucose by ~30% precisely due its beneficial effects of mitochondria, and 3) there may be such a thing as “too much of a good thing” when it comes to red light exposure since longer exposure periods would likely lead to glycogen depletion and a stress reaction, unless one supplies more carbohydrates through a snack/drink. This last caution is actually coming from Ray, who warned people to not overdo red light and to be wary of the stress reaction it can cause by lowering blood glucose too much, which is why he advised drinking a glass of orange juice before the light session.

https://pubmed.ncbi.nlm.nih.gov/38378043/

https://www.news-medical.net/news/20240222/Red-light-exposure-mitigates-blood-glucose-spikes-after-meals.aspx\

“…Shining a specific frequency of red light on a person’s back for 15 minutes can reduce blood sugar levels, according to a new study from City, University of London and UCL. The researchers found that 670 nm red light stimulated energy production within mitochondria, the tiny powerhouses within cells, leading to increased consumption of glucose. In particular, it led to a 27.7% reduction in blood glucose levels following glucose intake, and it reduced maximum glucose spiking by 7.5%. While the study was conducted in healthy individuals, the non-invasive, non-pharmacological technique has the potential to have an impact on diabetes control after meals, as it can reduce damaging fluctuations of blood glucose in the body that contribute to ageing. The study also highlights the significant long-term consequences for human health, including the potential dysregulation of blood sugars posed by lengthy exposure to blue light. Given the prominence of LED lighting in modern technology and environments, and the fact that LEDs emit towards the blue end of the spectrum with very little red, the authors suggest that this may be a potential public health issue. The research has been published in the Journal of Biophotonics. Mitochondria provide energy for vital cellular processes, using oxygen and glucose to produce the energy-rich nucleoside adenosine triphosphate (ATP). Previous research has established that long wavelength light between approximately 650-900 nm (spanning the visible through to the near-infrared range) can increase mitochondrial production of ATP which reduces blood glucose and also improves health/lifespan in animals.”

Via: http://haidut.me/?p=2474

The mainstream view on heart failure is that in most cases (when it is not congenital) it is a secondary morbidity caused by conditions such as diabetes, CVD, obesity, smoking, alcohol intake, etc. However, a direct causative agent and process has not been proposed so far. The study below demonstrates that a toxic byproduct of PUFA peroxidation known as 4-hydrodynonenal (4-HNE) is directly responsible for the cascade that results in heart failure. Reducing the levels of 4-HNE was able to actually reverse the already established heart failure. The drug used in the study is a patented chemical that increases the metabolism of 4-HNE into a less harmful substance, but I think it is obvious that a better approach would be to avoid synthesizing 4-HNE altogether. That can be achieved by restricting dietary PUFA while also supplementing with vitamin E, which largely prevents the peroxidation of PUFA into not only 4-HNE but also other toxic byproducts. Now, since 4-HNE is an aldehyde and as such is deactivated by the family of enzymes known as aldehyde dehydrogenases (ALDH), the speeding up of the activity of those enzymes can also be achieved by niacinamide or oxidizing agents, since the main co-factor of ALDH is NAD+. In addition, androgens have been shown to increase the expression of ALDH while estrogens lower it, which may explain why men with heart failure invariably present with symptoms of hypogonadism often combined with high estrogen. As such, supplementation with androgens and/or usage of anti-estrogenic substances such as aspirin, progesterone, vitamin E, vitamin K, etc may also be a viable prevention/remedy and in fact most of those substances have already shown good results in animal models of heart failure.

https://doi.org/10.1093/eurheartj/ehad662

https://newatlas.com/medical/drug-reverse-mitochondria-malfunction-mitigate-heart-failure/

“…“When a car engine isn’t running properly, energy conversion is impaired, efficiency drops, and pollution increases,” said Julio Ferreira, co-corresponding author of the study. The ‘pollutant’ Ferreira is referring to is the toxic aldehyde 4-hydroxynonenal (4-HNE), a byproduct of mitochondrial dysfunction in heart failure. “Every cell has hundreds or sometimes thousands of mitochondria, which produce enough aldehyde to poison the entire cell when they aren’t running properly,” Ferreira said. “We discovered in this latest study that too much of 4-hydroxynonenal switches off a vital event for the cell: processing of microRNAs.””

“…microRNAs (miRNAs) are small, non-coding RNAs that play an important role in gene regulation. Disruption of miRNA formation is associated with several diseases, including cancer, neurodegenerative and cardiovascular disorders. Using mass spectrometry, the researchers observed that 4-HNE irreversibly binds to and inactivates Dicer, an enzyme encoded by the DICER1 gene essential to miRNA formation. It’s a mechanism that hadn’t been seen before. “In this study, we identified the chemical alterations that inactivate Dicer in rodents and humans owing to the accumulation of aldehyde caused by heart failure,” Ferreira said. “This was a hitherto unknown mechanism. The point is that Dicer is a limiting enzyme for formation and maturation of the microRNAs responsible for overall control of cellular biology.” Using a drug called AD-9308 on samples of human heart tissue, the researchers were able to restore Dicer activity and reverse the effect of heart failure, improving cardiac function in rodent models. In a previous study, AD-9308 was shown to activate mitochondrial aldehyde dehydrogenase 2 (ALDH2), the major enzyme that detoxifies 4-HNE, to effectively treat cardiomyopathy in mice.”

Via: http://haidut.me/?p=2469

I think the claim that obesity can be caused by lower metabolism is not something contentious, even though mainstream medicine will claim that it only happens in clinical hypothyroidism. The so-called idiopathic obesity in the general population (now affecting 40%+ of people) is claimed to be due to nothing more than the gluttony of said population, combined with not performing enough physical exercise. The study below demonstrates that obesity can be caused even in the context of normal caloric intake, if the mitochondria in the enterocytes lining the GI tract are not functioning properly. When there is such a GI tract mitochondrial dysfunction, the enterocytes cannot properly form/create chylomicrons, which distribute dietary fat to the peripheral tissues, where it usually is quickly oxidized by muscles and organs as fuel. In fact, muscles at rest oxidize predominantly fat. However, if that fat cannot reach the muscles the fat remains in the abdominal area (and if transported, it is exclusively to the liver), accumulating over time and causing the dreaded “central obesity” combined with liver diseases such as NAFLD/NASH/fibrosis/cirrhosis/etc. If that mechanism can explain obesity to a great degree then it matches perfectly with the lifestyle and diet of the Western population. Acute or chronic stress causes mitochondrial dysfunction by inhibiting blood flow to the GI tract, and cortisol has a direct mito-suppressive effect. In addition, there is myriad of chemicals in our food and drinks that act as metabolic/mitochondrial inhibitors. PUFA is obviously a major mitochondrial inhbitor, but there are more cunning ones used as food additive and approved as “safe” by the regulatory agencies. Things such as emulsifier, dyes, artificial flavors, silicon dioxide, talc, titanium dioxide, etc are all known mitochondrial inhibitors and a majority of the Western population ingests at least one such inhibitor on a daily basis. Conversely, the study suggests that things like niacinamide, aspirin, quinones, thyroid, saturated fats, sucrose, etc would be good approaches to restoring mitochondrial function and thus resolving, or at least stopping, the obesity process. Interestingly, feeding a fat free diet to the animals used in the study was also able to reverse the mitochondrial dysfunction and the accumulation of lipids in the GI tract. This matches quite well with Peat’s recommendations to lower fat intake in cases of obesity, or chronic diseases.

https://www.nature.com/articles/s41586-023-06857-0\

“…Digested dietary fats are taken up by enterocytes where they are assembled into pre-chylomicrons in the endoplasmic reticulum followed by transport to the Golgi for maturation and subsequent secretion to the circulation1. The role of mitochondria in dietary lipid processing is unclear. Here we show that mitochondrial dysfunction in enterocytes inhibits chylomicron production and the transport of dietary lipids to peripheral organs. Mice with specific ablation of the mitochondrial aspartyl-tRNA synthetase DARS2 (ref. 2), the respiratory chain subunit SDHA3 or the assembly factor COX10 (ref. 4) in intestinal epithelial cells showed accumulation of large lipid droplets (LDs) in enterocytes of the proximal small intestine and failed to thrive. **Feeding a fat-free diet suppressed the build-up of LDs in DARS2-deficient enterocytes**, which shows that the accumulating lipids derive mostly from digested fat.”

Warning: High Levels of Niacin (Vitamin B3) Linked to Heart Disease

“…The researchers studied the function of mitochondria – organelles acting as powerhouses of the cell – in enterocytes, cells that line the intestine and specialize in the absorption and transport of nutrients from digested food. They found that disruption of mitochondrial function in the intestines of mice caused abnormal accumulation of dietary fat in enterocytes and impaired delivery of lipids to the peripheral organs. A key finding of the study was that, when mitochondria did not function properly, enterocytes showed impaired packaging and transport of lipids in the form of chylomicrons. Chylomicrons are crucial carriers of dietary fats, and their proper formation and transport are essential for the absorption of nutrients. “This discovery marks a significant leap forward in understanding the crucial role of mitochondria in dietary lipid transport and metabolism,” said Dr Chrysanthi Moschandrea, the lead author of the study. The implications of this discovery go beyond the realm of basic research. “These findings provide new perspectives for the better understanding of the gastrointestinal symptoms in patients suffering from mitochondrial disease, and may also lead to new therapeutic approaches,” added Professor Aleksandra Trifunovic.”

Via: http://haidut.me/?p=2466

The study does not claim a cure but it is a direct corroboration of human trials with HIV-1 patients conducted back in the early 1990, as those trials used high dose niacinamide (3g daily) and found improvement in the general condition of the patients. The mechanism of actions was, again, elevations of NAD+ and thus NAD+/NADH ratio. Other human trials with 2g-3g aspirin daily, also conducted in the 1990s, showed even more promise for treating HIV-1, but were terminated early using the bleeding risks of aspirin as an excuse. In reality, the termination was demanded by Big Pharma due to concerns aspirin would kill the sales of the new anti-HIV drugs such as zidovudine. I suspect that if this study below had been conducted with a combination of aspirin and niacinamide, the effects would have been spectacular.

https://doi.org/10.1016/j.ebiom.2023.104877

https://www.news-medical.net/news/20231121/Breakthrough-in-HIV-treatment-NMN-shows-promise-in-reducing-CD42b-T-cell-activation.aspx

“…In this study, researchers explored the effects of NMN on HIV-1 infection in primary CD4+ T cells. They discovered that NMN treatment increased intracellular NAD levels and suppressed HIV-1 replication, as evidenced by reduced viral p24 protein production in infected cells. This suppression occurred without significant cell death, indicating that the reduced p24 production was not due to NMN’s cytotoxicity. Moreover, NMN did not significantly alter the HIV-1 receptor CD4 and co-receptor CCR5 expression in these cells. However, the study found increased frequency and mean fluorescence intensity (MFI) of C-X-C chemokine receptor type 4 (CXCR4) in NMN-treated CD4+ T cells. Despite these findings, NMN did not significantly affect the early stages of the HIV-1 life cycle, such as viral entry, reverse transcription, integration, and transcription. The researchers also examined the effects of NMN on CD25+ CD4+ T cells and HIV-1 replication. They found that NMN treatment reduced the frequency of CD25+ and Human Leukocyte Antigen – DR Positive (HLA-DR+) cells and significantly suppressed intracellular p24 in CD25+ CD4+ T cells. This suggested that NMN might affect the proliferation of infected cells. Additionally, NMN was found to modulate CD25 expression in specific CD4+ T cell subsets and reduced the proliferation of primary p24+ CD4+T cells via CD25 downregulation. Transcriptomic analysis revealed that NMN treatment altered the expression of several genes related to cell activation and proliferation. In the present in vivo study using a humanized mouse model infected with HIV-1, the researchers found that combined NMN and cART treatment significantly improved CD4+ T cell reconstitution compared to cART alone. This combination also resulted in lower frequencies of apoptotic, hyperactivated, and CD25+ activated CD4+ T cells in the spleens of these mice. Furthermore, the cART-plus-NMN group exhibited significantly lower frequencies of p24+ CD4+ T viz CD4+ T cells that have the HIV-1 p24 antigen cells and proliferating ki67+ CD4+ T viz CD4+ T cells that express the Ki-67 protein cells, suggesting a suppressive effect on T cell hyperactivation and HIV-1 replication.”

Via: http://haidut.me/?p=2464

A very interesting study, which used a relatively high dose of nicotinamide riboside (NR) to treat Parkinson Disease (PD). The dosage used was 3,000mg daily for 4 weeks and it resulted in improvement of motor and cognitive symptoms of PD, while producing no side effects. The study references prior clinical studies with lower doses, which also showed benefit. However, that benefit was weaker and corresponded to the less robust elevations of NAD+ and the NAD+/NADH ratio produced by the lower doses NR. I would venture a guess that combining a lower doses niacinamide with an oxidizing agent such as methylene blue, emodin, vitamin K, etc would probably allow for no more than 500mg niacinamide to be used daily and still achieve the same effects on NAD+ and NAD+/NADH ratio as the study below with NR monotherapy.

https://www.nature.com/articles/s41467-023-43514-6

“…Our study met its primary outcome and established that orally administered NR at a dose of 3000 mg daily is well tolerated in PD over a course of 4 weeks. NR-recipients developed no moderate or severe adverse events. Furthermore, there were no mild adverse events likely attributed to NR, and no other clinical or biochemical signs of toxicity. While our data do not guarantee long-term safety, they allow future dose-optimization and efficacy studies to extend the tested dose range of NR to 3000 mg daily, provided that appropriate safety monitoring is implemented. In our opinion, adequate dose experimentation in clinical trials will be paramount, in order to adequately explore and exploit potential dose-dependent beneficial effects in PD, as well as the multitude of other neurological and non-neurological diseases, for which NR is currently being tested. Indicatively, there are 44 NR-related trials registered at www.clincaltrials.gov at the time of submission. Furthermore, our results suggest that NR doses up to 3000 mg daily do not need to be gradually increased and can be initiated directly in NR-naïve individuals.”

“…NR-treatment improved clinical symptoms of PD, measured by MDS-UPDRS, while this remained unchanged in the placebo group. This improvement was driven mostly by MDS-UPDRS part III, which assesses motor function, and part I, which assesses non-motor aspects of daily living. Interestingly, a qualitatively similar but weaker effect was seen in the NADPARK trial where participants consumed 1000 mg NR daily18. Taken together, these observations suggest that NAD augmentation may have a symptomatic anti-Parkinson effect.”

“…At a dose of 3000 mg daily, NR treatment greatly augmented the NAD-metabolome, including a ~3.7-fold (range 1.8–5.8-fold) increase in whole blood NAD+ levels. This increase is considerably higher compared to that reported with 1000 mg or 2000 mg NR daily, which increased blood NAD+ levels 1.37–2.8-fold26,28,33,35,36. However, in addition to the applied NR dose these studies also vary in terms of both sample type (e.g., whole blood, peripheral blood mononuclear cells or serum), and duration of exposure. Therefore, while providing an indication of a dose effect, the results of these studies are not fully comparable.”

“…In addition to prominently elevated NAD+ levels, the NR-group exhibited a clear increase in the NAD+/NADH ratio, which has been reported to be decreased in PD43. Furthermore, NR supplementation was associated with an increase in whole blood NADP. An elevated NADP pool may be beneficial in several ways. NADP is a major redox factor in anabolic synthesis reactions, but also mediates cellular defense against oxidative stress, is involved in cytochrome P450 dependent detoxification mechanisms, and plays a role in immune response by generating oxidative bursts, among others44,45. With regard to PD, the reduced form of NADP, NADPH, has been shown to ameliorate MPTP-induced dopaminergic neurodegeneration in cultured cells46, and to exert anti-neuroinflammatory and anti-neurotoxic effects in an MPTP-induced mouse model of PD47. Thus, it is possible that NADP augmentation may contribute to NR-associated neuroprotective effects in PD.”

Via: http://haidut.me/?p=2462

Another great win for aspirin, especially considering the prevalence of NAFLD, NASH, fibrosis/cirrhosis and even liver cancer. This post comes mere minutes after the post on a single tablet aspirin (300mg) daily putting a terminal liver cancer in remission. This study below used a low-dose (81mg) aspirin, but given the benefits of the “high-dose” (300mg) in the prior study I don’t see a reason not to try higher doses for even stronger effects in NAFLD/NASH/fibrosis cases.

https://www.natap.org/2023/AASLD/AASLD\_100.htm

https://www.medscape.com/viewarticle/998550

“…Patients with metabolic-associated steatotic liver disease (MASLD, formerly NAFLD) without cirrhosis who took daily low-dose aspirin in a double-blind randomized trial demonstated significant reductions in liver fat content over 6 months compared with similar patients who took a placebo, study results show. “In MASLD without cirrhosis, low-dose aspirin, 81 milligrams daily, led to decreases in liver fat and improved markers of hepatic inflammation and fibrosis,” reported Robert M. Wilechansky, MD, a transplant hepatology fellow at Massachusetts General Hospital in Boston.

“It was safe and well tolerated in this study, but we would like to see larger, longer-term clinical trials to test the efficacy of aspirin for improving histology and preventing adverse outcomes in MASLD,” he said here at The Liver Meeting 2023: American Association for the Study of Liver Diseases (AASLD).”

“…Aspirin was also associated with significantly greater reductions in liver transaminase levels and liver stiffness by VCTE. About one third of patients in each study arm had at least one adverse event. There was only one aspirin-related adverse event (heartburn) that led to discontinuation. There were no serious bleeding events in either arm. “We’re going to have to consider stratifying by aspirin use now in our trials,” said Mark Hartman, MD, from Eli Lilly & Co. in Indianapolis.”

Via: http://haidut.me/?p=2457

While the evidence for aspirin’s preventive effects on numerous cancer types is extensive and even mainstream medicine has begrudgingly acknowledged aspirin’s prophylactic potential, studies on the therapeutic effects of aspirin in already established cancers are very few, and most of them are in animals. This is why the study below is such a gem. Not only was it a human case study, but the cancer was quite advanced and declared terminal (hence the palliative therapy). On top of that, the study hilariously calls the 0.3g (300mg) aspirin daily a “high-dose” treatment. Oh boy, I wonder what would a “mega-dose” treatment of say 1g-3g daily do…Scared to even think about it. News on the effects of “mega-dose” treatment coming soon, through my own study:-)
https://pubmed.ncbi.nlm.nih.gov/34540977

“…A Chinese male patient with chronic hepatitis B infection was admitted to the Cancer Center of Sun Yat-sen University for the treatment of HCC identified in the S6 segment of the liver by contrast computed tomography (CT) scan in June 2012. Radical resection was performed. Tumor recurrence was observed in March 2014. Transcatheter arterial chemoembolization (TACE) was performed followed by radiofrequency ablation with radical intent. However, the tumor recurred at the juncture of the S2 and S3 sections in September 2014. The tumor was resected. The tumor recurred in February 2015. A series of TACE procedures were performed as palliative local regional therapy from February 2015 to October 2016 at the Third Affiliated Hospital of Sun Yat-sen University. Sorafenib was administered after the first cycle of palliative TACE, but the treatment was suspended one month later due to grade III diarrhea. In that period, tumor progression was noted three times, which made local regional therapy an inappropriate choice for disease control.”

“…Aspirin is reported to be effective in inducing β-catenin phosphorylation by activating GSK3β due to inhibition of the cyclooxygenase 2 (COX2) pathway[7]. As the COX2 pathway was assumed to act normally, high-dose aspirin (0.3 g/day) was chosen as a remedy from April 2016.” “…This strategy achieved disease control for almost 5 years until February 2021, as confirmed by magnetic resonance imaging and monitoring of alpha fetoprotein. The treatment was well tolerated (Figure ​(Figure1A1A and ​andC).C).”

Via: http://haidut.me/?p=2455

As many of my readers know, there is an epidemic of chronic pain disorders in Western countries, which has subsequently led to over-prescription and (ab)use of opioid medication, which has then acted as a gateway drug and fueled a massive and deadly opioid epidemic in those countries. In order to keep costs low, most addicts have started using potent opioids such as fentanyl, which can easily kill a person with even a minor dosage miscalculation since it is about 100 times more powerful than morphine/heroin. The study below is one of the first to demonstrate that chronic pain is not an organic disorder of its own, but a symptom of an underlying mitochondrial dysfunction. This not only explain why the intervention with niacinamide worked in alleviating the pain (by improving mitochondrial function), but also why treating chronic pain with opioids is about the worst intervention one could choose. Why? Because opioids are among the most potent suppressors of mitochondria, which means that as soon as one stops taking them the chronic pain will be much worse, leading to more opioid use and so on – a vicious cycle with usually lethal outcome (overdose). The niacinamide dose used in this study was on the high-side (HED ~35mg/kg daily), but considering it was administrated only once and the pain was completely resolved, it is a low-risk intervention in such doses for humans, especially compared to opioids. Also, there are prior animal studies showing that lower doses (HED 3mg/kg daily) taken for a few weeks can also relieve chronic pain, which lowers the risk of such intervention even more.

https://doi.org/10.1016/j.xcrm.2023.101265
https://doi.org/10.1016/j.xcrm.2023.101265
https://www.newscientist.com/article/2401405-a-type-of-vitamin-b3-might-treat-chronic-pain-related-to-inflammation/
https://www.newscientist.com/article/2401405-a-type-of-vitamin-b3-might-treat-chronic-pain-related-to-inflammation/

“…So, about a week after inducing inflammation in a separate group of 12 mice, Eijkelkamp and his team gave half of them a high dose of nicotinamide riboside – 500 milligrams per kilogram of body weight. By comparison, the recommended daily amount of vitamin B3 for most adults is between 14 and 16 milligrams. They then assessed the animals’ sensitivity to pain by measuring how quickly they pulled their paw away from heat. Mice that hadn’t received nicotinamide riboside retracted their paw twice as fast, on average, as those that did, suggesting the supplement alleviates pain. Together these findings indicate two things: first, that inflammation can impair mitochondrial function in sensory neurons and that these impairments increase the risk of chronic pain, even after inflammation has resolved. Second, that taking nicotinamide riboside supplements may help treat this chronic pain by restoring mitochondrial function.”

Via: http://haidut.me/?p=2478

The study is epidemiological and it did not distinguish between the various forms of vitamin B3 available through the diet or supplements. However, it was well-controlled and its findings match the known biochemical effects of vitamin B3, which the study authors cite themselves as the likely reasons for the observed results. Namely, vitamin B3 increases NAD and NADP levels, which results in improved glucose metabolism as well as higher tissue anabolism (through NADP). Perhaps the most useful finding of the study was the striking dose-dependence of the effects it discovered – i.e. for every extra 1mg/kg of weight of daily vitamin B3 consumed, a person lost 60g of fat and gained 60g of muscle. Oh, and if this was not already a spectacular result, the effects of vitami B3 were the strongest in people with obesity (high BMI), hypertension, or advanced age – precisely the people who need benefits the most. Now, the study did have a cutoff in its vitamin B3 intake range. The maximum intake included in the study was about 238mg daily. We don’t know if the benefits of vitamin B3 hold beyond those daily intake levels, but animal studies seem to suggest at least the metabolic benefits hold until at least a human-equivalent dose (HED) of 5mg/kg daily. Since muscle and fat mass are largely a function of the metabolic rate, the study seems to suggest that an intake of vitamin B3 up to 5mg/kg daily may be even more beneficial. The study does caution that when vitamin B3 is used as a lipid-lowering agent (i.e. in doses of 2g+ daily) negative effects and even reversal of the benefits may occur, so I’d suggest careful experimentation until the optimal daily dose is found, which will probably be different for each person. https://doi.org/10.1007/s12603-023-1967-0 “…In all models, niacin intake was significantly positively correlated with appendicular lean mass, total lean mass, and total bone mineral content, and negatively correlated with total fat and trunk fat (Table 2). Assuming linearity, for every 1 mg/ kg weight increase in the daily niacin amount, appendicular lean mass increased by 0.025 kg/kg weight (95% CI 0.018–0.033 kg/kg weight), total lean mass increased by 0.060 kg/kg weight (95% CI 0.045–0.074 kg/kg weight), and total bone mineral content increased by 0.005 kg/kg weight (95% CI 0.004–0.007 kg/kg weight). For every 1 mg/kg weight increase in daily niacin, total fat decreased by 0.061 kg/kg weight (95% CI −0.076 to −0.046 kg/kg weight) and trunk fat reduced by 0.041 kg/kg weight (95% CI −0.050 to −0.032 kg/kg weight). Subgroup analyses showed that age, sex, smoking status, BMI and hypertension were significant factors affecting niacin intake and body mass components. In subgroups of people aged 50–60 years, niacin intake had a stronger association with body mass components. Niacin intake had a stronger positive association with total lean mass and total bone mineral content and a stronger negative association with total fat in the female subgroup. In addition, increases in niacin intake in participants with hypertension resulted in enhanced increases in total lean mass and total bone mineral content and enhanced decreases in total fat and trunk fat. In addition, subgroups with a BMI >25 kg/m2 were more likely to experience an enhanced increase in total lean mass and appendicular lean mass and an enhanced decrease in total fat with dietary niacin supplementation (Fig. Figure 1, Figure 1, Pinteraction<0.05). The remaining subgroup analyses of niacin intake and body mass components is shown in Fig. S2 A–E. The nonlinear relationship between niacin intake and body mass components is shown in Fig. Figure 2, Figure 2.”

“…Our study found that daily dietary niacin intake was positively correlated with total lean mass, appendicular lean mass, total bone mineral content, and grip strength, and negatively correlated with sarcopenia risk, total fat and trunk fat. In addition, dietary niacin was negatively correlated with HOMA-IR and fasting insulin in participants with and without diabetes, and fasting blood glucose in participants without diabetes. To our knowledge, this is the first study to explore the relationship between dietary niacin and these outcomes of interest in a representative large cohort, while adjusting for a number of important covariates. Our results suggest that dietary niacin supplementation is an effective strategy for preventing and improving age-related muscle mass and strength loss. Higher dietary niacin intake improved muscle and fat distribution throughout the body, consistent with the findings of a previous randomized controlled trial. In this study involving overweight African-American women, niacin-bound chromium caused a significant loss of fat and sparing of muscle (22). In our study, subgroup analyses also found that dietary niacin was more significantly associated with changes in muscle and fat in participants aged 50–60years, with hypertension and a BMI ≥25 kg/m2. A large prospective cohort study by Han et al. showed that the skeletal muscle mass index measured by bioelectrical impedance was inversely associated with the risk of hypertension in men, which may be related to insulin resistance because of decreased muscle mass, enhanced inflammatory and oxidative pathways, and increased arterial stiffness (23, 24). Moreover, aging and obesity can lead to a decrease in skeletal muscle mass and performance (25, 26). Therefore, in people with increased skeletal muscle damage and fat accumulation, the effect of dietary niacin is more significant. In our study, dietary niacin intake was also significantly positively correlated with grip strength. This finding may be explained by the significant enhancement of skeletal muscle mass that results from dietary niacin because there is a strong positive correlation between skeletal muscle mass and strength (27). In addition, a cross-sectional study by Kim et al. showed that dietary niacin reduced levels of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor -α (TNF-α), in the elderly, thereby improving diet quality and reducing sarcopenia (28). Similar to the subgroup analysis of dietary niacin and skeletal muscle mass, dietary niacin had a stronger positive correlation with grip strength in subgroups with a BMI >25 kg/m2 or hypertension. This study found that in the range of daily dietary niacin intake in the general United States population (in the glucose homeostasis dataset, the maximum dosage of daily dietary niacin was 238 mg and the average dosage was 25 mg), dietary niacin was negatively correlated with HOMA-IR and fasting insulin, and in participants without diabetes, it was negatively correlated with fasting blood glucose. This means that niacin improves insulin resistance and glucose homeostasis at dietary doses. However, some previous studies have suggested that niacin promotes insulin resistance, which is a significant side effect when niacin is used as a lipid-lowering drug (29, 30). The reason for this inconsistent result lies in the dosage of niacin. When niacin is used as a lipid-lowering drug, its daily dose is 2–6 g, which far exceeds the daily dietary dose (31).”

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