Posts made by Amazoniac

• Comfortably Numb - Pink Floyd | Kent Nishimura (in one guitar)

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The rationale was: carbon dioxide goes through cells' lipids and releases a proton inside once hydrated. Then, let's find another compound that's also not barred by lipids and releases even more protons. This led to 2,6-DHBA.

It overlooks that the very property that makes the selected compound a greater acidifier is also what makes it extraordinarily prone to deprotonate prematurely. The ability to pass through lipids is likely to be compromised with the early proton release. If it could be injected into the tumor, it would still be uncertain if it could be taken up by target cells.

For direct internal acidification, it would be more fitting to seek weak rather than strong acids, those that can take advantage of the bump in transitioning from the extracellular to intracellular compartment (6.57.5) to deprotonate the molecule where intended.

A few issues concerning the salicylic acid analogue mentioned in this recent article.

Salicylic acid

• 2-hydroxybenzoic acid (2-HBA)

γ-Resorcylic acid

• 2,6-dihydroxybenzoic acid (2,6-DHBA)

Variations in the additional hydroxyl group relative to salicylic acid (orange):

Hydroxybenzoic acid isomers and the cardiovascular system

The coordination in 2,6-DHBA helps to stabilize the molecule in an ionized state:

Source: the internet.

I think that this property is responsible for its lower pKa, making it a 'stronger' acid, that's more prone to deprotonate (benzoic acid → benzoate⁻ + H⁺) and stay as such.

pKa:

• 2-HBA: 3.0
• 2,6-DHBA: 1.3

This does make 2,6-DHBA a molecule with greater acidification potential. However, the pH in the body is much higher than needed to ionize them, making the difference irrelevant:

• 50 mmol 2-HBA → 50 H⁺ mmol
• 50 mmol 2,6-DHBA → 50 H⁺ mmol

Once we adjust their doses to match for their alleged potencies and possible risk of toxicity, we may get something like:

• 50 mmol 2-HBA → 50 mmol H⁺
• 5 mmol 2,6-DHBA → 5 mmol H⁺

Which casts doubt on the benefit being from relying on a 'stronger' acid.

To counteract the inverted pH of cancer cells, we have to acidify the interior or alkalinize the exterior. 2,6-DHBA deprotonates already in the stomach, which only adds to the burden of extratumoral acidification. In contrast, I just shared with Jennifer a clinic that infuses baking soda in people with cancer.

Ray's suggestion to manipulate acidity through carbonic anhydrases has more basis. The hydrocarbonate ion recirculates in cancer cells and functions as a carrier of protons, taking them from inside, discharging outside, and repeating the process. Inhibition of carbonic anhydrases compromises this removal of protons and creates an unfavorable environment in cells.

Regarding lipophilicity, the greater the degree of hydroxylation, the less lipophilic a molecule tends to be. It's what happens to venom D when it goes from kilciol to kilcidiol and then to kilcitriol.

Plant-Derived and Dietary Hydroxybenzoic Acids—A Comprehensive Study of Structural, Anti-/Pro-Oxidant, Lipophilic, Antimicrobial, and Cytotoxic Activity in MDA-MB-231 and MCF-7 Cell Lines

"The obtained (experimental and theoretical) logP values for HBAs are in the range 0 < logP < 3; this means that these compounds possess from slightly hydrophilic (logP: 0–1) to moderately lipophilic properties (logP: 1–3) [101]. Generally, the disubstituted hydroxybenzoic acids were more lipophilic than the trisubstituted one (gallic acid has hydrophilic properties, and dissolves well in water and other polar solvents). According to the experimental logP values, the compounds can be ordered by increasing lipophilicity as follows: 3,4,5-THB→3,4-DHB~3,5-DHB→ 2,3-DHB→2,4-DHB →2,5-DHB →2,6-DHB."

"Dissociation and association phenomena affect the value of the partition coefficient. Therefore, we observed a relationship between the acid dissociation constants (expressed as pKa) and the values of partition coefficients. Each functional group that can be a hydrogen bond donor or acceptor increases the hydrophilic nature of the compound. Hydroxyl and carboxylic groups present in the structures of the compounds can form hydrogen bonds with water molecules in the aqueous environment, which affects their solubility in water. Therefore, in the case of 3,4,5-trihydroxybenzoic acid, an increase in the hydrophilic properties of the acid is noticeable. The more hydrogen bonds can be formed between a molecule and water molecules, the greater its solubility in water. In the case of ortho- substituted benzoates, the -OH group in the ortho- position is mostly engaged in hydrogen bond formation with the -COOH group, facilitating dissociation of the H+ carboxylic group and increasing the acidity of 2,6-DHB (pKa = 1.30) and, to a lesser extent, 2,3-DHB (pKa = 2.91), 2,5-DHB (pKa = 2.97), and 2,4-DHB (pKa = 3.11). In the case of 3,5-DHB (pKa = 4.04), 3,4-DHB (pKa = 4.26), and 3,4,5-THB (pKa = 4.40), the -OH groups are too far from -COOH to interact with this functional group, but may form hydrogen bonds with the solvent. As a result, the acidity of these acids decreases (higher values of pKa) compared to the ortho-substituted benzoates."

"The dependency between acidity (pKa exp.) and lipophilicity (logPexp.) in the series of studied hydroxybenzoic acids is shown in Figure 7. With the increase in the acidity of the compounds, the lipophilicity increases as well. Therefore, the hydroxybenzoic acids can be divided into three groups characterized by: (a) lower acidity and lipophilicity (3,4,5-THB; 3,4-DHB; 3,5-DHB), (b) moderate acidity and lipophilicity (2,3-DHB; 2,4-DHB; 2,5-DHB), and (c) higher acidity and lipophilicity (2,6-DHB)."

That's counterintuitive.

But here's the value for salicylic acid:

Lipophilicity Study of Salicylic and Acetylsalicylic Acids Using Both Experimental and Calculations Methods

"Experimental n-octanol-water partition coefficients (logPexp) determined by traditional shake-flask method were equal to 2.35 and 1.14 for salicylic and acetylsalicylic acids, respectively."

Aspirin is 'rapidly deacetylated' in the body, and salicylate is the main circulating metabolite, which must not differ a lot from 2,6-DHBA in terms of lipophilicity.

Aspirin, stroke and drug-drug interactions

They don't include the small intestine in the first-pass effect, when it's also responsible for the presystemic metabolism of the drug.

Acetyl transference appears to be a neutral reaction. But deacetylation through hydrolysis leads to proton release rather than the expected consumption (to reform the hydroxyl group). A proton from a water molecule is taken up by salicylate and the rest complexes with the freed acetyl group, which occurs deprotonated.

Aspirin and salicylate: An old remedy with a new twist

"Aspirin has a short half-life in circulating blood (~20 minutes) and is rapidly deacetylated and converted to salicylate in vivo. Salicylate does not affect COX-1 or COX-2 activity. Thus, the anti-inflammatory and antineoplastic actions of aspirin and salicylate remain a dilemma. Sodium salicylate paradoxically inhibited prostaglandin synthesis when added to intact cells.[7] Furthermore, healthy subjects taking sodium salicylate excreted a significantly lower amount of prostaglandin metabolites in urine than those not taking sodium salicylate, and their levels of inhibition were comparable to those of patients taking aspirin and indomethacin.[9] Aspirin also reduces human seminal prostaglandin levels.[10] These data suggest that salicylate inhibits COX metabolism by a mechanism different from a direct inhibition of COX activity."

So, part of aspirin won't reach the circulation, deacetylation can occur before systemic distribution, and the other part is soon deacetylated. Salicylate level can remain elevated for hours.

That we will be dealing with ionized forms conflicts with lipophilicity.

Effect of Enteric Coating on Antiplatelet Activity of Low-Dose Aspirin in Healthy Volunteers

"Aspirin is deacetylated to inactive salicylate at a number of sites, including the gut; thus, its bioavailability is about 50%. Plain aspirin is absorbed from the stomach, where the low pH protects aspirin against deacetylation and maintains aspirin in a nonionized form which encourages absorption."

The pKa of 2,6-DHBA is low enough that it can remain partially ionized even in the acidic pH of the stomach, which prevents intact absorption in an extreme scenario where gastric cancer cells were the desired target.

Therefore, I don't think that 2,6-DHBA being a 'strong' acid is a good reason to adopt it or a convincing explanation for the positive outcomes of use. Aspirin overdose can indeed result in acidosis, but would be an indirect effect.

The creator of Zettlr shared his work process. You can find throughout his Blog and Resources page.

@Jennifer, I brought it up because a clinic that doesn't reject conventional methods altogether might be faced with less resistance by him. Another advantage is that it's located in national territory, not giving him the impression that he's seeking clandestine treatments abroad.

@mar1kle

Not much glycine is lost with usual aspirin doses (30% or less of the aspirin weight).

The amount of sodium eliminated in pairing with salicylate ions should also be low. Approximations:

Aspirin

• 1 mmol per 180 mg (from 180 g/mol⇈)
• 5.5 mmol per 1000 mg

Sodium

• 5.5 mmol of sodium is 130 mg (from: 5.5 mmol × 23 mg/mmol)

Maximum direct sodium loss:

• 130 mg Na/g aspirin

It may seem negligible, but it depends on the amount consumed of each.

Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide

For a person ingesting an average amount of sodium (4 g), taking high doses of aspirin can induce the depletion of a considerable share of the sodium intake.

As for the alkalinization, it may enhance the activity of acyl-CoA synthetases (ACS), mentioned above as the limiting step, similar to the disinhibition effect on some glycolysis enzymes.

@Jennifer, another approach that might suit:

Cancer Treatments | Cancer Center for Healing
↳ Low Dose Chemotherapy

From them:

"Small portions of poultry or fish are also an option for patients who choose to adopt a “Mediterranean” style diet rather than a strictly plant-based (vegan) approach."

@Milk-Destroyer

Yes, alkalinization tends to improve excretion of acids that ionize. The unionized forms are prone to leak from the kidney filtrate and lead to unwanted reabsorption.

What I find confusing in overdosing aspirin is that the most abundant metabolite appears to be salicylate, but it only protonates to salicylic acid when the pH is too low for the typical of urine, let alone for kidneys' tubules.

The pH role in the transport of active principles of drugs through agitated bulk liquid membrane

Therefore, the principle above don't seem to apply, unless the urine is extremely acidic, a shy fraction gets reabsorbed, and it becomes significant over time.

@Jennifer, if your dad remains committed to conventional methods, perhaps he would be willing to consider this approach:

Immunotherapy in Cancer | Joseph Issels

"There are three general areas of prohost clinical management which are interwoven, and which overlap considerably:"

• "Correction of all known causal factors. This requires surgical elimination of foci of infection (notably head foci of dead teeth and nonfunctional diseased tonsils), immunization against pathogenic microbes and administration of appropriate flora, desensitization of local tissue pathologies caused by neural referral of disturbances from distant disease foci (Huneke), treatment of toxicoses and sensitivities caused by inherited latent phase cell wall deficient microbial forms (stemming from ancestral exposure to infections including syphilis and tuberculosis), which are passed on at birth and can persist for many generations (Enderlein, Spengler), replacement of pathogenic nutrition with a dietotherapy specifically designed to meet the special needs of cancer patients (Gerson, Hildenbrand), removal of environmental and psychological stressors as defined by Hans Selye, and the establishment of a more beneficial mind/body homeostasis according to the findings of psychoneuroimmunology."

• "Desensitization to causal factors. This is accomplished by systematic autogenous vaccination, application of microflora preparations and various specific vaccines."

• "Normalization of secondary damages to the host metabolism (impaired detoxification with subsequent suppression of natural defenses). Treatments include Gerson's dietotherapy, correction of the acid-base balance by treatment of the serum alkalosis and tissue acidosis paradox common in degenerative diseases, hyperthermia, fever therapy (Coley-Nauts), hyperbaric oxygen, ozone, ultraviolet blood irradiation, enzymes, glandulars, organ extracts, and neural therapy (Huneke)."

"Conventional anti-tumor treatments (surgery, radiation, chemotherapy) can be utilitarian and beneficial when modified to support the goals of whole-body comprehensive immunotherapy. In this context, they may be used concomitantly with vaccines, dietotherapy, and other host-protective medical measures. Dosages and duration of treatment with these drugs may be far less than is recommended in the randomized clinical trial protocols by which they achieved regulatory approval, but these modifications are justified by the outcomes of my patients, who achieve quite satisfactory tumor response without the typical side effects of hair loss, bone marrow suppression, and gut disturbances."

Invert colors for improvised dark mode when needed:

Windows:

• Start > Settings > Accessibility > Color filters

Mac:

• Menu > Settings > Accessibility > Display

Both have shortcuts to enable and disable.

F.lux has a 'darkroom mode' as well.

In Linux, you likely have means to configure the sun and clouds.

Unknown Features in Microsoft Word | Jojo

Zotero released an important update about a month ago. The app is free, and its source code is publicly available. Also:

Zotero Privacy Policy

"Zotero is designed as a local program that saves data to your own computer by default, and it doesn’t require sharing any data with us to be usable. However, some of Zotero’s advanced features require you to supply us with information."

The app has a built-in reader with superior text recognition than some other readers, making it easier to extract passages, which can be done in batches and respecting filters. Sometimes it's able to identify the sequence of a text in another page while excluding unrelated information.

It shows pop-ups when hovering on parenthetical information (figures, tables, references), to dispense frequent page jumps. It's capable of listing specific references with leaps between them [1,3,5-10]. It also has a 'return' feature, to go back to where you left after a click, although many readers have this as well.

It rotates pages individually rather than the entire document.

It has the basic tools for annotation, that spares the original copy by default, but gives the option to modify it as well. Annotation tools include an area selector, in case the person wants to capture a figure or table.

A file can be featured in different folders without duplicating it, and these can be highlighted by holding a key. Power, Strength, Courage, Polygamy. If you had such folders, where would you put Kvothe's biography if it fits in all of them?

When a folder is selected on the navigation pane, rather than showing sub-folders, it shows their content combined. In addition, it's possible to associate related documents.

The search function has the option to screen through the content of PDF files.

For those who are fond of dark modes, it now has the option to apply to content as well, not just the borders of the document.

It saves sessions to resume where you stopped, similar to other apps.

Browser add-ons are available for further ease, if you don't mind the intrusion. Metadata can also be retrieved automatically by adding a recognizable file to the library.

References managers are not necessary tools--I know authors who deal with complex information without relying on them--but they are convenient in helping with organization and saving time. Give it a try in case some function appealed to you.

Hello, Jorge (or your bot).

That these vitamins increase the risk of cancer complications is not a reason to avoid supplementation, but to be more cautious with them.

One suggestion was to offer B-vitamins in separate products, something like:

• Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism
• Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways

But it's challenging to have a clear separation of vitamins because of interrelationships. Pyridoxin was excluded from their 'energy metabolism' group, but it's directly involved in glycogen use and the transaminases to prepare amino acids for oxidation. Biotin was included, but associated with anabolic functions, and one of the catabolic pathways would be dependent on the vilified (adenosyl)cobalamin. If all came down to an energy problem, the nucleotides of the energy-releasing coenzymes involve folate in their syntheses.

Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides

Growth-promoting substances don't just fuel cancer, they're also needed for cell and tissue regeneration.

Supplementation is discouraged for folate, cobalamin, and choline (or betaine). We know that the message is reaching a community that doesn't consume a lot of leaves (foliage→folate), nor legumes. The availability of folate in oranges is arguably lower than expected.

• Properties of Food Folates Determined by Stability and Susceptibility to Intestinal Pteroylpolyglutamate Hydrolase Action

Tipping the reliance in favor of folate-cobalamin over choline might yield extra glycine, that can be formed for every folate cycled. The simultaneous restriction of these vitamins, along with a predisposition to their insufficiency, malabsorption syndromes, and the adoption of a diet low in methionine doesn't seem promising.

Do we have indications that the population is adequate in the anabolic vitamins and can afford a restriction? Because the typical consumption and positive reactions to supplementation suggest otherwise.

Not only a deficiency of any vitamin tends to predispose to cancer, but cancer is not the only disease to worry about. Cardiovascular problems and infections are major threats.

Digestion weakens in advanced age and disease, making it helpful to have available these vitamins in purified form. The issue here is that you're leaving for other vendors to do the dirty job of guaranteeing adequacy in a considerable number of people that would benefit from the carcinogenic nutrients.

On the generalization of our tropical, lazy nature:

Germanness, Civilization, and Slavery: Southern Brazil as German Colonial Space (1819-1888)

"The idea that tropical environments produced indolence and degeneration has a long history. Scholars of European thought regarding the connection between climate and behavior refer to the European paradigm of understanding the tropics as “tropicality.” David Arnold defines tropicality as “a belief in the intrinsic ‘inferiority’ of tropical as opposed to temperate environments and hence in the primitivism of the social and cultural systems to which the tropics gave rise.”[43] Beginning in the ancient world and continuing well into the modern age, Europeans have seen the tropics as a zone of “otherness.”[44] Additionally, Europeans have long asserted that the environment impacted (to varying extents) human behavior, including not only physical development, but mental and moral as well.[45]"

"Two basic tropes existed, often simultaneously, in the European vision of the tropics in relation to its impact on work ethic. The first was that of the tropics as a paradise of abundance, in fact, overabundance that rendered residents lazy. The other was that of the tropics as an oppressively hot and humid region, the effects of both also led to indolence."

"Regarding the image of the tropics as abundant to a demoralizing point, this discourse existed since the discovery of the New World, but Philip Curtain writes that by the eighteenth century, the “full-fledged myth of tropical exuberance” was common in Europe.[46] The basic premise of this notion was that since the tropical environment produced food so easily, residents did not have work to survive and this rendered them indolent.[47]"

"For example, John Crawfurd was surgeon, Fellow of the Royal Society, and leading member of the Ethnological Society of London. He lived in Southeast Asia for a time, and in 1820, he published his three volume History of the Indian Archipelago. In it, he asserts that peoples living in the tropics are marked by weakness and despotism. “The cause of this phenomenon is in good measure... the softness and fruitfulness of the climate, and the consequent facility of living with little exertion.” Able to survive without working, tropical peoples lack “habits of hardihood, enterprise, and independence” that is necessary for true freedom and civilization.[48] Alfred Russel Wallace was a British naturalist and biologist who spent time in both Brazil and the Malay Archipelago. In discussing the eastern region of that archipelago, Wallace concluded that the fecundity of the area had an adverse effect on the local peoples: “This excessive cheapness of food is... a curse rather than a blessing. It leads to great laziness... The habit of industry not being acquired by stern necessity, all labour is distasteful.” Wallace theorizes that if the whole planet was as verdant as the tropics, “the human race might have remained for a longer period in the low state of civilization” that he finds among natives in the eastern archipelago.[49]"

"In the case of German discussions of alleged Portuguese-Brazilian laziness, authors generally did not assert a connection between abundance and laziness. For example, G.H. von Langsdorf calls the assumption that the natural abundance of Brazil meant that no one worked “very hasty in the least.”[50] In fact, many Germanophone authors stressed how hard settlers had to work to succeed there.[51]"

"The second trope concerning the tropics and laziness related to climate, wherein heat and humidity deleteriously impacted people, and Europeans especially. The relation between temperature and moral/physical development has a long history in European thought. Sixteenth-century thinker Jean Bodin argued that heat produced drunkenness and lust in Europeans, although hotter regions tended to yield better philosophers, since the heat cultivated a stronger sense for inward thinking. According to Bodin, colder climates help spur people to external forms of work, such as the crafts and the arts.[52] In the seventeenth century, French poet Guillaume de Salluste du Bartas described the Garden of Eden as a temperate place, while in the eighteenth century, Bernard Le Bovier de Fontenelle argued that extremes of heat and cold were not conducive to scientific thinking. Many Europeans thinkers saw heat as detrimental to mental and moral development. Trader and traveller Sir John Chardin asserted that hot climates slowed people’s thinking, and Scottish physician John Arbuthnot argued that constant heat produced laziness due to a lack of expansion and contraction of “Fibres” (sic) that greater variations in temperature produced.[53]"

"In 1748, Scottish philosopher David Hume wrote that those living in the extreme cold and heat were “inferior to the rest of the species, and are incapable of all the higher attainments of the human mind.” However, while he believed that people in the coldest climates were crippled by “poverty and misery” brought on by their struggles surviving in the harsh environment, indolence was the weakness of those from warmer climates. Hume argued that while there were many examples of early intellectual contributions from the warmer regions of Southern Europe, it was Northern European countries where recent advances occurred, while thinkers in the south grew less productive.[54]"

"In 1748’s The Spirit of the Laws, Baron de Montesquieu asserted that due in part to the positive effects of cold on blood flow, cold climates produced more energetic people, while heat robbed residents of warmer regions of their initiative and rendered them lazy. He also argued that people from colder regions were braver and less prone to cunning. He related those from warmer areas to old men, calling them “timorous” and lacking the courage that marked northerners. Furthermore, warmer regions breed a strong love of pleasure that is lacking in the coldest areas and well-balanced in temperate zones. This imbalance fueled a passion that dominated southerners, producing an immorality that did not plague those in the north: “If we travel towards the North, we meet with people who have few vices... If we draw near the South, we fancy ourselves entirely removed from the verge of morality.”[55]"

"German thinkers, too, saw climate as shaping humanity’s development. Eberhardt August Wilhelm von Zimmermann, a zoologist and geographer best known for his three volume Geographical History of Man and General Diffused Quadrupeds, asserted that climate was central to the development of the races, although he saw environmental influence as malleable and temporary. In the first volume of the Geographical History, compared the racial character of Europeans and Africans, including those of African descent living in the United States. He called White Europeans “actually comparatively wiser and more active” than Blacks, but this was “a consequence of climate” and not permanent. In fact, he argued that if a group of Senegalese Africans were relocated to a cold climate, such as Denmark, and allowed to live on their own without mixing with the native Europeans, the Africans would, after some time, become “Nordic white,” by which he meant not only in terms of their appearance, but also their mental capacities.[56] Hence, in Zimmermann’s racial system, climate was the determining factor, and hotter climates bred a slowness of mind and activity."

"Christophe Meiners also believed that climate made people mentally and physically weak. Meiners was a historian and philosopher who believed was a vocal defender of polygyny, or the notion that different races were actually wholly different species. While in the minority of German philosophers by supporting polygyny, Meiners was nevertheless highly influential.[57] In fact, John Zammito argues that Immanuel Kant and Johann Blumenbach first became engaged with the question of race so as to counter Meiners.[58]"

"Regarding climate’s effect on people, Meiners believed it was central to the physical and mental development of the races. In his Outline of the History of Humanity, Meiners wrote that the “strongest men and nations only... live in the mildest climates.”[59] He argued that due in part to the effect of climate, the Caucasians possessed “not only greater strength of body, but also of mind,” and that both of these traits were due in no small part to the cooler climate in which Caucasians developed. Meiners also argued that warmer environments had a deleterious effect on peoples, writing that “even the noblest of human natures are inevitably corrupted and degraded in certain areas and climates,” of which he cited Africa, Southeast Asia, most of India, and assorted regions of South America.[60]"

"In their discussions of Portuguese-Brazilians and their alleged laziness, some German writers did assert a climatic explanation. J. Friedrich von Weech wrote that climate, combined with a cavalier attitude toward religion, “seems to awaken too soon some natural instinct which was supposed to lie dormant until a person is developed fully,” and this leads very young Brazilians to become sexually active. This, in turn, leads to the loss of vitality and energy among young Brazilian men: “the decrepit young figures, the lack of the bold fire that is normally so beautiful in the youth, is only too clearly visible on the pale and lifeless faces of the urban youth.” Having lost their energy through this “early enervation,” young Brazilians turn to even greater debauchery, and in doing so, risk the future of their country.[61]"

"Thomas Davatz also connected Brazilians’ immorality and indolence to the effects of climate. Davatz was selected by the Swiss government to investigate alleged mistreatment of Swiss settlers in the sharecropping system in São Paulo. He penned a scathing report that accused Portuguese-Brazilian planters of a host of abuses, prompting further investigations in Brazil and outrage in the European German press.[62]"

"Regarding the impact of climate on Brazilians, Davatz writes that the Brazilians are unable to control their passions, often leading not only to fights, but even murder. Furthermore, Brazilians are marked by a love of idleness. Davatz relates all of this to heat and humidity, writing that “[t]hose vices... are promoted throughout the Brazilian’s life by the luxuriance of the tropical climate.”[63] Like Weech, Davatz argues that the heat drove Brazilians, and the young especially, to succumb to their base sexual desires, leading to a loss of vitality and adolescents marrying too early. However, in the subtropical region of southern Brazil, Davatz argues, there are many people who live to an exceptionally old age: “People of more than 100 years should be no great rarity, indeed some of these will live to 120-130 years of age.”[64] Davatz hence makes a distinction between the hotter climates of northern Brazil and the cooler region of southern Brazil."

"Beyond relating climate to Portuguese-Brazilian indolence, Germanophone authors also expressed concern regarding the impact of the climate on Germans settling in the country. Carl Schlichthorst, a German who served as a mercenary in the Brazilian army between 1820 and 1822, in part blames climatic effects for the laziness of nativeborn Brazilians.[65] Still, he writes that the “person born in the southern lands has many and great faults,” but that Brazilians balance such faults, including a tendency to lie and a general laziness, with their friendly nature and tendency to avoid over-drinking. However, the hot climate affects the Germans, and Northern Europeans in general, terribly: “almost all northerners who live in hot climates do not bear the particular virtue of their people, they merge in a very short time with the vices of the natives and their national faults.” German settlers bear none of the loyalty that Schlichthorst sees as marking European-Germans, instead turning to indolence and drunkenness.[66]"

"Some Germanophone writers believed that Germans could not work in tropical heat. J. Friedrich von Weech argued that slavery was a necessity in tropical environments. According to Weech, Europeans are unsuited to the much of the climate in Brazil, making intensive farming impossible for them: “it as erroneous view of many learned men, that Europeans, in the hot climate of the tropics for the duration of their stay, could perform the same work previously done by the Negro.” Weech argues that based on his own experience with Europeans in Brazil, even the hardest working settlers lose their vitality within two years, reducing them subsistence farming.[67] In his entry “Regarding Emigration” in 1847’s Zeitschrift für die gesamte Staatswissenschaft, Robert von Mohl echoed Weech’s opinion that Europeans, and Germans in particular, could not work in the tropical heat. Mohl writes that “there can be no doubt that tropical countries are not good for Europeans, especially for Germans. Such climatic conditions do not allow members of the Caucasian tribe to work outdoors, and detrimental to their health, and nearly compel slave-holding.”[68]"

DemiGod's post reminded me of some opinions of Albert Einstein on his Brazil visit:

• "I have no desire to meet semi-acculturated Indians wearing tuxedos."
• "Here I am a kind of a white elephant to them, and they are monkeys to me."
• "[..]at noon, at Prof. Castro's house, a legitimate monkey, but interesting company."
• "Brazil is too hot and humid to do any intellectual work. They all give me the impression of having been softened by the tropics."
• "People there are empty and uninteresting - even more than those in Europe."
• In leaving, he wrote: "Finally free."

I'm not making them up, although Albie did praise the country's natural resources. Not sure what kind of event he was forced to attend, but as one of the monkeys, I feel so insulted by the generalization that it makes me want to circle in anger, beat my furry chest, and throw at him a banana.

Jeanne Fave

"She enjoyed chocolate, sometimes indulging in a kilogram (2.2 lb) per week."

"Her height was 150 cm (4 ft 11 in), and her weight 45 kg (99 lb), showing little variation from previous years."

Mike Calment

• ~1.1 kg chocolate/week

Assumptions: 90 kg bw (2 Jeannes) and 190 cm of height.

Calculating with Hyperbolas and Parabolas

A simple practice guide for dose conversion between animals and human

French animal (pink line) Km

• 45 (kg) ÷ 1.4 (m²) ≈ 32

Italian animal (blue line) Km

• 90 (kg) ÷ 2.2 (m²) ≈ 41

Km ratio

• 32 ÷ 41 ≈ 0.8

⠀
If Jeanne consumed..

• 1 kg chocolate/wk/45 kg

..the equivalent for Mike would be:

• 2 kg chocolate/wk/90 kg × 0.8 ≈ 1.6 kg chocolate/wk/90 kg

Not the meek ~1.1 kg chocolate/wk/90 kg that he's currently eating.

Pharmacokinetics of Salicylate in Man

"Only the nonionic form of salicylic acid is subject to tubular reabsorption. As a consequence, the renal clearance of salicylate is exquisitely sensitive to urine pH. As urine pH is increased from 5 to 8, the renal clearance of salicylate increases more than twenty-fold [39]. While this has a relatively small effect on the elimination kinetics of small single doses (≤0.65 g aspirin in adults), it has a profound effect on the elimination of larger doses, i.e., when the formation rates of salicyluric acid and salicyl phenolic glucuronide approach saturation. This is particularly apparent when urine pH is increased from below 6 to 7 or higher. Consequently, alkalinization of urine is a commonly employed measure for treating salicylate intoxication."

"The alkalinizing effect of sodium bicarbonate on urine pH is well known. Less widely appreciated is the fact that certain "nonsystemic" antacids can also increase urine pH. The term "nonsystemic" is therefore a misnomer. Such widely used antacids as aluminum and magnesium hydroxide and calcium carbonate-glycine mixture can increase urine pH significantly [40]. The lower the baseline urine pH, the greater is the effect of the antacid [40]. Since antacids are frequently taken concomitantly with aspirin (often without knowledge of the physician) to reduce or prevent aspirin-induced dyspepsia, an awareness of this potential interaction is important."

Metabolism of Aspirin after Therapeutic and Toxic Doses

"Caldwell et al.[28] reported a large inter-subject variation in the urinary recovery of salicyluric acid (range 5.9-71.6%, some 12-fold variation) and salicyl glucuronides (0.1-90%) in 85 healthy volunteers who took 900 mg ASA by mouth. Another recent report from the same laboratory[8] again showed that the urinary excretion of SA and metabolites in volunteers who ingested ASA 900 mg was highly variable. Such larger inter-individual variation was not observed in the present study (Figure 1)."

"The present work also explores the kinetics of SUA formation from SA under conditions of increasing aspirin load from therapeutic to toxic amounts. In the three groups of subjects from whom the mean values of total salicylate recovered were 246, 2999 and 8095 mg, the proportions comprising SUA were 75, 47 and 22% and those comprising SA were 9, 31 and 65%, respectively. Thus the effect of saturation of SUA formation is clearly demonstrated at doses that extend well into the toxic range, although we recognize that urine alkalinization would have influenced the pattern in the most severely poisoned group. Reduced excretion of salicylate as SUA in those that took overdoses of aspirin was accompanied by increased elimination as GA and SPG indicating that the processes that lead to the production of these metabolites continue to play a significant part (22-33%) in the inactivation of salicylate."

Since not all of the aspirin dose is conjugated to glycine, we may simplify as (85%):

• 0.85 glycine (75.07 g/mol) per 1 aspirin (180.16 mg/mmol).

Along with discounting the glycine-unrelated excretion, we have to adjust for mass differences:

• 75.07 g/mol ÷ 180.16 g/mol ≈ 0.4

Therefore..

• 0.85 (glycine conjugation fraction) × 0.4 (mass correction factor) ≈ 0.3

ASA has 3 letters, making it easy to remember the 30% for the corresponding glycine depletion.

If a victim takes 500 mg of aspirin, this dose will deplete only (500 mg × 0.3 = ) 150 mg of glycine.

From there, the higher the dose, the lower the fraction of glycine conjugation. Based on Table 1:

For the two 'overdose' groups of the report, it would be about 20% and 10% with the previous considerations. Suppose that they took 10 g of aspirin (those 8 g of SA equivalents), such dose would deplete 1 g of glycine.

Pharmacokinetics of aspirin: evaluating shortcomings in the literature

"Even though aspirin is one of the most widely used drugs, the literature on the detoxification of salicylic acid by the major glycine conjugation route is severely limited. Salicylic acid is detoxified via a two-step enzymatic process in the mitochondria of the liver (Figure 1).

• The xenobiotic/medium chain fatty acid:CoA ligase (ACSM2B, EC 6.2.1.2) uses ATP to activate salicylic acid to salicyl-CoA releasing AMP and pyrophosphate [70].
• Glycine N-acyltransferase (GLYAT, EC 2.3.1.13) forms salicyluric acid and releases CoA by conjugating salicyl-CoA to glycine [71]."

"The first enzyme involved in the pathway, namely ACSM2B, can form salicyl-CoA at a low efficiency (<1%); however, studies on bovine ACSM2B have shown an inhibitory effect of salicylate. The ACSM2 ligases and their role in xenobiotic metabolism is understudied, particularly the effect of genetic variation on enzyme activity; the identity of factors affecting ACSM ligase activity in vivo, the role of inhibitors on the conjugation ability of ACSM2B and the association between ACSM2B and detrimental health outcomes."

"Glycine conjugation is saturable and can, therefore, only detoxify a limited range and concentration of substrates. The rate of glycine conjugation can be affected by the formation of the acyl-CoA (ACSM2B) and/or the conjugation of the acyl-CoA to glycine (GLYAT)."

"The rate of glycine conjugation can be affected by:

• The available co-factors (ATP, CoA, and glycine);
• Genetic variants in the ACSM2B and GLYAT genes;
• Different expression levels of ACSM2B and GLYAT;
• Disease states.

Studies have shown that although ATP can limit glycine conjugation of salicylate, glycine concentration is not a limiting factor."

"The availability of glycine may be a limiting factor in glycine conjugation of benzoate [94,98,99]. It can influence the rate of detoxification as was demonstrated by the dose dependent increase in benzoylglycine (hippurate) formation after administration of glycine [94]. Benzoylglycine is formed from benzoate and is the preferred substrate for detoxification by the glycine conjugation pathway. However, even though the formation of salicylate has been found to be capacity-limited at therapeutic doses [69], oral administration of glycine does not increase the excretion of salicyluric acid. This indicates that glycine is not the limiting co-factor. However, the available amount of ATP for the reaction can be reduced by salicylate itself as it uncouples oxidation and phosphorylation [65]. This then limits the rate of the reaction."

"In a study investigating the effect of orally administered glycine on salicylate metabolism during aspirin overdose, it was found that the plasma glycine was lower in the overdose patients suggesting depletion of available glycine. Orally administered glycine increased the plasma glycine concentration while the fraction of total salicylate recovered as salicyluric acid remained the same. This supported previous studies, however, orally administered glycine did shorten the time it took to reach the maximum rate of salicyluric acid excretion [100]."

"The glycine conjugation pathway is often oversimplified, as it's not just limited to detoxifying benzoate into hippurate. This pathway plays a crucial role in metabolizing and detoxifying various substrates, including natural compounds from food like salicylate, dietary polyphenols, and medium-chain fatty acids (MCFAs), as well as xenobiotics and metabolites from organic acidemias [98,101,157,158] (Figure 2). Xenobiotics, such as salicylate and MCFAs, are first activated to acyl-CoA. Salicyl-CoA is conjugated to glycine, while MCFA acyl-CoAs are further processed by β-oxidation [159]."

"The glycine conjugation pathway evolved to metabolize endogenous substrates (e.g. MCFAs), and therefore, xenobiotics such as salicylate add an additional detoxification load. It has not been determined if these multiple substrates have a deleterious effect on the rate of glycine conjugation, but it is known that the pathway can be saturated [64,92,93,97,109,162,163]. This probably indicates that the preferred substrate will be detoxified at a rate that does not exceed a threshold concentration and that less preferred substrates will accumulate."

"[..]salicylate first needs to be activated to a salicyl-CoA before it can be conjugated to glycine to form the glycine conjugate (Figure 2). Previous studies have shown that the activation step occurs at a much slower rate than the glycine conjugation rate [69,74,154,155]. This is because salicylate is not the preferred substrate for ACSM2B [70]."

"[..]the formation of salicyluric acid reaches a maximum rate at higher doses of aspirin (1 g or more) [153]."

"Furthermore, benzoate, a preservative found in many food items, can outcompete salicylate for glycine conjugation, increasing the half-life of salicylate. Microorganisms in the gut produce benzoylCoA from dietary polyphenols. This contributes a very large load that needs to be metabolized by the glycine conjugation pathway [161]."

"Humans are consuming and increasing concentration of substrates that need to be detoxified by the glycine conjugation pathway. These include natural sources (e.g. salicylate found in berries [158]), polyphenols [196], and xenobiotics [197,198]. Therefore, the ability of an individual to detoxify salicylate will also depend on the type of diet they follow, as a diet high in preservatives (benzoate) will reduce the amount of salicyluric acid that is formed. Salicyluric acid formation can be inhibited for long periods if even small amounts of benzoate are repeatedly ingested [199]."

"Salicylates are [..] found in many common food items, e.g. vegetables, fruits, herbs/spices, and beverages [35,36]. Significantly higher levels of salicylic acid were found in the serum of vegetarians not taking aspirin, with the reported levels comparable to that of patients taking 75 mg of aspirin [37]."

"The metabolism of salicylic acid in cancer patients are severely limited [153] and it has been shown that the GLYAT gene is transcriptionally downregulated in hepatocellular carcinoma [118,203]. Cancer cells have a high demand for glycine and serine for growth [204]. The inhibition of glycine uptake or biosynthesis can impair cancer cell growth [123]. Therefore, the GLYAT gene is downregulated in cancer cells to prevent the enzyme from depleting hepatic glycine, which would inhibit the rapid proliferation of cancer cells [118,123,124,205,206]. It is possible that aspirin may exert its anticarcinogenic properties via the induction of expression of GLYAT which then leads to the depletion of hepatic glycine and inhibition of cancer cell growth. It has been shown that the long-term use of salicylate may increase the production of salyciluric acid by induction [97,207,208]."

From an exchange with cool people:

Vitamin D (978-0-12-809965-0) - David Feldman

"It is now widely believed the enzyme [CYP27B1; calcidiol → calcitriol] exists in nonrenal tissues to boost local production of cellular 1,25(OH)2D3 in a paracrine/intracrine system. Such a role would suggest that cellular 1,25(OH)2D3 concentrations in extrarenal CYP27B1 tissues might be higher than in the tissues of the classical endocrine system, which depend on renally synthesized blood-derived 1,25(OH)2D3 at a concentration around 10^−10 to 10^−9 M (e.g., intestine, bone, parathyroid gland). In turn, the genes regulated in extrarenal tissues (e.g., macrophage, colon, prostate) might be a less-sensitive cell differentiation and antiproliferative subset, known to be regulated in cancer cell lines at 1,25(OH)2D3 concentrations of 10^−8 to 10^−7 M under cell culture conditions. A role for the extrarenal CYP27B1 is also consistent with the finding that serum 25(OH)D levels are associated with various health outcomes from bone health to cardiovascular health. In particular, low serum 25(OH)D levels are associated with increased mortality for colon, breast, and prostate cancer; increased autoimmune diseases and greater susceptibility to tuberculosis; increased cardiovascular diseases and hypertension. The presence of CYP27B1 in cells of the colon, breast, prostate, monocyte/macrophage, and vasculature could explain why serum 25(OH)D levels are so critical to the normal functioning of these tissues."

"Patients with hyperthyroidism (high serum levels of thyroxine, T4 and/or triiodothyronine hormone, T3) have been reported to have low circulating levels of 1,25(OH)2D [55,56]. Recent studies in mice with T3-induced hyperthyroidism showed markedly suppressed serum levels of 1,25(OH)2D and renal expression of Cyp27b1 [26]. Functional studies using PCT cells demonstrated the presence of a negative thyroid hormone response element (TRE) −50 to −20 bp upstream of the transcriptional start site of the CYP27B1 gene with this TRE overlapping the sterol regulatory element (1α-SRE) and TATA box [26]. Data in this study indicated that SRE-binding protein 1c acts as a transcriptional inducer of CYP27B1, but this effect is compromised following treatment with T3. Transcriptional repression effects of T3 on CYP27B1 appear to be due to thyroid hormone receptor (TR)α, and TRβ1 heterodimerizing with retinoid X receptor (RXR)α, to prevent binding of SRE-binding protein to its DNA target. In this way, T3 indirectly suppresses expression of CYP27B1 [26]."

"The serum phosphate concentration is another major regulator of renal 1,25(OH)2D production. In adult humans, dietary phosphorus restriction causes an increase in circulating concentrations of 1,25(OH)2D to 80% above control values, an increase not due to accelerated metabolic clearance of this hormone [38]. Dietary phosphorous supplementation has the opposite effect. Although the mechanism by which decreased serum phosphate increases renal 1,25(OH)2D production remains uncertain [39], it is clear that in humans the calcium-phosphorous-PTH axis cooperates to regulate the conversion of 25(OH)D to 1,25(OH)2D in the kidney. For example, decreased serum calcium concentrations are immediately registered by the parathyroid chief cell calcium-sensing receptors, which, in turn, relax inhibition of PTH production and secretion. The resulting rise in circulating PTH levels directly stimulates the renal 1α-OHase, while a PTH-mediated phosphaturic response and a subsequent decrement in the serum phosphate concentrations indirectly promotes 1,25(OH)2D production (Fig. 8.1)."

↳ [38] https://raypeatforum.com/community/threads/is-vitamin-d-supplementation-even-neccessary.23844/post-797842

Hypophosphatemia: the common denominator of all rickets

"In contrast to its renal counterpart, the macrophage 1α-OHase is unaffected by the stimulatory effects of PTH and phosphate [95,102]. The macrophage plasma membrane is not enriched with PTH receptors [103], and there is no evidence macrophages are responsive to PTH or PTH-related protein in terms of stimulating the protein kinase signaling pathways that are associated with induction of renal 1α-OHase. Similarly, the macrophage enzyme appears to be uninfluenced by changes in the extracellular phosphate concentration [95]. Moreover, exposure of activated macrophages expressing 1α-OHase to a calcium ionophore stimulates the hydroxylation reaction [104], while increasing the extracellular calcium concentration has the opposite inhibitory effect on the renal 1α-OHase [105]."

"Although effects of extracellular phosphate and serum FGF23 on macrophage 1α-OHase activity have yet to be documented, decreased expression of the enzyme has been shown in peripheral blood monocytes treated with FGF23 in vitro [106]. However, the general conclusion is that the key extracellular signaling systems for renal 1α-OHase activity are not heeded by the macrophage enzyme. This provides an explanation for why 1,25(OH)2D production by the macrophage in diseases such as sarcoidosis is not subject to the same negative feedback control that is mediated by a drop in the serum PTH concentration and an increase in the circulating calcium and phosphate level. By contrast, macrophage 1α-OHase activity is potently inhibited by antiinflammatory agents such as glucocorticoids which have little or no effect on the renal enzyme. In vivo this is likely to be due in part to the effects of glucocorticoids on macrophage differentiation and apoptosis. However, studies in vitro suggest that there is also direct inhibition of macrophage 1α-OHase activity by glucocorticoids [74]."

"Of the various bioactive cytokines concentrated in the alveolar space of patients with active sarcoidosis [77,78,130,131], interferon γ (IFNγ) was found to be the principal stimulator of the sarcoid macrophage 1α-hydroxylation reaction, with IFNα having minimal affect only at higher concentrations [74]. However, it is now clear that many other cytokines are also able to stimulate macrophage 1α-OHase. Recent studies have shown that interleukin-15 (IL-15) [132] and IL-32 [133] play pivotal roles in the induction of macrophage CYP27B1 during innate immune responses to bacterial infection. Elevated expression of IL-15 is frequently associated with inflammatory diseases, notably sarcoidosis [134]; as such, IL-15-mediated induction of 1α-OHase activity may provide a link between the regulation of 1α-OHase in normal innate immunity and the dysregulated 1,25(OH)2D production associated with granulomatous disease. Other cytokines such as tumor necrosis factor α (TNFα) [43,79] and IL-2 [102] are also know to stimulate macrophage 1α-OHase. As all of these factors have been implicated in the maturation of macrophage responsiveness within the innate immune system, it seems likely that upregulated 1α-OHase activity is a common feature of activated, but not quiescent, macrophages. More recently and in contrast to the effects of type 2 IFN, IFN-γ, it has been shown that type 1 IFN, IFN-β, negatively regulates the expression of 1α-OHase in human monocytes through increasing the expression of IL-10, which, in turn, inhibits CYP27B1 expression. This results in attenuated 1,25(OH)2D synthesis and consequent reduction in the antimicrobial peptide cathelicidin [135]. Similar observations have also been made for IL-4 that potently suppresses 25(OH)D-induced antibacterial responses in macrophages [136]. In this case, the precise effects of IL-4 on CYP27B1 are unclear, and may involve indirect effects via CYP24A1 [136]."

"Signaling via cytokines such as IFNγ may also lead to the activation of other calcium-dependent pathways in the macrophage, specifically the PKC [143] and phospholipase A2 (PLA2) pathways [144,145]. Because the macrophage 1α-OHase was not influenced by attempts to directly stimulate or inhibit PKC, attention has focused on the PLA2 pathway and the endogenous arachidonic acid metabolic cascade as the signal transduction pathway of most influence over the macrophage enzyme. Further dissection of the intracellular arachidonate metabolic pathway in this cell demonstrated that signal transduction through the 5-lipoxygenase pathway, specifically with the generation of leukotriene C4, was most critical to an increase in 1,25(OH)2D synthesis [146]. These studies were extended to investigate another compound with potential actions in the PLA2-arachidonic acid pathway, the 4-amino quinoline derivative chloroquine. Synthesis of 1,25(OH)2D by macrophages was completely inhibited by exposure to chloroquine in vitro [86]. Furthermore, this effect is independent of chloroquine’s apparent ability to alter the pH of intracellular organelles. When given orally to a hypercalcemic patient with sarcoidosis, chloroquine [83,86] or its analog hydroxychloroquine [84] can effectively reduce the serum 1,25(OH)2D and calcium concentration within 36 hours."

"Pathogen-associated molecular patterns such as the bacterial LPS are potent inducers of macrophage 1α-OHase expression and activity [95,102]."

"As outlined above, LPS and IFNγ commonly activate different signal transduction pathways but, as outlined previously, there is potential for cross talk between these pathways, which may have a significant impact on transactivation of CYP27B1. Notably, IFNγ and LPS are also the two most effective stimulators of nitric oxide (NO) synthesis in macrophages, and this has supported the hypothesis that production of NO and 1,25(OH)2D in macrophage-like cells may be functionally linked [151–153]."

"It is therefore interesting that two of the major stimulators of the human macrophage 1α-OHase, IFNγ, and LPS, are also key transcriptional regulators of the iNOS gene (NOS2) [156,157], which is itself a CYP-linked oxidase [158]. These observations coupled with the fact that NO has established inhibitory effects on other CYPs [159,160] suggest a possible link with the enzymes involved in vitamin D metabolism."

Cytochrome P450 Vitamin D Hydroxylases in Inflammation and Cancer

"Regulation of CYP27B1 expression is tissue dependent.

• In the kidney, the main regulators are PTH, serum calcium and phosphate, FGF-23, and 1,25(OH)2D3 (Armbrecht, Boltz, & Hodam, 2003; Perwad & Portale, 2011). Inhibition of CYP27B1 expression by 1,25(OH)2D3 involves complex epigenetic regulation of its promoter through VDR (Kim et al., 2009). However, there are tissues where 1,25(OH)2D3 either induces CYP27B1 expression or has no effect.
• In extrarenal tissues, CYP27B1 expression and activity are independent of circulating PTH. In prostate epithelial cells, the epidermal growth factor (EGF) induces, while 1,25(OH)2D3 inhibits CYP27B1 expression (Wang, Flanagan, et al., 2004). In macrophages and keratinocytes, the expression is increased by different cytokines, e.g., interferon gamma (IFN-γ), or tumor necrosis factor α (TNF-α) (Hewison et al., 2007), while nuclear factor kappa B (NFκB) is a potent inhibitor of CYP27B1 expression (Fig. 4)."

"There is evidence from in vitro studies that inflammatory cytokines influence expression of vitamin D metabolizing enzymes. While renal CYP27B1 expression is tightly controlled by PTH and 1,25(OH)2D3, in extra-renal tissues, CYP27B1 is regulated independently of those factors in a tissue-specific manner (Fig. 4). Soluble factors like cytokines and growth factors from the microenvironment affect cellular levels of this enzyme. IL1, IFN-γ, and TNF-α increase CYP27B1 expression in immune cells (van Etten, Stoffels, Gysemans, Mathieu, & Overbergh, 2008). TNF-α stimulated activity of CYP27B1 in untransformed cells such as human keratinocytes, endothelial cells (Zehnder et al., 2002), and peripheral blood monocytes (Gyetko, Hsu, Wilkinson, Patel, & Young, 1993). In cells of the human placenta, TNF-α induced expression of both CYP27B1 and CYP24A1, the latter to a greater extent (Noyola-Martínez et al., 2014). In the alveolar macrophages of patients with sarcoidosis, an inflammatory granulomatous disorder, CYP27B1 is expressed at a very high level, leading to pathologic increase of systemic 1,25(OH)2D3 levels and to hypercalcemia (Inui et al., 2001; Jones, 2008). In addition to the high CYP27B1 expression and activity, 1,25(OH)2D3-induced upregulation of CYP24A1 leads to the expression of a splice variant that lacks the mitochondrial targeting sequence thereby blunting the negative feedback regulation (Zehnder et al., 2002), contributing to the high circulating 1,25(OH)2D3 levels. CYP27B1 expression in macrophages is controlled by immune signals, such as IFN-γ, LPS, or by viral infections (van Etten et al., 2008)."

"In DCs, as in other extrarenal tissues, the level of the precursor 25(OH)D3 is often the limiting factor in the synthesis of the active metabolite (Jeffery et al., 2012). LPS, the ligand for TLRs, increased gene expression of CYP27B1 in DCs and human macrophages (Liu et al., 2006). 1,25(OH)2D3 synthesis in monocyte-derived DC is impaired due to a truncated, less active CYP27B1, while catabolism is not affected. Regulation of VDR targets in these cells seems to occur in a paracrine manner. It is the 1,25(OH)2D3 produced by macrophages that induces expression of vitamin D target genes in the neighboring DCs, inhibits maturation of DC, and reduces DC-dependent T-cell responses (Kundu, Chain, Coussens, Khoo, & Noursadeghi, 2014)."

"T-cell-derived cytokines regulate expression of the activating enzyme CYP27B1 in monocytes via TLR 2/1. IFN-γ increased the activity of CYP27B1 and decreased that of CYP24A1 (Noyola-Martínez et al., 2014). Mechanistic studies using promoter–reporter constructs in monocytes revealed that IFN-γ-induced increase of CYP27B1 is mediated via JAK– STAT, NFκB, and p38-MAPK pathways (Stoffels et al., 2006). Activation of TLR1 and 2 by Mycobacterium tuberculosis or IFN-γ increases expression of VDR and CYP27B1, (Adams et al., 2009; Liu et al., 2006). The resultant, locally synthesized 1,25(OH)2D3 induces the expression of antimicrobial peptides, such as cathelicidin (Gombart, 2009; Hoyer-Hansen, Nordbrandt, & Jaattela, 2010) or defensin 4β (Wang, Nestel, et al., 2004)."

@LetTheRedeemed

From what I can remember in posting about it on the Ray Peat Forum, supplementation is safe. In support:

• Sub-chronic (13-week) oral toxicity study with d-ribose in Wistar rats