Incomprehensive/ble Notes On Choline

Terma

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Thanks for those summaries, I read them before but my memory is not that good sometimes and it provides good bullet points I can just copy-paste.

Astolfo's thread made me wonder: what if you took an anticholinergic (it was cyproheptadine there) that can stop acetylcholine synthesis - together with something that can halt the development of new cholinergic neurons** - and then you pumped the body full of alpha-GPC and uridine (and all supporting cofactors)?

I imagine you could heal stuff in the brain that way. I'm just not sure how to ensure **.
 
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Thanks for those summaries, I read them before but my memory is not that good sometimes and it provides good bullet points I can just copy-paste.

Astolfo's thread made me wonder: what if you took an anticholinergic (it was cyproheptadine there) that can stop acetylcholine synthesis - together with something that can halt the development of new cholinergic neurons** - and then you pumped the body full of alpha-GPC and uridine (and all supporting cofactors)?

I imagine you could heal stuff in the brain that way. I'm just not sure how to ensure **.
Guru, you're a nice person. I read your offering there.

As commented elsewhere, fat-soluble forms of choline are a minority in milch, I'm not sure how exactly they're metabolized but this has to make water-soluble ones safe and possibly supportive for what you want.

You must be familiar with these:

- Choline Composition in Breast Milk–A Systematic Review and Meta-Analysis
- The choline content of human breast milk expressed during the fust few weeks of lactation
- Choline and choline esters in human and rat milk and in infant formulas

upload_2019-9-7_10-32-42.png

One of the advantages is that they will pass through the liver first, contrary to lymph distribution that might feed cancer more easily. The rate of appearance might have an effect, if taken in small amounts throughout the day (as if you were a fetus consuming milch), it won't lead to sharp blood rises and unwanted spillover.

Betaine must also be less risky than choline in case there's suspicion of cancer because although it can fuel it, it's more indirect than choline, which can be incorporated directly.

- Cancer Is A Metabolic Disease, Diet Is Its Drug
 

Terma

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(The guy is 17 years old man :\)

No I didn't read all those! I will a bit later in time.

That's an interesting perspective though I'll just point out I tend to avoid cancer in these topics because it can easily throw you off track depending on the context of what you're trying to achieve. Regardless in that case you might have a point. I would preemptively avoid betaine however because methylation is used by cancer cells (remember I treat that from a circadian perspective, but with cancer you won't want to take too many chances) [oh that's what you said - too tired to read, so I won't!].
 
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Amazoniac

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(The guy is 17 years old man :\)
What's the compassion threshold? In other words, how many birthdays a person can pass suffering before being spit and abandoned by society without mercy?

Before we move on, I would like to tell you a story. Unfortunately, I have none. This paragraph should then be ignored just like the distress of those in your indifferent range.

It's not about the possibility that intestinal phosphatases break down the citicoline molecule just like they do with the ingested vitamins in their coenzyme forms (Mito, 2019).

Your finding on the changes in composition of phosphatidylcholine depending on how it's synthesized can have serious implications, I don't know why it wased not received by the community with the importance that it deserved. It should've caused SSC (Systemic Sphincter Contraction) in everyone and relaxation only after clarification. I tried to find if the original experiments were run under shady conditions given that some were on isolated tissues, but they wasn't. An example would be suboptimal temperature:
[Saturation and unsaturation of fats] refers to the chain of carbon atoms in the fatty acid. In one case they have all of the hydrogen atoms attached to them that’s possible, so they are saturated with hydrogen. And if some of the carbons atoms lack the hydrogen, they just have their electron bonds more exposed to the environment. The absence of the hydrogen makes them more flexible instead of being sort of like a bottle brush bristling with the hydrogen surrounding the chain of carbons. It's more like a necklace of beads, flexible, where the hydrogens are missing; the bonds can rotate more freely. You get 2 or 3 or 4 or 5 of those double bonds, and the chain is bent at each place there's a double bond. And at the single bonds, the molecule rotates freely so you can get very flexible shapes when you have the highly unsaturated molecules. That flexibility you can see when you put a bottle of oil in the refrigerator: coconut oil is hard when it is just a little cool, just below room temperature or even at room temperature. But olive oil has to be much cooler before it starts to solidify; that’s because it's relatively saturated. Canola and corn oil have to be extremely cold before they all solidify. That's biologically important; one of its meanings is that if the organism lives at 40ºF for example and it contained butter fat or olive oil, it’s fats would be solid and wouldn't be manageable. For example, if an animal contained 30% fat and it all hardened, it’s subcutaneous fat would become stiff, just the way a steak, when it's in the refrigerator, the fat is stiff; when it's in very warm conditions it becomes soft and flexible. So, in the tropics, even fish in the Amazon river for example, have fat as saturated as butter fat. If you grow soy beans or corn in a very warm climate, their fat is saturated according to the temperature. Chocolate and coconuts grow in a place where the temperatures are probably averaging close to 90ºF, and so they need to have very saturated fats just for the biochemical manipulation (the molecules to happen). And if you had unsaturated fats, like is necessary for the cold water polar fish, for them to be flexible, they have to have triply or quadruply unsaturated fats. But if you had those in a fish in the Amazon river, the fish would oxidize its fats in just a couple of days. Even with a median unsaturated oil, such as soy oil or corn oil, if you put a rubber hose into a cork at the top of the bottle and put the other end of the hose in a cup of water, and leave the bottle at room temperature; the water will rise up the tube as the oil is consuming oxygen; it's just a constant process even at room temperature. And if you raise it to body temperature 95-100ºF then the process is much faster and you'll have sticky, rancid oil very quickly. So it's a biological adaptation. You can make a pig have subcutaneous unsaturated fat depending on the temperature of the weather that it's exposed to. If you put a sweater on the pig, it'll get more saturated.

Then, when I started to consider a possible impact that usual rodent diet composition might have in priming pathways to function in a certain way, having preference for specific fats, the thought was interrupt'd by the publication below. They injected humanoids and mouse with choline chloride having the hydrogens from the methyl groups radiolabelled like this..


..making it possible to tell not only the composition after extraction but the fate since when it's produced from scratch, it willn't have its radiolabelled composition intact.

- Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo

Is it familiar?
 
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Amazoniac

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Guru, will is intact apsorbtion?

- Dephosphorylation of Endotoxin by Alkaline Phosphatase in Vivo

"Endotoxin is a product of gram-negative bacteria and is abundantly present in the external environment and in the intestinal lumen tract.[six] This lipopolysaccharide (LPS) elicits fulminant inflammatory reactions that may be lethal, particularly when the compound enters the general circulation.[nine] The toxic moiety of LPS (lipid A) contains two phosphate groups[ten to twelve] that are considered to be essential for its biological actions.[eleven to thirteen] Monophosphoryl lipid A is only a weak activator of macrophages and is much less toxic as compared with diphosphoryl lipid A.[thirteen] In fact, we found that exogenous AP is able to attenuate the inflammatory response upon LPS in rats[fourteen] and mice.[fifteen]"

"Endotoxin may not be the only endogenous substrate of AP. Other authors suggested that phosphorylcholine may be a substrate for intestinal AP.[fifty] In addition, in bone tissue, with a high AP content, anti-endotoxin activity does not seem relevant. There is evidence that AP enzymes directly play a role in the mineralization process in the bone matrix,[fifty-one] although its role is not quite clear due to the high pH levels necessary for this enzyme activity."​
 

LLight

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Guru, you're a nice person. I read your offering there.

As commented elsewhere, fat-soluble forms of choline are a minority in milch, I'm not sure how exactly they're metabolized but this has to make water-soluble ones safe and possibly supportive for what you want.

You must be familiar with these:

- Choline Composition in Breast Milk–A Systematic Review and Meta-Analysis
- The choline content of human breast milk expressed during the fust few weeks of lactation
- Choline and choline esters in human and rat milk and in infant formulas


One of the advantages is that they will pass through the liver first, contrary to lymph distribution that might feed cancer more easily. The rate of appearance might have an effect, if taken in small amounts throughout the day (as if you were a fetus consuming milch), it won't lead to sharp blood rises and unwanted spillover.

Betaine must also be less risky than choline in case there's suspicion of cancer because although it can fuel it, it's more indirect than choline, which can be incorporated directly.

- Cancer Is A Metabolic Disease, Diet Is Its Drug

Your discussion is well over my head, however, I think you might be interested by this one, if you have not already read/found it: https://www.sciencedirect.com/science/article/pii/S0006291X14021706 (Betaine is a positive regulator of mitochondrial respiration).
 

Terma

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I don't think I read those but those are very nice. No big surprises, although the mechanism for the extra choline in lactation isn't fully elucidated.

They say:
In addition to the supplemental choline chloride (Balchem), study participants consumed a daily over-the-counter choline-free prenatal multivitamin supplement (Pregnancy Plus; Fairhaven Health, LLC), a daily 200mg docosahexaenoic acid supplement (Neuromins; Nature's Way Products) and a thrice-weekly potassium/magnesium supplement (General Nutrition Corp.). When eating on site, these supplements were consumed under the supervision of study personnel.
It's not that much but you would expect even 200mg DHA to force the liver to prime PEMT a little to package that. Not to mention whatever else was in their food. A little annoying.

The study they quote as copying is:
Sci-Hub | Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans. The American Journal of Clinical Nutrition, 95(5), 1060–1071 | 10.3945/ajcn.111.022772
Supplemental choline chloride (Balchem) was used to achieve the target intakes and was consumed with a meal chosen by the participant as a single bolus of 100 or 550 mg choline/d.
550mg is definitely more than I would take at once personally even though it was with a meal. That's 4 egg yolks (speaking of which, given their PUFA/AA/LA and methionine content, plus other things, I wonder if they're really the best for this; I don't do great on 4 eggs, Jaminet be damned - he pushed the idea of extra choline and especially eggs during pregnancy).

The hint about PUFA was ethanolamine, which is already known to associate more with PUFA in the human brain compared to choline (phosphatidylserine loves omega-3 too but it works by base exchange). Between that and homocysteine it's very hard to love PEMT. Then there's estrogen. Sometimes all the hints point in the same direction. I think you could do that without me :)

That said, I'm the guy getting high off methylfolate... Ideally I would want the liver to use only Kennedy and the brain to use the methylfolate (powerful substance but there's no way around at least one trip through methionine synthase) - but I don't know how to make that happen. The brain is the place methylation seems most critical, given histamine, homocysteine, and all the tyrosine and tryptophan derivatives. It's too bad we don't have some form of bioavailable methylene-tetrahydrofolate to experiment with (or tetrahydrofolate + SHMT) - only formyl/folinic. Folate is really critical, we should have all the forms individually, in some kind of carrier.

About AP: Interesting but can't say I've spent that much time on it. Are you saying phosphorylcholine or things containing it might overwhelm its ability to detox LPS? I suppose. The bone part was clever deduction of them.

(I'm going a little fast so could easily have missed something. let's just say I'm twice his age - that's always a good metric)
 
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Terma

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Or are you saying that induction of AP by LPS may lead to breakdown of phosphorylcholine-containing molecules as a side effect?
 
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Amazoniac

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Your discussion is well over my head, however, I think you might be interested by this one, if you have not already read/found it: https://www.sciencedirect.com/science/article/pii/S0006291X14021706 (Betaine is a positive regulator of mitochondrial respiration).
:nomnompopcorn Cool!
I don't think I read those but those are very nice. No big surprises, although the mechanism for the extra choline in lactation isn't fully elucidated.

They say:

It's not that much but you would expect even 200mg DHA to force the liver to prime PEMT a little to package that. Not to mention whatever else was in their food. A little annoying.

The study they quote as copying is:
Sci-Hub | Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans. The American Journal of Clinical Nutrition, 95(5), 1060–1071 | 10.3945/ajcn.111.022772

550mg is definitely more than I would take at once personally even though it was with a meal. That's 4 egg yolks (speaking of which, given their PUFA/AA/LA and methionine content, plus other things, I wonder if they're really the best for this; I don't do great on 4 eggs, Jaminet be damned - he pushed the idea of extra choline and especially eggs during pregnancy).

The hint about PUFA was ethanolamine, which is already known to associate more with PUFA in the human brain compared to choline (phosphatidylserine loves omega-3 too but it works by base exchange). Between that and homocysteine it's very hard to love PEMT. Then there's estrogen. Sometimes all the hints point in the same direction. I think you could do that without me :)

That said, I'm the guy getting high off methylfolate... Ideally I would want the liver to use only Kennedy and the brain to use the methylfolate (powerful substance but there's no way around at least one trip through methionine synthase) - but I don't know how to make that happen. The brain is the place methylation seems most critical, given histamine, homocysteine, and all the tyrosine and tryptophan derivatives. It's too bad we don't have some form of bioavailable methylene-tetrahydrofolate to experiment with (or tetrahydrofolate + SHMT) - only formyl/folinic. Folate is really critical, we should have all the forms individually, in some kind of carrier.

About AP: Interesting but can't say I've spent that much time on it. Are you saying phosphorylcholine or things containing it might overwhelm its ability to detox LPS? I suppose. The bone part was clever deduction of them.

(I'm going a little fast so could easily have missed something. let's just say I'm twice his age - that's always a good metric)
The first link was just to comment on the method used in the (second) main publication, which reinforces your work.

Intestinal phosphatases in theory should cleave off phosphate molecules from water-soluble choline forms, separating a great part (when not all) of it prior to absorption. On the other hand, the reaction to each of these supplements is quite different and I have the impression that it's beyond the ligand, it seems to be metabolized differently. For some reason the synthetic cheap forms are nasty, it can be due to poor quality compared to those derived from foods, I don't know.

However, if you're returning to more supplemental choline, the following might interest you (section #3):
- Citicoline: A Superior Form of Choline?

It's claimed that glycerophosphocholine increases (probably to a mild extent) non-heme iron apsorbtion.

--
Guru, by the time you're 120, you'll have to guard everyone that's less than 60.000000000000000000000000000000000000000001010000202020 years.
 
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Terma

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That's good to know, thanks. I never left alpha-GPC. It doesn't sound too bad in my case because dinnertime is the only time I really eat any iron-containing foods, and that's precisely the time I want the lowest dose or no alpha-GPC. It's nice how things just work out sometimes.

I suppose that fits with what I read about alpha-GPC being a choline prodrug in that rat study somewhere (that's what I've assumed it was). But I do not remember the name they used for the enzyme and now I cannot look it up.

I won't make it to retirement with the sheer weight of all these health problems. So I gotta make the best use of my time. Not having to care about as many people must be the silver lining?
 

Terma

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I suppose they have a point in that CDP-choline is a natural bioavailable and valued intermediate so it is naturally found in animal tissues so it is likely to be a well-treated form from an evolutionary perspective (i.e. wr.t. to TMAO). [Edit: This was a poor argument, but there is something to be said about how the intestinal cells value certain substances]

I mean it is a quite adequate way to get both choline and uridine. My only trouble with uridine was the notion of sublingual administration or very high/bioavailable oral doses since that may have undesirable side effects on the brain (not well enough described). But a low- to moderate- dose of CDP-choline with food (or a lower dose without food) seems fine to me, and I've used that before.

I will read that some other day. Right now I just want to feel softness.
 
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Amazoniac

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- Nutrient Metabolism: Structures, Functions, and Genes (978-0-12-387784-0)

"Choline synthesis and metabolism [] depend on several Mg-requiring enzymes, including phosphatidylcholine synthase (EC2.7.8.24) and choline monooxygenase (EC1.14.15.7)."​
 
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Amazoniac

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Below they claim that triacylglycerols are preferentially cleaved at the extremities of the glycerol molecule, whereas the opposite occurs with phosphatidylcholine. Consuming lipids that have specific fatty acids in the conserved positions makes them prone to be kept afterwards.

- Digestion and absorption of dietary glycerophospholipids in the small intestine: Their significance as carrier molecules of choline and n-3 polyunsaturated fatty acids

"The digestion of dietary TAGs with long-chain fatty acids, the main components of the emulsified lipid droplets, occurs mostly in the duodenum with pancreatic lipase being the predominant enzyme. Pancreatic lipase, with the aid of colipase, cleaves the ester linkages specifically at sn-1 and -3 positions of TAG, and thus, the digestive products are two free fatty acids liberated from sn-1 and -3 positions and sn-2-monoacylglycerol (2-MAG)."

"In the case of phospholipids, phospholipase A2 in the pancreatic juice is the predominant digestive enzyme. The pancreatic phospholipase A2 (sPLA2 1B) hydrolyzes phospholipids into sn-1–acyl lysophospholipids and a free fatty acid is liberated from the sn–2 position in the proximal small intestine. Since the majority of dietary phospholipids is PC, the main digestive products from dietary phospholipids are free fatty acids from the sn-2 position and 1-acyl lysophosphatidylcholine (1-lysoPC)."

"A part of lysoPC is further hydrolyzed to fatty acid and glycerophosphocholine (GPC) and/or free choline by intestinal enzymes in the intestinal lumen. We previously reported that human intestinal Caco-2 cells at the apical side and rat intestinal mucosa hydrolyzed lysoPC to GPC (Inaba et al., 2014). GPC was produced from lysoPC but not directly from PC in the intestinal perfusion in rats. Both GPC and choline were produced from lysoPC in the Caco-2 medium. Using several inhibitors, we confirmed that Caco-2 cells produce free choline from GPC, and direct choline production from lysoPC did not occur. GPC was also further degraded to free choline in the rat intestinal perfusate (Fig. 2)."

upload_2020-10-9_18-56-24.png

"[..]two studies indicate that half of the dietary PC would be re-synthesized as PC, whereas other the half would be converted to TG and GPC and/or choline."

"After the hydrolysis by lysoPLA/PLB, GPC is absorbed as a choline precursor. The absorption of α-GPC in rats (Abbiati et al., 1993) and in humans (Kawamura et al., 2012) has been reported previously. The administration of GPC with radiolabeled glycerol and choline showed that both were absorbed and distributed in various tissues including brain, although undegraded GPC was not found in the blood (Abbiati et al., 1993). These results indicate the further degradation of GPC prior to entering the systemic circulation. However, the behavior of intact GPC such as its transmembrane transport pathway in the enterocyte have not yet been fully clarified. Choline transporter-like proteins (CTLs) are expressed in the small intestine (Horie et al., 2014; Yuan et al., 2006), and it is presumed that GPC could be degraded at the apical membrane prior to the cellular uptake. The GDE activity was found in the conditioned medium released from the Caco-2 monolayer, and in addition, free choline derived from GPC (and lysoPC) was detected in the rat intestinal perfusate (Inaba et al., 2014). GDE activity in the rat intestinal mucosa was detected as 11% in the brush-border fraction, 69% in the brush-border free particles, and 15% in the particle-free supernatant (Parthasarathy et al., 1974), suggesting the intracellular degradation of GPC, which is possibly produced from intracellular lysoPC and/or taken up directly from the intestinal lumen."

"In the case of enterocyte, lysophosphatidylcholine acyltransferase-3 (LPCAT3) is the enzyme responsible for the resterification of LPC to phosphatidylcholine (Hui, 2016). It is reported that absorbed free FAs, which are taken up from the apical side of the enterocyte, are more likely to be incorporated into TG, whereas FAs from the basal side of the enterocyte, that is the bloodstream, are more likely to be incorporated into mucosal phospholipids or oxidized (Gangl and Ockner, 1975; Mansbach and Dowell, 1992; Storch et al., 2008). Reesterified PC is incorporated in the chylomicron and transported to the lacteals. PC is assembled with apolipoprotein B (apoB-48) in the ER, and then merged with TAG-rich particle, detailed elsewhere (Hussain et al., 1996; Xiao et al., 2019)."

"It is implied that the synthesis of PC in the enterocytes is necessary for the dietary lipid absorption and chylomicron assembly. LPCAT3 is the major isoform in the liver and the intestine, and prefers lysoPC with a saturated fatty acid at the sn-1 position, and favors an acyl donor to have PUFA to bind at the sn-2 position, such as linoleoyl-CoA and arachidonoyl-CoA (Kazachkov et al., 2008). PC reesterification in the cell is an important reaction for membrane remodeling (Wang et al., 2016). LPCAT3 KO mice showed lower plasma levels of cholesterol, phospholipid, and triglyceride via reduced lipid absorption (Li et al., 2015) (Wang et al., 2016). These reports indicate that PC production in the enterocyte is necessary to assemble the chylomicron as well as maintain the cell remodeling."

- Methods and compositions for enriching DHA levels in the brain (US10555957B2) | Google Patents

upload_2020-10-9_18-57-0.png

- Studies on plasma lipoproteins during absorption of exogenous lecithin in man
- Phospholipid fatty acid composition and sterospecific distribution of soybeans with a wide range of fatty acid composition "PL fatty acid stereospecific distribution"

Something that Franklin pointed out before:

"PL compositional changes in the membranes of organisms in response to environmental temperature have been studied extensively (10,11). Soybeans produced under drought and high-temperature conditions contain PL with altered fatty acid compositions that affect the ability of the seed to maintain optimum rates of metabolism and germination (12)."​
 
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Amazoniac

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- Wolfgang Bernhard | ResearchGate

Choline in cystic fibrosis: relations to pancreas insufficiency, enterohepatic cycle, PEMT and intestinal microbiota

"Cystic Fibrosis (CF), also named Mucoviscidosis, is an autosomal recessive disease, caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)[.]"

"There is a strong link between digestive/pancreas and lung function [17]. In this context, choline deficiency due to exocrine pancreas insufficiency was shown to correlate with impaired one-carbon status, and lung and liver function in these patients [18–20]. 85–87% of CF patients develop exocrine pancreas insufficiency and these patients show increased fecal choline loss [21], so that choline deficiency potentially impacts on ~5,000–6,000 CF patients in Germany, ~25,000–30,000 in Europe as well as the USA, and ~85,000–170,000 worldwide."

"The CFTR gene (chromosome 7q31.3.) was identified in 1989, and encodes for the 1480 amino acid CFTR protein, belonging to the adenosine triphosphate binding cassette (ABC) transporter class [25]. CFTR functions as a cyclic adenosine monophosphate (cAMP)-regulated channel for the conductance of several anions, of which chloride is the most acknowledged one and is used for clinical diagnosis via its increased concentration in sweat. However, CFTR functions as a transporter of hydrogen carbonate (HCO3−), sphingosine-1-phosphate (S1P) and γ-glutamyl-cysteoyl-glycine (reduced glutathione, GSH) as well. They are all essential to organ function, and are altered in this disease. Via membrane transport of HCO3−, CFTR is essential to physiological pH regulation, via S1P and other components it contributes to sphingolipid homeostasis and apoptosis, whereas GSH contributes to anti-oxidative capacity [26–29]. HCO3−, sphingolipids and GSH are linked to choline metabolism. Particularly, intestinal HCO3− secretion is essential to the enterohepatic cycle of bile Ptd’Cho, while sphingomyelin (SPH) as the major sphingolipid in all organs and GSH are linked to choline metabolism (see below)."

"Most choline is present in the membranes of cells in the form of phosphatidylcholine (Ptd’Cho) and sphingomyelin (SPH) (~90%), and their concentrations are highest in parenchymal organs like liver and lung, with ~18-22 μmol (= 1.9–2.3 mg) lipid-bound choline per g tissue, comprising ~90% of total choline (Fig. 3). About 2 μmol/g (~0.2 mg/g) are present as water-soluble components, mainly free choline, phosphocholine and α-glycerophosphocholine (αGPC), and betaine, the first downstream metabolite of choline and main methyl donor [34, 35]. Betaine concentrations are particularly high in liver and plasma (Fig. 3)."

1610890755803.png

"For its synthesis, choline is oxidized to betaine aldehyde by choline dehydrogenase (CHDH; EC 1.1.99.1) using pyrrolochinoline chinone (PQQ) as a cofactor, followed by niacin-dependent betaine-aldehyde dehydrogenase (BADH; EC 1.2.1.8) [36, 37] (Fig. 1)."

1610890769361.png

"As a major fraction of exogenous choline is oxidized to betaine rather than directly used for Ptd’Cho synthesis, it is not astonishing that with low choline also betaine is low in CF patients, and that choline supplementation normalizes betaine levels [19, 20, 24]. Moreover, frequent SNPs of the PEMT gene (like rs12325817, 25–44% in Caucasians) increase exogenous choline requirements (see section “Single nucleotide polymorphisms affecting choline homeostasis in CF”) so that healthy individuals with normal hepatic lipid homeostasis develop severe hepatosteatosis at low choline intake [39, 40]. This probably not only applies to healthy persons with low choline intake, but similarly to CF patients with their increased choline requirements due to increased fecal loss, particularly in children with increased basal choline requirements [9, 18, 21, 24]."

"To improve normal growth, lean body mass and body mass index in CF patients, the concept of optimized nutrient supply [41–43] has been addressed for the increased requirements in energy (+20–50% of age-matched healthy persons) and protein (20% rather than 10–15% of energy), for critical nutrients like sodium chloride, calcium, iron, zinc, and selenium, and for the fat-soluble vitamins A, D, E and K. These are all critical due to increased loss or decreased bioavailability [3, 44]. However, choline depletion and its low plasma concentrations in CF patients, although described 15 years ago (2005), has not (yet) emerged as clinically relevant, but systematic evaluation of the usefulness of supplementation is ongoing [19–21, 24, 45–47]."

"[..]choline is a component of acetylcholine, which is a neurotransmitter and is present and functionally important in leucocytes as well [63]."

"[..]similar to choline and betaine, phospholipids have a rapid turnover in plasma, liver and lungs, as shown by stable isotope labeling [19, 20, 38, 52, 64]. Due to such rapid turnover, cultured cells die from apoptosis in the absence of choline, and in mice choline deficiency causes rapid death due to acute liver failure [65–67]. Ptd’Cho is a major component of many secretions, and is either released at the apical plasma membrane, like bile and lung surfactant, or together with SPH, cholesterol and triglycerides at the basolateral membrane to serve systemic lipid metabolism. This occurs via chylomicrons (intestine), very low density lipoproteins (VLDL, liver) and high density lipoproteins (HDL, lung and other organs) (Fig. 2)."

1610890777691.png

"Particularly in the kidneys betaine serves as an osmolyte to stabilize proteins against denaturation by urea."

"80%, i.e., 17-23 mmol/d (= 2.53–3.43 g/d) or more, of total methionine is used for the synthesis of S-adenosylmethionine (SAM) rather than for protein synthesis, and at an adequate intake of choline (550 mg = 5.2 mmol) and other related nutrients, the BHMT and MS reactions cover ~50% of all methylations via SAM.[9, 83–86]."

"About 60% of these patients are born with and 85–90% of them early end up in exocrine pancreas insufficiency, i.e., an (pro) enzyme and HCO3− secretion below normal digestive requirements, together with impaired fluidity of mucus and its plugging within the small intestine. 20% of patients suffer from meconium ileus, and 4% later on develop distal intestinal obstruction syndrome (DIOS). Notably, pancreas insufficiency correlates with poor lung function, pointing to the importance of optimal nutrient assimilation for organ development and homeostasis [3, 93–95]. Impaired choline/Ptd’Cho metabolism in CF patients with pancreatic insufficiency is characteristic [21, 24], and relates choline homeostasis with CFTR function and HCO3− and phospholipases secreted into the small intestine."

"Adjusting pH in epithelial lining and luminal fluids via HCO3− as the main buffer system is a key function of CFTR in many epithelia, applying to the airways as well as to exocrine pancreas, bile ducts and enterocytes [100–104]. One HCO3− function is discharging the newly secreted mucus by scavenging calcium ions, thereby promoting its swelling and low viscosity. High mucus viscosity and sticking to the epithelia facilitates bacterial colonization and choline degradation (see section “Small intestinal bacterial overgrowth (SIBO) and its impact on choline bioavailability”) [105–107]. Additionally, and in contrast to gastric lipase and pepsin, alkaline pH is critical to digestive enzymes in the small intestine. This also applies to phospholipases digesting Ptd’Cho, which is important to choline homeostasis. Additionally, low pH causes bile acid precipitation impairing the formation of mixed micelles for lipid digestion, which is all characteristic to CF patients and impairs choline homeostasis [108–110]."

"Regularly, the pancreas secretes 1500-3000 mL/d and the liver ~700 mL/d ductal bile so that chymus is neutralized after passing the pylorus (pH 8–8.5), while intestinal HCO3− secretion maintains such alkaline pH until the ileocecal valve. HCO3− concentration of human pancreatic juice increases proportional to its secretion rate up to 140 mmol/L and that of bile is 30 mmol/L. Consequently, the amount of CFTR-dependent HCO3− secretion into the duodenum is 210-420 mmol from pancreas and 21 mmol/d from liver equaling ~15-30 g/d [26, 27, 111, 112]. Impaired or absent CFTR function, however, results in defective HCO3− secretion and postprandial hyperacidity (pH below 4) in the duodenal lumen, compromising the activity of digestive enzymes as a hallmark of exocrine pancreas insufficiency in CF and impairing micelle formation of bile components with fat [113–115]. Particularly, lack of pancreatic phospholipase A2 IB (sPLA2IB) activity at acidic pH is responsible to the impaired cleavage and recycling of bile Ptd’Cho as well as triglyceride digestion. Notably, Ptd’Cho and lyso-Ptd’Cho are essential to micelle formation. However, while they inhibit triglyceride digestion by pancreas lipase, the presence of sPLA2IB assures optimal triglyceride cleavage. Therefore, steatorrhea is characteristic for CF patients, in spite of pancreatic enzyme substitution, but can be improved by increasing duodenal pH which consequently improves phospholipase activity [109, 116–119]. Hence, optimal intestinal HCO3− concentration and pH, together with sPLA2IB, are essential to choline/Ptd’Cho homeostasis and triglyceride assimilation which is impaired in CF patients."

"24 g bile acids, synthesized from cholesterol, are secreted daily into bile, requiring a six-eight- fold turnover at a pool of 3-4 g. Cholesterol secretion is 1–2 g/d, but only 20–80% are reabsorbed. The secretion of Ptd’Cho into bile is ~11.4 g/d (15 mmol/d). This equals 1563 mg choline, the three-four fold the adequate choline intake (400-550 mg/d) according to NAM and EFSA [32, 33]. Moreover, with 20 μmol/g parenchymal concentration and 1561 g mean liver mass, this organ comprises 23.7 g Ptd’Cho, so that 48% of the total organ pool is daily secreted into bile [109, 125, 131]. This requires an effective enterohepatic cycle of bile Ptd’Cho to prevent liver damage and choline deficiency [126, 127], but is not assured in CF with exocrine pancreas insufficiency [21]: Ptd’Cho recycling requires its cleavage to lyso-Ptd’Cho, mainly by sPLA2IB. Other enzymes may contribute, like pancreatic lipase-related protein 2 (PLRP2) in newborns, small intestinal secretory phospholipase A2 (sPLA2X) or jejuno-ileal brush-border phospholipase B (PLB) [109, 116, 119, 128]. Defective HCO3− secretion and deficient phospholipase activity in CF patients blunt the enterohepatic cycle of bile Ptd’Cho, explaining fecal choline loss and low pools and plasma concentrations of choline, betaine and Ptd’Cho [19–21, 24]."

"Systemic choline and Ptd’Cho homeostasis is dominated by the liver, comprising 2% of the body weight (1561 g at 76.4 kg), containing ~4.25% of an organisms choline pool and using 20–25% of resting energy consumption [129–131]. Aside from Ptd’Cho synthesis for its cell membranes, and opposite to bile secretion across the apical plasma membrane, hepatocytes secrete very low density lipoproteins (VLDL) at their basolateral membrane. VLDL comprise 91% lipids of which ~20% is Ptd’Cho, 25% cholesterol (esters) and 55% triglycerides [132]."

"The compromised enterohepatic cycle of bile Ptd’Cho in CF patients affects their VLDL/plasma Ptd’Cho homeostasis [19, 21], and up to 60% develop hepatosteatosis [3, 67, 137], where choline and one-carbon donor deficiency is generally causative [138]. In addition to this, inflammation and oxidized lipoproteins may further contribute to impaired hepatic Ptd’Cho synthesis [139–141]."

"Lung Ptd’Cho is synthesized de novo (CDP-choline pathway), mostly followed by acyl remodeling at position 2 via deacylation: reacylation (Lands cycle), and requires exogenous choline supply. Contrary to enterocytes and hepatocytes, AT-II express LPCAT1 rather than LPCAT3, preferring saturated rather than polyunsaturated acyl-CoA for the generation of surfactant-specific Ptd’Cho. The PEMT pathway, however, is absent from lung tissue [146, 148]. As in other peripheral organs, pulmonary choline uptake depends on high capacity-low affinity transporters, and therefore on plasma choline concentration [53] that is decreased in CF [19]."

"As for the intestine, low HCO3− concentrations and hyperacidity in CF reduce pulmonary airway lining fluid volume and increase mucus viscosity, predisposing the airways to mucus sticking, and impaired mucociliary clearance [35, 105, 151]. Altered Ptd’Cho homeostasis in CF lungs is well described [70, 152, 153], and in patients is partly due to bacterial phospholipases [154]. Up to 7% of alveolar surfactant is daily cleared into the airways, serving small airway patency in the form of airways surfactant [35, 146]. Pseudomonas aeruginosa releases phospholipase C that degrades Ptd’Cho to phosphocholine and diacylglycerol, thereby impairing surface tension function in small airways [154]. Expectorated airway contents are swallowed so that phosphocholine, having a rapid turnover, will be lost into the portal and systemic circulation [19, 20, 71, 155]."

"At a total lung weight of 840 g, of which ~50% belong to the central blood volume and bronchial tissue, lung parenchyma counts ~420 g and comprises ~5.8 g (7.6 mmol) Ptd’Cho, compared to ~23 g (30.2 mmol) in the liver (see section “CF and the enterohepatic cycle of bile Ptd’Cho”). This is equivalent to ~800 mg choline, while 1.2 mmol = 0.85 g SPH contribute another ~125 mg choline. Notably, although the pulmonary Ptd’Cho pool accounts for only 1/4 of that of the liver, in choline deficiency lung parenchyma serves to supply the liver with this nutrient via high density lipoproteins [127]. Moreover, and in addition to impaired choline uptake at low plasma concentrations, chronic lung inflammation and parenchymal destruction in the form of emphysema and fibrosis further decreases pulmonary Ptd’Cho pools [3, 19, 24, 156]."

"CFTR is weakly expressed in the stomach, but strongly all along the intestinal tract [196]. Its impact on defective HCO3− secretion in CF, was studied by the teams of Quinton and Hansson, providing conclusive evidence that HCO3− is essential for proper mucus release and unfolding, to achieve its normal rheological properties and to avoid adhesion to the mucosal surface [108, 197, 198]. Impaired intestinal motility characteristic for CF [199], together with poor mucus rheology, facilitates mucus sticking, bacterial colonization of the small intestine and choline degradation prior to absorption."

"Slow propagation of luminal contents, thickened mucus accumulation and plugging serve as an ideal milieu for the development of SIBO, chronic intestinal inflammation and the time of nutrient exposition to bacteria for degradation prior to absorption [208, 209]. Such degradation of essential nutrients applies to choline, too, as concentrations of TMAO are high in part of CF patients."

"Human adult, but not fetal liver is able to oxidize TMA to TMAO by flavin-containing monooxygenase 3 (FMO3; EC 1.14.13.148), also called trimethylamine monooxigenase [212]."

"To assess an adequate dosage of choline supplementation to CF patients only few data exist so far. Growth rate, organ size, metabolic fluxes, SIBO and SNPs must be taken into account to assess additional choline requirements in CF patients. Estimation of total choline pools and turnover is helpful here."

"At a mean body concentration of 10 mmol/kg phospholipid-bound choline plus 10% water-soluble metabolites and derivatives (Fig. 3), equaling ~ 1.1 g total choline per kg body weight [9], a 70 kg healthy adult comprises ~ 77 g total choline, of which ~ 800-1000 mg (1.0–1.3%) and ~ 3500 mg (4.5%) are present in the lungs and liver, respectively. Whereas pulmonary and hepatic Ptd’Cho/SPH/choline turnover via lipoproteins is so far unknown, that of the liver via bile is ~ 1500–1600 mg, equaling the three-four fold of EFSA and NAM values for the adequate intake (AI) of adolescents and adults (400–550 mg/d) [32, 33], and accounts for ~ 2% of the total choline pool per day. Such estimates do not include the higher requirements in children and the fraction of choline being used for SAM formation."

"Notably, betaine supplementations alone is similarly effective in liver protection as choline in CF and other patients, accentuating the function of choline as a betaine progenitor [24, 217, 218]. Moreover, betaine absorption occurs in the duodenum rather than more distally, which might be advantageous in CF patients suffering from SIBO [218] (Table 1)."

Choline Supplementation in Cystic Fibrosis—The Metabolic and Clinical Impact

- Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity
- Choline: An Essential Nutrient for Skeletal Muscle
- Choline and phosphatidylcholine, but not methionine, cysteine, taurine and taurocholate, eliminate excessive gut mucosal lipid accumulation in Atlantic salmon (Salmo salar L)
- Effect of Choline Forms and Gut Microbiota Composition on Trimethylamine-N-Oxide Response in Healthy Men
- The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases
- Discovery of a Cyclic Choline Analog That Inhibits Anaerobic Choline Metabolism by Human Gut Bacteria
- Effects of choline supplementation on liver biology, gut microbiota, and inflammation in Helicobacter pylori-infected mice
 
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"The principle metabolic fate of choline is via irreversible oxidation to betaine in the liver and kidney (28–32) via a two-step process (Figure 1). First, choline is oxidized to betaine aldehyde by the enzyme choline dehydrogenase. This enzyme can also convert betaine aldehyde to betaine in the presence of NAD+ (33). Choline dehydrogenase activity occurs in the mitochondria, on the matrix side of the inner membrane (34–36). Betaine aldehyde is then oxidized to betaine by the NAD+-dependent enzyme betaine aldehyde dehydrogenase both in mitochondria and in the cytosol (37). The remainder of dietary choline is used to make acetylcholine and phospholipids such as phosphatidylcholine."​

There are sources claiming that the main fate is synthesis of phosphatidylcholine, but the oxidation to betaine should be substantial.

- Human choline dehydrogenase: Medical promises and biochemical challenges

1622378615334.png

They were simplified here.

Alcohol → aldehyde → carboxylic acid is what occurs with poison A. Factors required must be common (niassassin, nausium, ripofflavin, morbydenum) and impairments in any step might coincide.

- Caffeine: A vitamin-like nutrient, or adaptogen

"One of the ways in which uric acid functions as an “antioxidant” is by modifying the activity of the enzyme xanthine oxidase, which in stress can become a dangerous source of free radicals. Caffeine also restrains this enzyme. There are several other ways in which uric acid and caffeine (and a variety of intermediate xanthines) protect against oxidative damage."​

In the 'poison A' link, you can tell that the dehydrogenase form depends on the availability of NAD+.

Later on, nausium and ripofflavin are also needed.
If it goes towards cancertylbluesine, phantomtenic acid is probably involved.

Therefore, taking bluesine in isolation can be troubling.
 
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- Choline deficiency

"Betaine is formed from choline via the intermediate betaine aldehyde. Choline dehydrogenase (EC 1.1.99.1) catalyzes the conversion of choline to betaine aldehyde and uses molecular oxygen as the electron acceptor; this activity also is capable of converting betaine aldehyde to betaine in the presence of NAD.[74] Choline dehydrogenase in mammalian liver and kidney is mitochondrial, located on the matrix side of the inner membrane.[73,75,76] There is another enzyme, betaine aldehyde dehydrogenase (EC 1.2.1.8), which also catalyzes conversion of betaine aldehyde to betaine. This enzyme requires NAD+, and is found in both mitochondria (this mitochondrial enzyme may be identical to choline dehydrogenase) and cytosol.[76] Choline dehydrogenase activity is present in rat liver > kidney > brain > lung and is not detected in muscle.[77] Activities in rat liver and kidney are 100 fold higher than in other organs.[77] Human liver and kidney have activity (kidney 7-fold more than liver) but less than that measured in the rat.[77] In the kidney, choline dehydrogenase activity is located in the inner medulla and proximal tubules.[47] Mitochondria extracted with n-pentane lose choline dehydrogenase activity, which can be restored by addition of ubiquinone[78] or coenzyme Q2.[74] It has been suggested that pyrroloquinoline quinone (PQQ) is the endogenous cofactor.[79,80]"​
 
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Seems like a good idea to consume some venom D with bluesine.

- Vitamin D Decreases Plasma Trimethylamine-N-oxide Level in Mice by Regulating Gut Microbiota

Abstract said:
As a metabolite generated by gut microbiota, trimethylamine-N-oxide (TMAO) has been proven to promote atherosclerosis and is a novel potential risk factor for cardiovascular disease (CVD). The objective of this study was to examine whether regulating gut microbiota by vitamin D supplementation could reduce the plasma TMAO level in mice. For 16 weeks, C57BL/6J mice were fed a chow (C) or high-choline diet (HC) without or with supplementation of vitamin D3 (CD3 and HCD3) or a high-choline diet with vitamin D3 supplementation and antibiotics (HCD3A). The results indicate that the HC group exhibited higher plasma trimethylamine (TMA) and TMAO levels, lower richness of gut microbiota, and significantly increased Firmicutes and decreased Bacteroidetes as compared with group C. Vitamin D supplementation significantly reduced plasma TMA and TMAO levels in mice fed a high-choline diet. Furthermore, gut microbiota composition was regulated, and the Firmicutes/Bacteroidetes ratio was reduced by vitamin D. Spearman correlation analysis indicated that Bacteroides and Akkermansia were negatively correlated with plasma TMAO in the HC and HCD3 groups. Our study provides a novel avenue for the prevention and treatment of CVD with vitamin D.

- 25(OH)D3-enriched or fortified foods are more efficient at tackling inadequate vitamin D status than vitamin D3
 
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Raj suggests a broth made with leaves and I was wondering how extractable betraine is.

- Betaine in Cereal Grains and Grain-Based Products

"Betaine is known to be a thermostable compound which survives the severe treatment during sugar beet processing (extracting with water, treatment with CaOH2 and CO2, concentration, crystallization) and almost quantitatively accumulates in molasses [29]. Pure anhydrous betaine decomposes at >245 °C. Since food processing practices do not employ such high temperatures, betaine losses caused by food thermal treatments were initially not expected [30]."

"Only few studies exist that deal with the stability of betaine in food during processing. De Zwart et al. [2] compared the average betaine content in various food, before and after cooking. They concluded that the level of betaine varied widely, depending on the food and cooking method."

"Very high betaine losses (>90%) were observed after baking betaine-enriched bread [31]. It was assumed that this loss could be partly due to betaine consumption by baker’s yeast throughout dough fermentation since yeast can use betaine as a source of nitrogen."​

↳ [2] Glycine betaine and glycine betaine analogues in common foods

1627988717766.png



1627988725130.png

mcg/g = mg/kg
You can then decimate values for a 100 g serving.
 

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