Cottage Cheese & Fresh Flax Seed Oil Cures Cancer

[Travis]

how about Se-Methyl L-Selenocysteine does it work particucarly for detox for gluthation.
Does it boost the gluthation levels less effective then selenomethionine and also does brazil nuts contain selenomethionine or which plant does contain good amounts ?

I did read about that in the article above, and this apparently was just as good for cancer. But since it doesn't inhibit polyamine formation directly, I'm somewhat confused on how it does so.

The S‐linked methyl group isn't a particularly strong bond. These bonds are broken and formed all the time within the body; a classic example is S‐adenoslymethionine or pyruvate decarboxylase. In the body, acetyl groups and acyl chains are commonly transferred from sulfur to sulfur.

So I think you could expect glutathione to be made from this, after demethylation, but a glutathione with selenium instead of sulfur. I think you could also expect Se‐glutathione to have different properties than glutathione; inhibiting glutathione has been thought of as a line‐of‐attack against cancer cells in the past.

Glutathione, like spermine, is necessary for cell division; glutathione transfers to the nucleus before mitosis, and this is a prerequisite for cell division. Methylglyoxal also 'inhibits' glutathione as it spontaneously bonds to its sulfur. The inhibition of glutathione is actually how Thornally had explained methylglyoxal's anticancer effects, although Koch seemed to explain it through polyamines.

So I think understand how (CH₃)‐Se‐cysteine works would be similar to understanding how glutathione works.. .

 

[Obi-wan]

I too tracked dear Gilson and wonder about him. I consumed homemade chicken bone broth thinking it was good and it was a big mistake. PSA shot up big time! I will consume the Travisord Cocktail twice a day with two tablespoons of cottage cheese, 10 drops Lapodin, and a 200mcg capsule of selenium in each cocktail. Liking the chocolate fix for steric acid ala @Travis. As Travis said it's all about the linoleic acid intake. You can google to see which foods have the highest amounts. Eggs and meats depend on what the animal ate. I am thinking Foo noodle bowl would be ok since it is beef broth (Travis?)

I look at prostate and most cancers as being hormonal driven. As a Ray said Testosterone can be just as dangerous as Estrogen due to conversion. So turning off the testosterone signal LH and aromatase signal FSH makes sense ala Firmagon. Since an empty androgen receptor is also dangerous ala @Drareg, taking Estandi also makes sense. Wormwood also makes sense if you read Hulga Clark (forget zapping). Travis has mentioned parasites in meats. Progesterone works as I rub it into my shoulders and neck when I get what I call the advanced prostate cancer flair. Not happy being a test dummy but I can give you feedback and say Travis's linoleic pathway is solid.

Interesting note; when consuming oysters I would also get a flair up which I contribute to testosterone production.

Nice discussion on PPAR's, another Travis favorite on the Panquinone thread but Haidut chased us out of that classroom.

 

[Amazoniac]

200mcg capsule of selenium in each cocktail

I'm not here to tell other people what to do because my knowledge is limited and I have more questions than answers, but that sounds like a lot of selenium. I wouldn't supplement more than 100mcg a day. Probably half of that for most people because you obtain some from food already. I don't know anything about a therapeutic supplementation though.

 

[Obi-wan]

A review of the scientific literature concluded that selenium yeast from reputable manufacturers is adequately characterized, of reproducible quality, and shows no evidence of toxicity in long-term supplementation studies at doses as high as 400 and 800 micrograms per day (exceeding the EC tolerable upper intake level of 300 micrograms per day).[34]-Wikipedia

 

[Travis]

I'm not here to tell other people what to do because my knowledge is limited and I have more questions than answers, but that sounds like a lot of selenium. I wouldn't supplement more than 100mcg a day. Probably half of that for most people because you obtain some from food already. I don't know anything about a therapeutic supplementation though.

I think we have to consider what the selenium atom is bound to. Like free iron, copper, and zinc, free selenium appears‐redox active; but when carbon‐linked to methionine or cysteine, selenium is a different animal. In plants and Asians, there seems to be no limit to how much protein‐incorporated methionine can safely be replaced by Se‐methionine. And since S‐adenosylmethionine is required for polyamine synthesis, having Se‐adenosylmethionine in the cell inhibits this. Due to the disparity between inorganic selenium species and selenium amino acids, extrapolating toxicity data between the two could appear unrealistic.

Plants can have both inorganic selenium and amino acid selenium, but this varies by species and soil. When measured by flame spectroscopy, it is impossible to tell which is which. For this reason, old toxicity data on selenium in plants should be viewed with caution; any article which does not distinguish between organic selenium should perhaps be considered crude.

Selenomethionine is actually considered an essential amino acid, and selenocysteine has recently been classified as the '21st amino acid.'

 

[Obi-wan]

Foods High In Linoleic Acid (Omega-6) List. You will be surprised at the foods with the highest amounts!

 

[Obi-wan]

linoleic acid ⟶ arachidonic acid ⟶ prostaglandin E₂ ⟶ ornithine decarboxylase ⟶ polyamines ⟶ proliferation!


The dreaded pathway ala Travis!

 

[haidut]

The other polyunsaturated fatty acids (i.e. DHA) are only beneficial in the extent that they inhibit linoleic acid

Yep, EPA and DHA are good in regards to their ability to displace LA, ALA and linolenic acid from tissues and receptors...at the high price of increased MDA and more hydrophillic cell, which has the effects of making the cell vulnerable to a lot of insults. So, a very bad way to oppose omega-6, and I agree that something like stearic acid (but really any fully saturated fat) would be much better. Actually, an even better approach may be adamantane and its more lipophillic derivatives. I think it opposes entry of all (omega-6, omega-3, and some omega-9) PUFA into the cell.
Long-chain n-3 fatty acids and inflammation: potential application in surgical and trauma patients
"...
Eicosapentaenoic acid as an arachidonic acid antagonist

When fish oil is provided, EPA is incorporated into cell membrane phospholipids, partly at the expense of ARA. Thus, there is less ARA available for eicosanoid synthesis (Figure 3). In addition, EPA inhibits the oxidation of ARA by COX (7). Hence, fish oil decreases production of prostaglandins like PGE2, of thromboxanes like TXA2 and of leukotrienes like LTB4. This has been demonstrated many times in cell culture, animal feeding and healthy volunteer studies. Thus, n-3 PUFAs can potentially reduce platelet aggregation, blood clotting, smooth muscle contraction, and leukocyte chemotaxis, and can modulate inflammatory cytokine production and immune function (Figure 3).

In addition to inhibiting metabolism of ARA, EPA is able to act as a substrate for both COX and 5-LOX (Figure 3), giving rise to derivatives which have a different structure to those produced from ARA (i.e., 3-series PG and TX and 5-series LT). Thus, the EPA-induced suppression in the production of ARA-derived eicosanoids is accompanied by an elevation in the production of EPA-derived eicosanoids (e.g., 8-11). The eicosanoids produced from EPA are considered to be less biologically potent than the analogues synthesised from ARA (e.g., 12,13), although the full range of biological activities of these compounds has not been investigated. The reduction in generation of ARA-derived mediators which accompanies fish oil consumption has led to the idea that fish oil is anti-inflammatory (Figure 3). Additionally, recent studies suggest that metabolism of EPA by COX gives rise to a novel series of eicosanoids that are anti-inflammatory in nature (14).

The isolated, perfused rabbit lung has been used as a model to study the pathophysiological effects of ARA- and EPA-derived eicosanoids. Infusion with Escherichia coli hemolysin was shown to induce vasoconstriction/hypertension, mediated by TXB2, and vascular permeability/leakage, mediated by 4-series LT (15). Inclusion of free ARA in the perfusate increased TXB2 and 4-series LT generation, arterial pressure and vascular leakage (15,16). In contrast, inclusion of EPA decreased TXB2 and 4-series LT generation, arterial pressure and vascular leakage and increased generation of TXB3 and 5-series LT (15). Perfusion of isolated rabbit lungs with a fish oil-containing emulsion markedly attenuated the vascular inflammatory reaction (hypertension) induced by calcium ionophore (17). Compared with perfusion with a soybean oil-rich emulsion, fish oil decreased the concentration of LTC4 in the perfusate by >50% and increased the concentration of LTC5 from barely detectable (<10 pg/ml) to a concentration very similar to that of LTC4 (approximately 150 pg/ml) (17). These observations indicate that n-3 PUFAs can significantly inhibit the acute inflammatory responses induced, or at least marked, by production of ARA-derived eicosanoids."

 

[Travis]

Yep, EPA and DHA are good in regards to their ability to displace LA, ALA and linolenic acid from tissues and receptors...at the high price of increased MDA and more hydrophillic cell, which has the effects of making the cell vulnerable to a lot of insults. So, a very bad way to oppose omega-6, and I agree that something like stearic acid (but really any fully saturated fat) would be much better.

While true that myristic and palmitic acids can be incorporated into the cell membrane, they aren't statistically correlated with reduced cancer nearly to the extent as is stearic acid. I can think of two reasons for this: (1) perhaps it could be because stearic acid increases membrane rigitidy more than the shorter chained fatty acids, being longer, or (2) it doesn't displace arachidonic acid; the second point needs a bit of elaboration: Arachidonic acid is preferentially incorporated into the sn‐2 position of the glycerol backbone—the same reason why phospholipase A₂ increases prostaglandin flux to the degree that it does, and phospholipase C (cleaving lipids at the sn‐3 position) does not. Since myristic and palmitic acids are: (1) found on the cell membrane, yet (2) don't statistically lower cancer incidence—and the fact that inositol phosphates are usually found in the sn‐3 position—I will predict that they myristic and palmitic acids are preferentially incorporated in the sn‐1 position of the glycerol backbone and thus do not displace linoleate.

(And both linoleic acid and stearic acid have 18 carbons.)​

The eicosanoids produced from EPA are considered to be less biologically potent than the analogues synthesised from ARA (e.g., 12,13), although the full range of biological activities of these compounds has not been investigated.

They are talking about the prostaglandin‐3 series. In the only study I had read on these, prostaglandin E₃ showed about ¹⁄₄ the activity of prostaglandin E₂. You have to give them credit for knowing about these; you still often see authors authoritatively write 'that linoleic acid is the only single precursor for prostaglandins.'

 

[Obi-wan]

I was consuming palmitic acids when my PSA started climbing again this past summer (another test dummy result). More Chocolate!

Chicken bone broth really kicked my ****. What was I thinking? Gelatin consumption...

 

[Travis]

I was consuming palmitic acids when my PSA started climbing again this past summer (another test dummy result). More Chocolate!

Chicken bone broth really kicked my ****. What was I thinking? Gelatin consumption...

Nibbling chocolate while drinking coffee + pau d'arco from a French press sounds good. I was thinking about putting some cinnamon bark in my French press today, but hadn't.

I also saw the 100% Ghiradelli chocolate at the grocery store the other day: no sugar, no milk, no childish graphics on the label . . . just pure unadulterated chocolate—something you could probably even eat around bikers without getting your **** kicked. I didn't buy it, but bought coconut and dates for my coffee. Coconut has stearic acid too, although about 10× less than chocolate (3% vs 30%).

 

[Obi-wan]

I like dark chocolate around 62%. I would spit out 100%. I would like to see your face eating 100%

 

[Travis]

I like dark chocolate around 62%. I would spit out 100%. I would like to see your face eating 100%

I've done it before, and it keeps me moderate with the chocolate‐eating. About one year ago was the last time I ate chocolate, and it was a 100% chocolate bar.

You should get dates and dip them in chocolate! I've done this. As a very sweet fruit, this both goes good with pure chocolate and has minerals and such. A date stuffed with shredded coconut and dipped in chocolate—consumed with coffee—would be one hell of a treat, and not really unhealthy at all (as far as I can tell).

 

[Jackson Chung]

Travis,

What do you think about 100% chocolate from Hershey's?

https://www.amazon.com/HERSHEYS-Unsweetened-Cocoa-Beverage-Gluten-Free/dp/B005CUM0J2

 

[Travis]

Travis,

What do you think about 100% chocolate from Hershey's?

https://www.amazon.com/HERSHEYS-Unsweetened-Cocoa-Beverage-Gluten-Free/dp/B005CUM0J2

Looks great. Besides the stearic acid in chocolate, the procyanidins in the cocoa fraction inhibit polyamine biosynthesis. But if you read labels, you will find that most so‐called chocolate bars are mostly sugar and milk solids; these would more appropriately be called 'sugar–milk' bars.

I don't think refined sugar or pasteurized milk from cows is particularly healthy, but 100% chocolate really seems to be okay.

Carnésecchi, Stéphanie. "Flavanols and procyanidins of cocoa and chocolate inhibit growth and polyamine biosynthesis of human colonic cancer cells." Cancer Letters (2002)​

 

[bionicheart]

Dairy does have steroid hormones, and flaxseed oil does have linoleic acid. Flaxseed oil is actually synonymous with linseed oil, which—despite its name—has only about 20% of the eponymous linoleic acid (some oils actually have far more). As Ray Peat had alluded to, these are the only precursor to the prostaglandins.* These are lipid hormones, and prostaglandin E₂ has been shown to stimulate cancer cells directly in dozens of studies. It ostensibly does so by transcribing for ornithine decarboxylase, the main enzyme in polyamine biosynthesis. Polyamines are so intertwined with cancer as to have become nearly synonymous with it; these small molecules bind with dNA directly, induce the Z‐dNA configuration, and enhance the rate of replication. Inhibitors of this enzyme are powerful anticancer drugs, selenomethionine being similar. Although Se‐methionine can't be said to be a classic inhibitor, it displaces regular sulfur‐methionine leading to low amounts of polyamines. This is a convincing anticancer drug, and it's actually just an amino acid.

Another amino acid which would act to inhibit cancer is L‐threonine; excessive amounts of this amino acid become methylgloxal, which is a classic tumor‐inhibitor. There's been a few molecular modes of action proposed for this including, but not limit to: occupying glutathione (Thornalley), displacing NADH from glycolytic enzymes (Me), and even acting on transcription factor mSin3A directly (Thornalley). However, the classic ideas of medical doctor and chemist William Koch are probably most relevant: methylglyoxal can disable polyamines directly through forming a Schiff base.

The enzyme glyoxylase I converts methylglyoxal into lactic acid, a known species found in tumors (Warburg, 1956). The activity of this enzyme is commonly found reduced in tumors, meaning less methylgloxal, and the activity of ornithine decarboxylase is very often found increased (more polyamines). Inhibiting glyoxylase I lowers the lactate concentration and increases methylgloxal levels. The most powerful natural inhibitors of glyoxylase I are baicalein, lapachol, and β-lapachone—the latter two found in Pau d'Arco. The polyphenol baicalein also inhibits lipoxygenase, perhaps another reason for its anti‐cancer effects. The enzyme lipoxygenase also produces lipid hormones, cousins of prostaglandins called leukotrienes.

Of all of the alternative cancer diets, the Budwig one seems to be the worst. It is truly bizarre and sounds dangerous to me.

[*] Exception being the 3‐series prostaglandins made from eicosapentaenoic acid; but these do have much lower biological activity. ​

Thank you @Travis , I appreciate the time and thought you put into your comments. I will not proceed with adding these things to my diet. I new something wasn't right about flaxseed oil.

Glad to see Travis comment on this post. I will tell you personally that Flax seed oil is pure poison and will make your cancer worse. I was trying to treat my prostate cancer with the Budwig diet along with taking fish oils and it metastasized!!! I think Ray mentioned that Johanna had mental issues. DO NOT DO THIS DIET!

thanks @Obi-wan for your insight. I will not do this! I knew something was off about flaxseed oil.

 

[haidut]

While true that myristic and palmitic acids can be incorporated into the cell membrane, they aren't statistically correlated with reduced cancer nearly to the extent as is stearic acid. I can think of two reasons for this: (1) perhaps it could be because stearic acid increases membrane rigitidy more than the shorter chained fatty acids, being longer, or (2) it doesn't displace arachidonic acid; the second point needs a bit of elaboration: Arachidonic acid is preferentially incorporated into the sn‐2 position of the glycerol backbone—the same reason why phospholipase A₂ increases prostaglandin flux to the degree that it does, and phospholipase C (cleaving lipids at the sn‐3 position) does not. Since myristic and palmitic acids are: (1) found on the cell membrane, yet (2) don't statistically lower cancer incidence—and the fact that inositol phosphates are usually found in the sn‐3 position—I will predict that they myristic and palmitic acids are preferentially incorporated in the sn‐1 position of the glycerol backbone and thus do not displace linoleate.

(And both linoleic acid and stearic acid have 18 carbons.)​

They are talking about the prostaglandin‐3 series. In the only study I had read on these, prostaglandin E₃ showed about ¹⁄₄ the activity of prostaglandin E₂. You have to give them credit for knowing about these; you still often see authors authoritatively write 'that linoleic acid is the only single precursor for prostaglandins.'

Out of curiosity, do you know of actual linoleic acid antagonists/displacers/competitors? Apparently, there is a highly effective non-metabolizable fatty acid that is a true arachidonic acid antagonist (see below). It both competes with arachidonic acid for cell uptake and also for metabolism by COX/LOX, thus making it a highly effective anti-inflammatory chemical with relevance for pretty much any disease. I would be interested if you know of anything that can do the same for linoleic acid. Maybe stearic acid is the actual linoleic antagonist?
Eicosatetraynoic acid (ETYA), a non-metabolizable analogue of arachidonic acid, blocks the fast-inactivating potassium current of rat pituitary mel... - PubMed - NCBI

 

[Travis]

Oleic acid can be found in the sn‐2 position, but I'm getting the impression that stearic acid only really occupies the sn‐1 position:

Abbreviations:
PE: Phosphotidylethanolamine
PC: Phosphotidylcholine
PI: Phosphotidylinositol
PS: Phosphotidylserine
MG: Monoacylglycerol
DG: Dioacylglycerol​

'To account for these results it has been proposed that sn‐1-stearoyl‐2‐arachidonoyl phospholipids may be formed by a multistep pathway. First, phospholipids that contain palmitic acid in the sn‐1 position and a monoenoic, dienoic, or hexaenoic fatty acid in the sn‐2 position are formed de novo by the classical pathways of phospholipid biosynthesis. Then these phospholipids are “remodeled” by reactions that selectively replace the sn‐1 palmitoyl group with a stearoyl group and replace the sn‐2 fatty acyl group with an arachidonoyl group. In support of this possibility, phospholipase A and acyltransferase activities that might catalyze this type of phospholipid “remodeling” have been identified (see, for example, 9-12). Nevertheless, alternative possibilities remain to be excluded. For example, one could imagine that sn‐2‐arachidonoyl monoacylglycerol (MG), formed from intracellular triacylglycerol (TG) by the action of a TG lipase or formed from sn‐1‐palmitoyl‐2‐arachidonoyl PC by the successive action of a phospholipase C and a neutral lipase, might be “recycled” into phospholipids by a stearoyl‐specific pathway. We addressed this possibility in the study of quiescent Swiss 3T3 cells that is described below. A preliminary report of some of the results has appeared (13).' ―Simpson

'Furthermore, when radioactive PI, PE, and PC from cells that had been incubated for 1 h with [³H]MG (“Experimental Procedures”), were separately analyzed by a procedure that involved mild treatment with TG lipase, 82-98% of the activity recovered in the phospholipid products was found to comigrate with arachidonic acid-containing species. This provided evidence that only sn-2-arachidonoyl MG had been incorporated into these phospholipids, although other isomers of the labeled MG were clearly present in the cell incubation medium (“Experimental Procedures”).' ―Simpson

'The most noteworthy result of the molecular species analysis was that the distribution of radioactivity among individual arachidonic acid-containing species differed in the different lipid classes. In PI the sn-1-stearoyl-2-arachidonoyl species accounted for about 90% of the recovered radioactivity at each time point. This was the highest proportion of radioactivity observed in this species in any lipid class (Table 11). Somewhat lower proportions of radioactive sn-l-stearoyl-2-arachidonoyl species were found in PS and PE, while the lowest proportions were found in PC and DG, where sn-l-stearoyl-2-arachidonoyl species accounted for only about 40% of the total radioactivity. The remainder of the radioactivity in PC and DG was mainly present in sn-1-palmitoyl-2-arachidonoyl and sn-1-myristoyl-2-arachidonoyl species.' ―Simpson

'The distribution of radioactivity in molecular species of PC, DG, and PE seemed to change during the 24-h chase, although that in molecular species of PI did not. The percentage of radioactive sn-1-myristoyl-2-arachidonoyl- and sn-1-palmitoyl-2-arachidonoyl species of PC, DG, and PE decreased, and species of PC that comigrated with sn-2-stearoyl-2-linoleoyl-, sn-l-stearoyl-2-oleoyl-, sn-1-palmitoyl-2- linoleoyl-, and sn-1-palmitoyl-2-oleoyl- or sn-1,2-dioleoyl PC appeared (data not shown). These changes presumably reflected phospholipid remodeling activities.' ―Simpson

'However, the relatively high content of labeled sn-1-stearoyl-2-arachidonoyl PE observed (Table 11) suggests that a stearoyl-specific pathway, such as the stearoyl-specific branch of the MG kinase-initiated pathway, may also have been involved. Furthermore, the stearic acid-containing PE that was formed may have been converted into PS.' ―Simpson​

It seems as thought the classical pathways for phospholipid synthesis incorporates unsaturated fatty acids in the sn‐2 position and saturated fatty acids in the sn‐1 position. But enzymes in the vicinity of the membrane bilayer work to remodel the membrane phospholipids with a tendency to form sn‐1‐stearoyl‐2‐arachidonoyl phospholipids. Stearic acid has been shown to increase membrane rigidity, so this process should probably be supported with chocolate (100% dark = 30% stearic acid). I am getting the impression that the best lipid to displace arachidonic acid could be oleic acid, known to occupy the sn‐2 position. As a monounsaturated fatty acid, oleic acid does not spontaneously undergo peroxidation and can perhaps be seen closer to stearic than linoleic acid. Oleic acid, of course, does not form prostaglandins directly but can be desaturated.. .

Another interesting thing about the article is the substrate they used, sn‐2‐arachidonoylglycerol, is the molecule with the highest affinity to our cannabinoid receptors—it makes us stoned. Since the fate of a phopholipid usually seems to end with the cleavage of arachidonic acid from the sn‐2 position, separating it from glycerol and forming an eicosanoid, perhaps the cannabinoid system is more involved in lipid synthesis signalling than it is in sensing lipid breakdown? Perhaps the feeling of hunger after smoking cannabis is telling the body to eat the saturated fatty acids necessary to occupy the sn‐1 position of the glycerol backbone?

Simpson, C. M. "Swiss 3T3 cells preferentially incorporate sn-2-arachidonoyl monoacylglycerol into sn-1-stearoyl-2-arachidonoyl phosphatidylinositol." Journal of Biological Chemistry (1991)​

 

[haidut]

Oleic acid can be found in the sn‐2 position, but I'm getting the impression that stearic acid only occupies the sn‐1 position:

Abbreviations:
PE: Phosphotidylethanolamine
PC: Phosphotidylcholine
PI: Phosphotidylinositol
PS: Phosphotidylserine
MG: Monoacylglycerol
DG: Dioacylglycerol​

'To account for these results it has been proposed that sn‐1-stearoyl‐2‐arachidonoyl phospholipids may be formed by a multistep pathway. First, phospholipids that contain palmitic acid in the sn‐1 position and a monoenoic, dienoic, or hexaenoic fatty acid in the sn‐2 position are formed de novo by the classical pathways of phospholipid biosynthesis. Then these phospholipids are “remodeled” by reactions that selectively replace the sn‐1 palmitoyl group with a stearoyl group and replace the sn‐2 fatty acyl group with an arachidonoyl group. In support of this possibility, phospholipase A and acyltransferase activities that might catalyze this type of phospholipid “remodeling” have been identified (see, for example, 9-12). Nevertheless, alternative possibilities remain to be excluded. For example, one could imagine that sn‐2‐arachidonoyl monoacylglycerol (MG), formed from intracellular triacylglycerol (TG) by the action of a TG lipase or formed from sn‐1‐palmitoyl‐2‐arachidonoyl PC by the successive action of a phospholipase C and a neutral lipase, might be “recycled” into phospholipids by a stearoyl‐specific pathway. We addressed this possibility in the study of quiescent Swiss 3T3 cells that is described below. A preliminary report of some of the results has appeared (13).' ―Simpson

'Furthermore, when radioactive PI, PE, and PC from cells that had been incubated for 1 h with [³H]MG (“Experimental Procedures”), were separately analyzed by a procedure that involved mild treatment with TG lipase, 82-98% of the activity recovered in the phospholipid products was found to comigrate with arachidonic acid-containing species. This provided evidence that only sn-2-arachidonoyl MG had been incorporated into these phospholipids, although other isomers of the labeled MG were clearly present in the cell incubation medium (“Experimental Procedures”).' ―Simpson

'The most noteworthy result of the molecular species analysis was that the distribution of radioactivity among individual arachidonic acid-containing species differed in the different lipid classes. In PI the sn-1-stearoyl-2-arachidonoyl species accounted for about 90% of the recovered radioactivity at each time point. This was the highest proportion of radioactivity observed in this species in any lipid class (Table 11). Somewhat lower proportions of radioactive sn-l-stearoyl-2-arachidonoyl species were found in PS and PE, while the lowest proportions were found in PC and DG, where sn-l-stearoyl-2-arachidonoyl species accounted for only about 40% of the total radioactivity. The remainder of the radioactivity in PC and DG was mainly present in sn-1-palmitoyl-2-arachidonoyl and sn-1-myristoyl-2-arachidonoyl species.' ―Simpson

'The distribution of radioactivity in molecular species of PC, DG, and PE seemed to change during the 24-h chase, although that in molecular species of PI did not. The percentage of radioactive sn-1-myristoyl-2-arachidonoyl- and sn-1-palmitoyl-2-arachidonoyl species of PC, DG, and PE decreased, and species of PC that comigrated with sn-2-stearoyl-2-linoleoyl-, sn-l-stearoyl-2-oleoyl-, sn-1-palmitoyl-2- linoleoyl-, and sn-1-palmitoyl-2-oleoyl- or sn-1,2-dioleoyl PC appeared (data not shown). These changes presumably reflected phospholipid remodeling activities.' ―Simpson

'However, the relatively high content of labeled sn-1-stearoyl-2-arachidonoyl PE observed (Table 11) suggests that a stearoyl-specific pathway, such as the stearoyl-specific branch of the MG kinase-initiated pathway, may also have been involved. Furthermore, the stearic acid-containing PE that was formed may have been converted into PS.' ―Simpson​

It seems as thought the classical pathways for phospholipid synthesis incorporates unsaturated fatty acids in the sn‐2 position and saturated fatty acids in the sn‐1 position. But enzymes in the vicinity of the membrane bilayer work to remodel the membrane phospholipids with a tendency to form sn‐1‐stearoyl‐2‐arachidonoyl phospholipids. Stearic acid has been shown to increase membrane rigidity, so this process should probably be supported with chocolate (100% dark = 30% stearic acid). I am getting the impression that the best lipid to displace arachidonic acid could be oleic acid, known to occupy the sn‐2 position. As a monounsaturated fatty acid, oleic acid does not spontaneously undergo peroxidation and can perhaps be seen closer to stearic than linoleic acid. Oleic acid, of course, does not form prostaglandins directly but can be desaturated.. .

Another interesting thing about the article is the substrate they used, sn‐2‐arachidonoylglycerol, is the molecule with the highest affinity to our cannabinoid receptors—it makes us stoned. Since the fate of a phopholipid usually seems to end with the cleavage of arachidonic acid from the sn‐2 position, separating it from glycerol and forming an eicosanoid, perhaps the cannabinoid system is more involved in lipid synthesis signalling than it is in sensing lipid breakdown? Perhaps the feeling of hunger after smoking cannabis is telling the body to eat the saturated fatty acids necessary to occupy the sn‐1 position of the glycerol backbone?

Simpson, C. M. "Swiss 3T3 cells preferentially incorporate sn-2-arachidonoyl monoacylglycerol into sn-1-stearoyl-2-arachidonoyl phosphatidylinositol." Journal of Biological Chemistry (1991)​

Very interesting, thanks. For some reason, Peat is not very keen on oleic acid. I asked him the same question about displacing PUFA several years ago and both times he said saturated fats as in butter and coconut oil would be the best route. Doesn't butter contain a decent amount of stearic acid?

 

[Koveras]

@Obi-wan

Lancet Oncol. 2018 Jan;19(1):76-86. doi: 10.1016/S1470-2045(17)30906-3. Epub 2017 Dec 14.
Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study.
Teply BA1, Wang H2, Luber B2, Sullivan R2, Rifkind I2, Bruns A2, Spitz A2, DeCarli M2, Sinibaldi V2, Pratz CF2, Lu C3, Silberstein JL3, Luo J3, Schweizer MT4, Drake CG5, Carducci MA2, Paller CJ2, Antonarakis ES2, Eisenberger MA2, Denmeade SR6.

BACKGROUND:
Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide.

METHODS:
We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0-2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114.

FINDINGS:
Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15-49; p<0·0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33-71; p<0·0001) achieved a PSA50 response. During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment.

INTERPRETATION:
BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients.