Cottage Cheese & Fresh Flax Seed Oil Cures Cancer

[Obi-wan]

Fats and oils rich in stearic acid are more abundant in animal fat (up to 30%) than in vegetable fat (typically <5%). The important exceptions are cocoa butter and shea butter, where the stearic acid content (as a triglyceride) is 28–45%. -Wikipedia

 

[Obi-wan]

Thanks Koveras,

Latest PSA went from 185 down to 112. That why the Travis discussions are so interesting

 

[Obi-wan]

In the United States, 100% cocoa butter must be used for the product to be called chocolate.

Typical Fatty acid composition (%)[10]
Fatty acid Percentage
Arachidic acid (C20:0) 1.0%
Linoleic acid (C18:2) 3.2%
Oleic acid (C18:1) 34.5%
Palmitic acid (C16:0) 26.0%
Palmitoleic acid (C16:1) 0.3%
Stearic acid (C18:0) 34.5%
Other Fatty Acids 0.5%

Cocoa butter is a major ingredient in practically all types of chocolates (white chocolate, milk chocolate, and dark chocolate). This application continues to dominate consumption of cocoa butter. Cocoa butter can be found in most supermarkets, and the process of preparing small amounts of chocolate from cocoa butter and cocoa powder means that the practice of making chocolate at home has become relatively popular. -Wikipedia

 

[Obi-wan]

Shea butter extract is a complex fat that in addition to many nonsaponifiable components (substances that cannot be fully converted into soap by treatment with alkali) contains the following fatty acids: oleic acid (40–60%), stearic acid (20–50%), linoleic acid (3–11%), palmitic acid (2–9%), linolenic acid (<1%) and arachidic acid (<1%).[10]

Shea butter melts at body temperature. Proponents of its use for skin care maintain that it absorbs rapidly into the skin, acts as a "refatting" agent, and has good water-binding properties.[11] -Wikipedia

 

[Obi-wan]

https://www.amazon.com/s/?ie=UTF8&k...qmt=e&hvbmt=be&hvdev=c&ref=pd_sl_5dktbjidzw_e

Travis, what are your thoughts on transdermal application?

 

[noordinary]

@haidut may the reason for that:

Interestingly, it is worth noting that when the palmitate ester (an SFA) was used on its own it only had androgenic effects. However, combined with an oleate ester (a MUFA) it also raised T levels in the castrated rats. This synergistic effect of saturated and mildly unsaturated substances has been seen in many other studies with steroids where the effects of combining a saturated steroids like androsterone are much more potent when it is combined with an unsaturated steroid like DHEA. The same effects have been seen with combinations of T/DHT and DHT/DHEA. So, I doubt the findings of this study are a coincidence, and this is what led me to add both the palmitate and oleate esters to the product.

be what @Travis explained above about displacing Arachidonic and Linoliec acids? Or i'm getting it all wrong? and that's completely different thing?

 

[Travis]

I found this biochemistry book while doing a search:

Mayes, Peter A. "Metabolism of unsaturated fatty acids and eicosanoids." Harper’s Illustrated Biochemistry, 26th Ed. (2003)​

They gave me a chapter from an entire book. I think this deserves to be posted because it seems more straightforward than Lehninger and doesn't have any corny or unrealistic graphics. It does suffer from the Halworth projection for carbohydrates, yet this is compensated by its inclusion of the chair conformation for steroids—a rare event:

click to embiggen: Textbook showing medical students what steroids look like when viewed from the side.​

I think I've found an addition to the thread on—or the Ray Peat Forum list of—biochemistry textbooks.

This chapter will inform the reader that oleic acid can be created by a Δ⁹‐desaturate working on an fully‐saturated lipid—which would, of course, be the C₁₈‐stearic acid. So regardless of whether we eat olives or chocolate, we will have this fatty acid in our bodies.

'The first double bond introduced into a saturated fatty acid is nearly always in the Δ⁹ position. An enzyme system—Δ⁹ desaturase—in the endoplasmic reticulum will catalyze the conversion of palmitoyl-CoA or stearoyl-CoA to palmitoleoyl-CoA or oleoyl-CoA, respectively.' ―Mayes​

This textbook is under the false impression that 'we need linoleic acid,' but this can perhaps be forgiven since ~99% of textbooks are under the same impression.

'Arachidonic acid is present in membranes and accounts for 5–15% of the fatty acids in phospholipids. Docosahexaenoic acid (DHA; ω−3, 22:6), which is synthesized from α-linolenic acid or obtained directly from fish oils, is present in high concentrations in retina, cerebral cortex, testis, and sperm.' ―Mayes​

They tell us why corticosteroids can be 'anti‐inflammatory.' But I think it must be pointed‐out that cortisone can quickly be converted to cortisol through the ubiquitous enzyme 11β-HSD₁, completely abrogating any 'anti‐inflammatory' effects it once had. (The enzyme PGHS₂ is essentailly synonymous with COX-2):

'Transcription of PGHS₂—but not of PGHS₁—is completely inhibited by anti-inflammatory corticosteroids.' ―Mayes​

But they leave off at the short summary, but more details can be had elsewhere:

'Animals are capable of desaturating stearic acid (18:0) to oleic acid (18:1‐Δ⁹) by means of a Δ⁹-desaturase enzyme. However, with certain exceptions, animals in general lack the Δ¹² and Δ¹⁵-desaturases, which are required for the production of linoleic acid (LA, 18:2‐Δ⁶˙⁹) and α-linolenic acid. Thus, these fatty acids are considered to be essential and must be derived from the diet. The essential fatty acids can be further desaturated and elongated to varying degrees depending on the animal species, Δ⁶ and Δ⁵-desaturase enzyme activity and tissue location (Fig. 1). ' ―Pereira

'The stearoyl CoA (Δ⁹) desaturase is one of the beststudied desaturases to date. This enzyme catalyzes the first step in the PUFA biosynthetic pathway, namely the incorporation of a double bond at carbon #9 of stearic acid to generate oleic acid. This enzyme is a microsomal membrane-bound protein and functions in conjunction with cytochrome b5 and NADH-dependent cytochrome b5 reductase.' ―Pereira

'Delta six desaturase is a membrane-bound, acyl-CoA desaturase found in the endoplasmic reticulum of animals. It catalyzes the rate-limiting conversion of essential fatty acids to long-chain PUFAs. This enzyme desaturates LA to γ-linolenic acid, and ALA to stearidonic acid. The Δ⁶ (and Δ⁵) desaturases are classified as ‘front-end’ desaturases because they are capable of introducing a double bond between a pre-existing double bond and the ‘front’/ carboxyl end of the fatty acid.' ―Pereira

'The Δ⁵ desaturase catalyzes the final step in the production of the C₂₀ PUFAs AA and EPA. This desaturase is also considered a front-end desaturase and shares all the conserved structural characteristics displayed by other front-end desaturases like the Δ⁶ desaturase. Delta five desaturase genes have been identified from several animals including human, rat, and C. elegans [47–49].' ―Pereira​

So with having the Δ⁹, Δ⁶, and Δ⁵‐desaturases you might expect a trienic acid to be produced from either stearate or oleate—perhaps being the infamous Mead Acid:

'The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are antiinflammatory, and some of which act on the "bliss receptor," or the cannibinoid receptor. In the adult, tissues such as cartilage, which are protected by their structure or composition from the entry of exogenous fats, contain the Mead acid despite the presence of linoleic acid in the blood.' ―Ray Peat​

An experimentalist confirms this in the Journal of Biological Chemistry:

'Oleic acid, following a sequence of steps, is converted into octadeca-6,9-dienoic, eicosa-5,8,11-trienoic, and docosa-7,10,13-trienoic (1) acids; linoleic is transformed into [prostate cancer]' ―Brenner​

And Mead himself reports the same in an article from 1959:

'The major triene component of the fat deficient rat has been characterized as 5,8,11-eicosatrienoic acid (5). Since the increase in this triene during fat-deficiency disease has been found to parallel roughly a decrease in arachidonic (5,8,11,14-eicosatetraenoic) acid, the suggestion has been made that triene was formed by hydrogenation of the double bond in the 14 position of arachidonic acid (6). However, the work to date on the transformations of unsaturated fatty acids in animal tissues would seem to argue against this hypothesis. A more likely possibility is that 5,8,11-eicosatrienoic acid is actually a dehydrogenation product of oleic acid as has been suggested by several workers (7,8). A transformation of this type, involving chain lengthening by two carbons and the introduction of two methylene-interrupted double bonds, is exemplified by the conversion of linoleic to arachidonic acid in the animal body (9). The experiments reported in this paper were designed to test the hypothesis that oleic acid, in an analogous series of transformations, is converted to 5,8,11-eicosatrienoic acid in the fat-deficient rat.' ―James Mead​

It appears to me at the moment that oleic acid and stearic acid both become Mead acid, which competes with arachidonic acid. Oleic acid also seems to inhibit Δ⁹‐desaturase, sparing stearic acid in the attempt of maintaining a steady‐state oleic acid concentration. Since Pereira informs us that we have Δ⁹, Δ⁶, and Δ⁵‐desaturases, perhaps the formation of Mead acid from stearic acid can be explained something like: Δ⁹‐desaturase⟶Δ⁵‐desaturase⟶Δ‐C₂‐elongase⟶Δ⁹‐desaturase. The formation of Mead acid from oleic acid would be the same, but minus the first Δ⁹‐desaturase step.

And oleic acid is more resistant to peroxidation than linoleic, and here's why:

'Using azo initiators, Cosgrove found that the oxidizability of PUFA is linearly dependent on the number of bis-allylic methylenes present in the fatty acid. Thus, it is reasonable that oxidizability is controlled by the initial event of hydrogen abstraction by radicals from this relatively weak C–H bond of the bis-allylic methylene with a bond dissociation energy (BDE) of about 75 kcal/mol. For monounsaturates, like oleic acid, oxidizability is much less because mono-allylic methylene hydrogens (C–H BDE ≈ 88 kcal/mol) are more resistant to abstraction.' ―Gardner​

But olive oil does have linoleic acid, and this is variable. Coconut oil, shea butter, and milk butter are better choices for cooking, but I wouldn't be afraid to eat olives once‐in‐awhile (especially after drinking a martini). I like olives and they are mostly monounsaturated; the same can be said about macadamia nuts.

Gardner, Harold W. "Oxygen radical chemistry of polyunsaturated fatty acids." Free Radical Biology and Medicine (1989)
James F. Mead. "Metabolism of essential fatty acids. 8. Origin of 5, 8, 11-eicosatrienoic acid in the fat-deficient rat." Journal of Biological Chemistry (1959)
Pereira, Suzette L. "Recent advances in the study of fatty acid desaturases from animals and lower eukaryotes." Prostaglandins, leukotrienes and essential fatty acids (2003)
Brenner, Rodolfo R. "Effect of saturated and unsaturated fatty acids on the desaturation in vitro of palmitic, stearic, oleic, linoleic, and linolenic acids." Journal of Biological Chemistry (1966)
​

 

[Mito]

Doesn't butter contain a decent amount of stearic acid?

vs cocoa butter

 

[Travis]

View attachment 8055

vs cocoa butter
View attachment 8057

Butter is good: chocolate is better!

 

[Koveras]

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

It appears to me at the moment that oleic acid and stearic acid both become Mead acid, which competes with arachidonic acid. Oleic acid also seems to inhibit Δ⁹‐desaturase, sparing stearic acid in the attempt of maintaining a steady‐state oleic acid concentration. Since Pereira informs us that we have Δ⁹, Δ⁶, and Δ⁵‐desaturases, perhaps the formation of Mead acid from stearic acid can be explained something like: Δ⁹‐desaturase⟶Δ⁵‐desaturase⟶Δ‐C₂‐elongase⟶Δ⁹‐desaturase. The formation of Mead acid from oleic acid would be the same, but minus the first Δ⁹‐desaturase step.

​

Peat has talked about the synthesis of Mead acid being increased during an "EFA" deficiency and the desaturases seem to be upregulated under these conditions

Delta-6-desaturase and delta-5-desaturase in human Hep G2 cells are both fatty acid interconversion rate limiting and are upregulated under essential fatty acid deficient conditions​

Andrew Kim also spoke about the impact of thyroid (↑), insulin (↑), and cholesterol (↓) on desaturases

"Thyroid hormone, in parallel with insulin, decreases the saturation indices of membranes by activating certain desaturase enzymes (Δ5- and Δ6-desaturases), thereby increasing the proportion of the highly unsaturated fats, like arachidonate, to their parents, like linoleate (Van Doormaal, Muskiet, Martini, & Doorenbos, 1986)."

"Across taxa, the membrane peroxidizability index correlates with maximum lifespan years. This has been proposed as the main mechanism by which caloric restriction extends lifespan, and is probably due to the slight decrease in thyroid hormone and insulin levels in the blood of those who embark on eating less food, as insulin and thyroid hormone modulate the activity of the desaturase enzymes. "

"Cholesterol also has a modulating effect on the activity of the desaturase enzymes, decreasing the synthesis of the highly unsaturated fatty acids (Brenner, Bernasconi, González, & Rimoldi, 2002; Garg, Sebokova, Thomson, & Clandinin, 1988). "

Andrew Kim Blog: Thyroid Hormone, Desaturase Enzymes, and the Implications on Membranes and Energy Generation
Andrew Kim Blog: PUFA, Lipid Peroxidation Processes, and the Implications for Atherosclerosis and Diet
​

---

"These enzymes are modulated by various factors. They are inhibited by desaturase products (1,2) and cholesterol-rich diets (3), whereas ∆6 desaturase activity is induced by low EFA intakes, i.e., in the presence of low substrate concentrations, and is suppressed by diets rich in vegetable or marine oils (4,5), i.e., by the excess of substrates. The enzymatic activities are also modulated by hormones—activated by insulin and reduced by adrenaline, glucagon, and steroids (6). Different classes of xenobiotics, e.g., peroxisome proliferators (7), calcium antagonists (8), and statins (9), also affect the activity of desaturases."

Pharmacological modulation of fatty acid desaturation and of cholesterol biosynthesis in THP-1 cells.
​

Statins do not drive your cholesterol that low, but they do drive it low enough to increase risk of cancer (https://www.sciencedaily.com/releases/2012/03/120326113713.htm).

Maybe some of that connection between low cholesterol/statins and cancer has to do with a low cholesterol/statin induced increase in desaturase?

"In THP-1 cells, simvastatin decreases, in a concentration-dependent manner, cholesterol synthesis and increases linoleic acid (LA) conversion to its long-chain derivatives, in particular to arachidonic acid, activating delta6 and delta5 fatty acid (FA) desaturases."

"Moreover, the serum concentration of C-reactive protein measured by high sensitivity methods (hs-CRP) also increased progressively across AA/LA tertile. Thus, it appeared reasonable to hypothesize that inappropriately high desaturase activity may indicate a peculiar susceptibility to the inflammatory stimuli involving the arterial wall during the atherosclerotic process. "

Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease.​

Maybe desaturase inhibitors are a solution?

"The anti-inflammatory properties of essential fatty acid deficiency or n-3 polyunsaturated fatty acid supplementation have been attributed to a reduced content of arachidonic acid (AA; 20:4 n-6). An alternative, logical approach to depleting AA would be to decrease endogenous synthesis of AA by selectively inhibiting the delta5 and/or the delta6 fatty acid desaturase."

"In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids."

Identification and characterization of a novel delta6/delta5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent.

"A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes."

Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis.​

(Semi-)Natural ones seem to be sesamin, curcumin, & alkyl gallate

"On the other hand, sesamin significantly reduced the index of delta5 desaturation but not delta6 desaturation. These results suggested that sesamin reduced the delta5 desaturation index without the changing of the delta5 desaturase mRNA level."

Effects of sesamin and capsaicin on the mRNA expressions of delta6 and delta5 desaturases in rat primary cultured hepatocytes.

"In addition, we found that curcumin in a yellow spice, turmeric, which is known to be an antioxidant, and an inhibitor of mammalian 5-lipoxygenase and cyclooxgenase, had an inhibitory effect on A5 desaturase and a relatively weak inhibitory effect on A6 desaturase.

"Alkyl gallate, which is known as an antioxidant, intensively inhibited delta 5 and delta 6 desaturation in both rat liver microsomes and an arachidonic acid-producing fungus Mortierella alpina 1S-4. The rat liver microsomal delta 5 and delta 6 desaturases were inhibited by gallic acid esterified with alcohols with various numbers of carbons, suggesting that the necessary structure in an esterified alcohol for the inhibition is not so strict. Among the three hydroxy groups in gallic acid, the m-hydroxy group was shown to be the necessary structure. Kinetic analyses revealed that propyl gallate is a noncompetitive inhibitor of delta 5 desaturase (Ki = 2.6.10(-5)M) and delta 6 desaturase (Ki = 1.7.10(-4) M). These data indicate that alkyl gallate is a new type of desaturase inhibitor and different from known natural inhibitors, i.e., sesamin and curcumin."

Inhibitory effects of alkyl gallate and its derivatives on fatty acid desaturation.
​

 

[Travis]

Peat has talked about the synthesis of Mead acid being increased during an "EFA" deficiency and the desaturases seem to be upregulated under these conditions

Delta-6-desaturase and delta-5-desaturase in human Hep G2 cells are both fatty acid interconversion rate limiting and are upregulated under essential fatty acid deficient conditions​

Andrew Kim also spoke about the impact of thyroid (↑), insulin (↑), and cholesterol (↓) on desaturases

"Thyroid hormone, in parallel with insulin, decreases the saturation indices of membranes by activating certain desaturase enzymes (Δ5- and Δ6-desaturases), thereby increasing the proportion of the highly unsaturated fats, like arachidonate, to their parents, like linoleate (Van Doormaal, Muskiet, Martini, & Doorenbos, 1986)."

"Across taxa, the membrane peroxidizability index correlates with maximum lifespan years. This has been proposed as the main mechanism by which caloric restriction extends lifespan, and is probably due to the slight decrease in thyroid hormone and insulin levels in the blood of those who embark on eating less food, as insulin and thyroid hormone modulate the activity of the desaturase enzymes. "

"Cholesterol also has a modulating effect on the activity of the desaturase enzymes, decreasing the synthesis of the highly unsaturated fatty acids (Brenner, Bernasconi, González, & Rimoldi, 2002; Garg, Sebokova, Thomson, & Clandinin, 1988). "

Andrew Kim Blog: Thyroid Hormone, Desaturase Enzymes, and the Implications on Membranes and Energy Generation
Andrew Kim Blog: PUFA, Lipid Peroxidation Processes, and the Implications for Atherosclerosis and Diet
​

---

"These enzymes are modulated by various factors. They are inhibited by desaturase products (1,2) and cholesterol-rich diets (3), whereas ∆6 desaturase activity is induced by low EFA intakes, i.e., in the presence of low substrate concentrations, and is suppressed by diets rich in vegetable or marine oils (4,5), i.e., by the excess of substrates. The enzymatic activities are also modulated by hormones—activated by insulin and reduced by adrenaline, glucagon, and steroids (6). Different classes of xenobiotics, e.g., peroxisome proliferators (7), calcium antagonists (8), and statins (9), also affect the activity of desaturases."

Pharmacological modulation of fatty acid desaturation and of cholesterol biosynthesis in THP-1 cells.
​

Maybe some of that connection between low cholesterol/statins and cancer has to do with a low cholesterol/statin induced increase in desaturase?

"In THP-1 cells, simvastatin decreases, in a concentration-dependent manner, cholesterol synthesis and increases linoleic acid (LA) conversion to its long-chain derivatives, in particular to arachidonic acid, activating delta6 and delta5 fatty acid (FA) desaturases."

"Moreover, the serum concentration of C-reactive protein measured by high sensitivity methods (hs-CRP) also increased progressively across AA/LA tertile. Thus, it appeared reasonable to hypothesize that inappropriately high desaturase activity may indicate a peculiar susceptibility to the inflammatory stimuli involving the arterial wall during the atherosclerotic process. "

Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease.​

Maybe desaturase inhibitors are a solution?

"The anti-inflammatory properties of essential fatty acid deficiency or n-3 polyunsaturated fatty acid supplementation have been attributed to a reduced content of arachidonic acid (AA; 20:4 n-6). An alternative, logical approach to depleting AA would be to decrease endogenous synthesis of AA by selectively inhibiting the delta5 and/or the delta6 fatty acid desaturase."

"In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids."

Identification and characterization of a novel delta6/delta5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent.

"A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes."

Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis.​

(Semi-)Natural ones seem to be sesamin, curcumin, & alkyl gallate

"On the other hand, sesamin significantly reduced the index of delta5 desaturation but not delta6 desaturation. These results suggested that sesamin reduced the delta5 desaturation index without the changing of the delta5 desaturase mRNA level."

Effects of sesamin and capsaicin on the mRNA expressions of delta6 and delta5 desaturases in rat primary cultured hepatocytes.

"In addition, we found that curcumin in a yellow spice, turmeric, which is known to be an antioxidant, and an inhibitor of mammalian 5-lipoxygenase and cyclooxgenase, had an inhibitory effect on A5 desaturase and a relatively weak inhibitory effect on A6 desaturase.

"Alkyl gallate, which is known as an antioxidant, intensively inhibited delta 5 and delta 6 desaturation in both rat liver microsomes and an arachidonic acid-producing fungus Mortierella alpina 1S-4. The rat liver microsomal delta 5 and delta 6 desaturases were inhibited by gallic acid esterified with alcohols with various numbers of carbons, suggesting that the necessary structure in an esterified alcohol for the inhibition is not so strict. Among the three hydroxy groups in gallic acid, the m-hydroxy group was shown to be the necessary structure. Kinetic analyses revealed that propyl gallate is a noncompetitive inhibitor of delta 5 desaturase (Ki = 2.6.10(-5)M) and delta 6 desaturase (Ki = 1.7.10(-4) M). These data indicate that alkyl gallate is a new type of desaturase inhibitor and different from known natural inhibitors, i.e., sesamin and curcumin."

Inhibitory effects of alkyl gallate and its derivatives on fatty acid desaturation.
​

View attachment 8058

I think lots of curcumin could work. Even though gram‐sized doses lead to undetectable blood concentrations, I am pretty sure that I remember that some had been detected in the liver.

In addition to Δ⁵‐desaturase, curcumin inhibits glyoxylase I and cyclooxygenase. I think this would be a good phytochemical to use for colon cancer, where it's low absorption actually becomes useful.

 

[Koveras]

I think lots of curcumin could work. Even though gram‐sized doses lead to undetectable blood concentrations, I am pretty sure that I remember that some had been detected in the liver.

In addition to Δ⁵‐desaturase, curcumin inhibits glyoxylase I and cyclooxygenase. I think this would be a good phytochemical to use for colon cancer, where it's low absorption actually becomes useful.

There seems to be various novel formulations that overcome the low bioavailability

J Am Coll Nutr. 2018 Jan;37(1):51-59. doi: 10.1080/07315724.2017.1358118. Epub 2017 Oct 18.
A Comparative Pharmacokinetic Assessment of a Novel Highly Bioavailable Curcumin Formulation with 95% Curcumin: A Randomized, Double-Blind, Crossover Study.
Stohs SJ1, Ji J2, Bucci LR3, Preuss HG4.
OBJECTIVE:
Curcumin exhibits many beneficial health-promoting characteristics. However, its poor oral absorption precludes its general use. This study assessed the bioavailability of a novel curcumin formulation compared to 95% curcumin and published results for various other curcumin formulations.
METHODS:
A randomized, crossover, double-blind, comparator-controlled pharmacokinetic study was performed in 12 healthy adult subjects to determine the appearance of free curcumin and its metabolites curcumin sulfate and curcumin glucuronide in plasma after a single dose of a novel proprietary curcumin liquid droplet micromicellar formulation (CLDM) and unformulated 95% curcumin powder in capsule form. An equivalent 400-mg dose of each product was administered. The 95% curcumin contained 323 mg curcumin, and the CLDM contained 64.6 mg curcumin. Blood samples were drawn and plasma was analyzed for curcumin and its 2 conjugates without enzymatic hydrolysis by liquid chromatography-tandem mass spectroscopy.
RESULTS:
Plasma levels of curcumin sulfate and curcumin glucuronide after 1.5 hours from CLDM were approximately 20 and 300 ng/mL, respectively, whereas the levels for 95% curcumin were near baseline. Free curcumin reached a maximum level of 2 ng/mL for CLDM and 0.3 ng/mL for 95% curcumin at 1.5 hours. For the CLDM, a small secondary free curcumin peak occurred at 12 hours and a tertiary 1.5-ng/mL peak occurred at 24 hours. The total curcumin absorbed as represented by the area under the curve (AUC)/mg administered curcumin for CLDM was 522 times greater than for the 95% curcumin.
CONCLUSIONS:
The novel CLDM formulation facilitates absorption and produces exceedingly high plasma levels of both conjugated and total curcumin compared to 95% curcumin. A comparison of the Cmax/mg curcumin and AUC/mg of administered curcumin for CLDM with data from pharmacokinetic studies of various enhanced absorption formulations indicate that the greatest absorption and bioavailability are produced with the novel CLDM formulation.

Eur J Pharm Sci. 2009 Jun 28;37(3-4):223-30. doi: 10.1016/j.ejps.2009.02.019. Epub 2009 Mar 10.
Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer.
Shaikh J1, Ankola DD, Beniwal V, Singh D, Kumar MN.
Curcumin, a derived product from common spice turmeric that is safe and beneficial in several aliments was formulated into biodegradable nanoparticles with a view to improve its oral bioavailability. The curcumin encapsulated nanoparticles prepared by emulsion technique were spherical in shape with particle size of 264nm (polydispersity index 0.31) and 76.9% entrapment at 15% loading. The curcumin encapsulated nanoparticles were able to withstand the International Conference on Harmonisation (ICH) accelerated stability test conditions for refrigerated products for the studied duration of 3 months. X-ray diffraction analysis revealed the amorphous nature of the encapsulated curcumin. The in vitro release was predominantly by diffusion phenomenon and followed Higuchi's release pattern. The in vivo pharmacokinetics revealed that curcumin entrapped nanoparticles demonstrate at least 9-fold increase in oral bioavailability when compared to curcumin administered with piperine as absorption enhancer. Together the results clearly indicate the promise of nanoparticles for oral delivery of poorly bioavailable molecules like curcumin.

Biol Pharm Bull. 2011;34(5):660-5.
Innovative preparation of curcumin for improved oral bioavailability.
Sasaki H1, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashimoto T, Wada H, Katanasaka Y, Kakeya H, Fujita M, Hasegawa K, Morimoto T.
Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. We have successfully developed a highly absorptive curcumin dispersed with colloidal nano-particles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concentration-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addition, THERACURMIN exhibited an inhibitory action against alcohol intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concentration of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available preparations. Thus, THERACURMIN may be useful to exert clinical benefits in humans at a lower dosage.

 

[haidut]

Peat has talked about the synthesis of Mead acid being increased during an "EFA" deficiency and the desaturases seem to be upregulated under these conditions

Delta-6-desaturase and delta-5-desaturase in human Hep G2 cells are both fatty acid interconversion rate limiting and are upregulated under essential fatty acid deficient conditions​

Andrew Kim also spoke about the impact of thyroid (↑), insulin (↑), and cholesterol (↓) on desaturases

"Thyroid hormone, in parallel with insulin, decreases the saturation indices of membranes by activating certain desaturase enzymes (Δ5- and Δ6-desaturases), thereby increasing the proportion of the highly unsaturated fats, like arachidonate, to their parents, like linoleate (Van Doormaal, Muskiet, Martini, & Doorenbos, 1986)."

"Across taxa, the membrane peroxidizability index correlates with maximum lifespan years. This has been proposed as the main mechanism by which caloric restriction extends lifespan, and is probably due to the slight decrease in thyroid hormone and insulin levels in the blood of those who embark on eating less food, as insulin and thyroid hormone modulate the activity of the desaturase enzymes. "

"Cholesterol also has a modulating effect on the activity of the desaturase enzymes, decreasing the synthesis of the highly unsaturated fatty acids (Brenner, Bernasconi, González, & Rimoldi, 2002; Garg, Sebokova, Thomson, & Clandinin, 1988). "

Andrew Kim Blog: Thyroid Hormone, Desaturase Enzymes, and the Implications on Membranes and Energy Generation
Andrew Kim Blog: PUFA, Lipid Peroxidation Processes, and the Implications for Atherosclerosis and Diet
​

---

"These enzymes are modulated by various factors. They are inhibited by desaturase products (1,2) and cholesterol-rich diets (3), whereas ∆6 desaturase activity is induced by low EFA intakes, i.e., in the presence of low substrate concentrations, and is suppressed by diets rich in vegetable or marine oils (4,5), i.e., by the excess of substrates. The enzymatic activities are also modulated by hormones—activated by insulin and reduced by adrenaline, glucagon, and steroids (6). Different classes of xenobiotics, e.g., peroxisome proliferators (7), calcium antagonists (8), and statins (9), also affect the activity of desaturases."

Pharmacological modulation of fatty acid desaturation and of cholesterol biosynthesis in THP-1 cells.
​

Maybe some of that connection between low cholesterol/statins and cancer has to do with a low cholesterol/statin induced increase in desaturase?

"In THP-1 cells, simvastatin decreases, in a concentration-dependent manner, cholesterol synthesis and increases linoleic acid (LA) conversion to its long-chain derivatives, in particular to arachidonic acid, activating delta6 and delta5 fatty acid (FA) desaturases."

"Moreover, the serum concentration of C-reactive protein measured by high sensitivity methods (hs-CRP) also increased progressively across AA/LA tertile. Thus, it appeared reasonable to hypothesize that inappropriately high desaturase activity may indicate a peculiar susceptibility to the inflammatory stimuli involving the arterial wall during the atherosclerotic process. "

Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease.​

Maybe desaturase inhibitors are a solution?

"The anti-inflammatory properties of essential fatty acid deficiency or n-3 polyunsaturated fatty acid supplementation have been attributed to a reduced content of arachidonic acid (AA; 20:4 n-6). An alternative, logical approach to depleting AA would be to decrease endogenous synthesis of AA by selectively inhibiting the delta5 and/or the delta6 fatty acid desaturase."

"In the livers of mice treated chronically with the maximally tolerated dose of CP-24879 (3 mg/kg, t.i.d.), combined delta5/delta6 desaturase activities were inhibited approximately 80% and AA was depleted nearly 50%. These results suggest that delta5 and/or delta6 desaturase inhibitors have the potential to manifest an anti-inflammatory response by decreasing the level of AA and the ensuing production of eicosanoids."

Identification and characterization of a novel delta6/delta5 fatty acid desaturase inhibitor as a potential anti-inflammatory agent.

"A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes."

Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis.​

(Semi-)Natural ones seem to be sesamin, curcumin, & alkyl gallate

"On the other hand, sesamin significantly reduced the index of delta5 desaturation but not delta6 desaturation. These results suggested that sesamin reduced the delta5 desaturation index without the changing of the delta5 desaturase mRNA level."

Effects of sesamin and capsaicin on the mRNA expressions of delta6 and delta5 desaturases in rat primary cultured hepatocytes.

"In addition, we found that curcumin in a yellow spice, turmeric, which is known to be an antioxidant, and an inhibitor of mammalian 5-lipoxygenase and cyclooxgenase, had an inhibitory effect on A5 desaturase and a relatively weak inhibitory effect on A6 desaturase.

"Alkyl gallate, which is known as an antioxidant, intensively inhibited delta 5 and delta 6 desaturation in both rat liver microsomes and an arachidonic acid-producing fungus Mortierella alpina 1S-4. The rat liver microsomal delta 5 and delta 6 desaturases were inhibited by gallic acid esterified with alcohols with various numbers of carbons, suggesting that the necessary structure in an esterified alcohol for the inhibition is not so strict. Among the three hydroxy groups in gallic acid, the m-hydroxy group was shown to be the necessary structure. Kinetic analyses revealed that propyl gallate is a noncompetitive inhibitor of delta 5 desaturase (Ki = 2.6.10(-5)M) and delta 6 desaturase (Ki = 1.7.10(-4) M). These data indicate that alkyl gallate is a new type of desaturase inhibitor and different from known natural inhibitors, i.e., sesamin and curcumin."

Inhibitory effects of alkyl gallate and its derivatives on fatty acid desaturation.
​

View attachment 8058

Thanks. I seem to remember that aspirin also inhibits the desaturases. So, this could be another pathway through aspirin protects from cancer and other inflammatory diseases.

 

[Koveras]

What's the Delta6-desaturated metabolite of CLA?

"Inhibition of Delta6-desaturase prevented CLA from being able to cause a body fat loss. Therefore, a desaturated metabolite of CLA appears to be involved in the CLA antiobesity effect."​

IS CLA a fatty acid synthase inhibitor?

"CLA caused more extensive changes in adipose tissue fatty acid profile. Myristic, palmitic, and palmitoleic acids were all decreased by CLA, indicating that CLA may inhibit de novo fatty acid synthesis. CLA has previously been reported to downregulate the mRNA abundance of fatty acid synthesis genes such as acetyl CoA carboxylase and fatty acid synthase (27) as well as stearoyl-CoA desaturase mRNA, protein, and activity (27,28)"

Conjugated linoleic acid-induced fat loss dependence on Delta6-desaturase or cyclooxygenase.​

 

[Travis]

What's the Delta6-desaturated metabolite of CLA?

"Inhibition of Delta6-desaturase prevented CLA from being able to cause a body fat loss. Therefore, a desaturated metabolite of CLA appears to be involved in the CLA antiobesity effect."​

IS CLA a fatty acid synthase inhibitor?

"CLA caused more extensive changes in adipose tissue fatty acid profile. Myristic, palmitic, and palmitoleic acids were all decreased by CLA, indicating that CLA may inhibit de novo fatty acid synthesis. CLA has previously been reported to downregulate the mRNA abundance of fatty acid synthesis genes such as acetyl CoA carboxylase and fatty acid synthase (27) as well as stearoyl-CoA desaturase mRNA, protein, and activity (27,28)"

Conjugated linoleic acid-induced fat loss dependence on Delta6-desaturase or cyclooxygenase.​

We just have to get down with the IUPAC nomenclature:

Linoleic acid: 9,12-octadecadienoic acid

Conjugated linoleic acid: 9,11-octadecadienoic acid or 10,12-octadecadienoic acid​

We have to apply the Dirac Delta Function of unsaturation to each lipid (lol).

Δ⁶ × (9,11-octadecadienoic acid) = (6,9,11-octadecatrienoic acid)

Δ⁶ × (10,12-octadecadienoic acid) = (6,10,12-octadecatrienoic acid)​

And then have Google tell us if they have non‐IUPAC names.. .

 

[Obi-wan]

Aspirin is a lot cheaper than curcumin and does the same if not more. Heard this from Ray Peat somewhere...

 

[haidut]

We just have to get down with the IUPAC nomenclature:

Linoleic acid: 9,12-octadecadienoic acid

Conjugated linoleic acid: 9,11-octadecadienoic acid or 10,12-octadecadienoic acid​

We have to apply the Dirac Delta Function of unsaturation to each lipid (lol).

Δ⁶ × (9,11-octadecadienoic acid) = (6,9,11-octadecatrienoic acid)

Δ⁶ × (10,12-octadecadienoic acid) = (6,10,12-octadecatrienoic acid)​

And then have Google tell us if they have non‐IUPAC names.. .

The closest I was able to find was Calendic (calendulic) acid, which does seem to have some of the beneficial effects of CLA. See the "Effects" section below.
Calendic acid - Wikipedia

 

[Travis]

The closest I was able to find was Calendic (calendulic) acid, which does seem to have some of the beneficial effects of CLA. See the "Effects" section below.
Calendic acid - Wikipedia

A lipid known for its presence in the common marigold. That makes me want to eat flowers. I've done this, and it's not bad. There's actually a 'salad flower' that is known for this, if I can only find it.. .

Tropaeolum majus

'All its parts are edible. The flower has most often been consumed, making for an especially ornamental salad ingredient; it has a slightly peppery taste reminiscent of watercress, and is also used in stir fry. The flowers contain about 130 mg vitamin C per 100 grams (3.5 oz),[10] about the same amount as is contained in parsley.[11] Moreover, they contain up to 45 mg of lutein per 100 gr,[12] which is the highest amount found in any edible plant. The unripe seed pods can be harvested and dropped into spiced vinegar to produce a condiment and garnish, sometimes used in place of capers.[13]' ―Wikipedia​

 

[tara]

We actually do eat selenomethionine every day in small amounts, in food.

As long as there is some in the soil. Some places the soils are quite deficient, and the livestock get given supplements if they are to thrive. (and one has to be careful not to get poisoned handling the supplement.)

I could not agree more, yet he did not single out others for such comment. Are we just to conclude that a man of this experience and stature had a Se in his Bonnet about this mineral? Or did he understand better where Se compounds fit wrt S compounds and their oxidation/reduction potential and how Se as antioxidant could work against FCG? I do not know, hence my question. I do take note of all the literature since then of course to which Obi-wan's light saber has kindly re-cut a swathe.

Maybe there have been areas where the soils contributed more than optimal selenium amounts, and Koch had experience from some of these areas? Just speculating.

A lipid known for its presence in the common marigold. That makes me want to eat flowers. I've done this, and it's not bad. There's actually a 'salad flower' that is known for this, if I can only find it.. .

I've eaten marigold petals in salads in the past. And dandelions. Nasturtiums (Tropaeolum) are not unusual in salads here - add a nice spicy taste.

 

[Sheila]

Hello dear Tara

As long as there is some in the soil. Some places the soils are quite deficient, and the livestock get given supplements if they are to thrive. (and one has to be careful not to get poisoned handling the supplement.)

Maybe there have been areas where the soils contributed more than optimal selenium amounts, and Koch had experience from some of these areas? Just speculating.

What a clever thought. You may well be onto something here as reports from ~1945 was within his working time.

From Distribution - Selenium in Nutrition - NCBI Bookshelf Selenium in Nutrition: Revised Edition. (1983)
at para TOXIC SELENIFEROUS SOILS

....There are extensive areas of seleniferous soils in South Dakota, Wyoming, Montana, North Dakota, Nebraska, Kansas, Colorado, Utah, Arizona, and New Mexico that produce vegetation toxic to livestock (Rosenfeld and Beath, 1964). The occurrence of toxic vegetation and indicator plants is most widespread in Wyoming and South Dakota (Rosenfeld and Beath, 1964). The average selenium content of 500 samples of soil from seleniferous areas in the western United States was 4.5 ppm, with a maximum of 80 ppm (Trelease, 1945).
Seleniferous soils supporting toxic vegetation in Canada are associated with Cretaceous rocks in large areas of Alberta, Saskatchewan, and Manitoba (Rosenfeld and Beath, 1964). The range in total selenium content of 80 soil samples, taken where indicator plants were present, was 0.1 to 6 ppm, with 30 percent of the samples containing 1 ppm or more.

Given his results, and the depth and interconnectedness of his biological thinking, it would make sense to me that Dr Koch would not take against any compound without good reason. It also makes sense that he was as wary of over-supplementing as he was under-supplementing.
Thank you Tara, very helpful.
Sincerely,
Sheila