NAD/NADH Ratio - The One Metabolic Cause To Rule Them All

[Travis]

Vitamin A and Carotenoids as Antioxidants in a Physiological Contex
Summary:

@Travis ("Retinol [], which contains 5 conjugated double bonds"..)

Retinol has that head group and not a carboxyl group so it cannot be given a standard lipid number. I think we're stuck denoting it one of two ways: either by its common name, or retinol, or its more formal IUPAC designation:

IUPAC ID: (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraen-1-ol​

Which seems prolix, to be sure; but back in the time before Internet was Universal (circa < 1990, or < ~0 U.I. ), this name could could tell you how to draw the molecule having only a pencil and a piece of paper. So it's pretty amazing, really, as it defines a three dimensional line drawing with just words and numbers.

 

[Amazoniac]

Universal

The attention that you give to details is impressive! How am I supposed to insert a joke about ETs now?

 

[Texon]

Nice post. It's nice to see the Warburg Effect given context. And you brought-up pyruvate decarboxylase.
And this makes me want to rant about the Breslow Mechanism. This is just a minor detail in the grand scheme of things, but it's important in that it highlights how false paradigms can have inertia; there's serious reluctance to change it despite obvious errors. Authoritarianism plays an important role; especially when considering things that cannot even be seen directly – like molecules. Explanations printed in the shiniest books are usually considered to be the truth.

Doctor Alan J. Knell's 1970 doctroral dissertation† provides a 144-page β-slap of Breslow's mechanism for how exactly this enzyme works – for how thiamine removes carbon dioxide from pyruvate.


And he goes into great detail on all of his points.

The Breslow Mechanism in rarely drawn with the entire thiamine molecule. This is done partly to save space and time; but also, the rest of the thiamine molecule actually gets in the way if you try to do this. Knell mentioned in point (a) that it was impossible to build models ― Honestly, it's impossible to even draw.
View attachment 6798
And you would think that Breslow intermediate #3 would be practically irreversible, since this is a carbon-carbon double bond. Knell mentions that "attempts to prepare the pyruvate adduct itself were unsuccessful." So intermediate #2 might not have ever been made, anywhere. Not even inside the enzyme. And even if it had, #3 wouldn't easily be converted back to thiamine like it needs to be. Instead, Knell does one better:
View attachment 6799
The active coenzyme is actually though to be thiamine's isomer, xantho-thiamine.
View attachment 6800
Pyruvate is drawn here with partial charges; the ketone is polarized as usual. The sulfur nucleophilicly-attacks the carbonyl carbon of pyruvate. There is absolutely nothing unusual about such an interaction; this happens all of the time.
View attachment 6813
The σ-bond is free to rotate. [S-linked-pyruvate shown migrating towards pyrimidine rings]
View attachment 6804
It forms a transient bond as electrons are drawn through the heterocycle by the positively-charged histidine* side-chains of the enzyme. There are two of them in close proximity to the pyrimidine rings. (Electrons need to be removed from pyruvate to decarboxlate it to acetyl-.) The ring structure is electronically-conjugated with an extensive π-bond system, so electrons are free to move through it. Conjugated double-bond systems are much more conductive than saturated carbon chains with sigma bonds. Graphite is a semiconductor (~10⁻⁵Ωm) while diamond is not (~10¹¹Ωm). They are both pure carbon.

Another nice thing about this is that you end with an S-linked acetyl group, which is how they're usually shuttled around in the body by coenzyme A and others. It could be thought of as S-acetylthiamine, which transfers to CoA (forming acetyl-CoA) through the second complex (E2) of pyruvate decarboxylase by an enzyme-linked lipoic acid prosthetic group(s). This process also directly involves sulfur atoms; lipoic acid's ring opens to create primary thiols, and these are what bond with the acetyl group in transit to CoA.


Since Knell's paper other interesting things have appeared, and completely overlooked, which support him. Take this 1998 X-ray crystallographic study done on pyruvate decarboxylase and thiamine:
View attachment 6805‡
It shows an open-ring configuration; this is similar to the Knell configuration. The C2 carbon, Breslow's magic carbon that attacks pyruvate, between the nitrogen and sulfur of the thiazole ring is conspicuously absent. Thiamine cannot possible function in the way that Breslow imagined without the C2 carbon. It is so essential to Breslow's mechanism that it may-as-well be called the Breslow Carbon. The authors seem a bit puzzled by this:
Since X-rays were used to image the enzyme – and the thiamine molecule – the researchers just brushed-this-off as radiation damage.

And as late as 2009, the same thing was imaged by and entirely different research group of chemists. They were imaging a different enzyme, but this too was a thiamine-dependent decarboxylase.§
View attachment 6806(click to embiggen)
Again: No electron density where the elusive Breslow carbon should be, but they don't seem to be bothered by this.


Ronald Breslow was president of the American Chemical Society, so most people are careful not to offend him by telling him he's wrong. But he probably is wrong. Alan Knell's explanation is much more theoretically plausible, and is more in accord with experimental observations. This reminds me of Gilbert Ling.

The Breslow Mechanism should should be treated accordingly by being placed next to the membrane pump, the George Wald theory of retinal phototransduction, and the Huxley Crossbridge Theory folders in the filing cabinet; under the section marked "Unicorns."

Unicorn Folder

Dean, Robert B. "Theories of electrolyte equilibrium in muscle." Biol. Symp. Vol. 3. 1941.
Wald, George, Paul K. Brown, and Ian R. Gibbons. "The problem of visual excitation." JOSA 53.1 (1963): 20-35.
Huxley, Andrew F., and Ro M. Simmons. "Proposed mechanism of force generation in striated muscle." Nature 233.5321 (1971): 533-538.
Breslow, Ronald. "On the mechanism of thiamine action. IV. 1 Evidence from studies on model systems." Journal of the American Chemical Society 80.14 (1958): 3719-3726. ​

It's a minor detail, but is highlights a major problem in science. All of the textbooks beat to the same drum, they all have this mechanism; and they all basically just plagiarize each-other. It seems as thought once a wrong idea actually becomes firmly established it will not be corrected by the same people who had created it, or had accepted it, for fear of embarrassment.


*Histidine414 and Histidine114 (see Dobritzsch‡)
*To save space, the squiggly line depicts the pyrophosphate side-chain of thiamine pyrophosphate.
†Knell, Alan John. Thiamine: a study of its chemistry, biochemistry and mechanism of action. Diss. University of Warwick, 1970.
‡Dobritzsch, Doreen, et al. "High Resolution Crystal Structure of Pyruvate Decarboxylase from Zymomonas mobilis." Journal of Biological Chemistry 273.32 (1998): 20196-20204.
§Chakraborty, Sumit, et al. "Detection and time course of formation of major thiamin diphosphate-bound covalent intermediates..." Biochemistry 48.5 (2009): 981-994.

@haidut Good morning Travis and Haidut. I am not a scientist, so unfortunately most of this post is over my head, until the last paragraph, which describes perfectly Dr. Abram Hoffer's definition of a "factoid". Don't know if he coined the term or not btw. If anyone Google's "Hoffer + factoid" you will find his opinions/clinically known facts very strongly discussed about plain niacin, factoids about its and vitamin c's use, and plain niacin's benefits seen in several thousand cases to apparently attenuate the effects of adrenaline and adrenochrome among other benefits. Somehow I think the verdict must still be out concerning the detrimental effects of the histamine flush, etc. Maybe the niacin flush helps deplete histamine faster than it can be replaced?

 

[Travis]

@haidut Good morning Travis and Haidut. I am not a scientist, so unfortunately most of this post is over my head, until the last paragraph, which describes perfectly Dr. Abram Hoffer's definition of a "factoid". Don't know if he coined the term or not btw. If anyone Google's "Hoffer + factoid" you will find his opinions/clinically known facts very strongly discussed about plain niacin, factoids about its and vitamin c's use, and plain niacin's benefits seen in several thousand cases to apparently attenuate the effects of adrenaline and adrenochrome among other benefits. Somehow I think the verdict must still be out concerning the detrimental effects of the histamine flush, etc. Maybe the niacin flush helps deplete histamine faster than it can be replaced?

Are you saying that the 'factoid' is an Abram Hoffer neologism? I had no idea, and had only read one or two of his articles and part of his book (The Hallucinogens). This is interesting stuff and I was thinking about adrenochrome just a few hours ago, more specifically that it most work on the serotonergic system (being an indole). Perhaps this inhibits many of serotonin's functions and part of normal stress psychology? Perhaps the body uses the catacholamines (dopamine and adrenaline) primarily for energy, and then the catecholamine indole metabolites (dopachrome and adrenochrome) to inhibit serotonin—going the extra mile in sharpening the mind by nullifying emotional traits. After all, one must be serious in times of danger and the catecholamines are released with intent to do do this; they are 'seriousifiers.'

 

[Texon]

Are you saying that the 'factoid' is an Abram Hoffer neologism? I had no idea, and had only read one or two of his articles and part of his book (The Hallucinogens). This is interesting stuff and I was thinking about adrenochrome just a few hours ago, more specifically that it most work on the serotonergic system (being an indole). Perhaps this inhibits many of serotonin's functions and part of normal stress psychology? Perhaps the body uses the catacholamines (dopamine and adrenaline) primarily for energy, and then the catecholamine indole metabolites (dopachrome and adrenochrome) to inhibit serotonin—going the extra mile in sharpening the mind by nullifying emotional traits. After all, one must be serious in times of danger and the catecholamines are released with intent to do do this; they are 'seriousifiers.'

Re: your first question...I have no idea. What a great humanitarian he was though.

Interesting comments about the adrenochrome as an indole. I have felt adrenalized for longer than I can remember which I think relates to very impaired COMT genetics. I have also been told I have low serotonin and high histamine. Believe it or not, I recall seeing one and only one reference after a Google search to the DIM supplement being a neurotoxin with no follow up comments or discussion. I did try DIM one time recommended by an endocrinologist to control estrogen, and my reaction to it was bad enough that I never used it again. Never thought of this before but, maybe I should cut out cruciferous vegetables entirely from my diet? Also, maybe it would be good for me to eat a banana or two after sex...lol. Just another illustration that one man's meat is another man's poison I guess.

 

[Texon]

If DHT + estrogens solve the issues then plain T should work just as well as it feeds both DHT and E pathways, and is also an androgen agonist. Also, whether you take the steroid combo or the RU486 there seems to be the need for continuous on/off regimen. With the androgens the benefits are claimed to stop after you stop taking the steroids and for RU486 you have to periodically take it to keep re-sensitizing the receptors because after a course of RU486 you are supposed to stop it and then all of your hormones would surge, which will make you feel better but after a while will downregulate the receptors due to those same elevations. So, one way or another, cycling seems to be needed I know, I know, bodybuilders will just roll their eyes and say "I told you cycle and PCT is the way to go"
Maybe something like vitamin D would be better as it also re-sensitizes steroid receptors so lower androgen doses are needed, prevents androgen deactivation (glucuronidation) and it also acts as antagonist on GR (which is what RU486 does).
Calcirol - Liquid Supplement With Vitamin D3
I wonder how many PFS people have severe vitamin D deficiency...

Greetings Haidut @Travis
Haidut, this is a super interesting thread, but problematic in some ways for me, as I I tend to have counterintuitive responses to things discussed like ALA, NDT, supplemental vitamin D (sunshine...no problemo though), etc. And, lower doses of almost anything are safer in my case. Anything over 100 mgs niacinamide leaves me groggy and with a dull headache. Glycine I have found to be detrimental too. IOW, as a hospital worker once told me, I am one of the aliens among us. I was one of the 1,500 or so tryptophan poisoning victims in 1989, and I believe elevated histamine and serotonin have been pretty much lifelong issues for me. Lately. I believe I have uncovered an extreme problem with glutamate exitotoxicity...seeing disturbing neurological sides from milk, fermented foods, dark chocolate, etc. I was giving serious thought to ordering some oxaloacetate to try to alleviate some of this. I just recently started 0.5 to 1 mg of Periactin at night, and believe it or not, I think it is helping in different ways, particularly with sleep, possible liver detox (based mainly on darker fecal color and better consistency), easier breathing, calmer perspective, etc. Then better sleep is enough to make me ignore the grogginess and stick it out with cyproheptadine in hopes it will be a game changer. I've tried lots of supplements and herbs and am currently on T Cypionate 50 mgs E3D with approximately 1 mg arimidex as needed as well as methyl B12 as needed to lower homocysteine. Gut should be very clean due to recent antibiotics, but can't say for sure, and increasing food sensitivities are definitely an issue along with unfriendly EM frequencies. An MD once told me to get out of town every weekend. Anyway, based on all this, I would very much appreciate any ideas you might have about some of the items mentioned in this thread you feel might impart long term benefits in my case. I really appreciate your involvement on this forum, and if you would rather correspond via PM, I fully understand.

 

[haidut]

Greetings Haidut @Travis
Haidut, this is a super interesting thread, but problematic in some ways for me, as I I tend to have counterintuitive responses to things discussed like ALA, NDT, supplemental vitamin D (sunshine...no problemo though), etc. And, lower doses of almost anything are safer in my case. Anything over 100 mgs niacinamide leaves me groggy and with a dull headache. Glycine I have found to be detrimental too. IOW, as a hospital worker once told me, I am one of the aliens among us. I was one of the 1,500 or so tryptophan poisoning victims in 1989, and I believe elevated histamine and serotonin have been pretty much lifelong issues for me. Lately. I believe I have uncovered an extreme problem with glutamate exitotoxicity...seeing disturbing neurological sides from milk, fermented foods, dark chocolate, etc. I was giving serious thought to ordering some oxaloacetate to try to alleviate some of this. I just recently started 0.5 to 1 mg of Periactin at night, and believe it or not, I think it is helping in different ways, particularly with sleep, possible liver detox (based mainly on darker fecal color and better consistency), easier breathing, calmer perspective, etc. Then better sleep is enough to make me ignore the grogginess and stick it out with cyproheptadine in hopes it will be a game changer. I've tried lots of supplements and herbs and am currently on T Cypionate 50 mgs E3D with approximately 1 mg arimidex as needed as well as methyl B12 as needed to lower homocysteine. Gut should be very clean due to recent antibiotics, but can't say for sure, and increasing food sensitivities are definitely an issue along with unfriendly EM frequencies. An MD once told me to get out of town every weekend. Anyway, based on all this, I would very much appreciate any ideas you might have about some of the items mentioned in this thread you feel might impart long term benefits in my case. I really appreciate your involvement on this forum, and if you would rather correspond via PM, I fully understand.

Have you checked blood cortisol, prolactin, serotonin, DHEA, and thyroid?

 

[Texon]

Have you checked blood cortisol, prolactin, serotonin, DHEA, and thyroid?

At one time I did have issues with dhea/cortisol ratio. I managed to balance it with 5mgs x 2/day oral Dhea. May be I need to start it up again. Thyroid always shows normal values, except last time t4 was a bit low at 70. I took a small amount of prescription t3 and my body temp dropped to 95F, which was no fun at all. Never have been tested for prolactin or serotonin though. I get mixed results with Dhea as it seems to go to estrogen very easily. I do believe serotonin is a major issue though due to very severe reactions to even low dose SSRI meds which I simply cannot take. Thankfully I don't believe I need them anyway. In some ways this all seems not unlike ptsd in that I had to go through a couple of recent surgeries for a severe elbow injury. I am wondering if the anesthetics have permanently screwed me up somehow because my brain just seems dull most of the time.

 

[Texon]

Have you checked blood cortisol, prolactin, serotonin, DHEA, and thyroid?

Also, I due to trt, I have blood work scheduled very soon. My doc is usually willing to test whatever I ask him.

 

[TreasureVibe]

What would explain the cancer cell normalizing of IP6?

 

[RobertJM]

New pill could see humans live to 150 ‘for the price of a coffee’

New technique could see humans live to 150 and regrow organs ‘for the price of a coffee a day’ | Daily Mail Online

Not that it’s even remotely interesting. I read the comments section and people were moaning that they’d have to work longer and wait longer for retirement. Still, it made the Daily Mail news!

 

[lollipop]

New pill could see humans live to 150 ‘for the price of a coffee’

New technique could see humans live to 150 and regrow organs ‘for the price of a coffee a day’ | Daily Mail Online

Not that it’s even remotely interesting. I read the comments section and people were moaning that they’d have to work longer and wait longer for retirement. Still, it made the Daily Mail news!

WoW. Watching this one.

 

[managing]

This article was intentionally obtuse, but all of this guy's research is with Nicotinamide mononucleotide. So I assume that is what the claim is based on.

 

[Waynish]

yep, Riboflavin is the most important

"Riboflavin, vitamin B2, is an essential component of the mitochondrial respiratory enzymes, and it is very easily destroyed by light (blue light and especially ultraviolet). When it is excited by high energy light, it can spread the damage to other components of the mitochondria, including the cytochromes and the polyunsaturated fatty acids. The other B vitamins are affected when riboflavin's actions are disturbed.

Vitamin K is also extremely light sensitive, and it interacts closely with coenzyme Q in regulating mitochondrial metabolism. For example, mitochondrial Complex-I, NADH-ubiquinone reductase, is probably the most easily damaged part of the mitochondrion, and it is protected by vitamin K. "

"Furthermore, because of its structural similarity to coenzyme Q10, it is likely that MK-7 is a Q10 mimetic with respect to the mitochondria and supports mitochondrial adenosine triphosphate (ATP) production in the respiratory chain."

" Riboflavin
, coenzyme Q10,
vitamin K,
niacinamide,
thiamine, and
selenium
are the nutrients that most directly relate to mitochondrial energy production.
"

In terms of, "The other B vitamins are affected when riboflavin's actions are disturbed," I wonder how this would be affected by replacing b2 with methylene blue...

 

[Momado965]

Cells have memory and participate in a quorum. When enough cells are "yelling" in the chorus that the situation in the environment is bad or if a small number of cells ae very "vocal" (i.e. highly stressed as in cancer or trauma) than that is what the body will act upon as a unit. I think the easiest way to see this is if you have say a broken finger or had minor surgery on a limb. In those cases you do not feel well systemically even though the problem seems localized. Ray said this in the past adding that when this has been going on for some times only a very strong signal of "goodness" will snap the organism out of its predicament. As @tyw pointed out once, testosterone is one such signal (at least for males). I think progesterone, anti-serotonin drugs (may have to be taken for a few weeks), maybe anti-adrenaline (clonidine) or something as "simple" as falling in love can be other signals that can change the quorum.

Do you think this is why when people try DHT they feel better even after stopping it. Also can this be replicated with keto p4 or only testosterone?

 

[Soren]

New pill could see humans live to 150 ‘for the price of a coffee’

New technique could see humans live to 150 and regrow organs ‘for the price of a coffee a day’ | Daily Mail Online

Not that it’s even remotely interesting. I read the comments section and people were moaning that they’d have to work longer and wait longer for retirement. Still, it made the Daily Mail news!

Finally some in the mainstream catching on a bit. Downside though you can already tell by the way the article is written that it is being pitched as some magic wondrous new invention/discovery so it can be patented and sold at a high price. When it's essentially just niacinamide.

 

[haidut]

Do you think this is why when people try DHT they feel better even after stopping it. Also can this be replicated with keto p4 or only testosterone?

On DHT - very possibly so. Probably similar effects from T. Peat thinks that progesterone should provide the same benefit. I think 6-keto P4 combined with Pansterone may be able to provide some of that as well, but it is too early to tell.

 

[Momado965]

On DHT - very possibly so. Probably similar effects from T. Peat thinks that progesterone should provide the same benefit. I think 6-keto P4 combined with Pansterone may be able to provide some of that as well, but it is too early to tell.

I swear this great forum keeps getting better and better everyday haha. How much keto p4 are we talking here to replicate testosterone's "goodness signal" for predicament cessation? What are things to look for as a result of predicament cessation besides the usual things people report on the forum?

 

[haidut]

I swear this great forum keeps getting better and better everyday haha. How much keto p4 are we talking here to replicate testosterone's "goodness signal" for predicament cessation? What are things to look for as a result of predicament cessation besides the usual things people report on the forum?

It would depend on the issue at hand, but I think 10mg 6-keto P4 combined with one dose Pansterone taken once or twice daily should be enough to see an effect.

 

[Amazoniac]

- Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence

Spoiler: Poetry

"An important factor involved in mitochondrial damage is oxidative stress. Under normal physiological conditions mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced [30]. A slight shift in this balance can lead to the activation of important cell signalling pathways [30]. However, oxidative stress occurs when the mitochondrial ROS production significantly exceeds the capacity of the cellular antioxidant systems [31]. This can cause irreversible damage to the lipid mitochondrial membrane, enzymes and mtDNA and thereby induce cell damage and death [31]. Oxidative stress-mediated damage to mtDNA can lead to a vicious cycle of ROS production (ROS-induced ROS release) and further mtDNA damage [31], ultimately leading to loss of function of enzymes in the electron transfer system and/or cell death [32]. This is known as the ‘mitochondrial catastrophe hypothesis [31]."

"Oxidative stress in mitochondria probably decreases ATP production by direct inhibitory effects on complexes of the respiratory chain. It has been suggested that complex IV is temporarily inhibited by nitric oxide [33,34], while the inhibition of complex I is more stable and induced by peroxynitrite [34]."

"Antioxidants and antioxidant enzymes reduce oxidative stress by four mechanisms, thereby limiting damage to mitochondria [35]: (1)scavenging free radicals, (2)sequestration of transition metal ions into complexes, (3)repairing damage molecules and (4) breaking chain reactions initiated by free radicals, as in lipid peroxidation [36]. Dietary deficiencies of protein, selenium, and zinc are associated with cell injury. However, an excess of antioxidants may be harmful as well, and an overload of specific nutrients, such as iron and vitamin C, may lead to increased oxidation and cell injury [35]."

"In addition to oxidative stress, glucose homeostasis is also crucial for the proper functioning of mitochondria [37]."

Spoiler: Overview of relevant nutrients in bioenergetic mitochondrial processes

Check out their Table 2 in the document as well, it's interesting.

Spoiler: Notes

"Importantly, mitochondrial bio-energetic functioning will be optimal when substrates and cofactors in this network are available in optimal combinations. Combined deficiencies are probably more common than those of single-nutrient and therefore investigation of combined deficiencies and the role of combined supplementation will be of great interest. Consequently, it is difficult to draw conclusions on the effects of a single nutrient in the oxidative phosphorylation process, as many nutrients cooperate in metabolic pathways. It is likely that supplementation with one nutrient does not improve downstream effects when there is a deficiency of another micronutrient."

"Nutritional intervention and (or) supplementation studies should address the issue of combined effects, supplementation with single nutrients is discouraged."

"As the underlying mechanisms involve different pathways and processes, ‘multiple-target’ strategies are best suited to correct the imbalances."

- Linoleic Acid: Is This The Key That Unlocks The Quantum Brain?