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

[haidut]

Quote: NSAIDs inhibit the generation of prostaglandins by blocking cyclooxygenase enzymes, COX-1 and COX-2. Prostaglandins are mediators of inflammation and pain but also have important roles in maintenance of normal body functions including protection from stomach acid, maintenance of kidney blood flow, and contributing to platelet stickiness and vascular function. COX-2 selective inhibitors selectively block prostaglandins generated via COX-2 which have prominent roles in inflammation.

@haidut

Could simple NSAIDs like Azathioprine inibit Cytochrome c oxidase (COX) therefore disrupt oxidative phosphorylation ?

Cytochrome c Oxidase Dysfunction in Oxidative Stress:

Cytochrome c Oxidase Dysfunction in Oxidative Stress

"Four different gases, Nitric oxide (NO), Carbon monoxide (CO), Hydrogen Sulfide (H2S) and Hydrogen Cyanide bind to CcO and invariably inhibit the enzyme activity."

"Since O2 and NO compete for the same binding site in CcO, an important question has been whether endogenously generated NO can reach concentrations that are inhibitory to CcO under physiological oxygen levels. Several lines of experimental evidence indeed suggest that this is the case. In endothelial cells under basal conditions, NOS inhibitor N monomethyl l arginine, dramatically increased oxygen consumption"

"Except in cases of genetic defects, it is commonly seen that mitochondrial dysfunction is a cumulative effect of failure of more than one complex of the electron transport chain."

"The impact of these events include energy crisis due to lower ATP production, lactic acidosis and increased formation of ROS in mitochondria."


"Nitric oxide...... inhibits CcO activity by competing with oxygen for the binuclear center. Inhibition by NO is shown to be reversible.
Interestingly, DOX treatment resulted in both CcO inhibition and lower levels of CcO subunits. DOX effects were reversed by treatment with MitoQ, a mitochondria targeted antioxidant" - Q10

"Knockdown of CcO subunits that cause loss of activity also resulted in lower membrane potential and reduced ATP generation [58,61]. Cells compensate for decreased mitochondrial ATP production through oxidative metabolism by up regulating less efficient glycolytic pathway."

Big thanks @opiath !

Azathioprine is not really an NSAID. It is an immunosuppressant and antimetabolite, similar in action to methotrexate.
Azathioprine - Wikipedia

 

[managing]

Inhibition of FAS so far has been shown to work in diabetes, cancer, Alzheimer, obesity, kidney disease, etc. So yes, the lower it stays the healthier you'll probably be.

How would you inhibit FAS? What would you do simultaneously (ie in terms of oxidative metabolism). I assume the answer will be MB, thyroid, Niacinamide, Thiamine, Riboflavin . . . ?

 

[yerrag]

You can ask your doctor to check through his/her system. I don't think it is available for the general public. However, other tests that achieve the same goal are pyruvate/lactate, bicarbonate/lactate, and GSSG/GSH.

These tests are similarly hard to find. A search on www.labtestsonline.org come up empty, but that is expected as this site caters to the establishment medical institutions. A search on Quest Diagnostics' website www.questdiagnositics.com gave me a hit on pyruvate, but empty on glutathione and NAD/NADH.

On bicarbonate/lactate, would it just be a matter of using the venous bicarbonate and venous lactate test results? These two tests can easily be obtained. A high value would be better than a low value, within limits of course? As these tests are generally of the by-products of metabolism, I suppose they would be indirect measures of a healthy, fully functional oxidative metabolic system at work, where NAD/NADH ratio would be high when the bicarbonate/lactate ratio is high.

Incidentally, this table of tests from Quest Diagnostics and their clinical significance looks very helpful:

http://www.questdiagnostics.com/hcp/intguide/GeneralChemistry/TG_Chemistry_UtilityInterp_Table1.pdf

http://www.questdiagnostics.com/hcp/intguide/GeneralChemistry/TG_Chemistry_UtilityInterp_Table2.pdf

 

[yerrag]

But in anaerobic glycolysis there is no oxygen so the body will use pyruvate as the emergency oxidizing agent. So, the enzyme LDH will oxidize NADH back to NAD using pyruvate as the oxidant and this will generate NAD and lactate.

@haidut, does it necessarily follow that when serum LDH is very high, that serum lactate would be high also? I'm asking because a month or so ago, I got results for LDH and lactic acid. My serum LDH was very high at 238 U/L (range 135 - 225), but my serum lactate was low at 0.5 mmol/L (range 0.4 - 2.0). How can this anomaly be explained?

 

[haidut]

@haidut, does it necessarily follow that when serum LDH is very high, that serum lactate would be high also? I'm asking because a month or so ago, I got results for LDH and lactic acid. My serum LDH was very high at 238 U/L (range 135 - 225), but my serum lactate was low at 0.5 mmol/L (range 0.4 - 2.0). How can this anomaly be explained?

Actually, LDH is a mitochondrial enzyme and should not be present in blood in high amounts under normal circumstances. If it is then there is usually cell damage somewhere and the cell(s) ruptured and spilled these enzymes in the blood. It happens with overtraining, muscle damage, heart attacks, infections, burns, cancer, etc. Peat wrote that high estrogen is one of the main causes of LDH leaking into the blood. Lactate is what needs to be measured to get the pyruvate/lactate ratio and yes you can have discrepancy between LDH and lactate as LDH levels are simply indicative of cell damage, not how much lactate is produced. You can have normal or even low LDH with high lactate if the LDH enzyme is very active in the cell. So, I would test for pyruvate and lactate and get the ratio. A more worrying case would be where both LDH and lactate are high, but it seems this is not your case.

 

[aguilaroja]

@haidut... My serum LDH was very high at 238 U/L (range 135 - 225), but my serum lactate was low at 0.5 mmol/L (range 0.4 - 2.0). How can this anomaly be explained?

Actually, LDH is a mitochondrial enzyme and should not be present in blood in high amounts under normal circumstances. If it is then there is usually cell damage somewhere and the cell(s) ruptured and spilled these enzymes in the blood. It happens with overtraining, muscle damage, heart attacks, infections, burns, cancer, etc. Peat wrote that high estrogen is one of the main causes of LDH leaking into the blood. Lactate is what needs to be measured to get the pyruvate/lactate ratio
...yes you can have discrepancy between LDH and lactate as LDH levels are simply indicative of cell damage, not how much lactate is produced. You can have normal or even low LDH with high lactate if the LDH enzyme is very active in the cell. So, I would test for pyruvate and lactate and get the ratio. A more worrying case would be where both LDH and lactate are high, but it seems this is not your case.

An excellent topic and response. As a small addendum, LDH value reported would be within "normal" range for some lab references, and is above normal for the reference range given, but not drastically above. I agree the value is less than optimal.

LDH values are known to be possibly distorted by poor serum specimen handling.
Lactate dehydrogenase - Wikipedia
"A blood sample that has been handled incorrectly can show false-positively high levels of LDH due to erythrocyte damage."

If the LDH value was a single report, rather than a trend for a series of reults, it may be helpful to repeat the test as next serum testing before making decisions on a single lab test report.

 

[haidut]

LDH value reported would be within "normal" range for some lab references, and is above normal for the reference range given

I have always wondered about this. How can various labs have various ranges? If it was a sensitivity of equipment issue then the difference should be in units of measurement, not range. For example one lab may only be able to do say mcg/ml while another may be able to do pg/ml, etc. So, the range should be the same but the units may be multiples of say 1,000 of each other (pg vs. mcg).

 

[noodle]

@haidut

what does the ratio of pyruvate and lactate tell you then?

1: high pyruvate - low lactate
2: low pyruvate - low lactate
3: high pyruvate - high lactate
4: low pyruvate - high lactate

only 4 I would assume to be "healty" ?

 

[aguilaroja]

I have always wondered about this. How can various labs have various ranges? If it was a sensitivity of equipment issue then the difference should be in units of measurement, not range. For example one lab may only be able to do say mcg/ml while another may be able to do pg/ml, etc. So, the range should be the same but the units may be multiples of say 1,000 of each other (pg vs. mcg).

Beg pardon in advance for the vague response. (And maybe off topic.) Perhaps other forum readers have close links to laboratory medicine and may answer better.

It has been years since I tried to pursue this question. Different hospitals/health care networks used to have their own references ranges, sometimes slightly differing in the range numbers. Even accounting for different units, reference ranges also vary from country to country.

My impression was that the technical decisions were usually left to Laboratory Medicine specialist directors. These directors in turn took guidance from specialist physicians in their network, professional Laboratory Medicine association conclusions, and specialist physician group guidelines. Sometimes recommendations from equipment manufacturers also figured in. I was told there can be different decision making processes for different serum lab tests. Some specialized test are only done by a few labs in an entire nation, so the real specifics are internal to those specialty labs. The lab testing market in the U.S. for instance is now dominated by Quest & LabCorp. Only as a guess, the decision making of the huge corporate labs is even more encrusted. And once values are set, they seem to budge little over time, no matter what data emerges.

Recently, I have (non-Peating) friends whose physicians are making major cancer treatment recommendations based on very tiny number differences that would not generally be statistically significant.

In short, the “absoluteness” of reference ranges is far from absolute. Individual variation, diurnal variation, lab error, reproducibility of original research findings, and more push uncertainty further. Dr. Peat has of course written about the tautology of using estimates of the abnormal population to set normal values, which then set the percentage of abnormals.
- -
Preventing and treating cancer with progesterone.
"As the newer, more direct tests became available, their meaning was defined in terms of the statistical expectation of hypothyroidism that had become an integral part of medical culture. To make the new TSH measurements fit the medical doctrine, an 8- or 10-fold variation in the hormone was defined as “normal.” With any other biological measurement, such as erythrocyte count, blood pressure, body weight, or serum sodium, calcium, chloride, or glucose, a variation of ten or 20 percent from the mean is considered to be meaningful. If the doctrine regarding the 5% prevalence of hypothyroidism hadn't been so firmly established, there would have been more interest in establishing the meaning of these great variations in TSH."
"In recent years the “normal range” for TSH has been decreasing. In 2003, the American Association of Clinical Endocrinologists changed their guidelines for the normal range to 0.3 to 3.0 microIU/ml. But even though this lower range is less arbitrary than the older standards, it still isn't based on an understanding of the physiological meaning of TSH."

The TSH Reference Range: A Guide for Thyroid Patients

 

[Xisca]

@haidut

what does the ratio of pyruvate and lactate tell you then?

1: high pyruvate - low lactate
2: low pyruvate - low lactate
3: high pyruvate - high lactate
4: low pyruvate - high lactate

only 4 I would assume to be "healty" ?

I do not have blood results about them both, only urine tests of organic acids. Only lactate is high. Does it tell something too, or it has to be a blood test?

 

[peep]

I do not have blood results about them both, only urine tests of organic acids. Only lactate is high. Does it tell something too, or it has to be a blood test?

So you didnt test your lactate with a blood test?
Maybe try that first, before you interpret that much in it.

 

[haidut]

@haidut

what does the ratio of pyruvate and lactate tell you then?

1: high pyruvate - low lactate
2: low pyruvate - low lactate
3: high pyruvate - high lactate
4: low pyruvate - high lactate

only 4 I would assume to be "healty" ?

No, 4 would be the worse, you want a high pyruvate/lactate ratio. So, 1 would be best and potentially 3, while 2 would potentially mean ketosis or some sort of glycolysis disorder while 4 would be highly reduced state and metabolic acidosis.

 

[haidut]

Beg pardon in advance for the vague response. (And maybe off topic.) Perhaps other forum readers have close links to laboratory medicine and may answer better.

It has been years since I tried to pursue this question. Different hospitals/health care networks used to have their own references ranges, sometimes slightly differing in the range numbers. Even accounting for different units, reference ranges also vary from country to country.

My impression was that the technical decisions were usually left to Laboratory Medicine specialist directors. These directors in turn took guidance from specialist physicians in their network, professional Laboratory Medicine association conclusions, and specialist physician group guidelines. Sometimes recommendations from equipment manufacturers also figured in. I was told there can be different decision making processes for different serum lab tests. Some specialized test are only done by a few labs in an entire nation, so the real specifics are internal to those specialty labs. The lab testing market in the U.S. for instance is now dominated by Quest & LabCorp. Only as a guess, the decision making of the huge corporate labs is even more encrusted. And once values are set, they seem to budge little over time, no matter what data emerges.

Recently, I have (non-Peating) friends whose physicians are making major cancer treatment recommendations based on very tiny number differences that would not generally be statistically significant.

In short, the “absoluteness” of reference ranges is far from absolute. Individual variation, diurnal variation, lab error, reproducibility of original research findings, and more push uncertainty further. Dr. Peat has of course written about the tautology of using estimates of the abnormal population to set normal values, which then set the percentage of abnormals.
- -
Preventing and treating cancer with progesterone.
"As the newer, more direct tests became available, their meaning was defined in terms of the statistical expectation of hypothyroidism that had become an integral part of medical culture. To make the new TSH measurements fit the medical doctrine, an 8- or 10-fold variation in the hormone was defined as “normal.” With any other biological measurement, such as erythrocyte count, blood pressure, body weight, or serum sodium, calcium, chloride, or glucose, a variation of ten or 20 percent from the mean is considered to be meaningful. If the doctrine regarding the 5% prevalence of hypothyroidism hadn't been so firmly established, there would have been more interest in establishing the meaning of these great variations in TSH."
"In recent years the “normal range” for TSH has been decreasing. In 2003, the American Association of Clinical Endocrinologists changed their guidelines for the normal range to 0.3 to 3.0 microIU/ml. But even though this lower range is less arbitrary than the older standards, it still isn't based on an understanding of the physiological meaning of TSH."

The TSH Reference Range: A Guide for Thyroid Patients

Great, thanks for the details.

 

[Xisca]

No, 4 would be the worse, you want a high pyruvate/lactate ratio. So, 1 would be best and potentially 3, while 2 would potentially mean ketosis or some sort of glycolysis disorder while 4 would be highly reduced state and metabolic acidosis.

Is it possible to get those indications from the urine test?

 

[haidut]

Is it possible to get those indications from the urine test?

Don't know, have not seen metabolic testing done on urine except glucose.

 

[ecstatichamster]

Since B2 riboflavin at higher doses has totally transformed my body's functioning in the last two months, I would like to throw out there the idea that if the B1, B3 etc program discussed in this thread has not yielded the benefits expected, one might add 100 to 400mg B2 to the mix.

It's only logical to think that B2 is also integral to the processes discussed herein.

I remain shocked and astonished at what I can do today compared to what I have never ever been able to conceive of doing only about 2 months ago.

Should start a separate thread about it. I’m really interested in this. I have found some great results with Riboflavin also. I think it raises metabolism

 

[haidut]

Since B2 riboflavin at higher doses has totally transformed my body's functioning in the last two months, I would like to throw out there the idea that if the B1, B3 etc program discussed in this thread has not yielded the benefits expected, one might add 100 to 400mg B2 to the mix.

It's only logical to think that B2 is also integral to the processes discussed herein.

I remain shocked and astonished at what I can do today compared to what I have never ever been able to conceive of doing only about 2 months ago.

The FAD/FADH ratio is intimately connected to the NAD/NADH one. Of the 32 molecules of ATP produced from one glucose, about 80% are from the various mechanisms that use NAD as a cofactor while the remaining 20% are from the FAD/FADH reactions. So, riboflavin is also very important for metabolism and perhaps more responsive to supplementation as it is easier to get deficient in it.
Thanks for bringing it up and please feel free to start another thread if you want.
Rosacea, inflammation, and aging: The inefficiency of stress
"...All of the nutritional factors that participate in mitochondrial respiration contribute to maintaining a balance between excessive excitation and protective inhibition. Riboflavin, coenzyme Q10, vitamin K, niacinamide, thiamine, and selenium are the nutrients that most directly relate to mitochondrial energy production."

 

[haidut]

Do you think Epsom salt baths, 1-4lbs per bath can be powerful doses to retain magnesium and support ATP/Thyroid?

I think it is probably better than oral magnesium as most oral forms have very limited absorption with the possible exception of magnesium bicarbonate.

 

[haidut]

Is the maladaptation a state in which the body entered a cycle where everything that's becoming available is being used to prevent further harm and nothing is being left to actually restore? If so, it's a downward path if you don't intervene or provide "temporary excesses" as our manager mentioned. If that's the case I think I finally understood what it means, doing what you normally do won't be enough

Exactly. Or at least this is my understanding. Btw, the data in thiamine in that quote is only partially correct. More recent studies have found that thiamine is also an inhibitor of PDK just like DCA (as per the study I posted in the original thread, and it is also a carbonic anhydrase inhibitor like acetazolamide. But there are indeeed some cases where just giving extra thiamine won't be enough, hence the need to explore niacinamide, biotin, MB, thyroid, progesterone, emodin, vitamin K2, etc. But it is fully reversible as it has never been shown that these is actual damage to these enzymes, even in cancer.

 

[peep]

@haidut

what would help oxidative phosphorylation?
I was told that MB and Palmitic acid could be helpful. Are there any other things to take or not to take to help this?