Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways

[MeSci]

I don't know if this is useful, but I've just had a dietary experience of down-regulating my peroxynitrite levels. I've been working on this issue throughout this year, with various strategies. My weight had begun creeping up, seemingly in response to the high carrot and nut/seed spread intake that my body requested to cope with peroxynitrite symptoms.

I decided to shift my meal times, hoping to be able to use up more energy during the day. I realized that I'd evolved my current meal pattern a year and a half ago to accompany my coffee enema regimen. Bone broth with no added fat or meat in the AM, and broth + fat + small portion of meat in PM. With carrots and seed spread especially in the PM. I've found that (surprise!) I've had better energy eating the higher density meal in AM, and greatly reduced peroxy symptoms, hence decreased intake to cope with it. Has my body been experiencing oxidative stress because I haven't been giving it enough fuel to function during my awake hours?

What do you mean by peroxynitrite symptoms, @ahmo? I always find it difficult or impossible to attribute symptoms to any particular thing, as there is so much going on that affects the body - food, supplements, exertion, stress, sleep/lack of sleep, environmental chemicals, etc. I can only make guesses, and sometimes take action to correct any problems, sometimes with success, and then I can be slightly more confident that I'm on the right track!

 

[Gondwanaland]

could it cause excessive accumulation of oxaloacetate?

B6 is what you take to get rid of oxalates, so it causes "oxalate dump". Don't ask me details about it
The oxalate discussion started with the Clostridium butyricum thread then went to its own thread, both linked in my sig under Prebx Probx Ox.

 

[Gondwanaland]

There's no particular conclusion. The diagram is just showing us the positions in energy pathways where the different amino acids feed in when they are catabolised for energy.

I was hoping that someone would have concluded something from the diagram, b/c there is a lot of stuff (ca. 98%) I don't tolerate there in supplemental form...

 

[ahmo]

What do you mean by peroxynitrite symptoms, @ahmo? I always find it difficult or impossible to attribute symptoms to any particular thing, as there is so much going on that affects the body - food, supplements, exertion, stress, sleep/lack of sleep, environmental chemicals, etc. I can only make guesses, and sometimes take action to correct any problems, sometimes with success, and then I can be slightly more confident that I'm on the right track!

There's been a particular symptom cluster that I first attributed to ammonia, and after chasing the sources of that, peroxynitrite emerged as the next culprit. Mostly related to my head: not exactly headache, as in pain in the head. Rather, a feeling of fullness in my head, squinty eyes, a taste in my mouth that's not exactly metallic, but similar. Feeling as if I will crash if I don't do something now. If left to go on, then comes restlessness, tendency toward breathlessness. If I then consume antioxidants, the symptoms reduce or clear immediately.

I've been chipping away at this issue for these past 6 months. I found dramatic reduction in the occurance when I added FMN form of B2. And then, following a 3-day water fast, hoping for the advertised immune system/stem cell reset, an even further reduction. When it was at its worst, I was consuming more than 1kg carrots/day, in juice and raw carrots. Plus a range of antioxidant supps, and antihistamine supps. Now, I'm taking none of those supps, my need for carrots is greatly reduced, I'm less prone to PEM (if I'm careful, cautious in my activity.) I am so thrilled to have not only gotten on top of this oxidative stress response to such a degree, but to have stopped spending the bulk of my budget on bi-monthly iherb orders.

 

[Gondwanaland]

@ahmo I have similar symptoms - the dreaded squinty eyes, sometimes followed by a tightness in chest... I attribute to ammonia, usually lysine resolves it. Paradoxically a trigger for me is supplementing riboflavin (I have good news: family members are going to the US in August and they will bring me FMN and R5P )

I think that it is actually related to serotonin and its slow breakdown by +/+MAO-A.

According to Ray Peat eating raw carrots helps to reduce serotonin (=endotoxin). For those sensitive to it: BEWARE OF OXALATES

Ray Peat, PhD on the Benefits of the Raw Carrot
Besides avoiding foods containing fermentable fibers and starches that resist quick digestion, eating fibrous foods that contain antibacterial chemicals, such as bamboo shoots or raw carrots, helps to reduce endotoxin and serotonin

 

[alicec]

I was hoping that someone would have concluded something from the diagram, b/c there is a lot of stuff (ca. 98%) I don't tolerate there in supplemental form...

There is nothing to conclude. The diagram is just describing energy pathways and showing where amino acids feed in when they are catabolised for energy. It is saying nothing about how these pathways might go wrong, nor about supplementation nor any individuals particular metabolic problems.

 

[ahmo]

Paradoxically a trigger for me is supplementing riboflavin

Yes, I felt poisoned when I tried to supplement extra r5p. FMN has been a totally good-news story! Carrots also for Carotenoids (alpha-carotene, bixin, zeaxanthin and lutein)-lipid (fat) soluble peroxynitrite scavengers according to Martin Pall.

 

[alicec]

I wonder whether the B6 dependency you refer to could be relevant to the fact that a significant proportion of us appear somewhat intolerant of B6. I think I am one of these. For example, could it cause excessive accumulation of oxaloacetate?

All transaminase enzymes use B6 as a cofactor. This is a huge enzyme class involved in many metabolic processes. Transaminases in general seem to be adversely affected by oxidative stress which causes conformational change which means that the enzyme no longer binds B6 well and so becomes functionally inefficient.

The particular enzyme that started this discussion which has now morphed across three threads is alanine glyoxalate amino transferase (AGXT). When this enzyme starts to fail one can head down the slippery slope of endogenous oxalate production and in that condition, one can certainly become very sensitive to B6 since it can trigger oxalate dumping.

The discussion with @Sidereal which prompted the phrase you quoted is really speculative. She was concerned about oxaloacetate accumulation and whether this might relate to oxalate accumulation. I really have no information about what oxalaloacetate accumulation might mean but do know something about what oxalate accumulation can do. I speculated in return about general links between the two and then remembered one direct link, viz, the glyoxalate cycle.

This is only one reason for B6 sensitivity - there could be many others.

 

[JaimeS]

I think you were right about CO2 making rain acidic, MeSci, but that was normal rain, which was still acidic when we were kids but not acidic enough to kill the trees. I think it got more acidic with lightning generating nitric acid too, but that can't have been too often.

You guys make me cite everything!

Acid rain is caused by the release of the gases SO2 (sulphur dioxide) and NOX (nitrous oxides). The main sources of NOX emissions are vehicles and fuel combustion.

Sulphur dioxide reacts with water vapour and sunlight to form sulphuric acid. Likewise NOX form nitric acid in the air. These reactions takes hours, or even days, during which polluted air may move hundreds of kilometers. Thus acid rain can fall far from the source of pollution.

-J

 

[Gondwanaland]

There is nothing to conclude. The diagram is just describing energy pathways and showing where amino acids feed in when they are catabolised for energy. It is saying nothing about how these pathways might go wrong, nor about supplementation nor any individuals particular metabolic problems.

It was actually enlightening to find out why I was benefitting from L-Glutamine supplementation:

https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid

α-Ketoglutarate is one of the most important nitrogen transporters in metabolic pathways. The amino groups of amino acids are attached to it (by transamination) and carried to the liver where the urea cycle takes place.

I had no idea that Glutamine could "mop out" ammonia!

 

[Gondwanaland]

And I really wish to find out why I have so much trouble with that box of aminos that feed into the Acetyl-CoA

 

[JaimeS]

The added diagram doesn't draw any conclusions, guys; it just allowed me to see the relationships between the amino acids and the cycles a lot more swiftly. There was something in particular I was looking at, but I'm still waiting for the brainspace.

@Jonathan Edwards, it's been a long time since college statistics, but p = 0.05 or lower is considered significant, right? I know this was a small study, so you can't expect it to be very robust.

-J

 

[Gondwanaland]

OTOH L-Glutamine knocks DH out, and I wish I could find out what would help him

The added diagram doesn't draw any conclusions, guys

Yes, it does and I am very thankful to you for posting it!

 

[Valentijn]

@Jonathan Edwards, it's been a long time since college statistics, but p = 0.05 or lower is considered significant, right? I know this was a small study, so you can't expect it to be very robust.

P <= 0.05 is pretty much the least rigorous standard used for statistical significance. It seems to appear mostly in the not-so-scientific sciences, such as sociology and psychology. Though I do think there was one particularly hilarious CFS BPS study using 0.10.

So ... maybe significant, but not particularly impressive.

 

[Jonathan Edwards]

@Jonathan Edwards, it's been a long time since college statistics, but p = 0.05 or lower is considered significant, right? I know this was a small study, so you can't expect it to be very robust. -J

What worries me about this study is that they talk about all sorts of very complicated statistical manipulations like log transforming non normal data and using corrections for the number of items studied but they show no raw data and do not do simple things like tell us who the controls were. Statistical significance is a matter of judging how likely the results are to have occurred by chance having optimally taken into consideration all relevant confounding factors. That taking into consideration will include judgment of the likelihood that the controls might be a lot of lab staff who are too busy to have lunch so have lower glucose levels (a very realistic possibility in my experience) and use of corrections like Bonferroni. I get worried when I find the description of how the stats were arrived at impenetrable. It makes me think that maybe the taking into consideration is not optimal - which basically means that a value like '0.05' is meaningless. One should not be bamboozled by statistical numbers. If you cannot see that the data don't look as if they could be due to chance by eyeballing raw data and you do not have good background information then statistics are not to be taken too seriously. Almost everyone in science tweaks their results around until they get something significant because journals do not publish negative data very often. A young scientist cannot afford to write off six months of work just because correctly he found the answer was negative.

These comments apply to all studies and not particularly this one, except for the specific worries I have mentioned.

 

[user9876]

That taking into consideration will include judgment of the likelihood that the controls might be a lot of lab staff who are too busy to have lunch so have lower glucose levels (a very realistic possibility in my experience) and use of corrections like Bonferroni. .

I had assumed that controls were hung over students (if there isn't age matching). Psychology experiments generally use a student population which tends to bias their results.

 

[Jonathan Edwards]

I had assumed that controls were hung over students (if there isn't age matching). Psychology experiments generally use a student population which tends to bias their results.

I think there was age matching so they are probably poor female post docs roped in because they cannot say no. But they might have been patients with other illnesses.

 

[Sidereal]

Yes, I felt poisoned when I tried to supplement extra r5p. FMN has been a totally good-news story!

Are they not synonymous terms for the same thing?

 

[Snow Leopard]

P <= 0.05 is pretty much the least rigorous standard used for statistical significance. It seems to appear mostly in the not-so-scientific sciences, such as sociology and psychology. Though I do think there was one particularly hilarious CFS BPS study using 0.10.

So ... maybe significant, but not particularly impressive.

P values are a function of effect size vs sample size and statistical noise. If you repeat an experiment 100 times, you will get 100 different p values.

A very low p value is not necessarily more impressive than a larger p value if the sample size is very high (or for phenomena where the variance is low). Likewise a p value of 0.10 may well represent an actual effect, in an underpowered study and justify further investigation.

Consideration of the effect size and statistical power of the study (includes correcting for multiple comparisons) is often more important than the p value.

 

[Marco]

I noted that one of the less convoluted suggestions in the discussion is a 'trend' towards hyperglycemia/possible insulin resistance which would be consistent with a CDC finding linking 'CFS' with metabolic syndrome.

There are interesting parallels between ME/CFS symptoms and diabetic autonomic neuropathy from reduced heart rate variability and 'sympathetic dominance', through gastro disturbances to 'exercise intolerance'.