Members with knowledge of no/onoo hypothesis

[Wishful]

it is undisputated that peroxynitite is BAD because it is an oxidizer.

Nope. Peroxynitrite is not completely evil 100% of the time, and peroxynitrite scavengers are not completely good 100% of the time. Our bodies to produce scavengers, but evolution hasn't provided us with a superabundance of those, since there's an optimum level for health. ONOO- plays important roles in our bodies, at the appropriate levels. One task is to break down IDO, at the appropriate rate. We need IDO, and we need more during infections or other cellular hazards, but we need it to go away afterwards, rather than catalyzing TRP with no limit. Thus ONOO- is a mechanism for maintaining proper levels of IDO. ONOO- is also critical for various types of signalling in and between cells. So, for a healthy body, artificially boosting ONOO- scavenging may not be a good thing. For an unhealthy body, the optimum amount of ONOO- and scavengers depends on the situation.

We don't have a complete understanding of how all the various mechanisms in the body work together, so we can't be sure that a treatment that looks good from one theory won't cause harm via one of its other effects. So, if you take a ONOO- scavenger and it makes you feel better overall, you might keep taking it but should remain vigilant for unwanted side effects. If it doesn't provide a noticeable improvement, I think it would be unwise to continue taking it on the assumption that 'scavengers are 100% good for you'.

 

[vision blue]

@Wishful
Nothing is 100 percent evil. If you are happy with your current levels of ROS, then congrats.

For me, like some of these other posters, im trying to remove the eNOS uncoupling That i believe I have. Thus required having a strategy to get peri...under control before trying to increase NO or otherwise i the NO will lead to even more superoxide and the nitrate oxulidizer weve been Discussing (and continued uncoupling)

 

[muckledug]

@Wishful
Nothing is 100 percent evil. If you are happy with your current levels of ROS, then congrats.

For me, like some of these other posters, im trying to remove the eNOS uncoupling That i believe I have. Thus required having a strategy to get peri...under control before trying to increase NO or otherwise i the NO will lead to even more superoxide and the nitrate oxulidizer weve been Discussing (and continued uncoupling)

What strategy are you using to tackle eNOS uncoupling / peroxinitrite?
Are you taking methyl folate? If so, what dosage?

 

[Learner1]

This conversation has a lot of misinformation. The basic theory of peroxy nitrites affecting me/cfs is in the oxidative and nitrosative stress article by Morris and Maes, attached here. Peroxynitrites also impair mitochondria complex 1, and they damage mitochondrial membranes, causing them to be leaky and inefficient at making energy. So, any solution has to incorporate repairing the damaged membranes.

Kuvan: yes, I noted that. Support of BH4 production via methyl folate seems a more feasible tactic.

Folate is not adequate to discourage the formation of peroxynitrites. The elements needed are discussed in Martin Pall's ONOO article below.I Italso takes adequate B12, and C, and the nutrients.

I'vebeen working with this theory for 3 years with extensive testing and trying to improve peroxynitrites, which I was successful with to a point. But, I got major gains by adding Kuvan after I was already sufficient in the other nutrients. For me, it was the missing link.

But regardless of whether any theory that says peroxynitite is involved in CFS is true or not, it is undisputated that peroxynitite is BAD because it is an oxidizer. And when you increase NO, in the presense of superoxide (which alot of us have to excess), then the NO and the superoxide react to form peroxynitite .

So it is back to the original question to those who are trying to boost their NO levels, was wondering if they are doing something in addition to deal with an expected rise in peroxynite. Wishful had a good idea to then scavenge that oxidizer with assorted things she listed, but maybe those how have been increasing their NO have done other things (or those).

Actually NO does some good things, like alllow one to exercise better and reduce high blood pressure, and a lot of diseases are linked to low NO. Peroxynitrites production depletes NO. I believe some of the benefits I've been getting from Kuvan are because it increases NO, which I've been able to prove using NO test strips. I've also benefited from using the Berkeley Life NO booster supplement.

Peroxynitrite scavengers are readily available. Cinnamon, Rosemary, Resveratrol, turmeric come to mind. Check online for a list of the most effective ones

I was already taking all of those, but they did very little to help the peroxynitrite problem - High dose methylfolate, methylcobalamin, and C did do a lot to help - My nitrotyrosine levels dropped in response - nitrotyrosine is a marker of peroxynitrites. But, adding the Kuvan and Booster have added additional help on top of that.

- I had it chekced because of joint pains- but i have high oxalic acid in urine. (and my urine is very acidic plus have high urine ammonia levels. I eat very low protein, so not sure what that's all about-

High oxalic acid is due to the body absorbing oxalate toxins from plant-based foods, spinach, rhubarb, raspberries, almonds and other nuts, root vegetables, and many grains. The normal defense to this is some species of bacteria in the microbiome, particularly oxalobacter formogenes, but many ME/CFS patients have lost these due to use of antibiotics. A heavily plant-based diet can be very bad for this problem, as the toxins are sharp crystals that can cause pain and lodge in all kinds of tissues as well as damaging mitochondria. A low oxalate diet, taking a form of citrate before every meal, and ensuring B6 is adequate, are all steps helpful in reducing oxalate loads. Animal proteins all fats do not contain oxalates. This is a problem totally unrelated to peroxynitrites though.

 

[muckledug]

But if your boosting your NO, how are you keeping it from forming peroxynitrite ?

I think that NO production via diet is independent of NOS and therefore won't contribute to the NO/ONOO vicious cycle of peroxynitrite production.

 

[Learner1]

I think that NO production via diet is independent of NOS and therefore won't contribute to the NO/ONOO vicious cycle of peroxynitrite production.

I'm not sure that's correct. Do you have any evidence of this?

 

[kangaSue]

I'm not sure that's correct. Do you have any evidence of this?

Figure 1 in this article says nitrite/nitrate are a NOS-independent source of NO
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137939/

It says in this next paper about dietary nitrates;
[Nitrate itself is inactive and without effect. Nitrate must first be reduced by oral commensal bacteria to nitrite and then nitrite has biological activity. All biological effects of nitrate are abolished by antiseptic mouthwash that kills oral bacteria]
https://www.sciencedirect.com/science/article/abs/pii/S0271531715001359?via=ihub

 

[Learner1]

Then there's this:

Early after the discovery of the signal transducing physiological functions of the free radical nitric oxide (•NO) in the vasculature and nervous system (e.g., vasodilation and neurotransmission), it became evident that •NO could also participate as a cytotoxic effector molecule and/or a pathogenic mediator when produced at high rates by either inflammatory stimuli-induced nitric oxide synthase (iNOS) or overstimulation of the constitutive forms (eNOS and nNOS) (1). Much of •NO-mediated pathogenicity depends on the formation of secondary intermediates such as peroxynitrite anion (ONOO–) and nitrogen dioxide (•NO2) that are typically more reactive and toxic than •NO per se (2). The formation of reactive nitrogen species from •NO requires the presence of oxidants such as superoxide radicals (

), hydrogen peroxide (H2O2), and transition metal centers, the concentration of which can be increased either by •NO itself or by the same mediators that up-regulate •NO production. Nitrogen dioxide can also be formed in hydrophobic environments from the reactions of •NO with molecular oxygen, where these species concentrate.

https://www.pnas.org/content/101/12/4003

 

[vision blue]

@Learner1
I agree with you than NO can have some good effects- which is precisely why I am interested in inceaseing mine. However, as I say above, when excessive superoxide is present, the NO with the superoxide will lead to ONOO , which I happen not to want (perhaps others do, I do not).

That in turn lead to my question of whether those who iare increasing NO havee also done anything keeping it from producing ONOO. @Wishful had some good suggestions - let ONOO be formed, but then scavenge it with cinammon etc. @muckledug said she/he thought if you get it from food, then won't lead to the ONOO . you then said what is the evidence fo r that- i agree with you there - I have never seen evidience for that. @kangaSue then posted 2 bits of info i believe attempting to provide evidence for muckledug's claim. I looked at those, and neither provides evidence- even if NO is from a different source, if superoxide is there, "it" sure doesn't care where its from; biochem takes over, ONOO is formed. its possible though it prevents something else, so on my end i have to look up again and see what continues the eNOS uncoupling.

The abstract you paste in just above says exactly what I was said in a post a"The formation of reactive nitrogen species from •NO requires the presence of oxidants such as superoxide radicals" .That's what lead to my initial question

To continue the history, you do suggest another strategy above, which is nice:
"High dose methylfolate, methylcobalamin, and C did do a lot to help - My nitrotyrosine levels dropped in response - nitrotyrosine is a marker of peroxynitrites. But, adding the Kuvan and Booster have added additional help on top of that. "
if you by chance have a reference to the use of the methyl form of those vitamins and C helping prevent ONOO, would be great if you could post it.

I also need to see if I know if any of my tests have measured nitrotyrosine- off hand I don't remember any. Good suggestion. Have you been measuring it in plasma or urine? If you've watched it drop, you must have a test that lets you measure it relatively frequently?


(btw, genetiucally i'm an overmethylator, but that doesn't mean illness hasn't gotten in the way and tied up all my methyl donors).

To answer muckle...'s question- I don't have a strategy for doing so- that's why I was asking those who have been attempting to increase NO how they have handled this problem (I have not tried to increase NO)

 

[Learner1]

However, as I say above, when excessive superoxide is present, the NO with the superoxide will lead to ONOO , which I happen not to want (perhaps others do, I do not)

I understand the concern, and had thought so however there actually seems to be an opposite effect. I've found it helps to reduce peroxynitrites, and then increase NO.

However, as I say above, when excessive superoxide is present, the NO with the superoxide will lead to ONOO , which I happen not to want (perhaps others do, I do not).

I have an extraordinary amount of oxidative stress, and would suppose I make a lot of superoxide. And I was making a lot of peroxynitrites, or at least nitrotyrosine was high. And lipid peroxides and 8OHdG.

I used Pall's strategies to reduce peroxynitrites, by both oral and IV supplements, and was able to reduce peroxynitrites/nitrotyrosine as well as lipid peroxides and 8OHdG.

At this point, I measured NO and found it barely registering on the test strips. Using an NO booster increased my energy and reduced my blood pressure. (The Kuvan seemed to have the same effects, too.)

if you by chance have a reference to the use of the methyl form of those vitamins and C helping prevent ONOO, would be great if you could post it.

See attached

I also need to see if I know if any of my tests have measured nitrotyrosine- off hand I don't remember any. Good suggestion. Have you been measuring it in plasma or urine? If you've watched it drop, you must have a test that lets you measure it relatively frequently?

I've used the blood test from Health Diagnostics and Research International, HDRI. See their requisition form - you'll need to have your doctor contact them directly ; they won't take this out of date form.

that's why I was asking those who have been attempting to increase NO how they have handled this problem (I have not tried to increase NO)

I suspect peroxynitrite production is fairly common, at least in ME/CFS patients, as well as low NO.

 

[vision blue]

@Learner1
Awesome info; thanks much for taking the time to collect and post all that. Will read thru the papers and some other stuff you suggest. Sounds to me like you did things in the perfect order. Also going to see if can find a urine test instead of blood test- did see an article suggesting can be done that way. Have something else that took priority unfortuantely which i may post about.

thanks again

 

[Wishful]

@muckledug , I came across this in a paper ( http://www.bmrat.org/index.php/BMRAT/article/view/634 ) on cumin:

"Anti-inflammatoryAnimal model (rat)Nine weeks of intervention improved plasma nitric oxide, decreased the systolic blood pressure up-regulated the gene expression of eNOS, Bcl-2, TRX1, and TRXR1; and down-regulated Bax, TNF-α, and IL-6.Kalaivani, Saranya and Ramakrishnan (2013)24; Srinivasan (2018)27. "

I don't know whether that's what you're looking for boosting NO and eNOS, but have a look.

 

[Bobbi007]

@Wishful
Nothing is 100 percent evil. If you are happy with your current levels of ROS, then congrats.

For me, like some of these other posters, im trying to remove the eNOS uncoupling That i believe I have. Thus required having a strategy to get peri...under control before trying to increase NO or otherwise i the NO will lead to even more superoxide and the nitrate oxulidizer weve been Discussing (and continued uncoupling)

How did you do with this?