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Nitric Oxide, Peroxynitrite, and the Impairment of Mitochondrial Replication in CFS

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Hip, Apr 5, 2011.

  1. dbkita

    dbkita Senior Member

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    @LaurielL

    You always have such interesting posts :)

    My only caveats would be as follows:

    1) Careful with the amyloid hypothesis link to Alzheimer's and then using that to hook in KP. The classical tau phosphorylation and beta secretase models of plaque formation and their relevance to ALZ are falling out of favor. I actually am pretty close to some of this research for professional reasons. Some recent conferences suggest we really don't know what is going on. The shift is towards earlier and better diagnosis. Treatment has been for the most part ... unsuccessful.

    2) While ACAT may be relevant, there is again a population frequency problem. I think there must also be some sort of epigenetic factors. CFS / ME has a relatively abundant occupancy in the population (comparatively speaking). Homozygote ACAT is pretty darn rare. While heterozygote is too common. Maybe the genetics affects sensitivity but I still bet there are epigenetic factors.

    3) I concur Martin Pall's work is more intriguing. Ironically though from personal experience every time I have tried to lower arginine intake (at diet level) or introduce lysine (I have high CMV and other titers), I always feel worse. As I have posted before I feel better eating four to five 1 oz serving of nuts a day. My diet is typically otherwise lysine heavy so the net effect is about equal balance. If I lower the nuts, I feel worse. If I add lysine I feel worse. Complicated to say the least. Who knows maybe it is more for me to do with the urea cycle and ammonia clearance. So many unknowns.
  2. LaurieL

    LaurieL Senior Member

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    I am of the opinion that epigenetics are very possible. In fact, I have been all over this possibility since I had lab results showing klebsiella oxytoca outside of my GI tract as well as pathogenic e coli. So far as I can glean information, these two have the power to modify the tryptophan pathway, and so does Lyme, another gram-negative disease. In other words, they can and do take control. My questions are do the mutations make the difference in presentation, virulence, and the ability to get rid off them?

    As far as population frequency, I do not think a comparison is available by research or public citizen, to show a correlation or not in any of what I am trying to convey.

    Induction of Kyn is correlated with AB, but Alzheimer's is just one example of neurological disease. Look at schizophrenia with regards to Kyn induction. Not amyloid, but neurological it is. I don't think induction of Kyn always results in AB. But it surely has a correlation that shouldn't be overlooked or dismissed. Same with bipolar, OCD, ADHD, Parkinson's, and others. Look at the induction of Kyn, it can lead to all sorts of different places. NNow my caveat is, why? Genetics and the toxins produced, and the synergy.

    Within the CFS/ME model, those early cases do show something, in the fact that some of those patients experienced resolution, or the disappearance or movement of the bright spots. Overt bacterial or viral infection in the brain kills really fast, but toxins do not.

    Besides ACAT, COMT will also come into play and affects dopamine, nor-epi, and serotonin.

    My experiences mirror your own concerning arginine and lysine. I do not have CMV. And I also mirror the nut thing....:) One of the greatest, besides methylation protocol additions, was niacinamide and moly. My opinions expressed stems from my profound reactions to both, as well as the ammonia supp's that didn't work for me. Niacinamide directly correlates and is a product of Kyn.



    Lauriel
    merylg likes this.
  3. dbkita

    dbkita Senior Member

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    Niacinamide and molybdenum are very good for me. I upped niacinamide just in the last 3 months and added in molybdenum over the same time interval. Even added niacinamide at bed time in last 3 weeks or so and I sleep better most nights. I am stimmed at all at night, the niacinamide shuts that down in a hurry and I have much more dream activity and awake more refreshed. Been a long time since I have experienced that.

    The molybdenum helped some of my vicious reactionary reflux which led me to finding out the headaches and reflux are one of the most common symptoms of sulfite issues in the trans-sulfuration pathway. That led me to focusing on the some the other trans-sulfuration issues like ammonia, etc. and to testing the urine sulfate strips.

    On lower amounts of methylation my urine sulfates even on my high protein diet are like 400 or so at night. With my current methylation protocol it is about 600-800. One night last week when I went overboard and gorged on meat at dinner (don't ask why) my urine sulfates hit 1600+ and I had cramps all over my back, neck, jaw, etc. The yucca helped some the next day with the cramps but I am not convinced it is reasonable adjunct for me to take on a regular basis. I should say my normal diet is 200-250 grams of protein a day to prevent catabolism.

    Question ... what do you mean by "Niacinamide directly correlates and is a product of Kyn"? Product in what way? I must be missing something sorry.
  4. LaurieL

    LaurieL Senior Member

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    Better said.....a downstream product.

    [​IMG]
  5. dbkita

    dbkita Senior Member

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    Ahhh you meant NAD+ and NADP can be a product (which are of course very important to the body), though there is a more direct route from niacinamide down the middle of the diagram. I was just confused since while there are salvage pathways for B3, they generally have to be sourced from outside, hence my confusion. Thank you I did not know about the Quinolinic acid / Kyn production branch.

    Hmmm I wonder then if this is part of why B3 (niacinamide) is so beneficial to me even at night?
    Is it possible this also fits into low BH4 levels? In other words if tryptophan conversion to 5htp is poor due to low BH4 could this leave tryptophan around for other purposes? Probably an overly simplistic idea but I wonder.
    After all we know people with severe BH4 deficits end up with way to much phenylalanine running around (hence PKU).

    Point in fact in the past I have never had any use in taking tryptophan to stimulate serotonin. Hence I have to take 200 mg of 5htp every night (more for pain during the next day than for sleep at night, in fact I sleep better the first several nights on 150 mg 5htp, it is the pain that gets me eventually).

    Well I get a urine amino acids and serum amino acid results back soon. Could be instructive. I do eat 200-250 mg of protein a day. Poor kidneys.

    I should add to my question above regarding tryptophan redirection down the Kyn pathway, if this could play a role in NMDA activation with those of us with low BH4. Quite a potentially nasty cycle.
  6. LaurieL

    LaurieL Senior Member

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    I would like to expand this hypothesis. I posit those bright spots were the result of toxin upregulation, and that the known mutations associated with neurological disease, including those mutations in the methylation cycle, will determine the outcome of the toxin formation, amyloid or not. More to add....

    Lauriel
  7. Asklipia

    Asklipia Senior Member

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    Just a small addition to the list of methods to increase NO :
    Using an eye massage device seems to do the trick. Maybe a modern way to resonate OM?
  8. LaurieL

    LaurieL Senior Member

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    I couldn't resist commenting on frequency. :D Did you know that the eyes, the inner ear, and the skin not only responds to light but to frequency or sound. Kind of a no brainer when referring to the ears, but who knew about the skin and the eyes. The reason why is due to the melanin content, and melanin is a product of the Kyn pathway....

    Lauriel
  9. LaurieL

    LaurieL Senior Member

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    Speaking of melanin......anyone heard of pink adrenaline? A good read is the Adrenochrome Hypothesis (Osmond-Smithies Hypothesis).

    The production of adrenochrome is through the Kyn pathway, and I did a search on this site yesterday to see if it had been talked about. I found several posts in which it was mentioned by Rich VanK, but I would like to present the concept behind adrenochrome, and the indolechromes.

    The Adrenochrome Hypothesis is based on the assumption that methylated derivatives, (general class) are needed for its production. All indoles are methylated derivatives of the Kyn pathway. Indoles are derived from adrenaline.

    The Adrenochrome Hypothesis refers to conditions in which are required for formation of adrenochrome. These conditions would include substrate, catecholamines, enzymes/catalysts necessary for oxidation (the Reactive nitrogen species I have referred to in other previous posts), the products of oxidation (also mentioned in previous posts), and the production of melanins, which are chrome indole polymers.

    Most melanins are derived from tyrosine and require the enzyme tyrosinase. The chrome indoles can also be formed by aldehydes formed by MAO. And from there can be metabolized by three pathways. A decrease in amine oxidase or a surplus of amines would shift the amines into the indole pathway. I really believe the indole pathway and the subsequent increase in indoles by infection need to be looked at more closely by our professional researchers. The Kyn pathway has everything to do with tryptophan, tyrosine, dopamine, and serotonin, of which most of us have problems with. Although the problems encountered are not all the same, that is due to the genetic mutations we have in common or not, surrounding this pathway. Those mutations would be the MTHFR, MAO, COMT, and ACAT within the methylation cycle, and then IDO, TDO2, and IFN GR1 outside of the methylation cycle.

    The functions of the Kyn pathway are for endogenous production of antibiotics, and the production of melanin. Which again can also be a response to pathogens, and functions in the innate immune response system.

    The hypothesis states that melanins are increasinly being recognized as essential in a wide variety of roles, and one of those roles is toxin sequestration. Its in the precursors in which melanin can function as a cytotoxin, and the neurological issues we are suffering may have to do with some of the intermediates fromed in the melanin pathway. Adrenochrome. Its production is associated with being pyschotomimetic, and is being examined in neurological diseases such as schizophrenia, Parkinsons, and others.

    The path to adrenochrome formation is through the methylation of nor-epi to PNMT (phenylethanolamine N-methyltransferase). Also associated with PKU. And forming epi which can be oxidized by one of three mechanisms.

    1) Oxidation by MAO forming 3,4-dihydroxy-mandelic acid
    2) Methylated by COMT to form metanephrine and oxidized by MAO to form vanilmandelic acid
    3) Oxidation by copper ions, or copper ion containing enzymes to form adrenochrome
    (Implications in Wilsons Disease)

    IMO, the formation to adrenochrome is not exclusive to specific neurological diseases but is specific to inflammation resulting in neurological disease. Again, predisposition or mutations would then have a role in which way the neurological disease presents. Have to go to work....more on sunday.

    Lauriel
    Asklipia likes this.
  10. LaurieL

    LaurieL Senior Member

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    dbkita,

    It is in the adrenochrome formation, the indole pathway, and thus the Kyn pathway that you may find a likely answer to why nicotinamide or niacinamde is so helpful. :)

    Lauriel
  11. Dfox

    Dfox

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    Hi pretty new to pr, but wanted to ask if tyrosine will hurt if you have illness induced pku (hpu). I'm trying the Marty Hinz protocol right now, but I' m having a hard time getting my doseagd up as I get very acidic; my urine smells like vinegar. My sleep has improved overall, but I'm having a lot of nightmares. I talked with the Pfeiffer institute and the say if Labcorp does thd test right, they have good results. Do you know if you have kpu? Did you get your aminos back? I'm so exhausted chasing, could use help.

    Thanks
    Debbie
  12. Asklipia

    Asklipia Senior Member

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    Lauriel I find this fascinating, even though I do not have the background to understand you completely :(

    I would like to point out some clinical evidence: when I started to heal, came a point when I was "sunbathing with no tan", that is my whole body would turn apricot coloured, but there were no clear delineations where my bathing suit was. When I used to suntan before, my skin would go darker, with clear white parts under my bikini.
    So something is definitely linked to melanin.

    All of this of course has to do with the alpha-melanocyte stimulating hormone (α-MSH) and the disruption induced by glutamates.
    My hypothesis is that I got sick from fake folates (glutamates), and that I got well again thanks to extra α-MSH.
    As well as extra Thyrotropin Releasing Hormone (TRH) obtained by my Bains dérivatifs (http://forums.phoenixrising.me/index.php?threads/bains-dérivatifs.15574/), one helping the other.
    I suspect Fake Folates are creating the NPY trap.

    Of which I came out by stopping Fake Folates, upping α-MSH and TRH as much as I could.
    There is definitely a role for melanins.

    Best wishes
    Asklipia
    :devil: FFP :devil:
  13. Dfox

    Dfox

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    Hi is a-MSH a supplement. I know that Richie Shoemaker uses this in his mold toxin removal. What are the fake folates?

    Thanks, Dfox
  14. Dfox

    Dfox

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    Hi, I'm trying to so figure out my health issues. If you have time to reply I would appreciate it. I have been posting in different places all over the board questions about methylation. I started an amino brain repair program a few weeks back, and became VERY urinary acidic, and my underarms and urine smelled just like vinegar. I stopped the protocol and the smell went away, but I am still dumping protein and bilirubin is high and my ph is low on my diatech diabetic test strip. I have sulfide test strips but did not buy sulfate, as it looked to me like sulfites flow to sulfates. I guess I was wrong. My urine sulfate levels are high according to the doctor (did a urine 24 hr sulfate test). The doctor keeps telling me not to eat protein, sulfur vegetable and no starch! I am having a hard time keeping weight on, and I'm afraid to eat. I am watching starches because of the blood sugar issues.

    Am I over doing the methylation? I am taking high doeses of methyl b12, 5mth folate and adb. ANY advice would be helpful. I have a dr apt tomorrow, but I think his idea is DON"T EAT! Also, I'm VERY COLD!

    Thanks, Dfox
  15. Asklipia

    Asklipia Senior Member

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  16. dbkita

    dbkita Senior Member

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    The vinegar smell suggest sulfur processing issues even maybe high levels of H2s? Sulfate strips are in my opinion more reliable as an indicator / bio marker. Sulfite problems basically means molybdenum, vitamin E and a couple of other things to support conversion to sulfates. Sulfite strips should normally be low or negative if processing is reasonably.

    But high sulfates means high ammonia regardless of sulfite issues. You have to calibrate though. I thought I was fine on my high protein diet and methylation supplements at 700-800 on the sulfate strips at night. But a recent 24 hour urine sulfate tests says I am WAY above normal. So now I realize it has to be 400 or so for me otherwise I am too high. Also means my CBS gene and defective BHMT genes (all of mine are homozygous) are causing a large ammonia load. Even if I am successfully removing it (serum ammonia 50%-75% usually) doesn't mean I am not overloading things and killing my BH4.

    Bilirubin high is something else. Do you have protein in your urine? Done a urinanalysis? Other liver markers? That is not the fault of the trans-sulfuration pathway imo. That is something about your liver. Maybe an infection, inflammation or detox issues.

    I am like you in that I am in a catabolic state. I am also supposed to lower thiol rich vegetables and high protein. But I think personally the "don't eat" idea is BS. Your body is subconsciously trying to get you to get nutrients in. Try to figure out what you CAN eat. Maybe split up into smaller meals. Be careful that gut dysbiosis is not disrupting absorption. How many calories do you eat a day? I eat 3500-4000 and cannot gain weight. So I don't have an answer for myself, sorry.

    The cold is very likely your thyroid levels. But it could also be defective Krebs cycle. Or even an infection. I don't see how high methylation would affect your metabolic temperature to make you cold. However, high methylation will likely cause more flow down the trans-sulfuration pathway. One way is to address the BHMT defects with PC, TMG, or maybe even PS (careful it lowers cortisol, so don't take in morning). Methylation when complemented with Krebs cycle support means more energy, more neurotransmitters, etc.

    The blood sugar stuff is between you and your doctor. I won't touch talking about that with a ten foot pole. Sorry.
    I avoid starches because I have a leaky gut and the lectins are destructive. I also have a gut dysbiosis which is hard to rectify. My blood sugar is fine.

    What levels of methylation supplements are you on btw? Just curious. Still I think you have a lot more going on than just methylation.
  17. Lotus97

    Lotus97 Senior Member

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    Hmmm, there was a section on QUIN in Buhner's book Healing Lyme. I'm going to have to reread that. One of the things he recommended is selenium.
    http://www.ncbi.nlm.nih.gov/pubmed/12871589
    Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: in vitro and in vivo studies.
    Abstract
    Quinolinic acid (QUIN), a well known excitotoxin that produces a pharmacological model of Huntington's disease in rats and primates, has been shown to evoke degenerative events in nerve tissue via NMDA receptor (NMDAr) overactivation and oxidative stress. In this study, the antioxidant selenium (as sodium selenite) was tested against different markers of QUIN-induced neurotoxicity under both in vitro and in vivo conditions. In the in vitro experiments, a concentration-dependent effect of selenium was evaluated on the regional peroxidative action of QUIN as an index of oxidative toxicity in rat brain synaptosomes. In the in vivo experiments, selenium (0.625 mg per kg per day, i.p.) was administered to rats for 5 days, and 2 h later animals received a single unilateral striatal injection of QUIN (240 nmol/ micro L). Rats were killed 2 h after the induction of lesions with QUIN to measure lipid peroxidation and glutathione peroxidase (GPx) activity in striatal tissue. In other groups, the rotation behavior, GABA content, morphologic alterations, and the corresponding ratio of neuronal damage were all evaluated as additional markers of QUIN-induced striatal toxicity 7 days after the intrastriatal injection of QUIN. Selenium decreased the peroxidative action of QUIN in synaptosomes both from whole rat brain and from the striatum and hippocampus, but not in the cortex. A protective concentration-dependent effect of selenium was observed in QUIN-exposed synaptosomes from whole brain and hippocampus. Selenium pre-treatment decreased the in vivo lipid peroxidation and increased the GPx activity in QUIN-treated rats. Selenium also significantly attenuated the QUIN-induced circling behavior, the striatal GABA depletion, the ratio of neuronal damage, and partially prevented the morphologic alterations in rats. These data suggest that major features of QUIN-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that selenium partially protects against QUIN toxicity.
  18. kyzcreig

    kyzcreig

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    Fascinating thread. I'm currently re-exploring the ONOO theory after finding some success with Dr. Martin Pall's protocol. Initially, I reacted severely to it, I'm glad I stuck with it.

    Interestingly, ONOO dysfunction has been connected to Leaky Gut. Many of us have gut problems and fixate on trying to kill pathogens (candida, bacteria, etc.) when we might really have to address the ONOO cycle.
    http://sanjosefuncmed.com/intestinal-permeability-clinical-unwinding-leaky-gut/

    Last edited: Apr 24, 2014
  19. Thinktank

    Thinktank Senior Member

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    When i was still "healthy" and into hardcore weight lifting about 10 years ago i used several products that raise NO. One thing that i noticed was an improvement in cognitive functions. Would that make sense?

    Unfortunately i'm +/+ for SOD2 (MnSOD, mitochondrial). Will increased ROS from an elevation in NO eventually cause more mitochondrial damage?

    Edit: I just remember that 3 years ago when i had a healthy period i used a product with AKG, L-arginine and a few others compounds that enhance NO. Although i didn't notice much cognitive improvement from it i did gain weight and strength rapidly.
    Last edited: Apr 24, 2014
  20. kyzcreig

    kyzcreig

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    I can relate to that. I was into bodybuilding before the sudden onset of my illness.

    Arginine does indeed facilitate NOS production. But if your problem is an overregulation of NOS, specifically iNOS, as opposed to the good eNOS and nNOS, you may not want arginine. I took arginine the other day, for science, without anything else and severely reacted to it.

    I've found success downregulating iNOS with Martin Pall's ONOO protocol and supplementing the glutathione cycle. Specifically topical glutathione has benefited me much more than oral supplements, which makes sense given their poor bioavailability.
    Last edited: Apr 24, 2014
  21. Thinktank

    Thinktank Senior Member

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    I'll look into that ONOO protocol, looks interesting.

    I also benefit from supplementing GSH precursors and cofactors. NAC gives me a boost but causes intestinal problems after a few weeks. Oral reduced GSH on the other hand doesn't do anything.
    Maybe IV GSH is worth a shot.

    What's the brandname of the topical glutathione product you are referring to?

    I remember reading a paper by Maes et al. about leaky gut and upregulation(?) of iNOS. Man, if i could just remember the details of all the things i have read in the past few years....
  22. kyzcreig

    kyzcreig

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    x)

    I use Swanson
    http://www.amazon.com/L-Glutathione-Cream-Setria-59/dp/B0091QY1OU

    before that I was using Kirkman, which I think is slightly better but not enough to justify its greater cost. When I use it before sleeping the difference in my quality of rest is substantial.
  23. adreno

    adreno 3% neanderthal

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    I'm afraid so. You're gonna need more antioxidants to counter the ROS.

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