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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. Hip

    Hip Senior Member

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    Not bathing at all is perhaps a little extreme, but using less toxic soap might be a start.

    Apparently the general introduction to the populace of synthetic sulfonated detergents in the early 1960's rapidly killed off all the ammonia oxidizing bacteria (AOB) that were naturally found on human skin up until that time, according to Whitlock.

    It is these natural AOB flora on our skin that supply the body with nitric oxide. They are analogous to the natural friendly bacteria in our guts, that supply vitamins.

    Soaps made from synthetic sulfonated detergents are ubiquitous now, and are highly toxic to AOB bacteria. So synthetic sulfonated detergents wiped out our natural AOB skin flora - flora that had been with us for millions of year, throughout human evolution.

    As a consequence of this loss, our basal nitric oxide levels took a plunge, Whitlock says, and the loss of these commensal AOB flora is a major factor in the increase in autism since the 1960's, Whitlock thinks.

    He says that by re-introducing this natural skin flora, we can raise our nitric oxide levels back to an appropriate level, and perhaps treat autism and CFS.

    A fascinating theory.
     
  2. Freddd

    Freddd Senior Member

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    Hi Hip,

    Another effect of harsh soaps and detergents is the removal of fatty acids from the surface of the skin which are involved in the manufacture of vitamin D with ultraviolet light. Clothing itself changes the flora of the skin that flourish. The ones promoted by lack of air and sun cause quite a stink. Skin open to the air and sun has different bacteria establish and smells quite different.

    He says that by re-introducing this natural skin flora, we can raise our nitric oxide levels back to an appropriate level, and perhaps treat autism and CFS.

    I wonder if he knows which bacteria he is talking about, the stenchful ones that come with clothing or the others that establish without clothing. Body lice also don't exist in the absence of clothing. So which are the "natural" skin flora of which he speaks?
     
  3. Hip

    Hip Senior Member

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    I think he knows; he has submitted a patent for this approach to CFS/autism treatment, and is working on making these ammonia-oxidizing bacteria commercially available as treatment.
     
  4. drex13

    drex13 Senior Member

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    L-arginine increases NO production, and it's cheap. It also increases stomach acid production.
     
  5. Freddd

    Freddd Senior Member

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    Hi Drex,

    One word of caution with l-arginine. It can trigger herpes outbreaks for some people some times.
     
  6. Hip

    Hip Senior Member

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    Yes, it does. The enzymes that make NO (namely iNOS, eNOS, nNOS) do so using arginine directly. So if you increase arginine levels, you will get more NO. At least initially.

    But unfortunately Whitlock thinks that these simple methods of boosting nitric oxide will not work in the long term, because NO levels are VERY tightly regulated in the body by many feedback systems (this tight control is necessary as NO is such a fundamental molecule in the body). So you may get a temporary NO boost by L-arginine, but the feedback systems will soon kick in, and undo your gains.

    No harm in experimenting though. As Freddd points out, L-arginine can cause herpes outbreaks, so a better NO booster to try might be citrulline malate, which has equal if not better NO boosting potency. The malate is good in CFS anyway. There are also NO raising herbs like Gynostemma pentaphyllum (used in bodybuilding circles), which increase NO levels by reducing the NO-destroying free-radicals in the blood.

    I have tried all the above, and experimented with taking them together in various combinations too, and though I often get immediate benefits, the benefits unfortunately seem to quickly disappear (after a day or so), which I guess is a result of these regulating NO feedback systems kicking in and bringing NO levels down again.

    So the trick is not just raising NO, but raising NO in such a way that circumvents the NO level regulating mechanisms bringing NO levels back down again.

    Interestingly, when I did manage to produce what seemed like a boost in nitric oxide, I temporarily lost all those slightly autistic traits that you get in CFS (the social withdrawal, and needing your own space more, needing solitude more, etc, etc). Propelled by a NO boost, I suddenly found myself wanting to speak to people, make friends, create rapport, feel for other people, etc, etc - all the natural human responses that seem to get much diminished in CFS (well, at least for me).

    So this makes me think that there is something to this low NO theory of CFS and autism.
     
  7. Freddd

    Freddd Senior Member

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    because NO levels are VERY tightly regulated in the body by many feedback systems (this tight control is necessary as NO is such a fundamental molecule in the body).

    Eggs Acktly! And since mb12 is part of that control system and mb12 tends to restore things to normal and mb12 works much more easily than trying to thread a needle at 100 yards by trying to manipulate effects rather than causes you will likely achieve better effects with the mb12,adb12 Metafolin and cofactors. What you are doing is more like trying to hunt a moose with a bb gun.
     
  8. Hip

    Hip Senior Member

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    Freddd, do you have an nice weblinks for the way methylcobalamin B12 is involved in the control systems of nitric oxide? On first glance, since hydroxocobalamin B12 (which you say methylcobalamin converts to) is a powerful scavenger of nitric oxide, you might expect NO levels to go down when you take methylcobalamin B12. That is, unless methylcobalamin is working to alter the controls system in a way that boosts NO production more than hydroxocobalamin can scavenge it. Of course, perhaps there paradoxical reactions (for example, hydroxocobalamin reducing NO levels then causes the body to make more NO - something like that).
     
  9. Hip

    Hip Senior Member

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    I just found in an abstract which I think describes what your are saying Freddd. It is full of terms I am only vaguely familiar with, but the general gist is that vitamin B12 is intimately linked to manufacture and regulation of nitric oxide in the body:


    The return of the Scarlet Pimpernel: cobalamin in inflammation II cobalamins can both selectively promote all three nitric oxide synthases, particularly iNOS and eNOS, and, as needed, selectively inhibit iNOS and nNOS.

    J Nutr Environ Med. 2007 Sep PMID: 18836533

    Wheatley C. Orthomolecular Oncology, 4 Richmond Road, Oxford OX1 2JJ, UK.

    Abstract

    The up-regulation of transcobalamins [hitherto posited as indicating a central need for cobalamin (B12) in inflammation], whose expression, like inducible nitric oxide synthase (iNOS), is Sp1- and interferon-dependent, together with increased intracellular formation of glutathionylcobalamin, adenosylcobalamin, methylcobalamin, may be essential for the timely promotion and later selective inhibition of iNOS and concordant regulation of endothelial and neuronal NOS (eNOS and nNOS.)

    Cobalamin may ensure controlled high output of nitric oxide (NO) and its safe deployment, because:

    (1) Cobalamin is ultimately responsible for the synthesis or availability of the NOS substrates and cofactors heme, arginine, BH(4) flavin adenine dinucleotide/flavin mononucleotide (FAD/FMN) and NADPH, via the far-reaching effects of the two cobalamin coenzymes, methionine synthase (MS) and methylmalonyl CoA mutase (MCoAM) in, or on, the folate, glutathione, tricarboxylic acid (TCA) and urea cycles, oxidative phosphorylation, glycolysis and the pentose phosphate pathway.

    Deficiency of any of the NOS substrates and cofactors results in 'uncoupled' NOS reactions, decreased NO production and increased or excessive O(2) (-), H(2)O(2), ONOO(-) and other reactive oxygen species (ROS), reactive nitric oxide species (RNIS) leading to pathology.

    (2) Cobalamin is also the overlooked ultimate determinant of positive glutathione status, which favours the formation of more benign NO species, s-nitrosothiols, the predominant form in which NO is safely deployed. Cobalamin status may consequently act as a 'back-up disc' that ensures the active status of antioxidant systems, as well as reversing and modulating the effects of nitrosylation in cell signal transduction.

    New evidence shows that glutathionylcobalamin can significantly promote iNOS and eNOS NO synthesis in the early stages of inflammation, thus lowering high levels of tumour necrosis factor-alpha that normally result in pathology, while existing evidence shows that in extreme nitrosative and oxidative stress, glutathionylcobalamin can regenerate the activity of enzymes important for eventual resolution, such as glucose 6 phosphate dehydrogenase, which ensures NADPH supply, lactate dehydrogenase, and more; with human clinical case studies of OHCbl for cyanide poisoning, suggesting cobalamin may regenerate aconitase and cytochrome c oxidase in the TCA cycle and oxidative phosphorylation.

    Thus, cobalamin may simultaneously promote a strong inflammatory response and the means to resolve it.




    Notes:

    Cobalamin is the general name for the various different chemical forms of vitamin B12. These forms are: cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin (aka: dibencozide).

    Transcobalamins are carrier proteins which bind cobalamin (B12). Deficiency in these B12 carrier proteins can result in deficiency of B12 itself.
     
  10. Freddd

    Freddd Senior Member

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    Exactly, The Scarlet Pimpernel papers, 3 of them By Carman Wheatley
     
  11. mellster

    mellster Marco

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    I have been upping magnesium levels slowly (now between 500 mg and 1g per day) after being a bit cautious due to the low recommended daily supplement dosis (300 mg per day?) and it reduces my muscle tics quite a bit. I always had strong and dense bones, never a fracture and have had a high calcium diet all my life. I am starting to wonder whether there is some truth to calcium deposits related to FM. I always thought of calcium being one of the best minerals to consume..
     
  12. mellster

    mellster Marco

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    Regarding the soap/bath discussion, I remember an old chemistry teacher being laughed at when she said it is not good to shower every day, esp. with soap - every other day should suffice - due to killing the AOB flora. She might have been right all along..
     
  13. Freddd

    Freddd Senior Member

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    A comment on the bathing chemicals issue. Shampoo is a serious problem for me if it isn't entirely rinsed. If I get it under my arms I get terribly inflamed and can't seem to rinse cleanly. A lot of shower gels also cause me problems in areas that stay moist, under arms and groin, though not as bad as shampoo. I use an empty shower gel container and dilute the preferred gels, that don't cause me a problem generally, with equal amounts of water and mix well. That allows it to rinse more cleanly. Also after I finish with the shampoo and bath-gel I do a final wash under my arms and groin area with Dr Bronner's hemp oil soap, also diluted with about 5x as much water in a spray bottle. It rinses cleanly and doesn't cause me any irritation or inflammation.
     
  14. tealady

    tealady

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    Hi Hip,
    I've been browsing on here and fiddling with all of this for about a decade or so, still not "fixed" or understood..but a couple of points
    1. Is there anywhere that you got that high cortisol causes high RT3, as I doubt it meself from experience. I wouold think maybe whetever caused the high RT3 (inflammation frokm infection, stress etc) would also trigger the highish cortisol. the cortisol being a response to whatever, and a great response sorely needed in a functioning animal. the high cortisol wqould help overcome the stress effects, one of which would be (I suspect) to lower the highish RT3 and lower the T3. I know it hasn't been studied but I suspect if it ever is they will find that cortisol causes a more rapid breakdown of free T3 (and maybe also free RT3) - not a destruction but a use of T3 into its byporducts and it actually feels different to having no T3 and no cortisol..feels way better! Of course it may be as you say that the cortisol causes a cpnversion from T3 to RT3, all that I have read so far (but that was years ago) was that cortisol "broke down" free T3..maybe it does this by converting it to RT3, but I haven't seen anything on it, and it sure doesnt feel like it at all in my body when I trialled it. Then again , I didnt go too high on cortisol over an extended period of time..so I don't know...I guess I'm just saying that I don't think this is a known and cortisol is not the baddy some make it out to be

    slow relase T3, I've been taking for about a decade too. I just get T3 componded with metocele4m and rice powder (about 30% methocelE4m) from memory worked out to provide a good slow release. Take twice a day(or 3 times a day if you metabolise/excrete fastish).. andf this will provide a nice slow release.
    taking may times a day can approxiamte but it will still hit ans spike, but better than not breaking up. At one time I just got the power and dipping my finger in and took gradually thru the day, this approximates it if you are sitting beside the T3 ! :)
    I have enjoyed reading your posts,I need help with a reaction i have to hydropxycobalin but its a lONG story and involves all the stiuff on NO, peroxynitrates, oxidation, glutathione, nitrates especially, cobalamins methylation etc..and I started looking at this withy folk in the UK back in 2003!, so nI'm glad that there been something published in 2007. Thansk. I will try to get those papaers. I actually returned to uni, studies chem, biol and physiology (I was an old systems anayst..same as Fredddd it seems) ..to try to understnad all the stuff you mentioned...but gave up.
    I still get a simila reaction to an injection of hydroxocobalmain that I do to say prilocaine (a dental anesthetic) that induced methaemoglobulin, and a similar reaction to too much spinach(nitrates/nitrites)..its all very confusing.
    Also problems with sulfates/sulfites and sulfation as well I suspect
    Wiped, headachy, and intense tingling ad red/purplish soles of feet,palms of hand and lips (with the detal anesthetic and nitrates its more pronounced with blusih around lips and more blue-ish , and diffuclty breathing but simailr thing going on...
    something to do with methylation. Aklso tried path of taking NADH, NAC etc...sigh

    One point that I have not been able to figure out but hopefully someone may have come across somewhere,
    my blood tests for RBC folate (and also my Mum's) is always high (above normal range on labs). We BOTH have that purplish tinglish palms and soles on injection of hydroxocobalamin and also also both wiped , headachy and a tad depressed on the injection. Those RBC blood tests results have been consistently high for over a decade for both of us with NO supps , except what may be in flour I guess and cereals I guess. MLast time (after doing aand feeling better for a while trying to build up glutathione by foods mainly), my RBC folate was in normal range, but at top, and my serum folate was also high in normal range...only folate in a multi occassionally and in foods.
    I don't see why I shoudl suppleemnt with folate if I'overly high already.
    I tried to read asbout this, but have found nothing.

    Have you any idea what is happening when I try to take hydroxocobalin (injections..even at 0.25mg)

    I had similar reactions thru to years from nitrates in spinach (also corned beef etc), Prilocaine dental anesthetic (although more pronounced than hydroxocobalamin. It is probably spomething to do with methlation, and I cant work out why my RBC folate is high (both before and after these experiences? Any thoughts on this?
    Yes all the usual CFS symptoms and been on thryoid meds since 2001, my Mum is not on thryoid meds though and also has similar reactiosn to the hydroxocobalamin injection. She is also rapidely getting demetia and shows all the signs of low B12
     
  15. Freddd

    Freddd Senior Member

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    Hi Tealady,

    There is something about dental anesthetic: " In some patients, a metabolite of prilocaine may cause the unusual side effect of methemoglobinemia, which may be treated with methylene blue." http://en.wikipedia.org/wiki/Prilocaine


    Methemoglobinemia can also be acquired.[1] The protective enzyme systems normally present in red blood cells maintain methemoglobin levels at less than one percent of the total hemoglobin in healthy people. Exposure to exogenous oxidizing drugs and their metabolites (such as benzocaine, dapsone and nitrates) may accelerate the rate of formation of methemoglobin up to one-thousandfold, overwhelming the protective enzyme systems and acutely increasing methemoglobin levels.


    Methemoglobinemia can be treated with supplemental oxygen and methylene blue[4] 1% solution (10 mg/ml) 1 to 2 mg/kg administered intravenously slowly over five minutes followed by IV flush with normal saline. Methylene blue restores the iron in hemoglobin to its normal (reduced) oxygen-carrying state.
    This is achieved by providing an artificial electron acceptor (such as methylene blue, or flavin) for NADPH methemoglobin reductase (RBCs usually don't have one; the presence of methylene blue allows the enzyme to function at 5x normal levels[5]) The NADPH is generated via the hexose monophosphate shunt.


    http://en.wikipedia.org/wiki/Methemoglobinemia

    I still get a similar eraction to an injection of hydroxycobalain that I do to sya prilocaine

    If you have a problem reaction to hydrocycbl I would think that the solution would be to try the active b12s; mb12 and adb12. I have no idea how hycbl could produce that reaction
     
  16. Hip

    Hip Senior Member

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    I read that one this page http://www.medical-library.net/reverse_t3_dominance_syndrome.html

    which says (in the 4th paragraph) "Cortisol inhibits the conversion of T4 to T3 and favors the conversion of T4 to RT3".

    However, I just did some searches on PubMed, could not find any reliable sources to back up the statement that high cortisol causes high RT3. So I am not sure.
     
  17. lizw118

    lizw118 Senior Member

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    Hey guys
    I have RT3 problems. Every time I go on any type of T4 med I get Rt3 and don't feel as good as I do on cytomel only. I was on only 25 mcg of cytomel before a new doctor switched me to naturethroid which has both T3 and T4. After the naturethroid I had RT3 and then switched back to cytomel, only my body then needed 85 mcg instead of only 25 mcg, which has caused a lowering of sex hormones and related problems. Sustained release T3 didn't feel right either, but I had already been on cyto for years before I switched. I take 25 mg of HC in the day for adrenal fatigue, which I started right at the same time as naturethroid. Sometimes I wonder if that itself keeps making the RT3 worse. Of course I have also read that LOW cortisol worsens RT3, as does low B12 and fasting. I have low B12 and have just come off of a 3 1/2 day fast so there goes my chance of going back on T4 for now!
    Liz
     
  18. lizw118

    lizw118 Senior Member

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    Does a low nitrate diet help with no symptoms? I would like to try it but I can't find a good list of foods. Does anyone have a link to one?
    Thanks
    Liz
     
  19. tealady

    tealady

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    Yes just avoiding works its a cumulative level in blood

    Yes, I just avoided eating large amounts of nirtates/nitrites and avoided the dental anesthetic and no more blue (excepting perhaps that hydroxocob. reminds me of a les intense reaction for some reason). I'll have a look tomoroww, and reply to everyone then too..thanks for the replies everyone
     
  20. tealady

    tealady

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    thanks Fredd,
    I posted a message re folic acid and some studies for your consideration on the other forum but I dont think it made it thru moderation as yet. I'm "lost"re folic acid and undecided, mainly as I've no idea what chemicals they are giving us! I think maybe brewers yeast is OK? I'll definitely never touch folinic acid or 5-MTHFR again (racemic mixtures).
    I'm waiting for the Metafolin to be available (hopefully) on herb again. I never wanted the cyanocobalamin..it was jsent (4 bottles of it)m acciudentlayy by iher intead on the methylcobalamin and it wasnt worth the cost of poastege for me to return it. Its the ONLy type of tablets one can get in Oz, so I thought maybe occasionally they may be OK..but I've thrown them after reading thru the recent research. I still have some mthylcobalamin sublinguals from source Naturals (which I know you dont like but I can feel some effect from them..similar to the Jarrow)I trialled a bottle of each about 6 years ago and they seemed the same to me then..but I still get negaitve reactions and not as strong as the hydroxycobalain injection to both..I've ordered the Jarrow thougha dn waiting for the metafolin (which hopefully has not disappeared due to patent). Many thanks for your reply, it was interesting reading research NOW done (which wasntr there in 2003!). I did post on the web then and got some replied, which actually were probably right (I found them yesrterday) but at the time I was is no fit state at all and could not understand anything, sigh. Thansk for the links. I started reading then fell asleep, I am continuing to try again today. I think I came across something somewhere yerterday just before crashing that I seemed to be a link..and now I cant remeber, but thansk for your answer. Noone knew anything that would link them back in 2003, and it looks like noone still does:)...which is all I wanted to know. I found a reply from a clever guy who said his RBC folate was high too and he benfitted from then equivalent of Metafolin , TMG , methylcobalamin (it was a joint product listed as discontinued on iherb sadly-possibly due to that patent again!)....I must find that post again and I will fill you in.It was about the same as you have worked out.
    Thanks again,
    my lack of reply was due to crashing, but I really apreciated the feedback.
    Jan
     

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