NO/ONOO- cycle

Here is a very good book regarding Chronic Fatigue, Fibryomyalgia, Multiple Chemical Sensitivites.

There is also some very good information on how it may relate to MPB.


http://books.google.com/books?id=OHradOdFKfUC&pg=PA69&lpg=PA69&dq=NO/ONOO-+cycle+Pall&source=bl&ots=KkW7kROu2A&sig=_btDM_N6k52uJEcCipGAylN2Fuo&hl=en&ei=uHu2SsyLOM-G8QbEtK2TDw&sa=X&oi=book_result&ct=result&resnum=1#v=onepage&q=NO%2FONOO-%20cycle%20Pall&f=false


Also, the book is easier to read if you use Internet Explorer, go to google and type in NO/ONOO- cycle Pall The first link is the one you click on for the book.

Another interesting point about the NO/ONOO-cycle is that its main components, nitric oxide and peroxynitrite, tend to only act locally as they do not survive very long once they have been released. This means that they can only affect the body locally where they have been released, meaning that one body tissue might be quite badly affected whereas another body tissue nearby is not affected at all. This could explain the myriad of different symptoms the individual patients with these illnesses describe. There is an almost infinite variation of symptoms and signs that could be produced depending on which body tissues are affected.

http://www.fibromyalgia-associationuk.org/content/view/260/208/

jdp710 - Thanks for this, very interesting. This is a subject that I think "sheds" a some light on hair loss. One of the reasons I'm so fond of Ecklonia Cava is it's ability to quench peroxynitrite.

I've found over the years that many associate nitric oxide as only positive, but its dark side is affiliated with Matrix metalloproteinases. I found noticed in the past that the use of certain arginine products would raise inflammation in the scalp.

Here's a nice quote from a site that more or less sources from the book you listed:

The elevated nitric oxide/peroxynitrite vicious cycle (NO/ONOO- cycle) predominantly involves those two compounds but involves many other elements. These include superoxide, intracellular calcium, the transcription factor NF-kappaB, inflammatory cytokines (upper right corner), oxidative stress, vanilloid receptor activity, and NMDA receptor activity. Mitochondrial (energy metabolism) dysfunction is also involved in certain pathways of the arrows. Each arrow represents the stimulation of one element by another, and the sequences of arrows constitute positive feedback loops that maintain the cycle.

The root cause for this imbalance, yeast/dysbiosis:

http://www.prohealth.com/library/showarticle.cfm?id=3139&t=CFIDS_FM

In people with CFS, it has been found they have high levels of d-lactate and H2S, and related byproducts. It is important then to reduce fiber and drop "ordinary" probiotics and use only super-strains with proven clinical research.

I will continue posting very soon in the thread I started regarding making yogurt with selected super-strains that dont produce d-lactate and have been shown to be highly beneficial for dysbiosis, LGS and other conditions. To people interested on it, sorry for the delay, I've been very busy but at the same time very interested in continuing my research and experimention.

jdp710, it is very interesting that you posted this information. I hope to see more of this more often. Do you feel you have dysbiosis or any other disease caused by gut imbalances?

BTW, I found interesting what this article mentions about the inhibitory effect of dysbiosis in glands, particularly the thyroid:


In summary, chronic fatigue syndrome may develop over a lengthy period of time, during which there is a disturbance in the usual bowel yeast relationship. The latter may be due particularly to the eating of incorrect foods, especially those with a high fat content. The increase in the yeast content in the circulating blood will stimulate the production of large amounts of glutamic acid, which in turn will stimulate the appropriate receptors in the brain tissue. The latter action will result in excess amounts of nitric oxide and GABA being synthesized, and subsequently, having an inhibitory effect on brain activity. This suppression of brain activity, particularly at the hypothalamic level, will produce a reduction in the activity of the hormonal glands. This is particularly applicable to the thyroid gland. The resulting hypothyroidism (whether clinical or subclinical) will produce the signs and symptoms commonly seen in CFS.

Likewise, the effects of this excessive glutamic acid on the immune system will result in an increase in nitric oxide production, with concomitant enlarged lymph nodes and lymphatic tissue.

Thanks for the info CausticSymmetry and Littlefighter.


Littlefigher,

Like many here, I've also looked into probiotics for a long time but I haven't looked into the super strains so I'm curious how all this will pan out. Keep us updated no matter the results. Thanks.

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About the NO-OHNOO cycle, here is a good site that gives supplements to take to help keep the cycle in check. Curiously, a lot of the supplements that the 5 doctors' different protocols are what we talk about here everyday. It was also mentioned that those who couldn't afford to take the full protocol may not get as good of results in relieving their symptoms.

http://chronicfatigue.about.com/gi/o.htm?zi=1/XJ&zTi=1&sdn=chronicfatigue&cdn=health&tm=24&gps=328_1968_1142_554&f=21&su=p736.8.336.ip_&tt=2&bt=1&bts=1&zu=http%3A//sprident.com/martin-pall/

jdp710 - That's a great link. Like you stated, it discusses most the supplements we talk about here.

This nitric oxide/peroxynitrite cycle really explains a lot on what's going wrong with our scalps.

I thought this experimental NO inhibition effects was interesting:

Inhibitory effects of stress-activated nitric oxide on antioxidant enzymes and testicular steroidogenesis
Purchase the full-text article



References and further reading may be available for this article. To view references and further reading you must purchase this article.

Tatjana S. Kostic, Silvana A. Andric, Desanka Maric and Radmila Z. KovacevicCorresponding Author Contact Information, E-mail The Corresponding Author

Institute of Biology, Faculty of Sciences, University of Novi Sad, Dositeja Obradovica Square 2, 21000 Novi Sad, Serbia, Yugoslavia

Accepted 11 October 2000
Available online 26 March 2001.

Abstract

The messenger role of nitric oxide (NO) in immobilization stress-induced inhibition of testicular steroidogenesis has been previously suggested. In accord with this, here, we show that the intratesticular injection of isosorbide dinitrate (ISDN; 2×2.5 mg/testis), an NO donor, mimicked the action of stress on serum testosterone concentrations and hCG-stimulated testosterone production in rat testicular tissue. When added in vitro, ISDN inhibited testicular 3β-hydroxysteroid dehydrogenase and 17α-hydroxylase/lyase. Immobilization stress and injections of ISDN also decreased the activity of catalase, glutathione peroxidase, glutathione transferase, and glutathione reductase in the interstitial compartment of testis. When stressed rats were treated concomitantly with bilateral intratesticular injections of Nω-nitro-Image -arginine methyl ester, a non-selective NOS inhibitor (2×600 μg/testis), the activities of antioxidative enzymes, as well as serum testosterone concentration, were partially normalized. These results indicate that stress-induced stimulation of the testicular NO signalling pathway leads to inhibition of both steroidogenic and antioxidant enzymes.

Here's a study I've been looking for, finally found it:

J Mol Med. 2003 Feb;81(2):110-7.

Nitric oxide in the human hair follicle: constitutive and dihydrotestosterone-induced nitric oxide synthase expression and NO production in dermal papilla cells.

Wolf R, Schönfelder G, Paul M, Blume-Peytavi U.

Department of Dermatology, University Medical Center Benjamin Franklin, Free University of Berlin, Berlin, Germany.

The free radical nitric oxide, generated by different types of epidermal and dermal cells, has been identified as an important mediator in various physiological and pathophysiological processes of the skin, such as regulation of blood flow, melanogenesis, wound healing, and hyperproliferative skin diseases. However, little is known about the role of NO in the human hair follicle and in hair cycling processes. Here we demonstrate for the first time that dermal papilla cells derived from human hair follicles spontaneously produce NO by measuring nitrate and nitrite levels in culture supernatants. This biomolecule is apparently formed by the endothelial isoform of nitric oxide synthase, which was detected at the mRNA and protein levels. Remarkably, basal NO level was enhanced threefold by stimulating dermal papilla cells with 5alpha-dihydrotestosterone (DHT) but not with testosterone. Addition of N-[3-(aminomethyl)benzyl]acetamidine (1400W), a highly selective inhibitor of inducible nitric oxide synthase, restrained the elevation in NO level induced by DHT. Analyses of DHT-stimulated cells at the mRNA and protein levels confirmed the expression of inducible nitric oxide synthase. These findings suggest NO as a signaling molecule in human dermal papilla cells and implicate basal and androgen-mediated NO production to be involved in the regulation of hair follicle activity.

Nice info. So is there a time when the scalp can be experiencing too much NO causing detrimental effects?

hapyman - While Nitric Oxide (NO) is important and does increase hair follicle growth, not all forms of NO are good, such as with Peroxynitrite and iNOS (inducible nitric oxide synthase). Both Ecklonia Cava (inhibits Peroxynitrite), with GliSODin can mamizize the good nitric oxide and keep Peroxynitrite levels low.

Thanks for clarifying CS.

JDP do you have any info on hand about how LLLT may effect this cycle.

I've been experimenting with Butea Superba, which supposedly plays a role in increasing Nitric Oxide (hopefully the good kind), both internally and topically. It's impossible to make a conclusion just yet, but I ordered the extract from Ainterol today, which should be adequate for the purpose of my trial: my satisfaction.

Great studies CausticSymmetry! This quote was especially interesting as this is the first time I've heard this

"Remarkably, basal NO level was enhanced threefold by stimulating dermal papilla cells with 5alpha-dihydrotestosterone"



hapyman,

I did some searching and came across this study

Infrared pulse laser therapy was studied for its impact on the production of active forms of oxygen and nitrogen by neutrophils from patients with rheumatoid arthritis (RA). The authors determined the non-activated and PMA-activated production of superoxide anion-radical, peroxynitrite, peripheral neurophilic NAD.PH-oxidase and superoxide dismutase activities, and the red blood cell concentrations of reduced glutathione. Before therapy, non-activation RA neurophilic production of superoxide was much higher than in donors. Laser therapy made this parameter normal. Similarly, neutrophilic peroxynitrite production (defined by dihydrorhodamine oxidation) in RA patients was 1.7 times higher than the normal values. IF-laser therapy decreased peroxynitrite production to the values observed in donors. It is important that the therapy caused increased SOD activity (that was lower in RA patients prior to therapy) up to apparently control values. Thus, IF-laser therapy has a certain antioxidative effect by increasing SOD activity in RA patients' blood cells and reducing the production of highly reactive oxygen and nitrogen forms.

http://laserpaincenters.com/research/abstract10.html




I also thought this study was interesting ... especially considering how many of us MPB are night owls.

Earlier, it was reported that chronic UV exposure of hairless mice for 2 h per day with a source mainly emitting UVA including 2% UVB, resulted in a significant increase in SOD activity that, however, following continued irradiation for 24 wk, substantially decreased below the level of mock treated animals These results suggest that chronic UV exposure for months, even at suberythermal doses, may compromise the SOD-dependent antioxidant defense."

http://www.nature.com/jid/journal/v112/n1/full/5600376a.html

My thinking is that chronic UV exposure (maybe light exposure?) compromises our bodies production of SOD further reducing our ability to decrease peroxynitrite and thus doesn't help with the NO-OHNOO cycle.

Abstract

Nitric oxide (NO) can induce cell death; however, NO-induced cell death may be dependent/conditional on factors other than NO itself. Whether NO kills a particular cell depends on the amount of NO, source of NO, time of exposure to NO, cell type and the levels of other factors including, particularly oxygen, superoxide, H2O2, antioxidants, thiols and glycolysis.


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Introduction

NO is an important regulator of cell viability and death depending on its concentration, source of production and pathological conditions. In a variety of cell types, expression of iNOS (inducible nitric oxide synthase) can be induced by pathogens or cytokines, and iNOS-derived NO is generally believed to be a key cytostatic and cytotoxic molecule participating in the innate immune response. The expression of iNOS is also associated with inflammatory degeneration of host tissues. However, iNOS expression alone in activated cells is usually insufficient to cause cell death suggesting that NO requires some other factors or conditions to be present to cause cell death. The purpose of this review is to discuss this conditionality of NO-induced cell death.

NO itself is relatively unreactive; however, it may be converted to a number of more reactive derivatives [e.g. RNS (reactive nitrogen species)] [1–3]. NO and various RNS each have different lifetimes and kill cells with different potencies and by different mechanisms, and therefore when a cell is exposed to NO, whether it dies and by what mechanism depends on the rate at which NO is converted to these other species. Conversion of NO to particular RNS may depend on the simultaneous presence of particular ROS (reactive oxygen species), but NO or RNS can also induce the production of particular ROS.

Two main types of NO-induced cell death can be distinguished: (i) energy depletion-induced necrosis and (ii) oxidant-induced apoptosis [2]. NO-induced cell death can be induced either (a) by NO itself directly (mainly via inhibition of cytochrome oxidase, in which case death is promoted by hypoxia and low glycolysis) or (b) by derivative RNS or induced ROS, in which case death depends on overcoming antioxidant defences.

NO-induced cell death via energy depletion is dependent on oxygen and glycolysis

NO or RNS can cause necrosis by depleting the cell of energy (ATP) via: (i) inhibiting mitochondrial respiration, (ii) inducing MPT (mitochondrial permeability transition), (iii) inhibiting/uncoupling glycolysis and (IV) activating PARP [poly(ADP-ribose) polymerase]. NO itself (rather than RNS) is not potently cytotoxic, but can induce cell death by inhibiting cytochrome oxidase if oxygen is low and glycolysis is insufficient to compensate. NO inhibits cytochrome oxidase in competition with oxygen, raising the Km of cellular respiration into the physiological range of oxygen concentrations, thus potentially sensitizing cells to hypoxia. Short exposure of the aorta to hypoxia did not cause significant necrosis of the vessel wall in the absence of NO, but caused extensive necrosis in the presence of NO donor or iNOS expression [4]. Similarly, other investigators have reported that hypoxia sensitizes to NO donor-induced apoptosis in fibroblast cell line or cultured endothelial cells [5,6].

In neurons, NO inhibition of mitochondrial respiration results in glutamate release, which kills by excitotoxic mechanisms and this cell death is greater in hypoxic conditions [7–9]. Activated, iNOS-expressing glia or low concentrations of NO from NO donor synergize with hypoxia causing apoptosis of cerebellar granule neurons [8]. This NO plus hypoxia-induced neuronal apoptosis is switched to necrosis when glycolysis is inhibited with deoxyglucose, indicating that glycolytic ATP is required for apoptosis to proceed [8]. In macrophages, the glycolytic intermediate 3-phosphoglycerate reduced NO-induced necrosis, but stimulated NO-induced caspase activation and apoptosis [10]. In aorta, NO plus hypoxia-induced cell death was substantially reduced in the presence of 3-phosphoglycerate [4]. Thus high glycolysis may prevent NO-induced necrosis in some cells. However, long-term exposure to NO (or rather RNS) may cause glycolytic inhibition, which together with respiratory inhibition causes necrosis [10].

Dependence of NO-induced apoptosis on NO species, oxidants, antioxidants and glutathione levels

If glycolysis is sufficient to prevent necrosis, NO can still cause apoptosis via oxidative stress. Specific inhibitors of the mitochondrial respiratory chain have been shown to induce caspase-dependent cell death in such conditions; however, NO donor-induced apoptosis appears to be more rapid and potent [11], thus respiratory inhibition cannot fully explain NO-induced apoptosis. We have shown that in macrophages, NO increased H2O2 levels and induced rapid (in 4–6 h) caspase activation, which was prevented by antioxidants, particularly catalase, and was sensitive to inhibition of p38 protein kinase, suggesting that NO-induced apoptosis may be mediated by H2O2. Glutathione depletion before NO exposure blocked apoptosis, but increased NO-induced necrosis [10], probably because glutathione prevents NO inhibition of (a) caspases and (b) glycolysis.

Under some inflammatory conditions, S-nitrosothiols or peroxynitrite may be produced. In this case the mechanisms of cell death may be different. We and other groups have observed that S-nitrosothiols and peroxynitrite added to isolated mitochondria induced MPT-related cytochrome c release and this leads to caspase activation and apoptosis in macrophages, thymocytes and other cells [11–14]. S-nitrosothiols are particularly potent in inducing MPT and apoptosis in perfused heart, causing cyclosporin A-sensitive cytochrome c release and inhibition of mitochondrial functions within 15 min of perfusion [14].

Dependence of NO-induced cell death on superoxide production

In addition to expressing iNOS, inflamed tissues may activate the PHOX (phagocytic NADPH oxidase) producing superoxide within intracellular vesicles or outside the cell. Superoxide rapidly reacts with NO to produce peroxynitrite, which is more cytotoxic than NO, partly via activating PARP. We found that in macrophages, iNOS expres​sion(induced by bacterial endotoxin/interferon-g) or PHOX activation (by PMA) resulted in little or no cell death when present alone, but when present together they caused substantial necrosis. This death was completely prevented by iNOS inhibitor 1400 W, PHOX inhibitor apocynin or by a catalytic decomposer of peroxynitrite, FeTPPS [5,10,15,20-tetrakis(4-sulphonatophenyl)porphyrinato-iron(III)] and partially inhibited by PARP inhibitors. Another potential PHOX stimulator, arachidonate, also synergized with iNOS to induce cell death that was completely prevented by 1400 W, FeTPPS, PARP inhibitors and SOD (superoxide dismutase). In contrast, this cell death was insensitive to apocynin, but was blocked by the cyclo-oxygenase inhibitor ibuprofen suggesting that death-inducing peroxynitrite may be derived from a cyclo-oxygenase-dependent pathway in the case of arachidonate. Therefore iNOS expression alone can be relatively benign, but when combined with a major source of superoxide it may result in death mediated by peroxynitrite.

NO may also synergize with H2O2 to induce cell death

cont.

One contribution to this synergy may be the ability of NO to stimulate H2O2 production and inhibit H2O2 breakdown by cells [10]. Another mechanism may be via NO and H2O2 reaction at SOD to produce peroxynitrite [15].

Conclusions

NO by itself is relatively non-toxic to cells and may even protect against cell death. However, combined with hypoxia NO may induce necrosis if glycolysis is limiting and, combined with superoxide or H2O2, it may induce necrosis via peroxynitrite. In the absence of antioxidants, sustained exposure to NO results in production of ROS and RNS that induce apoptosis or necrosis (Scheme 1).

http://www.biochemsoctrans.org/bst/033/1394/bst0331394.htm#SCH1