Moving on to Nitrates and Nitrites

In our study, an acute UC was induced in Swiss mice using 3% Dextran Sulfate Sodium (DSS). The preventive effects of "Ultrabiotique®" (a probiotic) and inulin (a prebiotic) on the colitis were investigated. The production of NO was evaluated in the supernatants of peritoneal macrophages (pMφ) cultures. Colonic mucosa histology was subsequently examined. Results showed severe acute UC after administration of DSS. High levels of NO in pMφ cultures were also observed compared to control samples. These findings correlated with a significant destruction of the colonic mucosa.

Click to expand...

Oral administration of Ultrabiotique® or inulin decreased the severity of DSS-induced colitis. These treatments lead to a decrease in NO levels in pMφ cultures. A considerable reduction of colonic lesions was also noticed. Our findings suggest the involvement of NO in experimental UC pathogenesis. Pre- and pro-biotics, as discussed herein, seem to have an anti-inflammatory effect.

Click to expand...

The news may help restore the good name not only of mouth bacteria but also of nitrate, which has a long history of bad press. The worry about nitrate--a stable compound of a nitrogen atom and three atoms of oxygen--has been that it can lose an oxygen and become nitrite, a much more reactive compound. Nitrite, in turn, can hook up with food components called amines to form nitrosamines. Studies in rats, as well as some epidemiological studies, have linked those compounds to stomach cancer.

Click to expand...

An early test of this hypothesis produced promising results: if salivary nitrite is put in acid, the researchers found, it will indeed convert to E. coli- killing nitric oxide. We proved that if you took bacterial cultures and exposed them to acid, it didn’t do much, says Benjamin. But if you expose them to acid and a little bit of nitrite, it just wipes them out.

Click to expand...

The demineralization of teeth (enamel, dentine, and cementum) is caused by organic acid produced from the bacterial fermentation of dietary carbohydrates. The frequent ingestion of carbohydrates may lead to the selection of bacteria that are acidogenic (capable of producing acid from carbohydrates) and aciduric (capable of tolerating acid) and concurrently to a low-pH environment. These conditions favor the solubilization of tooth minerals. The pH at which this demineralization begins is known as the critical pH and ranges between pH 5.0 and 5.5 (275).

Click to expand...

Like the human tongue, the rat tongue is covered with tiny fingerlike projections known as papillae. The bacteria that convert nitrate live in clefts between papillae at the rear of the tongue, out of reach of airborne oxygen. They are the kind of bacterium--facultative anaerobes-- that can survive with or without oxygen. We use oxygen to burn up the glucose in our bodies to make energy, Benjamin explains. Whereas if you’re one of these bacteria, you have alternatives. One alternative is to use nitrate. You use that to burn up your fuel. It turns nitrate to nitrite. That’s fine, as long as the nitrite isn’t acidified. If it’s on the surface of the tongue, it isn’t, because the saliva is nice and alkaline.

Click to expand...

Similarly, Sildenafil citrate, popularly known by the trade name Viagra, stimulates erections primarily by enhancing signaling through the nitric oxide pathway in the penis.

Click to expand...

For example, in one study, the risk of colon cancer increased for certain susceptible subgroups (e.g., those with low vitamin C intake or high meat intake) whose water had nitrate levels > MCL/2 for at least 10 years (DeRoos et al. 2003).

Click to expand...

A significant positive correlation was found between serum nitrate levels in ulcerative colitis and erythrocyte sedimentation rate (ESR) (r = 0.30, p - 0.01), leucocyte count (r = 0.27, p = 0.02), and thrombocyte count (r = 0.24, p = 0.04). Comparing active Crohn's disease patients (median, 37.5 mumol/l; range, 13.2-143.2 mumol/l) with inactive Crohn's disease patients (median, 31.3 mumol/l; range, 14.5-92.3 mumol/l) also showed a significant difference in serum nitrate concentration (p < 0.009). Serum nitrate levels correlated with the ESR (r = 0.26, p = 0.028) and serum albumin (r = 0.38, p = 0.004) as well.

Click to expand...

Under physiological conditions, the production of peroxynitrite will be low and oxidative damage minimized by endogenous antioxidant defenses (1058, 1059). Even modest increases in the simultaneous production of superoxide and NO will greatly stimulate the formation of peroxynitrite; a 10-fold increase in superoxide and NO production will increase peroxynitrite formation 100-fold. Consequently, pathological conditions can greatly increase the production of peroxynitrite. Even the generation of a moderate flux of peroxynitrite over long periods of time will result in substantial oxidation and potential destruction of host cellular constituents, leading to the dysfunction of critical cellular processes, disruption of cell signaling pathways, and the induction of cell death through both apoptosis and necrosis (1334). Hence, the production of peroxynitrite can be instrumental in the development of many pathological processes in vivo.

Click to expand...

Only a few chemical groups directly react with peroxynitrite, which favors selective reactions with key moieties in proteins, such as thiols, iron/sulfur centers, and zinc fingers

Click to expand...

Disabling of several cytoskeletal proteins by nitration represents a further major cytotoxic effect attributed to peroxynitrite. Tubulin nitration by peroxynitrite or by direct incorporation of free nitrotyrosine has been reported in cell lines derived from intestine (54), neurons (1269), and muscle (199), resulting in the loss of normal physiological functions. Peroxynitrite also disorganizes actin polymerization through actin nitration, and via the nitration of profilin (658, 659), an important actin-binding protein. These effects have been associated with platelet dysfunction (659), disruption of both intestinal (55) and endothelial barrier function (940), as well as impaired migration and phagocytosis of activated polymorphonuclear cells (221).

Click to expand...

Supporting a role for iNOS-dependent generation of peroxynitrite in the pathogenesis of IBD, biochemical evidence of peroxynitrite generation (formation of nitrotyrosine) has been shown both in experimental models of colitis (885, 1170, 1464) and in human samples of active Crohn’s lesions, in which massive nitrotyrosine immunostaining has been reported (1170). The formation of peroxynitrite in such circumstances is largely favored, since not only NO but also superoxide are being formed in the inflamed intestines (268, 321), which explains the beneficial effects of SOD mimetics in experimental colitis (268). In addition, it is noteworthy that the direct application of authentic peroxynitrite within the gut elicits a severe, colitis-like, inflammatory response (1052). The pathogenic role of peroxynitrite has been firmly established by studies using pharmacological approaches to reduce peroxynitrite in the inflamed colon. Thus treatment of rats with the iNOS inhibitor and peroxynitrite scavenger mercaptoethylgaunidine markedly alleviated colonic injury induced by intrarectal instillation of TNBS (1456). Also, the peroxynitrite decomposition catalyst FP-15 exerted potent protective effect in mice fed with 5% dextran sulfate sodium (819). Treatment with this compound, when started simultaneously with dextran, largely reduced colon damage and inflammation, as assessed by histological evaluation, and reduced rectal bleeding, weight loss, and colon shortening. Furthermore, FP-15 reduced the colitis-induced increase in colonic malondialdehyde levels, indicative of the ability of the drug to attenuate oxidative stress, and reduced colonic infiltration by activated phagocytes, as determined by reduced myeloperoxidase levels (819).

As in the case of arthritis, there is large evidence that a common final pathway of peroxynitrite-dependent inflammatory changes in IBD depends on the activation of PARP. First, PARP is strongly activated in various rodent models of colitis, and second, pharmacological inhibition of PARP or PARP genetic suppression provided significant resistance against the development of colitis in these models (see Ref. 1230 for recent review). In addition to preventing cell necrosis by inhibiting ATP depletion, it has also been established that the absence of PARP exerted direct anti-inflammatory effects in TNBS-induced colitis as well as in the spontaneous colitis that develop in IL-10-deficient mice, as shown by decreased neutrophil infiltration, reduced release of proinflammatory cytokines and chemokines, and smaller increases in colon permeability (634, 818, 1461). In a recent work in mice challenged with intrarectal TNBS, reduced colon ulceration and apoptotic mucosal cell death were noted in PARP knockout mice and could be correlated with a reduced activation of the MAPK JNK. This was followed by a depressed activity of the transcription factor AP-1 in the colon, together with an enhanced expression of the antiapoptotic protein Bcl-2 (1458). These results represent a further illustration of the very complex interactions occurring in vivo between PARP, cell death, and inflammation, as exposed in detail in section IV.

Click to expand...

Results:

SOD activity and H2O2 production were significantly higher during active CD but returned to control levels in remission. ΔΨm was inhibited during active CD and, although it returned to control levels, its recovery took longer than clinical remission. CAT activity was permanently inhibited during CD, independent of the disease activity. MDA and 8-oxo-dG were permanently elevated.
Conclusions:

Oxidative stress during active CD depends on H2O2 production. The inhibition of ΔΨm suggests that this organelle is a source of ROS. CAT is permanently inhibited in CD, the biological significance of which is under study. The persistent oxidative damage detected may have implications for the evolution of the disease. Inflamm Bowel Dis 2010

Click to expand...

Under physiological conditions, the production of peroxynitrite will be low and oxidative damage minimized by endogenous antioxidant defenses (1058, 1059). Even modest increases in the simultaneous production of superoxide and NO will greatly stimulate the formation of peroxynitrite; a 10-fold increase in superoxide and NO production will increase peroxynitrite formation 100-fold.

Click to expand...

In addition to this, in a clinical condition (collagenous colitis) which is never associated with obvious macroscopic ulcerations, even higher levels of NO• than in ulcerative colitis are found.40 These studies suggest that NO• concentrations alone cannot dictate pathological inflammation in the intestine and makes the generation of peroxynitrite in vivo an exciting prospect, one which could explain the deleterious potential of both O2 −• and NO• in IBD.

Click to expand...

Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn's disease.

Oral administration of EA (10-20 mg/kg) diminished the severity and extension of the intestinal injuries induced by TNBS although there was no observed a significant dose-response. In addition, EA increased mucus production in goblet cells in colon mucosa, decreased neutrophil infiltration and pro-inflammatory proteins COX-2 and iNOS overexpression.

Click to expand...

David said:

Good natural toothpaste is hard to find. I picked up and put down every single one in our local whole foods. Most have carrageenan and/or SLS.

And yes, it's hard to know what to trust. The last thing I want to do is be paranoid or make others feel that way as I realize nothing is perfect, but the state of our food/water supply is really quite atrocious in my opinion.

Click to expand...