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I've seen a lot of research reports which investigate the phenomenon of elevated nitric oxide levels in the intestines of patients with inflammatory bowel diseases, but I haven't seen any that reach what I would call a "satisfactory" conclusion - they all leave more questions, than answers. Some researchers conclude that NO is harmful, and either causes the inflammation, or makes it worse, and they suggest trying to suppress it, while others speculate that it is a result of the body's efforts to control the disease, (the IBD), and it is being produced in an effort to suppress the disease. This explanation by Stephanie Seneff finally seems to make some sense of it. The problem with most researchers is that they never look beyond the parameters that they are investigating - never realizing that they are looking at symptoms, or intermediate chemical reactions - rather, they almost always view those parameters as either a cause or an effect. Their analysis is almost always too simplistic, for a complex problem.
The following is a quote from a long article about the effects of sulfur on several major health issues. It explains how Crohn's disease, (and presumably, all IBDs), are actually "muscle wasting" diseases, (which can occur even with adequate nutrition). This condition is also known as "low CG syndrome" to represent a situation where the amino acid, cysteine, and the tripeptide, glutathione, become deficient. According to Stephanie Seneff, this syndrome most likely occurs due to a sulfur deficiency, specifically, a cholesterol sulfate deficiency. Note that, as we have found with MC, the fat malabsorption problem becomes self-perpetuating, and leads to additional vulnerabilities.
http://people.csail.mit.edu/seneff/sulf ... sting.htmlI will use Crohn's disease as my primary focus for discussion: an inflammation of the intestines, associated with a wide range of symptoms, including reduced appetite, low-grade fever, bowel inflammation, diarrhea, skin rashes, mouth sores, and swollen gums. Several of these symptoms suggest problems with the interface between the body and the external world: i.e., a vulnerability to invasive pathogens. I mentioned before that cholesterol sulfate plays a crucial role in the barrier that keeps pathogens from penetrating the skin. It logically plays a similar role everywhere there is an opportunity for bacteria to invade, and certainly a prime opportunity is available at the endothelial barrier in the intestines. Thus, I hypothesize that the intestinal inflammation and low-grade fever are due to an overactive immune system, necessitated by the fact that pathogens have easier access when the endothelial cells are deficient in cholesterol sulfate. The skin rashes and mouth and gum problems are a manifestation of inflammation elsewhere in the barrier.
Ordinarily, the liver supplies cholesterol sulfate to the gall bladder, where it is mixed into bile acids, and subsequently released into the digestive system to assist in the digestion of fats. If a person consistently eats a low-fat diet, the amount of cholesterol sulfate delivered to the digestive system from the liver will be reduced. This will logically result in a digestive system that is more vulnerable to invasion by pathogens.
The sulfate that's combined with cholesterol in the liver is synthesized from cysteine (one of the two proteins that are deficient in low CG syndome). So insufficient bioavailability of cysteine will lead to a reduced production of cholesterol sulfate by the liver. This will, in turn, make it difficult to digest fats, likely, over time, compelling the person to adhere to a low-fat diet. Whether low-fat diet or sulfur deficiency comes first, the end result is a vulnerability to infective agents in the intestines, with a consequential heightened immune response.
[Dröge1997] further discussses how a reduction in the synthesis of sulfate from cysteine in the liver leads to increased compensatory activity in another biological pathway in the liver that converts glutamate to arginine and urea. Glutamate is highly significant because it is produced mainly by the breakdown of amino acids (proteins in the muscles); i.e., by muscle wasting. The muscle cells are triggered to cannibalize themselves in order to provide adequate glutamate to the liver, mainly, in my view, in order to generate enough arginine to replace the role of sulfate in muscle glucose metabolism (i.e., these activities in the liver and muscles are circular and mutually supportive).
Arginine is the major source of nitric oxide (NO) and NO is the next best thing for muscle glucose metabolism in the absence of cholesterol sulfate. NO is a poor substitue for SO4-2, but it can function in some of the missing roles. As you will recall, I propose that cholesterol SO4-2 accomplishes a number of important things in muscle cells: it delivers oxygen to myoglobin, it supplies cholesterol to the cell membrane, it helps break down glucose, protects the cell's proteins from glycation and oxidation damage, and provides energy to the cell. NO can help in reducing glycation damage, as nitrogen can be reduced from +2 to 0 (whereas sulfur was reduced from +6 to -2). It also provides oxygen, but it is unable to transfer the oxygen directly to myoglobin by binding with the iron molecule, as was the case for sulfate. NO does not supply cholesterol, so cholesterol deficiency remains a problem, leaving the cell's proteins and fats more vulnerable to oxidative damage. Furthermore, NO itself is an oxidizing agent, so myoglobin becomes disabled, due to both oxidation and glycation damage. The muscle cell, therefore, engages in mitochondrial oxidation of glucose at its own peril: better to revert to anaerobic metabolism of glucose to decrease the risk of damage. Anaerobic metabolism of glucose results in a build-up of lactic acid, which, as explained in [Dröge1997] further enhances the need for the liver to metabolize glutamate, thus augmenting the feedback loop.
Furthermore, as you'll recall, if I'm right about cholesterol sulfate seeding lipid rafts, then, with a cholesterol sulfate deficiency, the entry of both glucose and fat into the muscle cell are compromised. This situation leaves the cell with little choice but to exploit its internal proteins as fuel, manifested as muscle wasting.
In summary, a number of different arguments lead to the hypothesis that sulfur deficiency causes the liver to shift from producing cholesterol sulfate to producing arginine (and subsequently nitric oxide). This leaves the intestines and muscle cells vulnerable to oxidation damage, which can explain both the intestinal inflammation and the muscle wasting associated with Crohn's disease.
This explanation may not answer every last question that's involved, but it makes a heck of a lot of sense to me.
Tex
The point is, if a cholesterol level below 180 mg/dL increases mortality risk, then obviously a graduated risk scale exists, so that even at levels above 180 mg/dL, the risk of other adverse effects will likely be increased, and that risk will gradually decrease as the cholesterol level is increased.
