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| | From:  taka00381 (Original Message) | Sent: 8/30/2007 7:16 AM |
It seems that uric acid is not only responsible for gout and arthritis, but also for the metabolic syndrome and neurological diseases :-( It seems to me that there is quite solid evidence about fructose causing hyperuricemia. Maybe this is behind the success of low carb diets ...
Am J Physiol Renal Physiol. 2006 Mar;290(3):F625-31. Epub 2005 Oct 18.
A causal role for uric acid in fructose-induced metabolic syndrome.
Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ.
Division of Nephrology, Hypertension, and Transplantation, PO Box 100224, University of Florida, Gainesville, FL 32610, USA. [email protected]
The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.
PMID: 16234313
J Am Soc Nephrol. 2006 Dec;17(12 Suppl 3):S165-8.
Uric Acid, the metabolic syndrome, and renal disease.
Cirillo P, Sato W, Reungjui S, Heinig M, Gersch M, Sautin Y, Nakagawa T, Johnson RJ.
Address correspondence to: Dr. Pietro Cirillo, Division of Nephrology, Hypertension and Transplantation, Department of Medicine, University of Florida, PO Box 100224, Gainesville, FL 32608. [email protected].
Metabolic syndrome, characterized by truncal obesity, hypertriglyceridemia, elevated BP, and insulin resistance, is recognized increasingly as a major risk factor for kidney disease and also is a common feature of patients who are on dialysis. One feature that is common to patients with metabolic syndrome is an elevated uric acid. Although often considered to be secondary to hyperinsulinemia, recent evidence supports a primary role for uric acid in mediating this syndrome. Specifically, fructose, which rapidly can cause metabolic syndrome in rats, also raises uric acid, and lowering uric acid in fructose-fed rats prevents features of the metabolic syndrome. Uric acid also can accelerate renal disease in experimental animals and epidemiologically is associated with progressive renal disease in humans. It is proposed that fructose- and purine-rich foods that have in common the raising of uric acid may have a role in the epidemic of metabolic syndrome and renal disease that is occurring throughout the world.
PMID: 17130256
Cleve Clin J Med. 2006 Dec;73(12):1059-64.
Role of uric acid in hypertension, renal disease, and metabolic syndrome.
Heinig M, Johnson RJ.
Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville 32610, USA. [email protected]
Hyperuricemia has long been known to be associated with cardiovascular disease, and it is particularly common in people with hypertension, metabolic syndrome, or kidney disease. Most authorities have viewed elevated uric acid as a secondary phenomenon that is either innocuous or perhaps even beneficial, since uric acid can be an antioxidant. However, recent experiments have challenged this viewpoint. In this paper we argue that uric acid is a true risk factor for cardiovascular disease. Furthermore, we suggest that the recent increased intake in the American diet of fructose, which is a known cause of hyperuricemia, may be contributing to the current epidemic of obesity and diabetes.
PMID: 17190309
SOURCE: http://www.brightsurf.com/news/headlines/22059/UF_scientists_find_sugar_may_have_a_sour_side.html
UF scientists find sugar may have a sour side
December 08, 2005 - Fructose may trick you into thinking you are hungrier than you should be
Suddenly sugar isn't looking so sweet.
University of Florida researchers have identified one possible reason for rising obesity rates, and it all starts with fructose, found in fruit, honey, table sugar and other sweeteners, and in many processed foods.
Fructose may trick you into thinking you are hungrier than you should be, say the scientists, whose studies in animals have revealed its role in a biochemical chain reaction that triggers weight gain and other features of metabolic syndrome-the main precursor to type 2 diabetes. In related research, they also prevented rats from packing on the pounds by interrupting the way their bodies processed this simple sugar, even when the animals continued to consume it.
The findings, reported in the December issue of Nature Clinical Practice Nephrology and in this month's online edition of the American Journal of Physiology-Renal Physiology, add to growing evidence implicating fructose in the obesity epidemic and could influence future dietary guidelines. UF researchers are now studying whether the same mechanism is involved in people.
"There may be more than just the common concept that the reason a person gets fat is because they eat too many calories and they don't do enough exercise," said Richard J. Johnson, M.D., the J. Robert Cade professor of nephrology and chief of nephrology, hypertension and transplantation at UF's College of Medicine. "And although genetic predispositions are obviously important, there's some major environmental force driving this process. Our data suggest certain foods and, in particular, fructose, may actually speed the process for a person to become obese."
Physical inactivity, increased caloric intake and consumption of high-fat foods undoubtedly account for part of the problem, Johnson said. But Americans are feasting on more fructose than ever. It's in soft drinks, jellies, pastries, ketchup and table sugar, among other foods, and is the key component in high fructose corn syrup, a sugar substitute introduced in the early 1970s.
Since then, fructose intake has soared more than 30 percent, and the number of people with metabolic syndrome has more than doubled worldwide, to more than 55 million in the United States alone, Johnson said. The condition, characterized by insulin resistance, obesity and elevated triglyceride levels in the blood, is linked to the development of type 2 diabetes and hypertension.
"If you feed fructose to animals they rapidly become obese, with all features of the metabolic syndrome, so there is this strong causal link," Johnson said, "And a high-fructose intake has been shown to induce certain features of the metabolic syndrome pretty rapidly in people."
Now UF research implicates a rise in uric acid in the bloodstream that occurs after fructose is consumed, Johnson said. That temporary spike blocks the action of insulin, which typically regulates how body cells use and store sugar and other food nutrients for energy. If uric acid levels are frequently elevated, over time features of metabolic syndrome may develop, including high blood pressure, obesity and elevated blood cholesterol levels.
Researchers from UF and the Baylor College of Medicine studied rats fed a high-fructose diet for 10 weeks. Compared with rats fed a control diet, those on the high-fructose diet experienced a rise in uric acid in the bloodstream and developed insulin resistance.
"When we blocked or lowered uric acid, we were able to largely prevent or reverse features of the metabolic syndrome," Johnson said. "We were able to significantly reduce weight gain, we were able to significantly reduce the rise in the triglycerides in the blood, the insulin resistance was less and the blood pressure fell."
UF researchers are now studying the uric acid pathway in cell cultures in the laboratory, in animals and in people, and are also eyeing it as a possible factor in the development of cardiovascular and kidney diseases because of its effects on blood vessel responses. They are conducting a National Institutes of Health-funded trial to determine if lowering uric acid in blacks with hypertension improves blood pressure control and are collaborating with scientists at Baylor to determine if lowering uric acid will reduce blood pressure in adolescents with hypertension.
"We cannot definitively state that fructose is driving the obesity epidemic," said Johnson. "But we can say that there is evidence supporting the possibility that it could have a contributory role-if not a major role. I think in the next few years we'll have a better feel for whether or not these pathways that can be shown in animals may be relevant to the human condition."
Findings to date suggest certain sugar carbohydrates are actually better than others, he added, because some do not activate the uric acid pathway.
"It may well be we don't need to cut out carbohydrates but just certain types of carbohydrates," Johnson said. "So this may be an alternative to the Atkins type of approach, which cuts out carbohydrates indiscriminately."
As scientists learn more about the pathway, Johnson said, and as studies are completed in people, the findings may influence how to make wise choices about the foods we eat.
"With the caveat that people are different from rodents in many ways, the link between urate levels, blood pressure elevation and insulin resistance demonstrated in rats fed fructose is extremely provocative," said Brian F. Mandell, M.D., Ph.D., vice chairman of medicine for education and a professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. "Whether the fructose supplementation to the diet in the United States is partially responsible for the 'epidemic' of obesity remains to be proven-but this is an association which can be tested, and the work of Dr. Johnson and his collaborators makes the evaluation of the fructose-metabolic link in people an academic and public health imperative."
SOURCE: http://www.brightsurf.com/news/headlines/28243/High-normal_uric_acid_linked_with_mild_cognitive_impairment_in_the_elderly.html
High-normal uric acid linked with mild cognitive impairment in the elderly
January 02, 2007 - WASHINGTON - Researchers at the Johns Hopkins and Yale university medical schools have found that a simple blood test to measure uric acid, a measure of kidney function, might reveal a risk factor for cognitive problems in old age. Of 96 community-dwelling adults aged 60 to 92 years, those with uric-acid levels at the high end of the normal range had the lowest scores on tests of mental processing speed, verbal memory and working memory.
The findings appear in the January issue of Neuropsychology, which is published by the American Psychological Association (APA).
High-normal uric acid levels, defined in this study as 5.8 to 7.6 mg/dL for men and 4.8 to 7.1 mg/dL for women, were more likely to be associated with cognitive problems even when the researchers controlled for age, sex, weight, race, education, diabetes, hypertension, smoking and alcohol abuse. These findings suggest that older people with serum (blood) uric-acid levels in the high end of the normal range are more likely to process information slowly and experience failures of verbal and working memory, as measured by the Wechsler Adult Intelligence Scale and other well-established neuropsychological tests.
"It might be useful for primary-care physicians to ask elderly adults with high normal serum uric acid about any problems they might be having with their thinking, and perhaps refer those who express concern, or whose family members express concern, for neuropsychological screening," says lead author David Schretlen, PhD.
The link between high-normal uric acid and cognitive problems is also sufficiently intriguing for the authors to propose clinical studies of whether medicines that reduce uric acid, such as allopurinol, can help older people with high-normal uric acid avoid developing the mild cognitive deficits that often precede dementia.
For reasons that are not entirely clear, uric acid levels increase with age, says Dr. Schretlen. Higher levels of uric acid are linked with known risk factors for dementia, including high blood pressure, atherosclerosis, Type 2 diabetes and the "metabolic syndrome" of abdominal obesity and insulin resistance. Dr. Schretlen also says there is mounting evidence that end-stage renal (kidney) disease increases the risk of cognitive dysfunction and dementia in elderly adults. Given this web of connections, uric acid could potentially become a valuable biological marker for very early cognitive problems in old age.
The researchers say that it's unclear why mild cognitive problems appear with high-normal uric acid because, paradoxically, uric acid also has anti-oxidant properties that are thought to be protective in other situations. The authors are also researching links between uric acid and vascular damage in the brain and attempting to dissect which aspects of uric acid and its production help or hurt the nervous system. |
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There's going to be some uric acid, whereas there does not need to be any AA, by contrast. Therefore, to me, this sort of thing has to do with a problem with normal biochemistry. If something is causing the high uric acid level, then I think of that thing as the underlying cause, and I don't "blame" uric acid. One of the researchers said, "For reasons that are not entirely clear, uric acid levels increase with age..."
My guess is that it's just another AA overload issue, possibly combined with poor nutrition (not enough of certain electrolyte minerals, for example, or enough high-quality protein), and of course "oxidative stress" (some or most of which is due to the AA). |
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I am very much interested in the underlying cause. I agree that uric acid is quite important and also functions as a kind of endogenous antioxidant. But if its level is not properly regulated it causes deposits in joints which lead to cartilage destruction and osteoarthritis.
http://en.wikipedia.org/wiki/Uric_acid
http://en.wikipedia.org/wiki/Hyperuricemia
Most of the articles I have seen suggest that fructose or excessive sugar in general is the root cause (see e.g. http://www.thepaleodiet.com/newsletter/newsletters/PDN_Vol2No4.pdf , PMID: 16932373). But humans seem to be adapted to consuming fruits/honey (fructose) at least seasonaly.
Excessive uric acid is also produced from dying/damaged tissues - and oxidative stress as well as PUFAs induce apoptosis. My best guess is that kidney damage is mostly responsible for the hyperuricemia. Kidney functions are most affected by aging (Klotho) and I suspect I ruined mine by the long term omega-3 supplementation potentiated by exercise ...
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2331-6. Epub 2007 Feb 7.
Amelioration of progressive renal injury by genetic manipulation of Klotho gene.
Haruna Y, Kashihara N, Satoh M, Tomita N, Namikoshi T, Sasaki T, Fujimori T, Xie P, Kanwar YS.
Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan.
Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was approximately 30% in ICGN mice, and approximately 70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in beta-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.
PMID: 17287345 |
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In the full text of the following article:
Ann Rheum Dis. 1986 Oct;45(10):858-64.
Growth of monosodium urate monohydrate crystals: effect of cartilage and synovial fluid components on in vitro growth rates.
Burt HM, Dutt YC.
The effects of cartilage and synovial fluid components such as proteoglycans, chondroitin sulphate, hyaluronic acid, phospholipids, and albumin on the growth kinetics of monosodium urate monohydrate (MSUM) crystals were investigated. MSUM seed crystals were added to supersaturated sodium urate solutions, and the rate of decrease in the concentration of growth medium was used as a measure of the growth rate. A second order dependence of growth rate on supersaturation was found, and growth rate constants were determined with an integrated form of the growth equation. The additives, hyaluronic acid, proteoglycan monomer and aggregate, and phosphatidylserine, had no significant effect on the growth rate constant. Chondroitin sulphate and phosphatidylcholine increased the growth rate constant, possibly by promoting further nucleation in the growth medium. Albumin significantly inhibited MSUM crystallisation. The possible implications of these findings on in vivo MSUM crystallisation are discussed.
PMID: 3098195
They say: "There is a significant increase in the intracellular and extracellular lipid content of articular cartilage with age, and extracellular lipids are prominent in the surface layers of cartilage. These lipids consist of triglycerides, cholesterol or cholesterol esters, phospholipids, and glycolipids. Normal synovial fluid contains small amounts of phospholipids and cholesterol, and synovial fluid from patients with rheumatoid arthritis and osteoarthritis shows increased amounts of phospholipids, cholesterol, and neutral lipids. The phospholipid composition of normal synovial fluid is similar to that of plasma, with phosphatidylcholine being the major constituent. It is possible that the raised levels of phospholipids in aged or diseased cartilage and synovial fluid could accelerate the growth of MSUM crystals, resulting in MSUM deposition in these tissues."
In this context I remember the study on Mead acid in the young and healthy cartilage ... |
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"These lipids consist of triglycerides, cholesterol or cholesterol esters, phospholipids, and glycolipids."
This is the key point. If you have the wrong lipids in such places, you will likely develop a "chronic disease" when you get older. |
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| Perhaps I am getting to the root cause of my health problems. On the other forum you posted some articles showing that lipid peroxides are associated with kidney stones/damage. If the kidney functions are impaired (afterall kidney have to clean the dietary PUFA breakdown products and are likely to be in overload during the course of omega-3 supplementation) uric acid concentration in blood rises. Then it starts crystallize in different places like joints and the sharp crystals irritate the tissue resulting in chronic inflammation and cartilage breakdown. To melt the uric acid deposits potassium citrate or baking soda can be used and also certain alkaline mineral waters work (http://ehealthforum.com/health/gout.html). |
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| Well, it sounds like you have something to try there. Post back and let me know how it works out for you, after you've given it some time. |
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| Hans, have you ever noticed any grinding sound (crepitus) in your knees? It's bothering me lately. Not painful yet but most sources say it's a sign of osteoarthritis and can get only worst. But I can imagine that it is caused by uric acid "sand" deposited in the joints and that once removed/melted the cartilage would regenerate and the sound would be gone. |
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| No, I've never had that sort of condition. |
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The following interesting paper on the mechanism of atherosclerosis suggests that the much increased level of urate in primates is a compensatory response to the lost of the ability to synthesize VitC:
SOURCE:
http://www4.dr-rath-foundation.org/THE_FOUNDATION/About_Dr_Matthias_Rath/publications/pub05.htm
(PMID: 2143582)
Ascorbate, Uric Acid, and Lp(a) as Antioxidants
During evolution of primates a major factor in lengthening their life-span may have been improved protective mechanisms against damage by oxygen radicals. Free-radical-mediated lipid peroxidation seems to be critically involved in cardiovascular disease and in cancer, rheumatoid arthritis, and other pathological and degenerative processes, including aging. Ascorbate has been shown to completely protect plasma lipids against detectable peroxidative damage induced by aqueous peroxyl radicals, with other antoxidants (a -tocopherol, b -carotene, bilirubin, proteinthiols) being less effective (19).
Other investigators have reported similar results for the guinea pig (20). The primates after having lost the ability to synthesize ascorbate may well have been under evolutionary pressure to develop other antioxidative mechanisms. Uric acid has been reported to be a moderately effective antioxidant and the much increased level of urate in primates, in comparison with other animals, has been described as a response to the low level of ascorbate (21).
We now suggest that apoprotein(a), with over 100 disulfide groups per molecule, is also effective as an antioxidant, acting also in this way as a surrogate for ascorbate. It would be especially effective in preventing peroxidation of lipids in the Lp(a) particle because of its presence in the shell surrounding the lipid sphere, where it could destroy the peroxyl radicals before they reach the lipids. Some of the internal disulfide groups in the kringles of apoprotein(a) might be reduced by ascorbate to thiol groups.
Another possibility is the formation of disulfide radicals by adding or subtracting an electron, the latter giving a product analogous to the superoxide radical. Immunoblots of homogenized arterial wall taken at autopsy support this hypothesis (22). Twenty-four hours after death the apo(a) extracted was not degraded and had the same molecular size as the apo(a) in the pre-mortem blood. In contrast, apo B is known to be partially degraded under these conditions.
Lp(a), Ascorbic Acid, and Cardiovascular Disease Ascorbic acid levels were found to be decreased in the plasma and leukocytes of coronary heart disease (CHD) patients (23). Furthermore, the concentrations of ascorbate in atherosclerotic lesions of human arterial wall are considerably lower than in the areas without lesions (24). In contrast, plasma Lp(a) levels were found to be elevated in CHD patients and patients with other forms of atherosclerosis (25,26).
There is a thousand-fold range of Lp(a) blood concentrations in human beings determined largely by heredity (27, 28) and to some extent by environmental factors, especially nutrition (29). Lp(a) above 30 mg/dl doubles the risk of CHD, and if in addition LDL is elevated the risk is increased by a factor of 5 (30). There is no correlation between Lp(a) levels and cholesterol plasma levels, and in normolipemic CHD patients the only risk factor for CHD is found to be elevated Lp(a) (22). This observation indicates that Lp(a) can cause atherosclerosis without hyperlipidemia.
The importance of Lp(a) in human atherosclerosis has been revealed by a quantitative study of the amount of this lipoprotein in the wall of the ascending aorta of coronary bypass patients (22). Lp(a) deposition in the arterial wall was found to correlate with the extent of plaque development in both the human aorta and the coronary arteries (15). Furthermore, a selective accumulation of Lp(a) over LDL was established in both human arteries (22) and occluded coronary bypass vein grafts (31).
As discussed above, the development and retention of Lp(a) in evolution strongly support a beneficial role of Lp(a). The great range of concentrations of Lp(a) found in human plasma suggests that the control mechanisms for apo(a) synthesis at the optimum level have not yet been developed. In addition, the atherogenicity of Lp(a) seems to be closely related to the ascorbate concentrations in plasma and tissue. We suggest that ascorbate deficiency increases plasma Lp(a).
It is also known that ascorbate deficiency affects the integrity of the endothelial cell lining (32), thus promoting the infiltration of Lp(a) and other lipoproteins. On the basis of these considerations, we postulate that ascorbate can reduce or prevent the development of atherosclerosis by lowering plasma Lp(a), decreasing lipoprotein infiltration into the arterial wall, and preventing lipid peroxidation.
Ascorbate could prevent the atherogenicity of Lp(a) also in another way. Since the binding of Lp(a) to fibrin involves lysyl groups, we suggest that, because of its involvement in hydroxylation reactions, ascorbate could convert these groups to hydroxylysyl groups and thus contribute to preventing the attachment of Lp(a). The binding of Lp(a) might also be affected by chemical modification of the lysine-binding site of the Lp(a) particle itself and ascorbate could interfere with this modification.
See also: http://www4.dr-rath-foundation.org/THE_FOUNDATION/About_Dr_Matthias_Rath/publications/pub16.htm |
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| They are not controlling for AA vs. Mead acid people, though, which probably makes a much bigger difference than anything they are talking about - they do talk about lipid peroxidation, and of course that will be worse if you have AA in your cells as opposed to the Mead acid. |
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| One thing I am no longer experiencing after giving up the flax+fish oil supplements and restricting vegetable oils as much as possible in my current lifestyle is aching joints. After reading some literature I suspect the uric acid crystals play a role in this. They form when high uric acid concentration is present in blood and this frequently occurs when there is a lot of apoptosis occurring in the body. Perhaps high HDL is also a sign of dying cells since it's said to transport used cholesterol for disposal in the liver. When cells undergo apoptosis the body needs to get rid of the resulting nucleic acids (DNA, RNA) bases what is done through the uric acid as well as the damaged membrane components such as cholesterol. It is known that chemotherapy leads to massive cell death not only of the cancer cells what often causes dangerously high uric acid levels in the blood and may even lead to death if kidney functions are compromised. Well when I look back now I had been also performing a kind of chemotherapy on myself when supplementing with the omega-3 oils for 4 years and this probably caused uric acid from the dying bone marrow cells to accumulate in my joints. The only positive thing is that perhaps accidentally I could have killed some cancer cells in my body. I wonder whether also other compounds which induce apoptosis of cancer cells like resveratrol can raise uric acid levels in normal people. It is e.g. known that sleep apnea raises uric acid as well since cells are dying from the lack of oxygen. There are many people supplementing with fish oils even at large doses posting to the bodybuilding forums and seem to be in a good health. They may be protected from the rising uric acid by consuming low carbohydrate diets because fructose is known to raise uric acid as well. But they may exhaust their stem cell pools by the increased apoptosis and renewal rates in the long run and die prematurely compared to what lifespan they were genetically given. |
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This is an interesting post from the other group about uric acid - it seems like even the higher normal concentration may be too much in the long run :-(
Mini Strokes Linked to Uric Acid Levels
Libraries
Medical News Keywords
STROKE URIC ACID ALLOPURINOL OBESITY HYPERTENSION NEUROLOGY
Newswise - Researchers at Johns Hopkins have found that high-normal
uric acid (UA) levels may cause barely detectable mini strokes that
potentially contribute to mental decline in aging adults.
Diet, exercise and drugs like allopurinol (all of which lower UA
levels) could eventually be of value in reducing this risk, especially
for those with additional risk factors such as diabetes, obesity and
hypertension, the researchers say. But they caution that it would be
premature to try this now.
In a study published in the Oct. 2 issue of Neurology, lead author
David Schretlen, Ph.D., of the Department of Psychiatry at The Johns
Hopkins University School of Medicine, linked UA levels to high
volumes of so-called white matter hyperintensities (WMH), which are
small dead areas of the brain that occur when brain cells are deprived
of oxygen. Lack of oxygen due to clots or burst blood vessels in the
brain are hallmarks of classic large strokes.
"Over a lifetime, it is common to have a small number of these mini
strokes and not even notice," says Schretlen, "but as the overall
volume of WMH increases, the damage can seriously disrupt how quickly
we think and how effectively we learn and remember information."
The role of UA is best known in gout, where buildup of the fatty acid
creates pain and disability in the feet and toes. However, UA appears
to play contradictory roles in the brain, says Schretlen. For example,
UA is a powerful antioxidant that might even protect against Parkinson
disease and Alzheimer disease, possibly because antioxidants destroy
oxygen free radicals that damage tissue. On the other hand, elevated
UA accompanies diabetes, obesity and heart disease, and it is a well-
known risk factor for stroke. One possible explanation of its
seemingly contradictory nature is that, like a double-edged sword, UA
is beneficial, but processes leading to its production can be harmful
under some circumstances, says Schretlen.
In the study, Schretlen and his team obtained and analyzed brain MRI
scans of 85 men and 92 women between 20 and 92 years of age. All
participants had normal levels of UA. However, those with high-normal
levels showed 2.6 times the volume of WMH than those with average or
low UA. Among subjects 60 years of age or older, those with high-
normal levels of UA had four to five times the volume of WMH than
others.
Gender differences exist in normal UA ranges. The blood UA
concentrations of men are typically about 1 milligram per deciliter
(mg/dL) higher than those of women. In this study UA levels ranged
from 1.6 to 8.2 mg/dL for men and from 1.5 to 7.2 mg/dL for women.
Within these ranges, concentrations greater than or equal to 5.75 mg/
dL for men and 4.8 mg/dL for women were classified as high normal.
In a previous study, Schretlen and colleagues examined the
relationship between serum UA and cognitive functioning in adults age
60 and older. In that study, elderly adults with high-normal levels of
UA were 2.7 to 5.9 times more likely to score in the lowest 25 percent
of the group on measures of thinking speed and memory.
"Having found that UA levels are linked to both mild cognitive decline
and mini strokes," says Schretlen, "we need to learn how these are
related. We have to find out which of these factors steers the boat."
Schretlen says clinical trials with drugs like allopurinol, which have
been used safely for decades to treat gout, may be warranted if
further research confirms his hypothesis.
Additional authors of this study, all from The Johns Hopkins
University School of Medicine, are Anjeli B. Inscore, Psy.D., Tracy D.
Vannorsdall, Ph.D., and Godfrey D. Pearlson, M.D., of the Department
of Psychiatry and Behavioral Sciences; Barry Gordon, M.D., Ph.D., and
H.A. Jinnah, M.D., Ph.D., of the Department of Neurology, and Michael
Kraut, M.D., Ph.D., of the Department of Radiology and Radiological
Sciences. |
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And this is about free iron which stimulates xanthine oxidase - the enzyme responsible for making uric acid:
Med Hypotheses. 2001 Nov;57(5):539-43.
The possible crucial role of iron accumulation combined with low tryptophan, zinc and manganese in carcinogenesis.
Johnson S.
Iron can react with citric acid, interfering with the Krebs cycle, hence with oxidative phosphorylation. Free iron (Fe) can cause considerable oxidative damage both through Fenton reactions and by activating xanthine oxidase, which produces both superoxide (O(2-)) and uric acid (abundant in many cancers). It can also react with lactic acid, reducing its elimination and increasing the acidity of the cytoplasm. Fe can also wreak havoc by reacting with tryptophan, the least abundant and most delicate essential amino acid, which is necessary for the production of serotonin and other substances required by the immune system to fight cancer. On the other hand, in the presence of iron, the tryptophan metabolite quinolinate causes intense lipid peroxidation. Similarly, several other carcinogenic metabolites of tryptophan are particularly dangerous in the presence of Fe. Excess Fe may also interfere with manganese superoxide dismutase and impair the initiation of apoptosis by the mitochondrion, rendering the cells impervious to all the signals to undergo apoptosis from without and from within the cell. Moreover, Fe may also play a crucial role on telomere repair, by activating telomerase. Therefore, by inhibiting apoptosis and enhancing chromosome repair, Fe may bestow immortality upon the cancer cell. Furthermore, Fe is one of the triggers for mitosis. Therefore, increased Fe levels may be essential for the rapid growth characteristic of many malignancies. In turn, the rapid growth further depletes resources from the healthy tissues, exacerbating the deficiencies of the other elements and reducing the ability to fight the malignancy. Copyright 2001 Harcourt Publishers Ltd.
PMID: 11735307 |
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This is a post from another newsgroup mentioning again fructose being behind the elevated uric acid.
Editorials:
George A Bray
How bad is fructose?
Am J Clin Nutr 2007 86: 895-6.
This issue of the Journal contains another disturbing article on the
biology of fructose (1). Why is fructose of concern? First, it is
sweeter than either glucose or sucrose. In fruit, it serves as a
marker for foods that are nutritionally rich. However, in soft drinks
and other "sweets," fructose serves to reward sweet taste that
provides "calories," often without much else in the way of nutrition.
Second, the intake of soft drinks containing high-fructose corn syrup
(HFCS) or sucrose has risen in parallel with the epidemic of obesity,
which suggests a relation (2). Third, the article in this issue of the
Journal (1) and another article published elsewhere last year (3)
implicate dietary fructose as a potential risk factor for
cardiovascular disease.
The intake of dietary fructose has increased significantly from 1970
to 2000. There has been a 25% increase in available "added sugars" during this period (4). The Continuing Survey of Food Intake by Individuals from 1994 to 1996 showed that the average person had a daily added sugars intake of 79 g (equivalent to 316 kcal/d or 15% of energy intake), approximately half of which was fructose. More important, persons who are ranked in the top one-third of fructose consumers ingest 137 g added sugars/d, and those in the top 10% consume 178 g/d, with half of that amount being fructose. If there are health concerns with fructose, then this increased intake could aggravate those problems.
Before the European encounter with the New World 500 y ago and the development of the worldwide sugar industry, fructose in the humandiet was limited to a few items. For example, honey, dates, raisins, molasses, and figs have a content of >10% of this sugar, whereas a fructose content of 5-10% by weight is found in grapes, raw apples, apple juice, persimmons, and blueberries. Milk, the main nourishment for infants, has essentially no fructose, and neither do most vegetables and meats, which indicates that human beings had little dietary exposure to fructose before the mass production of sugar.
Most fructose in the American diet comes not from fresh fruit, but
from HFCS or sucrose (sugar) that is found in soft drinks and sweets, which typically have few other nutrients (2). Soft drink consumption, which provides most of this fructose, has increased dramatically in the past 6 decades, rising from a per-person consumption of 90 servings/y (2 servings/wk) in 1942 to that of 600 servings/y (2 servings/d) in 2000 (5). More than 50% of preschool children consume some calorie-sweetened beverages (6). Children of this age would not normally be exposed to fructose, let alone in these high amounts. Because both HFCS and sucrose are "delivery vehicles for fructose," the load of fructose has increased in parallel with the use of sugar.
Fructose is an intermediary in the metabolism of glucose, but there is
no biological need for dietary fructose. When ingested by itself,
fructose is poorly absorbed from the gastrointestinal tract, and it is
almost entirely cleared by the liver-the circulating concentration is
0.01 mmol/L in peripheral blood, compared with 5.5 mmol/L for
glucose. Fructose differs in several ways from glucose, the other half of the sucrose (sugar) molecule (4). Fructose is absorbed from the gastrointestinal tract by a different mechanism than that for glucose. Glucose stimulates insulin release from the isolated pancreas, but fructose does not. Most cells have only low amounts of the glut-5 transporter, which transports fructose into cells. Fructose cannot enter most cells, because they lack glut-5, whereas glucose is transported into cells by glut-4, an insulin-dependent transport system. Finally, once inside the liver cell, fructose can enter the pathways that provide glycerol, the backbone for triacylglycerol. The growing dietary amount of fructose that is derived from sucrose or HFCS has raised questions about how children and adults respond to fructose alone or when it is
accompanied by glucose. In one study, the consumption of high-fructose meals reduced 24-h plasma insulin and leptin concentrations and increased postprandial fasting triacylglycerols in women, but it did not suppress circulating ghrelin, a major appetite-stimulating hormone (4).
Fructose is metabolized, primarily in the liver, by phosphorylation on
the 1-position, a process that bypasses the rate-limiting
phosphofructokinase step (4). Hepatic metabolism of fructose thus
favors lipogenesis, and it is not surprising that several studies have
found changes in circulating lipids when subjects eat high-fructose
diets (4). In the study conducted by Aeberli et al (1), dietary
factors, especially fructose, were examined in relation to body mass
index, waist-to-hip ratio, plasma lipid profile, and LDL particle size
in 74 Swiss schoolchildren who were 6-14 y old. In that study, plasma triacylglycerols were higher, HDL-cholesterol concentrations were lower, and lipoprotein (LDL) particle size was smaller in the
overweight children than in the normal-weight children. Fatter
children had smaller LDL particle size, and, even after control for
adiposity, dietary fructose intake was the only dietary factor related
to LDL particle size. In this study, it was the free fructose, and not
sucrose, that was related to the effect of LDL particle size. Studies
in rodents, dogs, and nonhuman primates eating diets high in fructose or sucrose consistently show hyperlipidemia (4). The current report by Aeberli et al suggests that the higher intake of fructose by school-age children may have detrimental effects on their future risk of cardiovascular disease by reducing LDL particle size. It is interesting that this study did not find a relation of dietary
fructose with triacylglycerols but did find a relation with the more
concerning lipid particle, LDL cholesterol. Another recent report has
proposed a hypothesis relating fructose intake to the long-known
relation between uric acid and heart disease (3). The ADP formed from ATP after phosphorylation of fructose on the 1-position can be further metabolized to uric acid. The metabolism of fructose in the liver drives the production of uric acid, which utilizes nitric oxide, a key modulator of vascular function (3). The studies by Aeberli et al and Nakagawa et al suggest that the relation of fructose to health needs reevaluation. |
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