733 lines
46 KiB
HTML
733 lines
46 KiB
HTML
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<head><title>Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer</title></head>
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<body>
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<h1>
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Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer
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</h1>
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<p>
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<hr />
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<hr />
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</p>
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<p>
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<strong>
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GLOSSARY</strong>
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</p>
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<p>
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<strong>Aerobic glycolysis,</strong> the conversion of glucose to lactic acid even in the presence of
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oxygen. The presence of oxygen normally restrains glycolysis so that glucose is converted to carbon dioxide
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instead of lactic acid.
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</p>
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<p>
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<strong>Anaerobic glycolysis,</strong> the increased conversion of glucose to lactic acid when the supply of
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oxygen isn't sufficient, which is a normal event during intense muscle action.
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</p>
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<p>
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<strong>"Warburg Effect"</strong> refers to Otto Warburg's observation that cancer cells produce lactic acid
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even in the presence of adequate oxygen. Cancer cells don't "live on glucose," since they are highly adapted
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to survive on protein and fats.
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</p>
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<p>
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<strong>Pasteur Effect,</strong> the normal response of cells to restrain glycolysis in the presence of
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adequate oxygen.
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</p>
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<p>
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<strong>Crabtree Effect,</strong> observed originally in yeast, refers to the inhibition of respiration in
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the presence of glucose. This occurs in cancers (e.g., Miralpeix, et al., 1990) and in rapidly proliferating
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normal cells (e.g., Guppy, et al., 1993).
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</p>
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<p>
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<strong>"Cancer metabolism"</strong> or stress metabolism typically involves an excess of the adaptive
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hormones, resulting from an imbalance of the demands made on the organism and the resources available to the
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organism. Excessive stimulation depletes glucose and produces lactic acid, and causes cortisol to increase,
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causing a shift to the consumption of fat and protein rather than glucose. Increased cortisol activates the
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Randle effect (the inhibition of glucose oxidation by free fatty acids), accelerates the breakdown of
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protein into amino acids, and activates the enzyme fatty acid synthase, which produces fatty acids from
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amino acids and pyruvate, to be oxidized in a "futile cycle," producing heat, and increasing the liberation
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of ammonia from the amino acids. Ammonia suppresses respiratory, and stimulates glycolytic, activity.
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</p>
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<p>
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<hr />
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<hr />
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<hr />
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</p>
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<p>
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The presence of lactic acid in our tissues is very meaningful, but it is normally treated as only an
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indicator, rather than as a cause, of biological problems. Its presence in rosacea, arthritis, heart
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disease, diabetes, neurological diseases and cancer has been recognized, and recently it is being recognized
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that suppressing it can be curative, after fifty years of denial.
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</p>
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<p>
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The influence of politics on science is so profound that neither historians nor scientists often care to
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consider it honestly and in depth.
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</p>
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<p>
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From the 19th century until the second quarter of the 20th century, cancer was investigated mainly as a
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metabolic problem. This work, understanding the basic chemistry of metabolism, was culminating in the 1920s
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in the work of Otto Warburg and Albert Szent-Gyorgyi on respiration. Warburg demonstrated as early as 1920
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that a respiratory defect, causing aerobic glycolysis, i.e., the production of lactic acid even in the
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presence of oxygen, was an essential feature of cancer. (The formation of lactic acid is normal and adaptive
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when the supply of oxygen isn't adequate to meet energy demands, for example when running.)
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</p>
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<p>
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Many people recognized that this was likely to be the key to the "cancer problem." But in the US, several
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factors came together to block this line of investigation.
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</p>
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<p>
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The world wars contributed to the isolation of German scientists, and Warburg, of the famous Jewish banking
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family, continued his work in Germany with the support of the government, despite his open opposition to
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Nazism. In the years after the war, nothing positive could be said in the US about his work on cancer.
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</p>
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<p>
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The metabolic interpretation of disease that had been making progress for several decades was suddenly
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submerged when government research financing began concentrating on genetic and viral interpretations of
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disease.
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</p>
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<p>
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If an apparently non-infectious disease couldn't be explained on the basis of an inherited
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tendency---insanity, epilepsy, diabetes, toxemia of pregnancy, and cancer, for example---then genetic
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changes occurring in the individual, as a result of chance or a virus, were invoked. Nutrition and other
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conditions of life were until fairly recently said to have no influence on health if the person consumed
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sufficient calories and a minimum amount of the essential vitamins, minerals, and protein. The cult of
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genetic determinism was so powerful that it wasn't affected by the facts.
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</p>
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<p>
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In 1932, a pediatrician, Alexis Hartmann (with M. Senn) in St. Louis, injected intravenously a solution of
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sodium lactate into patients with metabolic acidosis, and several of them survived---despite the fact that
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some of them were already suffering from an excess of lactate. The subsequent widespread use of lactate
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solutions in hospitals has contributed to the general denial of its toxicity.
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</p>
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<p>
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Hartmann and Senn used racemic lactate, that is, a mixture of D-lactate and L-lactate. Our own tissues
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produce mostly L-lactate, but they can produce small amounts of D-lactate; larger amounts are produced by
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diabetics. Intestinal bacteria can produce large amounts of it, and it has many toxic effects. Methylglyoxal
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can be formed from either form of lactate, and it is an important factor in the glycation of proteins. It
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can also be formed from MDA, a product of lipid peroxidation. Protein glycation is an important factor in
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diabetes and aging, but glucose, rather than lactate and polyunsaturated fats, is commonly said to be the
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cause.
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</p>
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<p>
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About 50 years ago, lactate was known to induce the formation of new blood vessels, and for a much longer
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time it has been known to cause vasodilation and edema. In 1968, it was shown to stimulate collagen
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synthesis.
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</p>
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<p>
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Normally, collagen synthesis and neovascularization are caused by lack of oxygen, but lactate can cause them
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to occur even in the presence of oxygen. Maintenance of a normal extracellular matrix is essential for
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normal functioning and cellular differentiation. Abnormally stimulated collagen synthesis probably
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accelerates tumor growth (Rajkumar, et al., 2006).
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</p>
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<p>
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Nervous and hormonal factors can cause lactate to accumulate, even without prior damage to the mitochondria
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(e.g., B. Levy, et al., 2003). Psychological, as well as physical, stress and overactivation of glutamate
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receptors can cause harmful accumulation of lactate in the brain (Uehara, et al., 2005). Rather than just
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being "associated with" tissue damage, lactate directly contributes to the damage, for example in the brain,
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causing nerve cell loss by increasing the release of excitotoxic glutamate (Xiang, et al, 2004). When a
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panic reaction is produced by sodium lactate, the reduction of protective neurosteroids appears to
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contribute to the excitatory state (Eser, et al. 2006); this would make the brain more susceptible to
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damage.
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</p>
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<p>
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Lactate increases blood viscosity, mimics stress, causes inflammation, and contributes to shock. Lactated
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Ringer's solution contributes to the tissue damage caused by shock, when it's used to resuscitate shock
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victims (Deree, et al., 2007, 2008): it contributes to the inflammatory processes associated with shock,
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unlike the use of hypertonic saline and other solutions. Lactate contributes to diabetes, inhibiting the
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ability to oxidize glucose. It promotes endothelial cell migration and leakiness, with increased vascular
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permeability factor (VPF or vascular endothelial growth factor, VEGF) (Nagy, et al. 1985): this can lead to
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breakdown of the "blood-brain barrier."
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</p>
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<p>
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In the brain, lactate can cause nerve damage, increasing intracellular fat accumulation, chromatin clumping,
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and mitochondrial swelling (Norenberg, et al., 1987).
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</p>
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<p>
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The lactate in peritoneal dialysis solution impairs differentiation and maturation of (immune, monocyte
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derived) dendritic cells; according to the authors of the study, "These findings have important implications
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for the initiation of immune responses under high lactate conditions, such as those occurring within tumor
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tissues or after macrophage activation<strong>" </strong>
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(Puig-Kr"ger, et al., 2003).<strong> </strong>
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</p>
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<p>
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Lactate also causes macrophages and synovial fibroblasts to release PGE2, which can contribute to
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inflammation and bone resorption (Dawes and Rushton, 1994). This is the prostaglandin known to activate the
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formation of estrogen (Haffty, et al., 2008).
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</p>
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<p>
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Hartmann's lactated solution has been widely used in hospitals for resuscitation and for patients after
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heart surgery and other stressful procedures, but until recently only a few people have objected to its use,
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and most of the objection has been to the use of racemic lactate, rather than to lactate itself. In recent
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years several studies have compared hypertonic saline (lacking the minerals considered essential since
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Sydney Ringer formulated his solution around 1885), and have found it in some cases superior to the
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"balanced" lactate solution. Even hypertonic glucose, without minerals, has produced good results in some
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studies.
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</p>
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<p>
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A solution containing a large amount of lactate has been used for peritoneal dialysis when there is kidney
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failure, but several studies have compared solutions using bicarbonate instead of lactate, and found that
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they don't cause the severe damage that always happened with the traditional solution.
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</p>
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<p>
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While Warburg was investigating the roles of glycolysis and respiration in cancer,<strong> </strong>a
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physician with a background in chemistry, W.F. Koch, in Detroit, was showing that the ability to use oxygen
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made the difference between health and sickness, and that the cancer metabolism could be corrected by
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restoring the efficient use of oxygen. He argued that a respiratory defect was responsible for
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immunodeficiency, allergy, and defective function of muscles, nerves, and secretory cells, as well as
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cancer. Koch's idea of cancer's metabolic cause and its curability directly challenged the doctrine of the
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genetic irreversibility of cancer that was central to governmental and commercial medical commitments.
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</p>
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<p>
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Albert Szent-Gyorgyi respected Koch's work, and spent years investigating the involvement of the lactate
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metabolites, methylgyoxal and glyoxal, in cell physiology, but since the government's campaign against Koch
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was still active when Szent-Gyorgyi came to the U.S., he worked out many of the implications of Koch's work
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relating to cellular oxidation without mentioning his name.
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</p>
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<p>
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Lactate formation from glucose is increased when anything interferes with respiratory energy production, but
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lactate, through a variety of mechanisms, can itself suppress cellular respiration. (This has been called
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the Crabtree effect.) Lactate can also inhibit its own formation, slowing glycolysis. In the healthy cell,
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the mitochondrion keeps glycolysis working by consuming pyruvate and electrons (or "hydrogens") from NADH,
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keeping the cell highly oxidized, with a ratio of NAD+/NADH of about 200. When the mitochondrion's ability
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to consume pyruvate and NADH is limited, the pyruvate itself accepts the hydrogen from NADH, forming lactic
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acid and NAD+ in the process. As long as lactate leaves the cell as fast as it forms, glycolysis will
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provide ATP to allow the cell to survive. Oxygen and pyruvate are normally "electron sinks," regenerating
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the NAD+ needed to produce energy from glucose.
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</p>
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<p>
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But if too much lactate is present, slowing glycolytic production of ATP, the cell with defective
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respiration will die unless an alternative electron sink is available. The synthesis of fatty acids is such
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a sink, if electrons (hydrogens) can be transferred from NADH to NADP+, forming NADPH, which is the reducing
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substance required for turning carbohydrates and pyruvate and amino acids into fats.
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</p>
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<p>
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This transfer can be activated by the transhydrogenase enzymes in the mitochondria, and also by interactions
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of some dehydrogenase enzymes.
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</p>
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<p>
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The enzyme, fatty acid synthase (FAS), normally active in the liver and fat cells and in the
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estrogen-stimulated uterus, is highly active in cancers, and its activity is an inverse indicator of
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prognosis. Inhibiting it can cause cancer cells to die, so the pharmaceutical industry is looking for drugs
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that can safely inhibit it. This enzyme is closely associated with the rate of cell proliferation, and its
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activity is increased by both cortisol and estrogen.
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</p>
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<p>
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The first biochemical event when a cell responds to estrogen is the synthesis of fat. Estrogen can activate
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transhydrogenases, and early studies of estrogen's biological effects provided considerable evidence that
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its actions were the result of the steroid molecule's direct participation in hydrogen transfers, oxidations
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and reductions. E.V. Jensen's claim that estrogen acts only through a "receptor protein" which activated
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gene transcription was based on his experimental evidence indicating that estrogen doesn't participate in
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oxidation and reduction processes in the uterus, but subsequently his claim has turned out to be false.
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</p>
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<p>
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Glycolysis is very inefficient for producing usable energy compared to the respiratory metabolism of the
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mitochondria, and when lactate is carried to the liver, its conversion to glucose adds to the energy drain
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on the organism.
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</p>
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<p>
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The hypoglycemia and related events resulting from accelerated glycolysis provide a stimulus for increased
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activity of the adaptive hormones, including cortisol. Cortisol helps to maintain blood sugar by increasing
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the conversion of protein to amino acids, and mobilizing free fatty acids from fat stores. The free fatty
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acids inhibit the use of glucose, so the stress metabolism relies largely on the consumption of amino acids.
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This increases the formation of ammonia, yet the combination of glycolysis and fat oxidation provides less
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carbon dioxide, which is needed for the conversion of ammonia to urea. Ammonia stimulates the formation of
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lactate, while carbon dioxide inhibits it.
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</p>
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<p>
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Starving an animal with a tumor increases the stress hormones, providing free fatty acids and amino acids,
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and accelerates the tumor's growth (Sauer and Dauchy, 1987); it's impossible to "starve a tumor," by the
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methods often used. Preventing the excessive breakdown of protein and reducing the release of fatty acids
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from fat cells would probably cause many cancer cells to die, despite the availability of glucose, because
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of lactate's toxic effects, combined with the energy deficit caused by the respiratory defect that causes
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their aerobic glycolysis. Recently, the intrinsically high rate of cell death in tumors has been recognized.
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The tumor is maintained and enlarged by the recruitment of "stem cells." These cells normally would repair
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or regenerate the tissue, but under the existing metabolic conditions, they fail to differentiate properly.
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</p>
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<p>
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The extracellular matrix in the tumor is abnormal, as well as the metabolites and signal substances being
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produced there, and the new cells fail to receive the instructions needed to restore the normal functions to
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the damaged tissue. These abnormal conditions can cause abnormal differentiation, and this cellular state is
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likely to involve chemical modification of proteins, including remodeling of the chromosomes through
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acetylation of the histones (Alam, et al., 2008; Suuronen, et al., 2006). The protein-protective effects of
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carbon dioxide are replaced by the protein-damaging effects of lactate and its metabolites.
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</p>
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<p>
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The ability of lactic acid to displace carbon dioxide is probably involved in its effects on the blood
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clotting system. It contributes to disseminated intravascular coagulation and consumption coagulopathy, and
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increases the tendency of red cells to aggregate, forming "blood sludge," and makes red cells more rigid,
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increasing the viscosity of blood and impairing circulation in the small vessels. (Schmid-Sch"nbein, 1981;
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Kobayashi, et al., 2001; Martin, et al., 2002; Yamazaki, et al., 2006.)
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</p>
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<p>
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The features of the stress metabolism include increases of stress hormones, lactate, ammonia, free fatty
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acids, and fat synthesis, and a decrease in carbon dioxide. Factors that lower the stress hormones, increase
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carbon dioxide, and help to lower the circulating free fatty acids, lactate, and ammonia, include vitamin B1
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(to increase CO2 and reduce lactate), niacinamide (to reduce free fatty acids), sugar (to reduce cortisol,
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adrenaline, and free fatty acids), salt (to lower adrenaline), thyroid hormone (to increase CO2). Vitamins
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D, K, B6 and biotin are also closely involved with carbon dioxide metabolism. Biotin deficiency can cause
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aerobic glycolysis with increased fat synthesis (Marshall, et al., 1976).
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</p>
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<p>
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A protein deficiency, possibly by increasing cortisol, is likely to contribute to increased FAS and fat
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synthesis (Bannister, et al., 1983), but the dietary protein shouldn't provide an excess of tryptophan,
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because of tryptophan's role as serotonin precursor--serotonin increases inflammation and glycolysis
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(Koren-Schwartzer, et al., 1994).
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</p>
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<p>
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Incidental stresses, such as strenuous exercise combined with fasting (e.g., running or working before
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eating breakfast) not only directly trigger the production of lactate and ammonia, they also are likely to
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increase the absorption of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous and chronic
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stressor. It increases lactate and nitric oxide, poisoning mitochondrial respiration, precipitating the
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secretion of the adaptive stress hormones, which don't always fully repair the cellular damage.
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</p>
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<p>
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Aspirin protects cells in many ways, interrupting excitotoxic processes by blocking nitric oxide and
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prostaglandins, and consequently it inhibits cell proliferation, and in some cases inhibits glycolysis, but
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the fact that it can inhibit FAS (Beynen, et al., 1982) is very important in understanding its role in
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cancer.
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</p>
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<p>
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There are several specific signals produced by lactate that can promote growth and other features of cancer,
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and it happens that aspirin antagonizes those: HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme
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oxygenase.
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</p>
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<p>
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Lactate and inflammation promote each other in a vicious cycle (Kawauchi, et al., 2008).
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</p>
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<p>
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The toxic mechanism of bacterial endotoxin (lipopolysaccharide) involves inappropriate stimulation (Wang and
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White, 1999) of cells, followed by inflammation and mitochondrial inhibition. The stimulation seems to be a
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direct "biophysical" action on cells, causing them to take up water (Minutoli, et al., 2008), which is
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especially interesting, since estrogen's immediate excitatory effect causes cells to take up water.
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</p>
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<p>
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Hypoosmolarity itself is excitatory and anabolic. It stimulates lipolysis and fat oxidation (Keller, et al.
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2003), and osmotic swelling stimulates glycolysis and inhibits mitochondrial respiration (Levko, et al.,
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2000). Endotoxin causes hyponatremia (Tyler, et al., 1994), and a hypertonic salt solution is protective,
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lactate solutions are harmful. Other stresses and inflammations also cause hyponatremia.
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</p>
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<p>
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One of the effects of endotoxin that leads to prolonged cellular excitation is its inhibition of the
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glucuronidation system (B"nhegyi, et al., 1995), since this inhibition allows excitatory estrogen to
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accumulate.
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</p>
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<p>
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In women and rats, antibiotics were found to cause blood levels of estrogen and cortisol to decrease, while
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progesterone increased. This effect apparently resulted from the liver's increased ability to inactivate
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estrogen and to maintain blood sugar when the endotoxin stress was decreased.
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</p>
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<p>
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Now that hog farmers' use of antibiotics to stimulate growth has been discouraged, they have sought
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vegetables that have a natural antibiotic effect, reducing the formation and absorption of the intestinal
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toxins. The human diet can be similarly adjusted, to minimize the production and absorption of the bacterial
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toxins.
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</p>
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<p>
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In 2007, two Canadian researchers announced that they were investigating the drug dichloroacetate, which
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blocks glycolysis, stopping the production of lactic acid, as a cancer treatment, with success. The drug
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(dichloroacetate) has toxic side effects, but it is useful in several other conditions involving
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over-production of lactic acid. Other drugs that inhibit glycolysis have also shown anticancer effects in
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animals, but are in themselves very toxic. On the theoretical level, it would be better to inhibit only
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aerobic glycolysis, rather than inhibiting enzymes that are essential for all glycolysis.
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</p>
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<p>
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Since endotoxemia can produce aerobic glycolysis in an otherwise healthy person (Bundgaard, et al., 2003), a
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minimally "Warburgian" approach--i.e,, a merely reasonable approach--would involve minimizing the absorption
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of endotoxin. Inhibiting bacterial growth, while optimizing intestinal resistance, would have no harmful
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side effects. Preventing excessive sympathetic nervous activity and maintaining the intestine's energy
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production can be achieved by optimizing hormones and nutrition. Something as simple as a grated carrot with
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salt and vinegar can produce major changes in bowel health, reducing endotoxin absorption, and restoring
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constructive hormonal functions.
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</p>
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<p>
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Medical tradition and inertia make it unlikely that the connection between cancer and bowel toxins will be
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recognized by the mainstream of medicine and governemt. In another article I will describe some of the
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recent history relating to this issue.
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</p>
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<p>
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It's nice that some cancer researchers are now remembering Warburg, but unfortunately they are usually just
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fitting the fact of cancer's aerobic glycolysis into the genetic mutant cell paradigm, thinking of the
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respiratory defect as just another opportunity for killing the evil deviant cancer cell, rather than looking
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for the causes of the respiratory defect. Warburg, Koch, and Szent-Gyorgyi had a comprehensive view of
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biology, in which the aerobic production of lactate, resulting from a respiratory defect, itself was
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functonally related to the nature of cancer.
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</p>
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<p>
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A focus on correcting the respiratory defect would be relevant for all of the diseases and conditions
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(including heart disease, diabetes, dementia) involving inflammation and inappropriate excitation, not just
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for cancer.
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</p>
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<p><h3>REFERENCES</h3></p>
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<p>
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Resuscitation. 2008 Feb;76(2):299-310. <strong>Impact of resuscitation strategies on the acetylation status
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of cardiac histones in a swine model of hemorrhage.</strong>
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Alam HB, Shults C, Ahuja N, Ayuste EC, Chen H, Koustova E, Sailhamer EA, Li Y, Liu B, de Moya M, Velmahos
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GC.
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</p>
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<p>
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Mol Genet Metab 1998 Mar;63(3):235-8. <strong>Activation of membrane skeleton-bound phosphofructokinase in
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erythrocytes induced by serotonin.</strong> Assouline-Cohen M, Ben-Porat H, Beitner R. We show here that
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serotonin, both in vivo and in vitro, induced a marked activation of phosphofructokinase, the rate-limiting
|
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enzyme in glycolysis, in the membrane-skeleton fraction from erythrocytes. Concomitantly, the hormone
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|
induced a striking increase in lactate content, reflecting stimulation of glycolysis. The enzyme's activity
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in the cytosolic (soluble) fraction remained unchanged. These results suggest a defense mechanism in the
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erythrocytes against the damaging effects of serotonin, whose concentration in plasma increases in many
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diseases and is implicated as playing an important role in circulation disturbances.
|
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© Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
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