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Aerobic glycolysis, the conversion of glucose to lactic acid even in the presence of oxygen. The presence of oxygen normally restrains glycolysis so that glucose is converted to carbon dioxide instead of lactic acid. 有氧糖酵解，即使在有氧的情况下也能将葡萄糖转化为乳酸。氧气的存在通常会抑制糖酵解，从而将葡萄糖转化为二氧化碳而不是乳酸。

Anaerobic glycolysis, the increased conversion of glucose to lactic acid when the supply of oxygen isn't sufficient, which is a normal event during intense muscle action. 无氧糖酵解，当氧气供应不足时，葡萄糖向乳酸的转化增加，这是剧烈肌肉活动期间的正常现象。

“Warburg Effect” refers to Otto Warburg's observation that cancer cells produce lactic acid even in the presence of adequate oxygen. Cancer cells don't “live on glucose,” since they are highly adapted to survive on protein and fats. “Warburg 效应”是指 Otto Warburg 的观察，即癌细胞即使在氧气充足的情况下也会产生乳酸。癌细胞不会“靠葡萄糖生存”，因为它们非常适合靠蛋白质和脂肪生存。

Pasteur Effect, the normal response of cells to restrain glycolysis in the presence of adequate oxygen. 巴斯德效应，细胞在氧气充足的情况下抑制糖酵解的正常反应。

Crabtree Effect, observed originally in yeast, refers to the inhibition of respiration in the presence of glucose. This occurs in cancers (e.g., Miralpeix, et al., 1990) and in rapidly proliferating normal cells (e.g., Guppy, et al., 1993). 最初在酵母中观察到的Crabtree 效应是指在葡萄糖存在下抑制呼吸作用。这发生在癌症（例如，Miralpeix 等人，1990）和快速增殖的正常细胞中（例如，Guppy 等人，1993 年）。

“Cancer metabolism” or stress metabolism typically involves an excess of the adaptive hormones, resulting from an imbalance of the demands made on the organism and the resources available to the organism. Excessive stimulation depletes glucose and produces lactic acid, and causes cortisol to increase, causing a shift to the consumption of fat and protein rather than glucose. Increased cortisol activates the Randle effect (the inhibition of glucose oxidation by free fatty acids), accelerates the breakdown of protein into amino acids, and activates the enzyme fatty acid synthase, which produces fatty acids from amino acids and pyruvate, to be oxidized in a “futile cycle,” producing heat, and increasing the liberation of ammonia from the amino acids. Ammonia suppresses respiratory, and stimulates glycolytic, activity. 癌症代谢或压力代谢通常涉及过量的适应性激素，这是由于对生物体的需求和生物体可用资源的不平衡造成的。过度刺激会消耗葡萄糖并产生乳酸，并导致皮质醇增加，从而导致脂肪和蛋白质的消耗而不是葡萄糖的消耗。皮质醇增加会激活兰德尔效应（游离脂肪酸对葡萄糖氧化的抑制作用），加速蛋白质分解为氨基酸，并激活脂肪酸合成酶，从氨基酸和丙酮酸产生脂肪酸，在“无用循环”，产生热量，并增加氨从氨基酸中的释放。氨抑制呼吸并刺激糖酵解活动。

The presence of lactic acid in our tissues is very meaningful, but it is normally treated as only an indicator, rather than as a cause, of biological problems. Its presence in rosacea, arthritis, heart disease, diabetes, neurological diseases and cancer has been recognized, and recently it is being recognized that suppressing it can be curative, after fifty years of denial. 我们组织中乳酸的存在非常有意义，但它通常仅被视为生物问题的指标，而不是原因。人们已经认识到它在酒渣鼻、关节炎、心脏病、糖尿病、神经系统疾病和癌症中的存在，并且最近人们认识到，在五十年的否认之后，抑制它可以治愈。

The influence of politics on science is so profound that neither historians nor scientists often care to consider it honestly and in depth. 政治对科学的影响如此深远，以至于历史学家和科学家都不愿意诚实而深入地考虑它。

From the 19th century until the second quarter of the 20th century, cancer was investigated mainly as a metabolic problem. This work, understanding the basic chemistry of metabolism, was culminating in the 1920s in the work of Otto Warburg and Albert Szent-Gyorgyi on respiration. Warburg demonstrated as early as 1920 that a respiratory defect, causing aerobic glycolysis, i.e., the production of lactic acid even in the presence of oxygen, was an essential feature of cancer. (The formation of lactic acid is normal and adaptive when the supply of oxygen isn't adequate to meet energy demands, for example when running.) 从 19 世纪到 20 世纪下半叶，癌症主要作为代谢问题进行研究。这项了解新陈代谢的基本化学的工作在 1920 年代的 Otto Warburg 和 Albert Szent-Gyorgyi 关于呼吸的工作中达到高潮。Warburg 早在 1920 年就证明，导致有氧糖酵解的呼吸缺陷，即即使在有氧的情况下也会产生乳酸，是癌症的基本特征。（当氧气供应不足以满足能量需求时，例如跑步时，乳酸的形成是正常和适应性的。）

Many people recognized that this was likely to be the key to the “cancer problem.” But in the US, several factors came together to block this line of investigation. 许多人认识到，这很可能是解决“癌症问题”的关键。但在美国，有几个因素共同阻止了这一调查。

The world wars contributed to the isolation of German scientists, and Warburg, of the famous Jewish banking family, continued his work in Germany with the support of the government, despite his open opposition to Nazism. In the years after the war, nothing positive could be said in the US about his work on cancer. 世界大战导致德国科学家与世隔绝，著名的犹太银行家族的瓦尔堡在政府的支持下继续他在德国的工作，尽管他公开反对纳粹主义。在战后的几年里，美国对他在癌症方面的工作没有任何正面评价。

The metabolic interpretation of disease that had been making progress for several decades was suddenly submerged when government research financing began concentrating on genetic and viral interpretations of disease. 当政府研究资金开始集中于疾病的遗传和病毒解释时，几十年来一直在取得进展的疾病代谢解释突然被淹没了。

If an apparently non-infectious disease couldn't be explained on the basis of an inherited tendency—insanity, epilepsy, diabetes, toxemia of pregnancy, and cancer, for example—then genetic changes occurring in the individual, as a result of chance or a virus, were invoked. Nutrition and other conditions of life were until fairly recently said to have no influence on health if the person consumed sufficient calories and a minimum amount of the essential vitamins, minerals, and protein. The cult of genetic determinism was so powerful that it wasn't affected by the facts. 如果一种明显的非传染性疾病不能根据遗传倾向来解释——例如精神错乱、癫痫、糖尿病、妊娠毒血症和癌症——那么个体中发生的遗传变化，就会被作为偶然或病毒的结果来解释。直到最近，营养和其他生活条件才被认为对健康没有影响，如果一个人摄入足够的卡路里和最少量的必需维生素、矿物质和蛋白质。对基因决定论的崇拜是如此强大，以至于它不受事实的影响。

In 1932, a pediatrician, Alexis Hartmann (with M. Senn) in St. Louis, injected intravenously a solution of sodium lactate into patients with metabolic acidosis, and several of them survived—despite the fact that some of them were already suffering from an excess of lactate. The subsequent widespread use of lactate solutions in hospitals has contributed to the general denial of its toxicity. 1932 年，圣路易斯的儿科医生亚历克西斯·哈特曼 (Alexis Hartmann)（与 M. Senn 一起）向代谢性酸中毒患者静脉注射乳酸钠溶液，其中一些人幸存下来——尽管他们中的一些人已经遭受了痛苦来自过量的乳酸。随后在医院中广泛使用乳酸盐溶液导致人们普遍否认其毒性。

Hartmann and Senn used racemic lactate, that is, a mixture of D-lactate and L-lactate. Our own tissues produce mostly L-lactate, but they can produce small amounts of D-lactate; larger amounts are produced by diabetics. Intestinal bacteria can produce large amounts of it, and it has many toxic effects. Methylglyoxal can be formed from either form of lactate, and it is an important factor in the glycation of proteins. It can also be formed from MDA, a product of lipid peroxidation. Protein glycation is an important factor in diabetes and aging, but glucose, rather than lactate and polyunsaturated fats, is commonly said to be the cause. Hartmann 和 Senn 使用外消旋乳酸盐，即 D-乳酸盐和 L-乳酸盐的混合物。我们自己的组织主要产生 L-乳酸，但也能产生少量 D-乳酸；糖尿病患者会产生更多的量。肠道细菌可以产生大量它，并且它具有许多毒性作用。甲基乙二醛可以由任一形式的乳酸形成，它是蛋白质糖化的重要因素。它也可以由 MDA（脂质过氧化的产物）形成。蛋白质糖基化是糖尿病和衰老的一个重要因素，但通常认为是葡萄糖而不是乳酸和多不饱和脂肪是原因。

About 50 years ago, lactate was known to induce the formation of new blood vessels, and for a much longer time it has been known to cause vasodilation and edema. In 1968, it was shown to stimulate collagen synthesis. 大约 50 年前，已知乳酸会诱导新血管的形成，并且在很长一段时间内已知它会导致血管舒张和水肿。1968 年，它被证明可以刺激胶原蛋白的合成。

Normally, collagen synthesis and neovascularization are caused by lack of oxygen, but lactate can cause them to occur even in the presence of oxygen. Maintenance of a normal extracellular matrix is essential for normal functioning and cellular differentiation. Abnormally stimulated collagen synthesis probably accelerates tumor growth (Rajkumar, et al., 2006). 正常情况下，胶原蛋白合成和新血管形成是由缺氧引起的，但即使在有氧的情况下，乳酸也会导致它们发生。维持正常的细胞外基质对于正常功能和细胞分化至关重要。异常刺激的胶原合成可能会加速肿瘤生长（Rajkumar 等，2006）。

Nervous and hormonal factors can cause lactate to accumulate, even without prior damage to the mitochondria (e.g., B. Levy, et al., 2003). Psychological, as well as physical, stress and overactivation of glutamate receptors can cause harmful accumulation of lactate in the brain (Uehara, et al., 2005). Rather than just being “associated with” tissue damage, lactate directly contributes to the damage, for example in the brain, causing nerve cell loss by increasing the release of excitotoxic glutamate (Xiang, et al, 2004). When a panic reaction is produced by sodium lactate, the reduction of protective neurosteroids appears to contribute to the excitatory state (Eser, et al. 2006); this would make the brain more susceptible to damage. 神经和激素因素会导致乳酸积累，即使事先没有对线粒体造成损害（例如，B. Levy 等，2003）。心理以及身体方面的压力和谷氨酸受体的过度激活会导致乳酸在大脑中的有害积累（Uehara, et al., 2005）。乳酸不仅与组织损伤“相关”，还直接导致损伤，例如在大脑中，通过增加兴奋毒性谷氨酸的释放导致神经细胞损失（Xiang 等，2004）。当乳酸钠产生恐慌反应时，保护性神经类固醇的减少似乎有助于兴奋状态（Eser, et al. 2006）；这会使大脑更容易受到损害。

Lactate increases blood viscosity, mimics stress, causes inflammation, and contributes to shock. Lactated Ringer's solution contributes to the tissue damage caused by shock, when it's used to resuscitate shock victims (Deree, et al., 2007, 2008): it contributes to the inflammatory processes associated with shock, unlike the use of hypertonic saline and other solutions. Lactate contributes to diabetes, inhibiting the ability to oxidize glucose. It promotes endothelial cell migration and leakiness, with increased vascular permeability factor (VPF or vascular endothelial growth factor, VEGF) (Nagy, et al. 1985): this can lead to breakdown of the “blood-brain barrier.” 乳酸会增加血液粘度、模拟压力、引起炎症并导致休克。乳酸林格氏液用于使休克患者复苏时，会导致休克引起的组织损伤（Deree 等人，2007 年、2008 年）：与使用高渗盐水和其他溶液不同，它有助于与休克相关的炎症过程. 乳酸有助于糖尿病，抑制氧化葡萄糖的能力。它促进内皮细胞迁移和渗漏，增加血管通透性因子（VPF 或血管内皮生长因子，VEGF）（Nagy 等人，1985 年）：这会导致“血脑屏障”的破坏。

In the brain, lactate can cause nerve damage, increasing intracellular fat accumulation, chromatin clumping, and mitochondrial swelling (Norenberg, et al., 1987). 在大脑中，乳酸会导致神经损伤、增加细胞内脂肪堆积、染色质结块和线粒体肿胀（Norenberg 等，1987）。

The lactate in peritoneal dialysis solution impairs differentiation and maturation of (immune, monocyte derived) dendritic cells; according to the authors of the study, “These findings have important implications for the initiation of immune responses under high lactate conditions, such as those occurring within tumor tissues or after macrophage activation” (Puig-Kröger, et al., 2003). 腹膜透析液中的乳酸会损害（免疫的、单核细胞衍生的）树突细胞的分化和成熟；据该研究的作者称，“这些发现对于在高乳酸条件下启动免疫反应具有重要意义，例如发生在肿瘤组织内或巨噬细胞激活后的免疫反应” （Puig-Kröger 等人，2003 年）。

Lactate also causes macrophages and synovial fibroblasts to release PGE2, which can contribute to inflammation and bone resorption (Dawes and Rushton, 1994). This is the prostaglandin known to activate the formation of estrogen (Haffty, et al., 2008). 乳酸还会导致巨噬细胞和滑膜成纤维细胞释放 PGE2，这会导致炎症和骨吸收（Dawes 和 Rushton，1994）。这是已知可激活雌激素形成的前列腺素 (Haffty, et al., 2008)。

Hartmann's lactated solution has been widely used in hospitals for resuscitation and for patients after heart surgery and other stressful procedures, but until recently only a few people have objected to its use, and most of the objection has been to the use of racemic lactate, rather than to lactate itself. In recent years several studies have compared hypertonic saline (lacking the minerals considered essential since Sydney Ringer formulated his solution around 1885), and have found it in some cases superior to the “balanced” lactate solution. Even hypertonic glucose, without minerals, has produced good results in some studies. Hartmann 的乳酸溶液已被广泛用于医院的复苏以及心脏手术和其他压力手术后的患者，但直到最近只有少数人反对使用它，而且大多数反对的都是使用外消旋乳酸，而不是使用外消旋乳酸。而不是乳酸本身。近年来，一些研究比较了高渗盐水（自 1885 年左右悉尼林格制定了他的解决方案以来，缺乏被认为必不可少的矿物质），并发现它在某些情况下优于“平衡”乳酸溶液。在一些研究中，即使是不含矿物质的高渗葡萄糖也产生了良好的结果。

A solution containing a large amount of lactate has been used for peritoneal dialysis when there is kidney failure, but several studies have compared solutions using bicarbonate instead of lactate, and found that they don't cause the severe damage that always happened with the traditional solution. 当肾功能衰竭时，一种含有大量乳酸的溶液被用于腹膜透析，但一些研究比较了使用碳酸氢盐代替乳酸的溶液，发现它们不会造成传统溶液总是发生的严重损害.

While Warburg was investigating the roles of glycolysis and respiration in cancer, a physician with a background in chemistry, W.F. Koch, in Detroit, was showing that the ability to use oxygen made the difference between health and sickness, and that the cancer metabolism could be corrected by restoring the efficient use of oxygen. He argued that a respiratory defect was responsible for immunodeficiency, allergy, and defective function of muscles, nerves, and secretory cells, as well as cancer. Koch's idea of cancer's metabolic cause and its curability directly challenged the doctrine of the genetic irreversibility of cancer that was central to governmental and commercial medical commitments. 当 Warburg 正在研究糖酵解和呼吸在癌症 中的作用时，底特律的一位具有化学背景的医生 WF Koch 表明，使用氧气的能力决定了健康和疾病之间的差异，并且癌症的新陈代谢可能通过恢复氧气的有效利用来纠正。他认为呼吸缺陷是免疫缺陷、过敏、肌肉、神经和分泌细胞功能缺陷以及癌症的原因。科赫关于癌症的代谢原因及其可治愈性的观点直接挑战了癌症的遗传不可逆学说，这是政府和商业医疗承诺的核心。

Albert Szent-Gyorgyi respected Koch's work, and spent years investigating the involvement of the lactate metabolites, methylgyoxal and glyoxal, in cell physiology, but since the government's campaign against Koch was still active when Szent-Gyorgyi came to the U.S., he worked out many of the implications of Koch's work relating to cellular oxidation without mentioning his name. Albert Szent-Gyorgyi 尊重 Koch 的工作，并花了数年时间研究乳酸代谢物甲基乙二醛和乙二醛在细胞生理学中的作用，但由于 Szent-Gyorgyi 来到美国时政府对科赫的运动仍然很活跃，他得出了许多关于 Koch 与细胞氧化有关的工作的含义，没有提及他的名字。

Lactate formation from glucose is increased when anything interferes with respiratory energy production, but lactate, through a variety of mechanisms, can itself suppress cellular respiration. (This has been called the Crabtree effect.) Lactate can also inhibit its own formation, slowing glycolysis. In the healthy cell, the mitochondrion keeps glycolysis working by consuming pyruvate and electrons (or “hydrogens”) from NADH, keeping the cell highly oxidized, with a ratio of NAD+/NADH of about 200. When the mitochondrion's ability to consume pyruvate and NADH is limited, the pyruvate itself accepts the hydrogen from NADH, forming lactic acid and NAD+ in the process. As long as lactate leaves the cell as fast as it forms, glycolysis will provide ATP to allow the cell to survive. Oxygen and pyruvate are normally “electron sinks,” regenerating the NAD+ needed to produce energy from glucose. 当任何东西干扰呼吸能量的产生时，由葡萄糖形成的乳酸就会增加，但乳酸通过各种机制本身可以抑制细胞呼吸。 （这被称为 Crabtree 效应。）乳酸还可以抑制自身的形成，减缓糖酵解。 在健康细胞中，线粒体通过消耗丙酮酸和来自 NADH 的电子（或“氢”）保持糖酵解工作，使细胞保持高度氧化，NAD+/NADH 的比率约为 200。当线粒体消耗丙酮酸和 NADH 的能力时 是有限的，丙酮酸本身接受来自 NADH 的氢，在此过程中形成乳酸和 NAD+。 只要乳酸以形成的速度离开细胞，糖酵解就会提供 ATP 以允许细胞存活。 氧气和丙酮酸通常是“电子汇”，可再生从葡萄糖产生能量所需的 NAD+。

But if too much lactate is present, slowing glycolytic production of ATP, the cell with defective respiration will die unless an alternative electron sink is available. The synthesis of fatty acids is such a sink, if electrons (hydrogens) can be transferred from NADH to NADP+, forming NADPH, which is the reducing substance required for turning carbohydrates and pyruvate and amino acids into fats. 但是，如果存在过多的乳酸，会减慢 ATP 的糖酵解产生，除非有替代的电子汇可用，否则呼吸有缺陷的细胞就会死亡。脂肪酸的合成就是这样的一个汇，如果电子（氢）可以从NADH转移到NADP+，形成NADPH，它是将碳水化合物和丙酮酸以及氨基酸转化为脂肪所需的还原物质。

This transfer can be activated by the transhydrogenase enzymes in the mitochondria, and also by interactions of some dehydrogenase enzymes. 这种转移可以被线粒体中的转氢酶激活，也可以被一些脱氢酶的相互作用激活。

The enzyme, fatty acid synthase (FAS), normally active in the liver and fat cells and in the estrogen-stimulated uterus, is highly active in cancers, and its activity is an inverse indicator of prognosis. Inhibiting it can cause cancer cells to die, so the pharmaceutical industry is looking for drugs that can safely inhibit it. This enzyme is closely associated with the rate of cell proliferation, and its activity is increased by both cortisol and estrogen. 脂肪酸合成酶 (FAS) 通常在肝脏和脂肪细胞以及雌激素刺激的子宫中活跃，在癌症中非常活跃，其活性是预后的反向指标。抑制它会导致癌细胞死亡，因此制药业正在寻找可以安全抑制它的药物。这种酶与细胞增殖速度密切相关，皮质醇和雌激素都会增加其活性。

The first biochemical event when a cell responds to estrogen is the synthesis of fat. Estrogen can activate transhydrogenases, and early studies of estrogen's biological effects provided considerable evidence that its actions were the result of the steroid molecule's direct participation in hydrogen transfers, oxidations and reductions. E.V. Jensen's claim that estrogen acts only through a “receptor protein” which activated gene transcription was based on his experimental evidence indicating that estrogen doesn't participate in oxidation and reduction processes in the uterus, but subsequently his claim has turned out to be false. 当细胞对雌激素作出反应时，第一个生化事件是脂肪的合成。雌激素可以激活转氢酶，对雌激素生物学效应的早期研究提供了大量证据，证明其作用是类固醇分子直接参与氢转移、氧化和还原的结果。EV Jensen 声称雌激素仅通过激活基因转录的“受体蛋白”起作用，这是基于他的实验证据表明雌激素不参与子宫内的氧化和还原过程，但随后他的说法被证明是错误的。

Glycolysis is very inefficient for producing usable energy compared to the respiratory metabolism of the mitochondria, and when lactate is carried to the liver, its conversion to glucose adds to the energy drain on the organism. 与线粒体的呼吸代谢相比，糖酵解对于产生可用能量的效率非常低，当乳酸被运送到肝脏时，其转化为葡萄糖会增加生物体的能量消耗。

The hypoglycemia and related events resulting from accelerated glycolysis provide a stimulus for increased activity of the adaptive hormones, including cortisol. Cortisol helps to maintain blood sugar by increasing the conversion of protein to amino acids, and mobilizing free fatty acids from fat stores. The free fatty acids inhibit the use of glucose, so the stress metabolism relies largely on the consumption of amino acids. This increases the formation of ammonia, yet the combination of glycolysis and fat oxidation provides less carbon dioxide, which is needed for the conversion of ammonia to urea. Ammonia stimulates the formation of lactate, while carbon dioxide inhibits it. 由加速糖酵解引起的低血糖和相关事件刺激了适应性激素（包括皮质醇）的活性增加。皮质醇通过增加蛋白质向氨基酸的转化和从脂肪储存中调动游离脂肪酸来帮助维持血糖。游离脂肪酸抑制葡萄糖的使用，因此应激代谢主要依赖于氨基酸的消耗。这增加了氨的形成，但糖酵解和脂肪氧化的结合提供了较少的二氧化碳，这是将氨转化为尿素所需的。氨会刺激乳酸的形成，而二氧化碳会抑制乳酸的形成。

Starving an animal with a tumor increases the stress hormones, providing free fatty acids and amino acids, and accelerates the tumor's growth (Sauer and Dauchy, 1987); it's impossible to “starve a tumor,” by the methods often used. Preventing the excessive breakdown of protein and reducing the release of fatty acids from fat cells would probably cause many cancer cells to die, despite the availability of glucose, because of lactate's toxic effects, combined with the energy deficit caused by the respiratory defect that causes their aerobic glycolysis. Recently, the intrinsically high rate of cell death in tumors has been recognized. The tumor is maintained and enlarged by the recruitment of “stem cells.” These cells normally would repair or regenerate the tissue, but under the existing metabolic conditions, they fail to differentiate properly. 使患有肿瘤的动物挨饿会增加应激激素，提供游离脂肪酸和氨基酸，并加速肿瘤的生长（Sauer 和 Dauchy，1987）； 用常用的方法不可能“饿死肿瘤”。 防止蛋白质过度分解并减少脂肪细胞中脂肪酸的释放可能会导致许多癌细胞死亡，尽管葡萄糖是可用的，因为乳酸的毒性作用，再加上呼吸缺陷导致的能量不足，导致它们 有氧糖酵解。 最近，已经认识到肿瘤中固有的高细胞死亡率。 肿瘤通过“干细胞”的募集得以维持和扩大。 这些细胞通常会修复或再生组织，但在现有的代谢条件下，它们无法正常分化。

The extracellular matrix in the tumor is abnormal, as well as the metabolites and signal substances being produced there, and the new cells fail to receive the instructions needed to restore the normal functions to the damaged tissue. These abnormal conditions can cause abnormal differentiation, and this cellular state is likely to involve chemical modification of proteins, including remodeling of the chromosomes through acetylation of the histones (Alam, et al., 2008; Suuronen, et al., 2006). The protein-protective effects of carbon dioxide are replaced by the protein-damaging effects of lactate and its metabolites. 肿瘤中的细胞外基质异常，那里产生的代谢物和信号物质也异常，新细胞无法接收到使受损组织恢复正常功能所需的指令。 这些异常情况会导致异常分化，这种细胞状态可能涉及蛋白质的化学修饰，包括通过组蛋白乙酰化重塑染色体（Alam 等人，2008 年；Suuronen 等人，2006 年）。 二氧化碳的蛋白质保护作用被乳酸及其代谢物的蛋白质破坏作用所取代。

The ability of lactic acid to displace carbon dioxide is probably involved in its effects on the blood clotting system. It contributes to disseminated intravascular coagulation and consumption coagulopathy, and increases the tendency of red cells to aggregate, forming “blood sludge,” and makes red cells more rigid, increasing the viscosity of blood and impairing circulation in the small vessels. (Schmid-Schönbein, 1981; Kobayashi, et al., 2001; Martin, et al., 2002; Yamazaki, et al., 2006.) 乳酸置换二氧化碳的能力可能与其对凝血系统的影响有关。它有助于弥散性血管内凝血和消耗性凝血病，增加红细胞聚集的趋势，形成“血泥”，使红细胞变硬，增加血液粘度，损害小血管循环。(Schmid-Schönbein, 1981; Kobayashi, et al., 2001; Martin, et al., 2002; Yamazaki, et al., 2006。)

The features of the stress metabolism include increases of stress hormones, lactate, ammonia, free fatty acids, and fat synthesis, and a decrease in carbon dioxide. Factors that lower the stress hormones, increase carbon dioxide, and help to lower the circulating free fatty acids, lactate, and ammonia, include vitamin B1 (to increase CO2 and reduce lactate), niacinamide (to reduce free fatty acids), sugar (to reduce cortisol, adrenaline, and free fatty acids), salt (to lower adrenaline), thyroid hormone (to increase CO2). Vitamins D, K, B6 and biotin are also closely involved with carbon dioxide metabolism. Biotin deficiency can cause aerobic glycolysis with increased fat synthesis (Marshall, et al., 1976). 应激代谢的特征包括应激激素、乳酸、氨、游离脂肪酸和脂肪合成增加，二氧化碳减少。 降低压力荷尔蒙、增加二氧化碳并有助于降低循环游离脂肪酸、乳酸和氨的因素包括维生素 B1（增加二氧化碳和减少乳酸）、烟酰胺（减少游离脂肪酸）、糖（减少 减少皮质醇、肾上腺素和游离脂肪酸）、盐（降低肾上腺素）、甲状腺激素（增加二氧化碳）。 维生素 D、K、B6 和生物素也与二氧化碳代谢密切相关。 生物素缺乏会导致有氧糖酵解和脂肪合成增加 (Marshall, et al., 1976)。

A protein deficiency, possibly by increasing cortisol, is likely to contribute to increased FAS and fat synthesis (Bannister, et al., 1983), but the dietary protein shouldn't provide an excess of tryptophan, because of tryptophan's role as serotonin precursor–serotonin increases inflammation and glycolysis (Koren-Schwartzer, et al., 1994). 蛋白质缺乏，可能是由于皮质醇增加，可能导致 FAS 和脂肪合成增加（Bannister, et al., 1983），但膳食蛋白质不应提供过量的色氨酸，因为色氨酸作为血清素前体的作用 - -5-羟色胺会增加炎症和糖酵解 (Koren-Schwartzer, et al., 1994)。

Incidental stresses, such as strenuous exercise combined with fasting (e.g., running or working before eating breakfast) not only directly trigger the production of lactate and ammonia, they also are likely to increase the absorption of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous and chronic stressor. It increases lactate and nitric oxide, poisoning mitochondrial respiration, precipitating the secretion of the adaptive stress hormones, which don't always fully repair the cellular damage. 附带的压力，例如剧烈运动结合禁食（例如，在吃早餐前跑步或工作）不仅直接引发乳酸和氨的产生，还可能增加肠道对细菌内毒素的吸收。 内毒素是一种普遍存在的慢性压力源。 它增加乳酸和一氧化氮，使线粒体呼吸中毒，促进适应性应激激素的分泌，这些激素并不总是完全修复细胞损伤。

Aspirin protects cells in many ways, interrupting excitotoxic processes by blocking nitric oxide and prostaglandins, and consequently it inhibits cell proliferation, and in some cases inhibits glycolysis, but the fact that it can inhibit FAS (Beynen, et al., 1982) is very important in understanding its role in cancer. 阿司匹林以多种方式保护细胞，通过阻断一氧化氮和前列腺素来中断兴奋性毒性过程，从而抑制细胞增殖，并在某些情况下抑制糖酵解，但事实上它可以抑制 FAS (Beynen, et al., 1982) 重要的是了解其在癌症中的作用。

There are several specific signals produced by lactate that can promote growth and other features of cancer, and it happens that aspirin antagonizes those: HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme oxygenase. 乳酸产生的几种特定信号可以促进癌症的生长和其他特征，而阿司匹林正好拮抗这些信号：HIF、NF-κB、激酶级联、细胞周期蛋白 D1 和血红素加氧酶。

Lactate and inflammation promote each other in a vicious cycle (Kawauchi, et al., 2008). 乳酸和炎症在恶性循环中相互促进（Kawauchi 等，2008）。

The toxic mechanism of bacterial endotoxin (lipopolysaccharide) involves inappropriate stimulation (Wang and White, 1999) of cells, followed by inflammation and mitochondrial inhibition. The stimulation seems to be a direct “biophysical” action on cells, causing them to take up water (Minutoli, et al., 2008), which is especially interesting, since estrogen's immediate excitatory effect causes cells to take up water. 细菌内毒素（脂多糖）的毒性机制包括对细胞的不适当刺激（Wang 和 White，1999），然后是炎症和线粒体抑制。刺激似乎是对细胞的直接“生物物理”作用，导致它们吸收水分（Minutoli 等，2008），这尤其有趣，因为雌激素的直接兴奋作用会导致细胞吸收水分。

Hypoosmolarity itself is excitatory and anabolic. It stimulates lipolysis and fat oxidation (Keller, et al. 2003), and osmotic swelling stimulates glycolysis and inhibits mitochondrial respiration (Levko, et al., 2000). Endotoxin causes hyponatremia (Tyler, et al., 1994), and a hypertonic salt solution is protective, lactate solutions are harmful. Other stresses and inflammations also cause hyponatremia. 低渗本身是兴奋和合成代谢的。它刺激脂肪分解和脂肪氧化（Keller, et al., 2003），渗透性肿胀刺激糖酵解并抑制线粒体呼吸（Levko, et al., 2000）。内毒素会导致低钠血症 (Tyler, et al., 1994)，高渗盐溶液具有保护作用，而乳酸盐溶液则有害。其他压力和炎症也会导致低钠血症。

One of the effects of endotoxin that leads to prolonged cellular excitation is its inhibition of the glucuronidation system (Bánhegyi, et al., 1995), since this inhibition allows excitatory estrogen to accumulate. 内毒素导致细胞兴奋延长的作用之一是它对葡萄糖醛酸化系统的抑制（Bánhegyi 等，1995），因为这种抑制允许兴奋性雌激素积累。

In women and rats, antibiotics were found to cause blood levels of estrogen and cortisol to decrease, while progesterone increased. This effect apparently resulted from the liver's increased ability to inactivate estrogen and to maintain blood sugar when the endotoxin stress was decreased. 在女性和大鼠中，发现抗生素会导致雌激素和皮质醇的血液水平降低，而黄体酮增加。这种作用显然是由于肝脏在内毒素应激降低时使雌激素失活和维持血糖的能力增强所致。

Now that hog farmers' use of antibiotics to stimulate growth has been discouraged, they have sought vegetables that have a natural antibiotic effect, reducing the formation and absorption of the intestinal toxins. The human diet can be similarly adjusted, to minimize the production and absorption of the bacterial toxins. 现在养猪户不鼓励使用抗生素刺激生长，他们开始寻找具有天然抗生素作用的蔬菜，减少肠道毒素的形成和吸收。可以类似地调整人类饮食，以尽量减少细菌毒素的产生和吸收。

In 2007, two Canadian researchers announced that they were investigating the drug dichloroacetate, which blocks glycolysis, stopping the production of lactic acid, as a cancer treatment, with success. The drug (dichloroacetate) has toxic side effects, but it is useful in several other conditions involving over-production of lactic acid. Other drugs that inhibit glycolysis have also shown anticancer effects in animals, but are in themselves very toxic. On the theoretical level, it would be better to inhibit only aerobic glycolysis, rather than inhibiting enzymes that are essential for all glycolysis. 2007 年，两名加拿大研究人员宣布，他们正在研究药物二氯乙酸盐，该药物可阻止糖酵解，阻止乳酸的产生，作为一种癌症治疗方法，并取得了成功。该药物（二氯乙酸盐）具有毒副作用，但它可用于涉及乳酸过度生产的其他几种情况。其他抑制糖酵解的药物也已在动物身上显示出抗癌作用，但其本身毒性很大。在理论上，最好只抑制有氧糖酵解，而不是抑制所有糖酵解必不可少的酶。

Since endotoxemia can produce aerobic glycolysis in an otherwise healthy person (Bundgaard, et al., 2003), a minimally “Warburgian” approach–i.e,, a merely reasonable approach–would involve minimizing the absorption of endotoxin. Inhibiting bacterial growth, while optimizing intestinal resistance, would have no harmful side effects. Preventing excessive sympathetic nervous activity and maintaining the intestine's energy production can be achieved by optimizing hormones and nutrition. Something as simple as a grated carrot with salt and vinegar can produce major changes in bowel health, reducing endotoxin absorption, and restoring constructive hormonal functions. 由于内毒素血症可以在其他方面健康的人体内产生有氧糖酵解（Bundgaard 等人，2003 年），最低限度的“Warburgian”方法——即，仅仅合理的方法——将涉及最小化内毒素的吸收。抑制细菌生长，同时优化肠道抵抗力，不会产生有害的副作用。可以通过优化激素和营养来防止过度的交感神经活动和维持肠道的能量产生。像用盐和醋磨碎的胡萝卜这样简单的东西可以对肠道健康产生重大改变，减少内毒素的吸收，并恢复建设性的荷尔蒙功能。

Medical tradition and inertia make it unlikely that the connection between cancer and bowel toxins will be recognized by the mainstream of medicine and governemt. In another article I will describe some of the recent history relating to this issue. 医学传统和惰性使得癌症和肠道毒素之间的联系不太可能被主流医学和政府认可。在另一篇文章中，我将描述与此问题相关的一些近期历史。

It's nice that some cancer researchers are now remembering Warburg, but unfortunately they are usually just fitting the fact of cancer's aerobic glycolysis into the genetic mutant cell paradigm, thinking of the respiratory defect as just another opportunity for killing the evil deviant cancer cell, rather than looking for the causes of the respiratory defect. Warburg, Koch, and Szent-Gyorgyi had a comprehensive view of biology, in which the aerobic production of lactate, resulting from a respiratory defect, itself was functonally related to the nature of cancer. 很高兴一些癌症研究人员现在记住了 Warburg，但不幸的是，他们通常只是将癌症有氧糖酵解的事实纳入基因突变细胞范式，认为呼吸缺陷只是杀死邪恶的异常癌细胞的另一个机会，而不是寻找呼吸缺陷的原因。Warburg、Koch 和 Szent-Gyorgyi 对生物学有一个全面的看法，其中由呼吸缺陷导致的乳酸的有氧产生本身与癌症的性质在功能上有关。

A focus on correcting the respiratory defect would be relevant for all of the diseases and conditions (including heart disease, diabetes, dementia) involving inflammation and inappropriate excitation, not just for cancer. 专注于纠正呼吸缺陷将与所有涉及炎症和不适当兴奋的疾病和病症（包括心脏病、糖尿病、痴呆症）相关，而不仅仅是癌症。

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Nat Cell Biol. 2008 May;10(5):611-8. p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Kawauchi K, Araki K, Tobiume K, Tanaka N. “Cancer cells use aerobic glycolysis preferentially for energy provision and this metabolic change is important for tumour growth. Here, we have found a link between the tumour suppressor p53, the transcription factor NF-kappaB and glycolysis.” “Taken together, these data indicate that p53 restricts activation of the IKK-NF-kappaB pathway through suppression of glycolysis. These results suggest that a positive-feedback loop exists, whereby glycolysis drives IKK-NF-kappaB activation, and that hyperactivation of this loop by loss of p53 is important in oncogene-induced cell transformation.” 癌细胞优先使用有氧糖酵解来提供能量，这种代谢变化对肿瘤生长很重要。在这里，我们发现了肿瘤抑制因子 p53、转录因子 NF-kappaB 和糖酵解之间的联系。在 p53 缺陷原代培养细胞中，IKKalpha 和 IKKbeta 的激酶活性和随后的 NF-kappaB 活性得到增强。NF-kappaB 的激活，由于 p53 的缺失，导致有氧糖酵解速率的增加和 Glut3 的上调。在缺乏 p65/NF-kappaB 表达的情况下，致癌 Ras 诱导的细胞转化和有氧糖酵解加速在 p53 缺陷细胞中被抑制，并通过 GLUT3 表达恢复。还表明糖酵解抑制剂减弱了 p53 缺陷细胞中增强的 IKK 活性。而且，在表达 Ras 的 p53 缺陷细胞中，IKK 活性被 p65 缺陷抑制并被 GLUT3 表达恢复。总之，这些数据表明 p53 通过抑制糖酵解来限制 IKK-NF-kappaB 通路的激活。这些结果表明存在一个正反馈循环，由此糖酵解驱动 IKK-NF-kappaB 激活，并且通过 p53 丢失导致该循环的过度激活在癌基因诱导的细胞转化中很重要。

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