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Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer
伤口、疾病和衰老中的乳酸vs二氧化碳;
另一种治疗癌症的方法
by Raymond Peat
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GLOSSARY
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.
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.
"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.
Pasteur Effect, the normal response of cells to restrain glycolysis in the presence of adequate oxygen.
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).
"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.
术语表
有氧糖酵解，即在有氧的情况下将葡萄糖转化为乳酸的过程。氧气的存在通常会抑制糖酵解，使葡萄糖转化为二氧化碳而不是乳酸。
无氧糖酵解，当氧气供应不足时，葡萄糖转化为乳酸的增加，这是高强度肌肉运动中的一种正常现象。
“瓦尔堡效应”指的是瓦尔堡观察到，癌细胞即使在充足的氧气存在下也会产生乳酸。癌细胞不是“靠葡萄糖生存”的，因为它们非常适合靠蛋白质和脂肪生存。
巴斯德效应，细胞在充足氧气存在下抑制糖酵解的正常反应。
克勒勃屈利效应，最初在酵母中观察到，指的是在葡萄糖存在时对呼吸的抑制。这种情况发生在癌症(如Miralpeix等，1990)和快速增殖的正常细胞(如Guppy等，1993)中。
“癌症代谢”或应激代谢通常涉及适应激素的过量，这是由于对机体的需求和机体可用资源的不平衡造成的。过度的刺激会消耗葡萄糖并产生乳酸，导致皮质醇增加，导致消耗脂肪和蛋白质而不是葡萄糖。皮质醇的增加会激活Randle效应(抑制游离脂肪酸氧化葡萄糖)，加速蛋白质分解为氨基酸，并激活脂肪酸合酶，该酶从氨基酸和丙酮酸中生成脂肪酸，并在“无效循环”中被氧化，产生热量，并增加氨从氨基酸的释放。氨抑制呼吸，刺激糖酵解活性。
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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.
The influence of politics on science is so profound that neither historians nor scientists often care to consider it honestly and in depth.
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.)
在我们的组织中乳酸的存在是非常有意义的，但它通常只被当作一种指标，而不是生物学问题的原因。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已经被认识到，最近人们认识到，在50年的否认之后，抑制它可以治愈。
政治对科学的影响是如此深远，以至于无论是历史学家还是科学家都不愿意诚实而深入地思考它。
从19世纪到20世纪的第二季度，癌症主要是作为代谢问题进行研究的。这项了解新陈代谢基本化学的工作，在20世纪20年代奥托·沃伯格(Otto Warburg)和阿尔伯特·圣-乔吉尔(Albert Szent-Gyorgyi)关于呼吸的工作中达到顶峰。早在1920年，Warburg就证明了呼吸缺陷是癌症的一个基本特征，它会导致有氧糖酵解，即即使在有氧气的情况下也会产生乳酸。(乳酸的形成是正常的，当氧气供应不足以满足能量需求时，例如跑步时，乳酸是可以适应的。)
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.
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.
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.
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.
许多人意识到这可能是解决“癌症问题”的关键。但在美国，有几个因素共同阻碍了这一调查。
世界大战导致了德国科学家的孤立，而著名的犹太银行家族的瓦尔堡，尽管公开反对纳粹主义，仍在政府的支持下继续在德国工作。在战后的那些年里，他在癌症方面的工作在美国没有任何正面的评价。
当政府的研究资金开始集中于疾病的基因和病毒解释时，几十年来一直在取得进展的疾病代谢解释突然被淹没了。
如果一种明显的非传染性疾病不能以遗传倾向为基础来解释，例如精神错乱、癫痫、糖尿病、妊娠毒血症和癌症，那么就会援引个体中由于偶然或病毒而发生的基因变化。直到最近，营养和其他生活条件都被认为对健康没有影响，只要一个人摄入足够的卡路里和最低限度的必需维生素、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.
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.
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.
1932年，圣路易斯(St. Louis)的儿科医生亚历克西斯·哈特曼(Alexis Hartmann)(与M. Senn合作)向代谢性酸中毒患者静脉注射乳酸钠溶液，一些人活了下来——尽管事实上他们中的一些人已经遭受了乳酸过量的痛苦。后来，乳酸溶液在医院的广泛使用使得人们普遍否认其毒性。
哈特曼和森使用外消旋乳酸，即d -乳酸和l -乳酸的混合物。我们自己的组织主要产生l -乳酸，但它们也能产生少量的d -乳酸;糖尿病患者分泌的量更大。肠道细菌可以产生大量的它，它有许多毒性作用。任何一种形式的乳酸都可以形成甲基乙二醛，它是蛋白质糖基化的重要因素。它也可以由脂质过氧化的产物丙二醛形成。蛋白质糖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引起的。
大约50年前，乳酸被认为能诱导新血管的形成，而在更长的一段时间内，乳酸也被认为能引起血管舒张和水肿。1968年，它被证明能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).
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.
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."
正常情况下，胶原蛋白的合成和新生血管是由缺氧引起的，但乳酸可以使它们在氧气存在的情况下发生。维持正常的细胞外基质是正常功能和细胞分化的必要条件。异常刺激的胶原合成可能加速肿瘤的生长(Rajkumar等，2006)。
神经和激素因素可以导致乳酸积累，甚至在线粒体未受到损害的情况下(例如，B. Levy等，2003)。心理和生理上的压力和谷氨酸受体的过度激活会导致大脑中有害的乳酸积累(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，通过增加兴奋性谷氨酸的释放，导致神经细胞损失(Xiang, et al, 2004)。当恐慌反应由乳酸钠产生时，保护性神经类固醇的减少似乎有助于兴奋状态(Eser, et al. 2006);这将使大脑更容易受到损伤。
乳酸会增加血液粘度，造成压力，引起炎症，并导致休克。乳酸林格氏溶液用于休克患者的复苏时，有助于休克引起的组织损伤(Deree等，2007,2008):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, et al. 1985):这可导致“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).
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).
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).
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.
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.
在大脑中，乳酸可导致神经损伤，增加细胞内脂肪积累，染色质聚集和线粒体肿胀(Norenberg等，1987)。
腹膜透析液中的乳酸损害(免疫的、单核细胞来源的)树突状细胞的分化和成熟;根据该研究的作者，“这些发现对高乳酸条件下免疫反应的启动具有重要意义，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，2003)。
乳酸还会导致巨噬细胞和滑膜成纤维细胞释放PGE2，这可能会导致炎症和骨吸收(Dawes和Rushton, 1994)。这是已知的前列腺素激活雌激素的形成(Haffty, et al.， 2008)。
哈特曼的乳酸林格液解决方案已广泛应用于心脏手术后医院为复苏和病人和其他压力的过程,但直到最近,只有少数人反对它的使用,并且大多数反对使用外消旋乳酸,乳酸,而不是自己。近年来，几项研究比较了高渗盐水(自1885年悉尼·林格(Sydney Ringer)发明高渗盐水以来，人们就认为它缺乏必要的矿物质)，并发现在某些情况下，高渗盐水优于“平衡”的乳酸盐溶液。即使是不含矿物质的高渗葡萄糖，在一些研究中也产生了良好的结果。
当肾衰竭时，一种含有大量乳酸的溶液被用于腹膜透析，但几项研究比较了用碳酸氢盐代替乳酸的溶液，发现它们不会造成传统溶液经常发生的严重损害。
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.
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.
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.
虽然瓦尔堡正在调查的角色在癌症、糖酵解和呼吸内科医生化学背景,W.F.科赫,在底特律,表明利用氧气的能力是健康和疾病之间的区别,可以纠正和癌症代谢恢复有效的利用氧气。他认为呼吸系统的缺陷是导致免疫缺陷、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基因不可逆性这一理论，而这一理论是政府和商业医疗承诺的核心。
Albert Szent-Gyorgyi尊重科赫的工作，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，但由于政府反对科赫的运动仍然活跃，当Szent-Gyorgyi来到美国时，他在没有提及自己名字的情况下，发现了科赫的工作与细胞氧化有关的许多含义。
当任何东西干扰呼吸能量产生时，葡萄糖中乳酸的形成就会增加，但乳酸通过各种机制，自身可以抑制细胞呼吸。(这被称为克拉布特里效应。)乳酸也可以抑制自身的形成，减缓糖酵解。在健康细胞中，线粒体通过从NADH中消耗丙酮酸和电子(或“氢”)来维持糖酵解工作，保持细胞高度氧化，NAD+/NADH的比例约为200。当线粒体消耗丙酮酸和NADH的能力受到限制时，丙酮酸本身从NADH接受氢，在这个过程中形成乳酸和NAD+。只要乳酸在细胞形成时就迅速离开细胞，糖酵解就会提供ATP以使细胞存活。氧和丙酮酸通常是“电子汇”，能够再生从葡萄糖中产生能量所需的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.
This transfer can be activated by the transhydrogenase enzymes in the mitochondria, and also by interactions of some dehydrogenase enzymes.
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.
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.
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.
但是，如果存在过多的乳酸，减缓了糖酵解ATP的产生，除非有替代的电子汇，否则具有呼吸缺陷的细胞将会死亡。脂肪酸的合成就是这样一个水槽，如果电子(氢)可以从NADH转移到NADP+，形成NADPH, NADPH是将碳水化合物、丙酮酸和氨基酸转化为脂肪所需的还原性物质。
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。
脂肪酸合酶(FAS)通常在肝脏和脂肪细胞以及雌激素刺激的子宫中活跃，但在癌症中却高度活跃，其活性是预后的反向指标。抑制它会导致癌细胞死亡，所以制药行业正在寻找能够安全抑制它的药物。这种酶与细胞增殖速率密切相关，皮质醇和雌激素都能增加这种酶的活性。
当细胞对雌激素作出反应时，第一个生化反应就是脂肪的合成。雌激素可以激活转氢酶，早期对雌激素生物学效应的研究提供了大量证据，表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。简森声称雌激素只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中的氧化和还原过程，但后来他的说法被证明是错误的。
与线粒体的呼吸代谢相比，糖酵解在产生可用能量方面效率非常低，当乳酸被运送到肝脏时，它转化为葡萄糖增加了生物体的能量消耗。
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.
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.
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.
由加速糖酵解引起的低血糖和相关事件为包括皮质醇在内的适应性激素的活动增加提供了刺激。皮质醇通过增加蛋白质向氨基酸的转化，并从脂肪储备中调动游离脂肪酸，帮助维持血糖。游离脂肪酸抑制了葡萄糖的使用，因此应激代谢很大程度上依赖于氨基酸的消耗。这增加了氨的形成，然而糖酵解和脂肪氧化的结合提供了更少的二氧化碳，而二氧化碳是氨转化为尿素所需要的。氨刺激乳酸的形成，而二氧化碳抑制它。
让长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，加速肿瘤的生长(Sauer和Dauchy, 1987);用常用的方法“饿死肿瘤”是不可能的。防止蛋白质的过度分解和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，尽管葡萄糖是可获得的，因为乳酸的毒性作用，加上呼吸缺陷造成的能量不足，导致它们的有氧糖酵解。近年来，人们认识到肿瘤中固有的高细胞死亡率。肿瘤通过招募“干细胞”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。
肿瘤内的细胞外基质异常，代谢产物和信号物质也在那里产生，新细胞无法接收到恢复受损组织正常功能所需的指令。这些异常情况会导致异常分化，而这种细胞状态可能涉及蛋白质的化学修饰，包括通过组蛋白的乙酰化重构染色体(Alam等，2008;Suuronen等，2006)。二氧化碳对蛋白质的保护作用被乳酸及其代谢物对蛋白质的破坏作用所取代。
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.)
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).
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).
乳酸取代二氧化碳的能力可能与它对血液凝血系统的影响有关。它有助于弥散性血管内凝血和消耗凝血病，并增加红细胞聚集的倾向，形成“血泥”，使红细胞更加坚硬，增加血液粘度，损害小血管中的循环。(Schmid-Schonbein, 1981;小林等，2001;马丁等，2002;山崎等，2006。)
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的增加，以及二氧化碳的减少。降低压力荷尔蒙、增加二氧化碳、降低循环中的游离脂肪酸、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(减少皮质醇、肾上腺素和游离脂肪酸)、盐(减少肾上腺素)、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。生物素缺乏可导致有氧糖酵解增加脂肪合成(Marshall等，1976)。
蛋白质缺乏，可能通过增加皮质醇，可能有助于增加FAS和脂肪合成(Bannister, et al.， 1983)，但饮食中的蛋白质不应该提供过量的色氨酸，因为色氨酸是血清素的前体——血清素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.
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.
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.
Lactate and inflammation promote each other in a vicious cycle (Kawauchi, et al., 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.
偶然的压力，如剧烈运动加上禁食(如在吃早餐前跑步或工作)，不仅直接触发乳酸和氨的产生，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应激源。它增加乳酸和一氧化氮，毒害线粒体呼吸，促进适应性应激激素的分泌，而这些激素并不总是完全修复细胞损伤。
阿司匹林能保护细胞在许多方面,打断excitotoxic流程通过阻断一氧化氮和前列腺素,因此它能抑制细胞增殖,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)在理解它在癌症中的作用非常重要。
有几种由乳酸产生的特定信号可以促进生长和癌症的其他特征，而阿司匹林恰好可以拮抗这些信号:HIF、NF-kappaB、激酶级联、周期蛋白D1和血红素加氧酶。
乳酸和炎症在恶性循环中相互促进(Kawauchi, et al.， 2008)。
细菌内毒素(脂多糖)的毒性机制涉及细胞的不适当刺激(Wang和White, 1999)，其次是炎症和线粒体抑制。这种刺激似乎是对细胞的直接“生物物理”作用，导致细胞吸水(Minutoli等人，2008)，这尤其有趣，因为雌激素的即时兴奋效应导致细胞吸水。
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.
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.
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.
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.
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.
低渗透压本身是兴奋性和合成性的。它刺激脂肪分解和脂肪氧化(Keller等，2003)，渗透性肿胀刺激糖酵解并抑制线粒体呼吸(Levko等，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，乳酸溶液则有害。其他压力和炎症也会导致低钠血症。
内毒素导致细胞长时间兴奋的作用之一是抑制葡萄糖醛酸化系统(Bánhegyi, et al.， 1995)，因为这种抑制允许兴奋性雌激素积聚。
在女性和大鼠中，研究人员发现抗生素会导致血液中雌激素和皮质醇水平下降，而孕酮水平上升。这种效果显然是由于当内毒素压力降低时，肝脏失活雌激素和维持血糖的能力增强所致。
由于养猪场使用抗生素来刺激生长的做法已被禁止，他们开始寻找具有天然抗生素作用的蔬菜，以减少肠道毒素的形成和吸收。人类的饮食也可以进行类似的调整，以最大限度地减少细菌毒素的产生和吸收。
2007年，两名加拿大研究人员宣布，他们正在研究一种药物二氯乙酸，这种药物可以阻止糖酵解，停止乳酸的产生，并成功地用于癌症治疗。这种药物(二氯醋酸盐)有毒副作用，但它在其他几种乳酸生产过剩的情况下是有用的。其他抑制糖酵解的药物在动物身上也显示出抗癌效果，但它们本身毒性很大。在理论上，最好只抑制好氧糖酵解，而不是抑制所有糖酵解所必需的酶。
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.
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.
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.
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.
由于内毒素血症可在其他方面健康的人产生有氧糖酵解(Bundgaard等，2003)，一种最低限度的“Warburgian”方法——i。一种仅仅是合理的方法——包括尽量减少内毒素的吸收。抑制细菌生长，同时优化肠道耐药，不会产生有害的副作用。通过优化激素和营养，可以防止过度的交感神经活动和维持肠道的能量生产。一些简单的东西，如磨碎的胡萝卜加盐和醋，可以对肠道健康产生重大变化，减少内毒素吸收，并恢复有益的激素功能。
医学的传统和惯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所承认。在另一篇文章中，我将描述与这个问题有关的一些近期历史。
一些癌症研究人员现在想起了瓦伯格，这是件好事，但不幸的是，他们通常只是把癌症的有氧糖酵解与基因突变细胞范式相吻合，认为呼吸缺陷只是杀死邪恶的异常癌细胞的另一个机会，而不是去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，在生物学中，由呼吸缺陷引起的乳酸的有氧生产本身在功能上与癌症的性质有关。
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条件(包括心脏病、糖尿病、痴呆)相关，而不仅仅是癌症。
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