乳酸与二氧化碳在伤口、疾病和衰老中的对比；另一种治疗癌症的方法
[糖酵解代谢、大脑弹性和阿尔茨海默病](https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8113697/)
研究表明，神经元主要进行氧化磷酸化，而星形胶质细胞主要负责通过糖酵解产生乳酸（Hyder 等，2006；Belanger 等，2011）。
理论表明，神经元从星形胶质细胞中摄取细胞外乳酸作为能量底物，以支持神经元活动增强后的 ATP 生成（Magistretti 和 Allaman，2018 年）。
伴随谷氨酸-谷氨酰胺循环而增加的能量需求会诱导更多的葡萄糖从循环中摄取并增强星形胶质细胞的乳酸释放，从而减弱细胞外前列腺素 E2 的摄取，从而提供潜在的血管舒张和脑血流量增加的机制。( 2008 ; Howarth, 2014 ; MacVicar 和 Newman, 2015）
研究还表明，为响应神经元活动的增加，神经元不是从星形胶质细胞中获取乳酸，而是能够增加糖酵解以自身产生乳酸，从而强调糖酵解在维持神经元功能和维持大脑内稳态方面的作用。(耶伦，2018 年）。
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REFERENCES
Resuscitation. 2008 Feb;76(2):299-310. Impact of resuscitation strategies on the acetylation status of cardiac histones in a swine model of hemorrhage. Alam HB, Shults C, Ahuja N, Ayuste EC, Chen H, Koustova E, Sailhamer EA, Li Y, Liu B, de Moya M, Velmahos GC.
Mol Genet Metab 1998 Mar;63(3):235-8. Activation of membrane skeleton-bound phosphofructokinase in erythrocytes induced by serotonin. Assouline-Cohen M, Ben-Porat H, Beitner R. We show here that serotonin, both in vivo and in vitro, induced a marked activation of phosphofructokinase, the rate-limiting enzyme in glycolysis, in the membrane-skeleton fraction from erythrocytes. Concomitantly, the hormone induced a striking increase in lactate content, reflecting stimulation of glycolysis. The enzyme's activity in the cytosolic (soluble) fraction remained unchanged. These results suggest a defense mechanism in the erythrocytes against the damaging effects of serotonin, whose concentration in plasma increases in many diseases and is implicated as playing an important role in circulation disturbances. 我们在此表明，在体内和体外，血清素在来自红细胞的膜骨架部分中诱导了磷酸果糖激酶（糖酵解的限速酶）的显着激活。同时，该激素引起乳酸含量的显着增加，反映了糖酵解的刺激。细胞溶质（可溶性）部分中的酶活性保持不变。这些结果表明红细胞中的一种防御机制可以抵抗血清素的破坏作用，血清素在许多疾病中的血浆浓度增加，并且在循环障碍中起重要作用。
Biochem Pharmacol. 1995 Jan 6;49(1):65-8. Endotoxin inhibits glucuronidation in the liver. An effect mediated by intercellular communication. Bánhegyi G, Mucha I, Garzó T, Antoni F, Mandl J.
Br J Nutr. 1983 Sep;50(2):291-302. The effect of biotin deficiency and dietary protein content on lipogenesis, gluconeogenesis and related enzyme activities in chick liver. Bannister DW, O'Neill IE, Whitehead CC.
J Cell Biochem. 2004 Jan 1;91(1):47-53. Fatty acid synthase: a metabolic oncogene in prostate cancer? Baron A, Migita T, Tang D, Loda M.
Neurol Res. 2008 Mar;30(2):160-9. Skeletal muscle is enriched in hematopoietic stem cells and not inflammatory cells in cachectic mice. Berardi E, Aulino P, Murfuni I, Toschi A, Padula F, Scicchitano BM, Coletti D, Adamo S.
Scand J Clin Lab Invest 1977 May;37(3):235-41. Effects of different doses of acetylsalicylic acid on renal oxygen consumption. Berg KJ, Bergan A
Toxicology. 1982;24(1):33-43. Inhibition of hepatic lipogenesis by salicylate. Beynen AC, Buechler KF, van der Molen AJ, Geelen MJ.
Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H1028-34. Epub 2002 Nov 21. Endotoxemia stimulates skeletal muscle Na+-K+-ATPase and raises blood lactate under aerobic conditions in humans. Bundgaard H, Kjeldsen K, Suarez Krabbe K, van Hall G, Simonsen L, Qvist J, Hansen CM, Moller K, Fonsmark L, Lav Madsen P, Klarlund Pedersen B.
J Natl Cancer Inst. 1967 Jun;38(6):839-63. On the significance of glucolysis for cancer growth, with special reference to Morris rat hepatomas. Burk D, Woods M, Hunter J.
Arch Geschwulstforsch. 1967;28(4):305-19. Newer aspects of glucose fermentation in cancer growth and control. Burk D, Woods M.
Eur J Pharmacol. 2005 Jul 11;517(3):158-64. Aspirin inhibits NF-kappaB activation in a glycolysis-depleted lung epithelial cell line. Cuesta E, Boada J, Perales JC, Roig T, Bermudez J.
Clin Mater. 1994;17(4):157-63. The effects of lactic acid on PGE2 production by macrophages and human synovial fibroblasts: a possible explanation for problems associated with the degradation of poly(lactide) implants? Dawes E, Rushton N.
J Surg Res. 2007 Nov;143(1):99-108. Pentoxifylline attenuates lung injury and modulates transcription factor activity in hemorrhagic shock. Deree J, Martins J, de Campos T, Putnam JG, Loomis WH, Wolf P, Coimbra R.
J Trauma. 2007 Apr;62(4):818-27; discussion 827-8. Hypertonic saline and pentoxifylline attenuates gut injury after hemorrhagic shock: the kinder, gentler resuscitation. Deree J, de Campos T, Shenvi E, Loomis WH, Hoyt DB, Coimbra R.
J Trauma. 2007 Jan;62(1):104-11. Hypertonic saline and pentoxifylline reduces hemorrhagic shock resuscitation-induced pulmonary inflammation through attenuation of neutrophil degranulation and proinflammatory mediator synthesis. Deree J, Martins JO, Leedom A, Lamon B, Putnam J, de Campos T, Hoyt DB, Wolf P, Coimbra R.
J Trauma. 2008 May;64(5):1230-8; discussion 1238-9. Hepatic transcription factor activation and proinflammatory mediator production is attenuated by hypertonic saline and pentoxifylline resuscitation after hemorrhagic shock. Deree J, Loomis WH, Wolf P, Coimbra R.
Neuroscience. 2006;138(3):1041-8. Neuroactive steroids as modulators of depression and anxiety. Eser D, Romeo E, Baghai TC, di Michele F, Schüle C, Pasini A, Zwanzger P, Padberg F, Rupprecht R.
Cancer Res. 2003 Jul 15;63(14):3847-54. The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models. Gatenby RA, Gawlinski ET.
J Bioenerg Biomembr. 2007 Jun;39(3):251-7. Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? Gillies RJ, Gatenby RA.
Biochem J. 2002 May 15;364(Pt 1):309-15. Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Guppy M, Leedman P, Zu X, Russell V.
Surg Forum. 1958;9:614-9. An estradiol sensitive transhydrogenase in normal and malignant breast tissue. HERSHEY FB.
Eur J Clin Invest. 2003 Oct;33(10):875-82. Activation of p53 signalling in acetylsalicylic acid-induced apoptosis in OC2 human oral cancer cells. Ho CC, Yang XW, Lee TL, Liao PH, Yang SH, Tsai CH, Chou MY.
Cancer. 1959 Jan-Feb;12(1):135-8. Studies on estrogen-sensitive transhydrogenase: the effect of estradiol-17 beta on alpha-ketoglutarate production in noncancerous and cancerous human breast tissue. HOLLANDER VP, SMITH DE, ADAMSON TE.
Carcinogenesis. 2005 Dec;26(12):2095-104. Epub 2005 Jul 20. Breast carcinomas fulfill the Warburg hypothesis and provide metabolic markers of cancer prognosis. Isidoro A, Casado E, Redondo A, Acebo P, Espinosa E, Alonso AM, Cejas P, Hardisson D, Fresno Vara JA, Belda-Iniesta C, González-Barón M, Cuezva JM.
Cancer. 1959 Jan-Feb;12(1):127-34. The assay of estradiol-sensitive transhydrogenase. JONAS H, HOLLANDER V.
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。
Eur J Clin Nutr. 2003 Dec;57 Suppl 2:S69-74. Effects of changes in hydration on protein, glucose and lipid metabolism in man: impact on health. Keller U, Szinnai G, Bilz S, Berneis K.
Surg Today. 2001;31(10):853-9. Serial measurement of arterial lactate concentrations as a prognostic indicator in relation to the incidence of disseminated intravascular coagulation in patients with systemic inflammatory response syndrome. Kobayashi S, Gando S, Morimoto Y, Nanzaki S, Kemmotsu O.
FASEB J. 2005 Jun;19(8):1030-2. p53 is a suppressor of inflammatory response in mice. Komarova EA, Krivokrysenko V, Wang K, Neznanov N, Chernov MV, Komarov PG, Brennan ML, Golovkina TV, Rokhlin OW, Kuprash DV, Nedospasov SA, Hazen SL, Feinstein E, Gudkov AV.
Gen Pharmacol. 1994 Oct;25(6):1257-62. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R.
Agressologie. 1973;14(1):25-30. [Aspirin, catecholamines and blood lactic acid] Laborit G, Baron C, Laborit H.
Int J Cancer. 2008 Jun 1;122(11):2422-8. Metastasis is promoted by a bioenergetic switch: new targets for progressive renal cell cancer. Langbein S, Frederiks WM, zur Hausen A, Popa J, Lehmann J, Weiss C, Alken P, Coy JF.
Biochemistry (Mosc). 2000 Feb;65(2):223-9. *Bioenergetic response of isolated nerve terminals of rat brain to osmotic swelling. Levko AV, Rakovich AA, Konev SV Intensive Care Med. 2003 Feb;29(2):292-300. Epub 2003 Jan 14. Effects of epinephrine and norepinephrine on hemodynamics, oxidative metabolism, and organ energetics in endotoxemic rats. Levy B, Mansart A, Bollaert PE, Franck P, Mallie JP. Cancer Res. 2007 Oct 1;67(19):9013-7. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. López-Ríos F, Sánchez-Aragó M, García-García E, Ortega AD, Berrendero JR, Pozo-Rodríguez F, López-Encuentra A, Ballestín C, Cuezva JM J Biol Chem. 2002 Jun 28;277(26):23111-5. Epub 2002 Apr 9. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. Lu H, Forbes RA, Verma A. Nutr Metab. 1976;20(1):41-61. Biotin status and lipid metabolism in adult obese hypercholesterolemic inbred rats. Marshall MW, Haubrich M, Washington VA, Chang MW, Young CW, Wheeler MA. J Cardiothorac Vasc Anesth. 2002 Aug;16(4):441-6. A prospective, randomized comparison of thromboelastographic coagulation profile in patients receiving lactated Ringer's solution, 6% hetastarch in a balanced-saline vehicle, or 6% hetastarch in saline during major surgery. Martin G, Bennett-Guerrero E, Wakeling H, Mythen MG, el-Moalem H, Robertson K, Kucmeroski D, Gan TJ. J Biol Chem. 2008 Jun 9. [Epub ahead of print] Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A. Invest Ophthalmol Vis Sci. 2007 Apr;48(4):1615-21. Lactate treatment causes NF-kappaB activation and CD44 shedding in cultured trabecular meshwork cells. Miller AM, Nolan MJ, Choi J, Koga T, Shen X, Yue BY, Knepper PA. “To challenge human trabecular meshwork (TM) cells using lactate to mimic cell stress and observe the effects on cell viability, NF-kappaB, and membrane type 1 matrix metalloproteinase (MT1-MMP) expression and the ectodomain shedding of soluble (s)CD44.” “Lactate treatment resulted in dose- and time-dependent effects on human TM cell viability, translocation of NF-kappaB, and activation of MT1-MMP. Increased shedding of sCD44 occurred with the l mM dose of lactate.” Eur J Pharmacol. 2008 Apr 12. [Epub ahead of print] Trehalose: A biophysics approach to modulate the inflammatory response during endotoxic shock. Minutoli L, Altavilla D, Bitto A, Polito F, Bellocco E, Laganà G, Fiumara T, Magazù S, Migliardo F, Venuti FS, Squadrito F. Acta Neuropathol. 1985;68(2):160-3. Blood-brain barrier impairment by low pH buffer perfusion via the internal carotid artery in rat. Nagy Z, Szabó M, Hüttner I. Am J Physiol Endocrinol Metab. 2005 Oct;289(4):E534-42. Sodium lactate increases LPS-stimulated MMP and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-kappaB transcriptional activities. Nareika A, He L, Game BA, Slate EH, Sanders JJ, London SD, Lopes-Virella MF, Huang Y. Eukaryot Cell. 2003 Feb;2(1):143-9. Glucose regulation of Saccharomyces cerevisiae cell cycle genes. Newcomb LL, Diderich JA, Slattery MG, Heideman W. “These results indicate a link between the rate of glycolysis and the expression of genes that are critical for passage through G(1).” J Neuropathol Exp Neurol. 1987 Mar;46(2):154-66. Effects of lactic acid on astrocytes in primary culture. Norenberg MD, Mozes LW, Gregorios JB, Norenberg LO. Int J Gynecol Pathol. 1997 Jan;16(1):45-51. Expression of fatty acid synthase is closely linked to proliferation and stromal decidualization in cycling endometrium. Pizer ES, Kurman RJ, Pasternack GR, Kuhajda FP. J Leukoc Biol. 2003 Apr;73(4):482-92. Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate and glucose-degradation products. Puig-Kröger A, Pello OM, Selgas R, Criado G, Bajo MA, Sánchez-Tomero JA, Alvarez V, del Peso G, Sánchez-Mateos P, Holmes C, Faict D, López-Cabrera M, Madrenas J, Corbí AL. Cell Biol Int. 2006 Feb;30(2):164-8. Epub 2006 Jan 4. Influence of estradiol on mammary tumor collagen solubility in DMBA-induced rat mammary tumors. Rajkumar L, Balasubramanian K, Arunakaran J, Govindarajulu P, Srinivasan N. Mol Cell Biol. 2006 Jul;26(14):5449-69. Cyclin D1 determines mitochondrial function in vivo. Sakamaki T, Casimiro MC, Ju X, Quong AA, Katiyar S, Liu M, Jiao X, Li A, Zhang X, Lu Y, Wang C, Byers S, Nicholson R, Link T, Shemluck M, Yang J, Fricke ST, Novikoff PM, Papanikolaou A, Arnold A, Albanese C, Pestell R. Cancer Res. 1987 Feb 15;47(4):1065-8. Blood nutrient concentrations and tumor growth in vivo in rats: relationships during the onset of an acute fast. Sauer LA, Dauchy RT. Ric Clin Lab. 1981;11 Suppl 1:13-33. Blood rheology and physiology of microcirculation. Schmid-Schönbein H. Neurochem Int. 2006 Nov;49(6):610-8. Epub 2006 Jun 22. Characterization of the pro-inflammatory signaling induced by protein acetylation in microglia. Suuronen T, Huuskonen J, Nuutinen T, Salminen A. Am J Vet Res. 1994 Feb;55(2):278-87. Clinical and clinicopathologic changes in cows with endotoxin-induced mastitis treated with small volumes of isotonic or hypertonic sodium chloride administered intravenously. Tyler JW, Welles EG, Erskine RJ, Lin HC, Williams MA, Spano JS, Gaslin JT, McClure KA. Brain Res. 2005 Dec 14;1065(1-2):86-91. Epub 2005 Nov 23. Enhancement of lactate metabolism in the basolateral amygdala by physical and psychological stress: role of benzodiazepine receptors. Uehara T, Sumiyoshi T, Matsuoka T, Tanaka K, Tsunoda M, Itoh H, Kurachi M. Pharmacol Biochem Behav. 2008 Aug;90(2):273-81. Lactate production and neurotransmitters; evidence from microdialysis studies. Uehara T, Sumiyoshi T, Itoh H, Kurata K. J Natl Cancer Inst. 1968 Aug;41(2):267-86. Factors affecting anaerobic glycolysis in mouse and rat liver and in Morris rat hepatomas. Woods M, Burk D, Hunter J. Exp Neurol. 2004 Mar;186(1):70-7. Lactate induced excitotoxicity in hippocampal slice cultures. Xiang Z, Yuan M, Hassen GW, Gampel M, Bergold PJ. Masui. 2006 Jun;55(6):699-703. [Blood lactate concentrations as predictors of outcome in serious hemorrhagic shock patients] [Article in Japanese] Yamazaki Y, Saito A, Hasegawa K, Takahashi H. Cytokine. 1993 Sep;5(5):436-47. Cachectin/TNF-mediated lactate production in cultured myocytes is linked to activation of a futile substrate cycle. Zentella A, Manogue K, Cerami A. Chin Med J (Engl). 2002 Jul;115(7):1035-8.Effect of emodin on proliferation and differentiation of 3T3-L1 preadipocyte and FAS activity. Zhang C, Teng L, Shi Y, Jin J, Xue Y, Shang K, Gu J.
