Artykuły w czasopismach na temat „Glycolysis”
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Reiter, Russel J., Ramaswamy Sharma i Sergio Rosales-Corral. "Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases". International Journal of Molecular Sciences 22, nr 2 (14.01.2021): 764. http://dx.doi.org/10.3390/ijms22020764.
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Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.
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Chowdhury, Shomeek, Stephen Hepper, Mudassir K. Lodi, Milton H. Saier i Peter Uetz. "The Protein Interactome of Glycolysis in Escherichia coli". Proteomes 9, nr 2 (6.04.2021): 16. http://dx.doi.org/10.3390/proteomes9020016.
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Glycolysis is regulated by numerous mechanisms including allosteric regulation, post-translational modification or protein-protein interactions (PPI). While glycolytic enzymes have been found to interact with hundreds of proteins, the impact of only some of these PPIs on glycolysis is well understood. Here we investigate which of these interactions may affect glycolysis in E. coli and possibly across numerous other bacteria, based on the stoichiometry of interacting protein pairs (from proteomic studies) and their conservation across bacteria. We present a list of 339 protein-protein interactions involving glycolytic enzymes but predict that ~70% of glycolytic interactors are not present in adequate amounts to have a significant impact on glycolysis. Finally, we identify a conserved but uncharacterized subset of interactions that are likely to affect glycolysis and deserve further study.
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Connett, R. J. "Glycolytic regulation during an aerobic rest-to-work transition in dog gracilis muscle". Journal of Applied Physiology 63, nr 6 (1.12.1987): 2366–74. http://dx.doi.org/10.1152/jappl.1987.63.6.2366.
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Glycogen phosphorylase activity and several glycolytic intermediates were measured at rest and after 5, 10, 15, 30, 60, and 180 s of twitch stimulation at 4 Hz in fast-frozen samples of gracilis muscle. During an initial burst of glycolysis (0–5 s) only 3-phosphoglycerate and lactate accumulate. These changes are reversed during the period of low glycolytic flux (5–30 s). During a second burst of glycolysis (30–60 s) most glycolytic intermediates increase. The levels of glycogen phosphorylase a changes in parallel with the initial burst of glycolysis but remain at resting levels throughout the second burst. The phosphoglycerate mutase-enolase steps deviate from equilibrium during the initial burst of glycolysis, suggesting a transiently rate-limiting role. Analysis using a model of phosphofructokinase kinetics indicates that combined changes in cytosolic pH (R. J. Connett, J. Appl. Physiol. 63: 2360–2365, 1987) and free [ADP] and [AMP] can account for the initial burst of glycolysis. The second burst of glycolysis requires other regulatory factors. It is concluded that an initial alkalization is a major regulatory factor in the early burst of glycolysis during a rest-to-work transition in red muscle.
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Ghazi, Susan, Marcello Polesel i Andrew M. Hall. "Targeting glycolysis in proliferative kidney diseases". American Journal of Physiology-Renal Physiology 317, nr 6 (1.12.2019): F1531—F1535. http://dx.doi.org/10.1152/ajprenal.00460.2019.
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Glycolytic activity is increased in proliferating cells, leading to the concept that glycolysis could be a therapeutic target in cystic diseases and kidney cancer. Preclinical studies using the glucose analog 2-deoxy-d-glucose have shown promise; however, inhibiting glycolysis in humans is unlikely to be without risks. While proximal tubules are predominantly aerobic, later segments are more glycolytic. Understanding exactly where and why glycolysis is important in the physiology of the distal nephron is thus crucial in predicting potential adverse effects of glycolysis inhibitors. Live imaging techniques could play an important role in the process of characterizing cellular metabolism in the functioning kidney. The goal of this review is to briefly summarize recent findings on targeting glycolysis in proliferative kidney diseases and to highlight the necessity for future research focusing on glycolysis in the healthy kidney.
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Zhan, Huiwang David, Jane Borleis, Chris Janetopoulos i Peter Devreotes. "Abstract 288: Glycolysis is enriched to propagating waves in cell cortex as a new mechanism for cancer progression". Cancer Research 83, nr 7_Supplement (4.04.2023): 288. http://dx.doi.org/10.1158/1538-7445.am2023-288.
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Abstract Tumors preferentially metabolize glucose anaerobically through glycolysis with lower ATP production efficiency rather than aerobically even when oxygen is available. This was reported by Otto Warburg 100 years ago, yet the mechanism is hitherto not well-understood. Glycolysis is canonically thought to occur only in cytosol; if and how it is regulated by the actin cytoskeletal network is controversial. I found that, in epithelial cells, 6 of the 9 glycolytic enzymes (HK, PFK, ALDO, GAPDH, ENO, and PK, others not tested) are enriched at newly formed LifeAct labeled waves and protrusions, where mitochondria are barely detected by Mito-Tracker. The application of glycolysis inhibitors but not oxidative phosphorylation inhibitors abolishes cell migration. These results indicate that cells rely on the local ATP production from glycolysis enriched in the cortical waves and protrusions to move. We visualized and measured glycolysis production in confocal and TIRF microscopes using a series of biosensors for ATP, NADH/NAD+ ratio, and pyruvate. We then found glycolysis was enhanced by perturbations that increase wave formation such as EGF/Insulin stimulation or recruiting ActA to membrane, and reduced by wave decrease from PI3K inhibition, hyper- and hypo-osmotic shock, or F-actin assembly inhibition. This suggests that enriching glycolytic enzymes on waves results in higher glycolysis production. We do not think the changes of glycolysis by wave perturbations are merely due to direct regulation on glycolytic enzymes by canonical signaling pathways (e.g., Ras-PI3K-AKT), since ActA recruitment or F-actin inhibition does not lead to acute changes in these signaling pathways but mainly causes the assembly or disassembly of the F-actin/glycolytic waves. These findings together lead to our new theory that energy production from glycolysis is enhanced by recruiting the glycolytic enzymes to the waves and protrusions on the cell cortex. This is potentially paradigm-shifting because for many decades glycolysis - one of the two major ways in a cell to produce ATP - has been thought to only occur in cytosol. Interestingly, we also found glycolytic enzymes enriched in F-actin labeled protrusions of Dictyostelium cells, which indicates that this can possibly be an evolutionally conserved mechanism. Additionally, we investigated non-cancer MCF-10A cells (M1) and a series of M1-derived cancer cell lines (M2 - M4) with increased metastatic index and cancer malignancy, and found a sequential increase in actin wave and glycolysis activities from M1 to M4 cells. Cancer cells such as M3 had a larger drop in glycolysis than non-cancer parental M1 cells upon wave inhibition. These results provide a new explanation for the Warburg effect that increased cortical waves in cancer cells will accelerate and improve glycolysis, which will not only greatly contribute to our understanding of cancer but also the design of new interventions. Citation Format: Huiwang David Zhan, Jane Borleis, Chris Janetopoulos, Peter Devreotes. Glycolysis is enriched to propagating waves in cell cortex as a new mechanism for cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 288.
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Qu, Hengdong, Junli Liu, Di Zhang, Ruoyan Xie, Lijuan Wang i Jian Hong. "Glycolysis in Chronic Liver Diseases: Mechanistic Insights and Therapeutic Opportunities". Cells 12, nr 15 (26.07.2023): 1930. http://dx.doi.org/10.3390/cells12151930.
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Chronic liver diseases (CLDs) cover a spectrum of liver diseases, ranging from nonalcoholic fatty liver disease to liver cancer, representing a growing epidemic worldwide with high unmet medical needs. Glycolysis is a conservative and rigorous process that converts glucose into pyruvate and sustains cells with the energy and intermediate products required for diverse biological activities. However, abnormalities in glycolytic flux during CLD development accelerate the disease progression. Aerobic glycolysis is a hallmark of liver cancer and is responsible for a broad range of oncogenic functions including proliferation, invasion, metastasis, angiogenesis, immune escape, and drug resistance. Recently, the non-neoplastic role of aerobic glycolysis in immune activation and inflammatory disorders, especially CLD, has attracted increasing attention. Several key mediators of aerobic glycolysis, including HIF-1α and pyruvate kinase M2 (PKM2), are upregulated during steatohepatitis and liver fibrosis. The pharmacological inhibition or ablation of PKM2 effectively attenuates hepatic inflammation and CLD progression. In this review, we particularly focused on the glycolytic and non-glycolytic roles of PKM2 in the progression of CLD, highlighting the translational potential of a glycolysis-centric therapeutic approach in combating CLD.
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Chacon-Barahona, Jonathan A., Jeffrey P. MacKeigan i Nathan J. Lanning. "Unique Metabolic Contexts Sensitize Cancer Cells and Discriminate between Glycolytic Tumor Types". Cancers 15, nr 4 (11.02.2023): 1158. http://dx.doi.org/10.3390/cancers15041158.
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Cancer cells utilize variable metabolic programs in order to maintain homeostasis in response to environmental challenges. To interrogate cancer cell reliance on glycolytic programs under different nutrient availabilities, we analyzed a gene panel containing all glycolytic genes as well as pathways associated with glycolysis. Using this gene panel, we analyzed the impact of an siRNA library on cellular viability in cells containing only glucose or only pyruvate as the major bioenergetic nutrient source. From these panels, we aimed to identify genes that elicited conserved and glycolysis-dependent changes in cellular bioenergetics across glycolysis-promoting and OXPHOS-promoting conditions. To further characterize gene sets within this panel and identify similarities and differences amongst glycolytic tumor RNA-seq profiles across a pan-cancer cohort, we then used unsupervised statistical classification of RNA-seq profiles for glycolytic cancers and non-glycolytic cancer types. Here, Kidney renal clear cell carcinoma (KIRC); Head and Neck squamous cell carcinoma (HNSC); and Lung squamous cell carcinoma (LUSC) defined the glycolytic cancer group, while Prostate adenocarcinoma (PRAD), Thyroid carcinoma (THCA), and Thymoma (THYM) defined the non-glycolytic cancer group. These groups were defined based on glycolysis scoring from previous studies, where KIRC, HNSC, and LUSC had the highest glycolysis scores, meanwhile, PRAD, THCA, and THYM had the lowest. Collectively, these results aimed to identify multi-omic profiles across cancer types with demonstrated variably glycolytic rates. Our analyses provide further support for strategies aiming to classify tumors by metabolic phenotypes in order to therapeutically target tumor-specific vulnerabilities.
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McDowell, Ruth E., Kulwant S. Aulak, Allaa Almoushref, Celia A. Melillo, Brittany E. Brauer, Jennie E. Newman, Adriano R. Tonelli i Raed A. Dweik. "Platelet glycolytic metabolism correlates with hemodynamic severity in pulmonary arterial hypertension". American Journal of Physiology-Lung Cellular and Molecular Physiology 318, nr 3 (1.03.2020): L562—L569. http://dx.doi.org/10.1152/ajplung.00389.2019.
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Group 1 pulmonary hypertension (PH), i.e., pulmonary arterial hypertension (PAH), is associated with a metabolic shift favoring glycolysis in cells comprising the lung vasculature as well as skeletal muscle and right heart. We sought to determine whether this metabolic switch is also detectable in circulating platelets from PAH patients. We used Seahorse Extracellular Flux to measure bioenergetics in platelets isolated from group 1 PH (PAH), group 2 PH, patients with dyspnea and normal pulmonary artery pressures, and healthy controls. We show that platelets from group 1 PH patients exhibit enhanced basal glycolysis and lower glycolytic reserve compared with platelets from healthy controls but do not differ from platelets of group 2 PH or dyspnea patients without PH. Although we were unable to identify a glycolytic phenotype unique to platelets from PAH patients, we found that platelet glycolytic metabolism correlated with hemodynamic severity only in group 1 PH patients, supporting the known link between PAH pathology and altered glycolytic metabolism and extending this association to ex vivo platelets. Pulmonary artery pressure and pulmonary vascular resistance in patients with group 1 PH were directly associated with basal platelet glycolysis and inversely associated with maximal and reserve glycolysis, suggesting that PAH progression reduces the capacity for glycolysis even while demanding an increase in glycolytic metabolism. Therefore, platelets may provide an easy-to-harvest, real-time window into the metabolic shift occurring in the lung vasculature and represent a useful surrogate for interrogating the glycolytic shift central to PAH pathology.
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Ma, Yibao, Wei Wang, Michael Idowu, Unsong Oh, Xiang-Yang Wang, Sarah Temkin i Xianjun Fang. "Ovarian Cancer Relies on Glucose Transporter 1 to Fuel Glycolysis and Growth: Anti-Tumor Activity of BAY-876". Cancers 11, nr 1 (31.12.2018): 33. http://dx.doi.org/10.3390/cancers11010033.
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The recent progresses in understanding of cancer glycolytic phenotype have offered new strategies to manage ovarian cancer and other malignancies. However, therapeutic targeting of glycolysis to treat cancer remains unsuccessful due to complex mechanisms of tumor glycolysis and the lack of selective, potent and safe glycolytic inhibitors. Recently, BAY-876 was identified as a new-generation inhibitor of glucose transporter 1 (GLUT1), a GLUT isoform commonly overexpressed but functionally poorly defined in ovarian cancer. Notably, BAY-876 has not been evaluated in any cell or preclinical animal models since its discovery. We herein took advantage of BAY-876 and molecular approaches to study GLUT1 regulation, targetability, and functional relevance to cancer glycolysis. The anti-tumor activity of BAY-876 was evaluated with ovarian cancer cell line- and patient-derived xenograft (PDX) models. Our results show that inhibition of GLUT1 is sufficient to block basal and stress-regulated glycolysis, and anchorage-dependent and independent growth of ovarian cancer cells. BAY-876 dramatically inhibits tumorigenicity of both cell line-derived xenografts and PDXs. These studies provide direct evidence that GLUT1 is causally linked to the glycolytic phenotype in ovarian cancer. BAY-876 is a potent blocker of GLUT1 activity, glycolytic metabolism and ovarian cancer growth, holding promise as a novel glycolysis-targeted anti-cancer agent.
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Mao, Na, Honghao Yang, Jie Yin, Yaqian Li, Fuyu Jin, Tian Li, Xinyu Yang i in. "Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment". International Journal of Molecular Sciences 22, nr 18 (17.09.2021): 10063. http://dx.doi.org/10.3390/ijms221810063.
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Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We found that silica promotes the expression of the key glycolysis enzymes HK2, PKM2, LDHA, and macrophage activation factors iNOS, TNF-α, Arg-1, IL-10, and MCP1 in silicotic rats and silica-induced NR8383 macrophages. The enhancement of glycolysis and macrophage activation induced by silica was reduced by Ac-SDKP or siRNA-Ldha treatment. This study suggests that Ac-SDKP treatment can inhibit glycolytic reprogramming in silica-induced lung macrophages and silicosis.
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Kuijpers, Niels G. A., Daniel Solis-Escalante, Marijke A. H. Luttik, Markus M. M. Bisschops, Francine J. Boonekamp, Marcel van den Broek, Jack T. Pronk, Jean-Marc Daran i Pascale Daran-Lapujade. "Pathway swapping: Toward modular engineering of essential cellular processes". Proceedings of the National Academy of Sciences 113, nr 52 (12.12.2016): 15060–65. http://dx.doi.org/10.1073/pnas.1606701113.
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Recent developments in synthetic biology enable one-step implementation of entire metabolic pathways in industrial microorganisms. A similarly radical remodelling of central metabolism could greatly accelerate fundamental and applied research, but is impeded by the mosaic organization of microbial genomes. To eliminate this limitation, we propose and explore the concept of “pathway swapping,” using yeast glycolysis as the experimental model. Construction of a “single-locus glycolysis” Saccharomyces cerevisiae platform enabled quick and easy replacement of this yeast’s entire complement of 26 glycolytic isoenzymes by any alternative, functional glycolytic pathway configuration. The potential of this approach was demonstrated by the construction and characterization of S. cerevisiae strains whose growth depended on two nonnative glycolytic pathways: a complete glycolysis from the related yeast Saccharomyces kudriavzevii and a mosaic glycolysis consisting of yeast and human enzymes. This work demonstrates the feasibility and potential of modular, combinatorial approaches to engineering and analysis of core cellular processes.
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Diani-Moore, Silvia, Tiago Marques Pedro i Arleen B. Rifkind. "Organ-specific effects on glycolysis by the dioxin-activated aryl hydrocarbon receptor". PLOS ONE 15, nr 12 (15.12.2020): e0243842. http://dx.doi.org/10.1371/journal.pone.0243842.
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Activation of the aryl hydrocarbon receptor (AHR) by the environmental toxin dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) causes diverse toxicities, including thymus atrophy and hepatosteatosis. The mechanisms by which AHR activation by TCDD leads to these toxicities are not fully understood. Here we studied the effects of TCDD on a major energy pathway, glycolysis, using the chick embryo close to hatching, a well-established model for studying dioxin toxicity. We showed that 24 hr of TCDD treatment causes changes in glycolysis in both thymus and liver. In thymus glands, TCDD decreased mRNAs for glycolytic genes and glucose transporters, glycolytic indices and levels of IL7 mRNA, phosphorylated AKT (pAKT) and HIF1A, stimulators of glycolysis and promoters of survival and proliferation of thymic lymphocytes. In contrast, in liver, TCDD increased mRNA levels for glycolytic genes and glucose transporters, glycolytic endpoints and pAKT levels. Similarly, increases by TCDD in mRNA levels for glycolytic genes and glucose transporters in human primary hepatocytes showed that effects in chick embryo liver pertain also to human cells. Treatment with the glycolytic inhibitor 2-deoxy-d-glucose exacerbated the effects on thymus atrophy by TCDD, supporting a role for decreased glycolysis in thymus atrophy by TCDD, but did not prevent hepatosteatosis. NAD+ precursors abolished TCDD effects on glycolytic endpoints in both thymus and liver. In summary, we report here that dioxin disrupts glycolysis mediated energy metabolism in both thymus and liver, and that it does so in opposite ways, decreasing it in the thymus and increasing it in the liver. Further, the findings support NAD+ boosting as a strategy against metabolic effects of environmental pollutants such as dioxins.
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Shi, Lewis Zhichang, Ruoning Wang, Douglas Green i Hongbo Chi. "Metabolic control of T cell fate decision: the HIF1α-glycolysis axis in the differentiation of TH17 and iTreg cells (163.17)". Journal of Immunology 188, nr 1_Supplement (1.05.2012): 163.17. http://dx.doi.org/10.4049/jimmunol.188.supp.163.17.
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Abstract Activated T cells mainly use glycolysis to suffice their bioenergetic and biosynthetic demands. However, whether glycolysis actively controls the differentiation of activated T cell is not fully understood. As a master regulator of metabolism, HIF1α regulates multiple rate-limiting glycolytic enzymes. We previously reported that HIF1α deficiency inhibited TH17 differentiation and promoted induced Treg (iTreg) generation (Shi et al, J Exp Med 2011). To further explore the roles of the glycolytic pathway in T cell differentiation, we combined genetic and pharmacological approaches to examine T cell metabolism and signaling. Inhibition of glycolysis by multiple agents diminished TH17 differentiation and promoted iTreg induction, while supplementation of the products of the glycolytic flux partially rescued these defects. Importantly, blocking glycolysis ameliorated the pathogenesis of autoimmune neuroinflammation both prophylactically and therapeutically, suggesting that the glycolytic pathway is a potential therapeutic target for autoimmune pathogenesis elicited by TH17 cells. Mechanistic studies further revealed that downregulation of IL-23R expression contributed to the diminished TH17 differentiation in HIF1α-deficient T cells, as forced expression of IL-23R restored the TH17 defects. In conclusion, our results demonstrate that the HIF1α-mediated glycolytic pathway links T cell metabolism and signaling, thereby dictating the cell fate decision between TH17 and iTreg cells.
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Marcucci, Fabrizio, i Cristiano Rumio. "Tumor Cell Glycolysis—At the Crossroad of Epithelial–Mesenchymal Transition and Autophagy". Cells 11, nr 6 (18.03.2022): 1041. http://dx.doi.org/10.3390/cells11061041.
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Upregulation of glycolysis, induction of epithelial–mesenchymal transition (EMT) and macroautophagy (hereafter autophagy), are phenotypic changes that occur in tumor cells, in response to similar stimuli, either tumor cell-autonomous or from the tumor microenvironment. Available evidence, herein reviewed, suggests that glycolysis can play a causative role in the induction of EMT and autophagy in tumor cells. Thus, glycolysis has been shown to induce EMT and either induce or inhibit autophagy. Glycolysis-induced autophagy occurs both in the presence (glucose starvation) or absence (glucose sufficiency) of metabolic stress. In order to explain these, in part, contradictory experimental observations, we propose that in the presence of stimuli, tumor cells respond by upregulating glycolysis, which will then induce EMT and inhibit autophagy. In the presence of stimuli and glucose starvation, upregulated glycolysis leads to adenosine monophosphate-activated protein kinase (AMPK) activation and autophagy induction. In the presence of stimuli and glucose sufficiency, upregulated glycolytic enzymes (e.g., aldolase or glyceraldehyde 3-phosphate dehydrogenase) or decreased levels of glycolytic metabolites (e.g., dihydroxyacetone phosphate) may mimic a situation of metabolic stress (herein referred to as “pseudostarvation”), leading, directly or indirectly, to AMPK activation and autophagy induction. We also discuss possible mechanisms, whereby glycolysis can induce a mixed mesenchymal/autophagic phenotype in tumor cells. Subsequently, we address unresolved problems in this field and possible therapeutic consequences.
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Conley, K. E., M. L. Blei, T. L. Richards, M. J. Kushmerick i S. A. Jubrias. "Activation of glycolysis in human muscle in vivo". American Journal of Physiology-Cell Physiology 273, nr 1 (1.07.1997): C306—C315. http://dx.doi.org/10.1152/ajpcell.1997.273.1.c306.
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We tested the cytoplasmic control mechanisms for glycolytic ATP synthesis in human wrist flexor muscles. The forearm was made ischemic and activated by maximal twitch stimulation of the median and ulnar nerves in 10 subjects. Kinetic changes in phosphocreatine, Pi, ADP, ATP, sugar phosphates, and pH were measured by 31P magnetic resonance spectroscopy at 7.1-s intervals. Proton production was determined from pH and tissue buffer capacity during stimulation. Glycolysis was activated between 30 and 50 stimulations, and the rate did not significantly change through the stimulation period. The independence of glycolytic rate on [Pi], [ADP], or [AMP] indicates that feedback regulation by these metabolites could not account for this activation of glycolysis. However, glycolytic H+ and ATP production increased sixfold from 0.5 to 3 Hz, indicating that glycolytic rate reflected muscle activation frequency. This dependence of glycolytic rate on muscle stimulation frequency and independence on metabolite levels is consistent with control of glycolysis by Ca2+.
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Sharma, Pratibha, William Senapedis, Deepa Sampath i Vinay Puduvalli. "CBMT-22. REVERSING THE WARBURG EFFECT BY TARGETING NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT), THE RATE-LIMITING ENZYME OF NAD+ SALVAGE PATHWAY INCREASES, CHEMOSENSITIVITY TO TEMOZOLOMIDE IN GLIOMA CELLS". Neuro-Oncology 21, Supplement_6 (listopad 2019): vi37—vi38. http://dx.doi.org/10.1093/neuonc/noz175.144.
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Abstract BACKGROUND Glioma cells metabolize glucose primarily through incomplete, non-oxidative glycolysis even in the presence of oxygen (the Warburg effect) which provides a constant supply of substrate for proliferation and generates an acidic environment that favors invasion and immunosuppression. NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway, regulates key metabolic processes preferentially used in glioma energy metabolism. Inhibition of NAMPT could have global impact on glioma cell metabolism and could be a promising strategy for glioma therapy. This study examined the effect of NAMPT inhibition using KPT-9274 and FK866 (NAMPTi) on glycolysis and glioma cell metabolism. METHODS Metabolic changes related to NAMPT inhibition were examined in glioma cell lines and patient derived glioma stem-like cells (GSC). Mass spectrometry was used for metabolic profiles and the generated data was annotated by comparison against an extensive metabolite library to identify relevant metabolites. The Agilent Seahorse assay was utilized to determine treatment-related changes in glycolysis. RESULTS NAMPT inhibition caused NAD, NADH, NADP, NADPH, and ATP depletion in glioma cells. Global metabolomics results showed an accumulation of GMP, IMP, AMP and myo-inositol indicating reprogramming of glioma cell metabolism for de novo purine biosynthesis. Additionally, an accumulation of glucose- and fructose-1,6 bisphosphate in NAMPTi treated cells indicated dysfunctional glycolysis. This was confirmed by the Agilent glycolysis stress test by which NAMPTi-treated glioma cells showed a reduction in glycolysis, glycolytic capacity and reserves. NAMPTi treated cells showed downregulation of LDHA due to NAD depletion. Further, downregulation of LDHA enhanced the chemosensitivity of glioma cells to temozolomide. CONCLUSIONS NAMPTi cause profound disruption of glycolysis, reduced glycolytic capacity and glycolytic reserve in gliomas and GSCs irrespective of O[6]-methylguanine-DNA methyltransferase promoter methylation or IDH1 status. Targeting NAMPT to disrupt the Warburg effect is a novel strategy for developing effective therapies against glioma to overcome heterogeneity.
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KAR, SANDIP, i DEB SHANKAR RAY. "NONLINEAR DYNAMICS OF GLYCOLYSIS". Modern Physics Letters B 18, nr 14 (10.06.2004): 653–78. http://dx.doi.org/10.1142/s0217984904007207.
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Glycolysis is the most important cellular process yielding ATP, the universal energy carrier molecule in all living organisms. The characteristic oscillations of the intermediates of glycolysis have been the subject of extensive experimental and theoretical research over the last four decades. A conspicuous property of the glycolytic oscillations is their critical control by the substrate injection rate. In this brief review, we trace its experimental background and explore the essential underlying theoretical models to elucidate a number of nonlinear dynamical phenomena observed in the weak noise limit of the substrate injection rate. Simultaneous oscillations of glycolytic intermediates and insulin have also been discussed within the framework of a phenomenological model in the context of basic experimental issues.
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Fukushi, Abekura, Hee-Do Kim, Yu-Chan Chang i Cheorl-Ho Kim. "Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells". International Journal of Molecular Sciences 23, nr 17 (2.09.2022): 10037. http://dx.doi.org/10.3390/ijms231710037.
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Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a “metabolically abnormal system”. Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the “Warburg effect”. Energy–metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the “Warburg effect”, tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.
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Crowther, Gregory J., William F. Kemper, Michael F. Carey i Kevin E. Conley. "Control of glycolysis in contracting skeletal muscle. II. Turning it off". American Journal of Physiology-Endocrinology and Metabolism 282, nr 1 (1.01.2002): E74—E79. http://dx.doi.org/10.1152/ajpendo.2002.282.1.e74.
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Glycolytic flux in muscle declines rapidly after exercise stops, indicating that muscle activation is a key controller of glycolysis. The mechanism underlying this control could be 1) a Ca2+-mediated modulation of glycogenolysis, which supplies substrate (hexose phosphates, HP) to the glycolytic pathway, or 2) a direct effect on glycolytic enzymes. To distinguish between these possibilities, HP levels were raised by voluntary 1-Hz exercise, and glycolytic flux was measured after the exercise ceased. Glycolytic H+ and ATP production were quantified from changes in muscle pH, phosphocreatine concentration, and Pi concentration as measured by 31P magnetic resonance spectroscopy. Substrate (HP) and metabolite (Pi, ADP, and AMP) levels remained high when exercise stopped because of the occlusion of blood flow with a pressure cuff. Glycolytic flux declined to basal levels within ∼20 s of the end of exercise despite elevated levels of HP and metabolites. Therefore, this flux does not subside because of insufficient HP substrate; rather, glycolysis is controlled independently of glycogenolytic HP production. We conclude that the inactivation of glycolysis after exercise reflects the cessation of contractile activity and is mediated within the glycolytic pathway rather than via the control of glycogen breakdown.
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Ali, Hassan A., Andrew Metcalfe, James T. Topham, Cassia S. Warren, Joanna M. Karasinska, David F. Schaeffer i Daniel J. Renouf. "Abstract PO-021: Targeting the mitochondrial pyruvate complex to alter metabolic programming in pancreatic cancer". Cancer Research 81, nr 22_Supplement (15.11.2021): PO—021—PO—021. http://dx.doi.org/10.1158/1538-7445.panca21-po-021.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) can be stratified into distinct transcriptome subtypes, with the ‘basal-like’ or ‘squamous’ subtype being associated with worse prognosis, compared to the ‘classical’ subtype. Our group recently demonstrated that PDAC tumors have unique metabolic transcriptome profiles, and that genes involved in glycolysis and cholesterol synthesis pathways are positively correlated with basal-like and classical gene expression patterns, respectively. The mitochondrial pyruvate complex (MPC) mediates the transport of pyruvate into the mitochondria which attenuates the effect of glycolysis on tumor progression. The mitochondrial pyruvate carrier 1 (MPC1) gene, which encodes one of two subunits of MPC, is deleted in over 60% of metastatic PDAC and PDAC glycolytic tumors have lowest levels of MPC1 expression. Using PDAC tissue microarrays, we also found that reduced MPC1 protein expression correlates with reduced survival in patients. We hypothesized that targeting MPC1 will alter metabolic reprogramming and may modulate tumor aggressiveness and therapeutic vulnerability in PDAC tumor cells. Genomically and clinically annotated patient-derived tumor organoids (PDOs) were generated from metastatic biopsies from patients enrolled in the PanGen study (NCT02869802). PDOs from both basal and classical tumors were used in the study. In order to investigate glycolysis in PDOs, we adapted the Seahorse Glycolytic Stress Test. Glycolysis, glycolytic capacity and reserve were analyzed in PDOs under basal and treated conditions. To alter MPC1 activity, PDOs were treated for 48 hours with 5uM of UK-5099, an MPC1 inhibitor, or 2.5-5uM SRT1720. SRT1720 is an activator of sirtuin 1 (SIRT1) and the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α), which regulates the expression of MPC1. An unpaired t-test with an alpha of 0.05 was used for all statistical analysis. Glycolysis analysis revealed distinct glycolytic profiles in PDOs with differences in glycolytic capacity and reserves trending with different tumor subtypes. Treatment with UK-5099 resulted in an increase in both glycolytic rate and reserve in PDOs from basal and classical tumors. Treatment with SRT1720 resulted in significantly reduced glycolytic rate and capacity. These data suggest that PDAC PDOs exhibit distinct metabolic profiles and that targeting MPC1 can modulate glycolysis in PDOs. Our ongoing efforts aim to further characterize the subtype-specific effect of MPC1 modulators on glycolysis and chemotherapy response in PDAC PDOs. Citation Format: Hassan A. Ali, Andrew Metcalfe, James T. Topham, Cassia S. Warren, Joanna M. Karasinska, David F. Schaeffer, Daniel J. Renouf. Targeting the mitochondrial pyruvate complex to alter metabolic programming in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-021.
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Bell, Simon M., Toby Burgess, James Lee, Daniel J. Blackburn, Scott P. Allen i Heather Mortiboys. "Peripheral Glycolysis in Neurodegenerative Diseases". International Journal of Molecular Sciences 21, nr 23 (24.11.2020): 8924. http://dx.doi.org/10.3390/ijms21238924.
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Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases. We highlight there is potential for peripheral glycolysis to be developed into multiple types of disease biomarker, but large-scale bio sampling and deciphering how glycolysis is inherently altered in neurodegenerative disease in multiple patients’ needs to be accomplished first to meet this aim.
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Lyu, Haodi, Qin Na, Linlin Wang, Yafei Li, Zengtuo Zheng, Yinga Wu, Yuanyuan Li i in. "Effects of Muscle Type and Aging on Glycolysis and Physicochemical Quality Properties of Bactrian camel (Camelus bactrianus) Meat". Animals 14, nr 4 (14.02.2024): 611. http://dx.doi.org/10.3390/ani14040611.
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Poor tenderness of camel meat has seriously hampered the development of the camel meat industry. This study investigated the effects of muscle fiber composition and ageing time on meat quality, glycolytic potential, and glycolysis-related enzyme activities. Muscle samples of the longissimus thoracis (LT), psoas major (PM), and semitendinosus (ST) were collected from eight 8–10 year old Sonid Bactrian camels (females). Muscle fiber composition was examined by ATPase staining and immunohistochemistry. Meat quality indexes, glycolytic potential, and activities of major glycolytic enzymes were examined at 4 °C aging for 1, 6, 24, 72, and 120 h. The results showed that LT was mainly composed of type IIb muscle fibers, whereas PM and ST were mainly composed of type I muscle fibers. The PCR results of the myosin heavy chain (MyHC) were consistent with the ATPase staining results. During aging, the shear force of LT muscle was always greater than that of PM and ST, and its glycolysis was the strongest; type IIa, IIb, and IIx muscle fibers were positively correlated with muscle shear force and glycolysis rate, and type I muscle fibers were significantly and negatively correlated with the activities of the key enzymes of glycolysis within 6 h. The results showed that the muscle fibers of LT muscle had the greatest glycolysis capacity. These results suggest that an excessive type IIb muscle fiber number percentage and area in camel meat accelerated the glycolysis process, but seriously affected the sensory profile of the camel meat. The results of this study provide directions for the camel industry when addressing the poor tenderness of camel meat.
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Liu, Fei, Qing Yuan, Xiaocheng Cao, Jinlin Zhang, Jianguo Cao, Jiansong Zhang i Liqiu Xia. "Isovitexin Suppresses Stemness of Lung Cancer Stem-Like Cells through Blockage of MnSOD/CaMKII/AMPK Signaling and Glycolysis Inhibition". BioMed Research International 2021 (24.05.2021): 1–17. http://dx.doi.org/10.1155/2021/9972057.
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Background. Manganese superoxide dismutase (MnSOD) has been reported to promote stemness of lung cancer stem-like cells (LCSLCs) which had higher glycolytic rates compared with non-CSLCs. Isovitexin exhibited an inhibitory effect on the stemness of hepatocellular carcinoma cells. However, whether isovitexin could inhibit the promotion of stemness of LCSLCs mediated by MnSOD through glycolysis remains unclear. Objective. Our study was aimed at investigating whether isovitexin inhibits lung cancer stem-like cells (LCSLCs) through MnSOD signaling blockage and glycolysis suppression. Methods. Sphere formation and soft agar assays were conducted to determine self-renewal ability. The migration and invasion of LCSLCs were determined by wound healing and transwell assay. The glycolytic activity was assessed by determination of L-lactate metabolism rate. The influences of isovitexin on MnSOD, CaMKII, and AMPK activations as well as the metabolic shift to glycolysis were determined by manipulating MnSOD expression. Results. It was found that MnSOD and glycolysis enhanced simultaneously in LCSLCs compared with parental H460 cells. Overexpression of MnSOD activated CaMKII/AMPK signaling and glycolysis in LCSLCs with increased self-renewal, migration, invasion, and expression of stemness-associated markers in vitro and elevated carcinogenicity in vivo. Knockdown of MnSOD induced an inverse effect in LCSLCs. Isovitexin blocked MnSOD/CaMKII/AMPK signaling axis and suppressed glycolysis in LCSLCs, resulting in inhibition of stemness features in LCSLCs. The knockdown of MnSOD significantly augmented isovitexin-associated inhibition of CaMKII/AMPK signaling, glycolysis, and stemness in LCSLCs. However, the overexpression of MnSOD could attenuate the inhibition of isovitexin on LCSLCs. Importantly, isovitexin notably suppressed tumor growth in nude mice bearing LCSLCs by downregulation of MnSOD expression. Conclusion. MnSOD promotion of stemness of LCSLCs derived from H460 cell line is involved in the activation of the CaMKII/AMPK pathway and induction of glycolysis. Isovitexin-associated inhibition of stemness in LCSLCs is partly dependent on blockage of the MnSOD/CaMKII/AMPK signaling axis and glycolysis suppression.
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Fontaine, Krystal A., Erica L. Sanchez, Roman Camarda i Michael Lagunoff. "Dengue Virus Induces and Requires Glycolysis for Optimal Replication". Journal of Virology 89, nr 4 (10.12.2014): 2358–66. http://dx.doi.org/10.1128/jvi.02309-14.
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ABSTRACTViruses rely on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. Dengue virus (DENV), a member of theFlaviviridaefamily, is one of the most important arthropod-borne human pathogens worldwide. We analyzed global intracellular metabolic changes associated with DENV infection of primary human cells. Our metabolic profiling data suggested that central carbon metabolism, particularly glycolysis, is strikingly altered during a time course of DENV infection. Glucose consumption is increased during DENV infection and depriving DENV-infected cells of exogenous glucose had a pronounced impact on viral replication. Furthermore, the expression of both glucose transporter 1 and hexokinase 2, the first enzyme of glycolysis, is upregulated in DENV-infected cells. Pharmacologically inhibiting the glycolytic pathway dramatically reduced DENV RNA synthesis and infectious virion production, revealing a requirement for glycolysis during DENV infection. Thus, these experiments suggest that DENV induces the glycolytic pathway to support efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat DENV infection in the future.IMPORTANCEApproximately 400 million people are infected with dengue virus (DENV) annually, and more than one-third of the global population is at risk of infection. As there are currently no effective vaccines or specific antiviral therapies for DENV, we investigated the impact DENV has on the host cellular metabolome to identify metabolic pathways that are critical for the virus life cycle. We report an essential role for glycolysis during DENV infection. DENV activates the glycolytic pathway, and inhibition of glycolysis significantly blocks infectious DENV production. This study provides further evidence that viral metabolomic analyses can lead to the discovery of novel therapeutic targets to block the replication of medically important human pathogens.
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Kim, Seon Yoo, Dongwoo Kim, Jisu Kim, Hae Young Ko, Won Jin Kim, Youngjoo Park, Hye Won Lee i in. "Extracellular Citrate Treatment Induces HIF1α Degradation and Inhibits the Growth of Low-Glycolytic Hepatocellular Carcinoma under Hypoxia". Cancers 14, nr 14 (10.07.2022): 3355. http://dx.doi.org/10.3390/cancers14143355.
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HCC is well known for low glycolysis in the tumors, whereas hypoxia induces glycolytic phenotype and tumor progression. This study was conducted to evaluate the expression of SLCs in human HCCs and investigated whether extracellular nutrient administration related to SLCs in low-glycolytic HCC can prevent hypoxic tumor progression. SLCs expression was screened according to the level of glycolysis in HCCs. Then, whether extracellular nutrient treatment can affect hypoxic tumor progression, as well as the mechanisms, were evaluated in an in vitro cell line and an in vivo animal model. Low-glycolytic HCCs showed high SLC13A5/NaCT and SLC16A1/MCT1 but low SLC2A1/GLUT1 and HIF1α/HIF1α expression. Especially, high SLC13A5 expression was significantly associated with good overall survival in the Cancer Genome Atlas (TCGA) database. In HepG2 cells with the highest NaCT expression, extracellular citrate treatment upon hypoxia induced HIF1α degradation, which led to reduced glycolysis and cellular proliferation. Finally, in HepG2-animal models, the citrate-treated group showed smaller tumor with less hypoxic areas than the vehicle-treated group. In patients with HCC, SLC13A5/NaCT is an important SLC, which is associated with low glycolysis and good prognosis. Extracellular citrate treatment induced the failure of metabolic adaptation to hypoxia and tumor growth inhibition, which can be a potential therapeutic strategy in HCCs.
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Zheng, Yifeng, Pengxi Liu, Neng Wang, Shengqi Wang, Bowen Yang, Min Li, Jianping Chen i in. "Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway". Oxidative Medicine and Cellular Longevity 2019 (19.08.2019): 1–15. http://dx.doi.org/10.1155/2019/8781690.
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Targeting aberrant metabolism is a promising strategy for inhibiting cancer growth and metastasis. Research is now geared towards investigating the inhibition of glycolysis for anticancer drug development. Betulinic acid (BA) has demonstrated potent anticancer activities in multiple malignancies. However, its regulatory effects on glycolysis and the underlying molecular mechanisms are still unclear. BA inhibited invasion and migration of highly aggressive breast cancer cells. Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins. In this study, glucose-regulated protein 78 (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis. Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK. Subsequent phosphorylation of eIF2α led to the inhibition of β-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis. Coimmunoprecipitation assay revealed that BA interrupted the binding between GRP78 and PERK, thereby initiating the glycolysis inhibition cascade. Finally, the lung colonization model validated that BA inhibited breast cancer metastasis in vivo, as well as suppressed the expression of aerobic glycolysis-related proteins. In conclusion, our study not only provided a promising drug for aerobic glycolysis inhibition but also revealed that GRP78 is a novel molecular link between glycolytic metabolism and ER stress during tumor metastasis.
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Ding, Hao, Lei Jiang, Jing Xu, Feng Bai, Yang Zhou, Qi Yuan, Jing Luo, Ke Zen i Junwei Yang. "Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis". American Journal of Physiology-Renal Physiology 313, nr 3 (1.09.2017): F561—F575. http://dx.doi.org/10.1152/ajprenal.00036.2017.
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Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy.
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Xu, Rui-hua, Helene Pelicano, Yan Zhou, Jennifer S. Carew, Li Feng, Kapil N. Bhalla, Michael J. Keating i Peng Huang. "Inhibition of Glycolysis in Cancer Cells: A Novel Strategy to Overcome Drug Resistance Associated with Mitochondrial Respiratory Defect and Hypoxia". Cancer Research 65, nr 2 (15.01.2005): 613–21. http://dx.doi.org/10.1158/0008-5472.613.65.2.
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Abstract Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser112, relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.
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Blair, Derek, Fay J. Dufort i Thomas C. Chiles. "Protein kinase Cβ is critical for the metabolic switch to glycolysis following B-cell antigen receptor engagement". Biochemical Journal 448, nr 1 (18.10.2012): 165–69. http://dx.doi.org/10.1042/bj20121225.
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Signals derived from the BCR (B-cell antigen receptor) control survival, development and antigenic responses. One mechanism by which BCR signals may mediate these responses is by regulating cell metabolism. Indeed, the bioenergetic demands of naïve B-cells increase following BCR engagement and are characterized by a metabolic switch to aerobic glycolysis; however, the signalling pathways involved in this metabolic reprogramming are poorly defined. The PKC (protein kinase C) family plays an integral role in B-cell survival and antigenic responses. Using pharmacological inhibition and mice deficient in PKCβ, we demonstrate an essential role of PKCβ in BCR-induced glycolysis in B-cells. In contrast, mice deficient in PKCδ exhibit glycolytic rates comparable with those of wild-type B-cells following BCR cross-linking. The induction of several glycolytic genes following BCR engagement is impaired in PKCβ-deficient B-cells. Moreover, blocking glycolysis results in decreased survival of B-cells despite BCR engagement. The results establish a definitive role for PKCβ in the metabolic switch to glycolysis following BCR engagement of naïve B-cells.
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Jo, Min-Sik, Hyun-Woo Yang, Joo-Hoo Park, Jae-Min Shin i Il-Ho Park. "Glycolytic reprogramming is involved in tissue remodeling on chronic rhinosinusitis". PLOS ONE 18, nr 2 (16.02.2023): e0281640. http://dx.doi.org/10.1371/journal.pone.0281640.
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Background Glycolytic reprogramming is a key feature of chronic inflammatory disease. Extracellular matrix (ECM) produced by myofibroblasts plays an important role in tissue remodeling of nasal mucosa in chronic rhinosinusitis (CRS). This study aimed to determine whether glycolytic reprogramming contributes to myofibroblast differentiation and ECM production in nasal fibroblasts. Methods Primary nasal fibroblasts were isolated from the nasal mucosa of patients with CRS. Glycolytic reprogramming was assessed by measuring the extracellular acidification and oxygen consumption rates in nasal fibroblast, with and without transforming growth factor beta 1 (TGF-β1) treatment. Expression of glycolytic enzymes and ECM components was measured by real-time polymerase chain reaction, western blotting, and immunocytochemical staining. Gene set enrichment analysis was performed using whole RNA-sequencing data of nasal mucosa of healthy donors and patients with CRS. Result Glycolysis of nasal fibroblasts stimulated with TGF-B1 was upregulated along with glycolytic enzymes. Hypoxia-inducing factor (HIF)-1α was a high-level regulator of glycolysis, and increased HIF-1α expression promoted glycolysis of nasal fibroblasts, and inhibition of HIF-1α down-regulated myofibroblasts differentiation and ECM production. Conclusion This study suggests that inhibition of the glycolytic enzyme and HIF-1α in nasal fibroblasts regulates myofibroblast differentiation and ECM generation associated with nasal mucosa remodeling.
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Chandel, Navdeep S. "Glycolysis". Cold Spring Harbor Perspectives in Biology 13, nr 5 (maj 2021): a040535. http://dx.doi.org/10.1101/cshperspect.a040535.
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Bolon, Claire, Catherine Gauthier i Hélène Simonnet. "Glycolysis inhibition by palmitate in renal cells cultured in a two-chamber system". American Journal of Physiology-Cell Physiology 273, nr 5 (1.11.1997): C1732—C1738. http://dx.doi.org/10.1152/ajpcell.1997.273.5.c1732.
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A major shortcoming of renal proximal tubular cells (RPTC) in culture is the gradual modification of their energy metabolism from the oxidative type to the glycolytic type. To test the possible reduction of glycolysis by naturally occurring long-chain fatty acids, RPTC were cultured in a two-chamber system, with albumin-bound palmitate (0.4 mM) added to the basolateral chamber after confluency. Twenty-four hours of contact with palmitate decreased glycolysis by 38% provided that carnitine was present; lactate production was decreased by 38%, and the decrease in glycolysis resulted from a similar decrease of basolateral and apical net uptake of glucose. In contrast to the previously described effect of the nonphysiological oxidative substrate heptanoate, palmitate promoted a long-term decrease in lactate production and sustained excellent cellular growth. After 4 days of contact, decreased glycolysis was maintained even in the absence of carnitine and resulted from a decrease of basolateral uptake only, suggestive of long-term regulation different from the earlier effects. Thus, although cultured RPTC lost their oxidative phenotype, they exhibited a type of regulation (Randle effect) that is found in the oxidative-type but not in the glycolytic-type tissues, therefore unmasking a regulative capacity barely detectable in fresh RPTC. Low Po 2 (50 mmHg in the apical chamber) could be a major cause of elevated glycolysis and could hinder the effects of palmitate.
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Zlacká, Jana, Miroslav Murár, Gabriela Addová, Roman Moravčík, Andrej Boháč i Michal Zeman. "Synthesis of Glycolysis Inhibitor PFK15 and Its Synergistic Action with an Approved Multikinase Antiangiogenic Drug on Human Endothelial Cell Migration and Proliferation". International Journal of Molecular Sciences 23, nr 22 (18.11.2022): 14295. http://dx.doi.org/10.3390/ijms232214295.
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Activated endothelial, immune, and cancer cells prefer glycolysis to obtain energy for their proliferation and migration. Therefore, the blocking of glycolysis can be a promising strategy against cancer and autoimmune disease progression. Inactivation of the glycolytic enzyme PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase) suppresses glycolysis level and contributes to decreased proliferation and migration of cancer (tumorigenesis) and endothelial (angiogenesis) cells. Recently, several glycolysis inhibitors have been developed, among them (E)-1-(pyridin-4-yl)-3-(quinolin-2-yl)prop-2-en-1-one (PFK15) that is considered as one of the most promising. It is known that PFK15 decreases glucose uptake into the endothelial cells and efficiently blocks pathological angiogenesis. However, no study has described sufficiently PFK15 synthesis enabling its general availability. In this paper we provide all necessary details for PFK15 preparation and its advanced characterization. On the other hand, there are known tyrosine kinase inhibitors (e.g., sunitinib), that affect additional molecular targets and efficiently block angiogenesis. From a biological point of view, we have studied and proved the synergistic inhibitory effect by simultaneous administration of glycolysis inhibitor PFK15 and multikinase inhibitor sunitinib on the proliferation and migration of HUVEC. Our results suggest that suppressing the glycolytic activity of endothelial cells in combination with growth factor receptor blocking can be a promising antiangiogenic treatment.
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Zhang, Xin, Long Wu, Russell H. Swerdlow i Liqin Zhao. "Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease". Cells 12, nr 3 (25.01.2023): 410. http://dx.doi.org/10.3390/cells12030410.
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Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer’s disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD.
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Luo, Xiaonuan, Yin Peng, Xinmin Fan, Xiaoxun Xie, Zhe Jin i Xiaojing Zhang. "The Crosstalk and Clinical Implications of CircRNAs and Glucose Metabolism in Gastrointestinal Cancers". Cancers 15, nr 8 (10.04.2023): 2229. http://dx.doi.org/10.3390/cancers15082229.
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The majority of glucose in tumor cells is converted to lactate despite the presence of sufficient oxygen and functional mitochondria, a phenomenon known as the “Warburg effect” or “aerobic glycolysis”. Aerobic glycolysis supplies large amounts of ATP, raw material for macromolecule synthesis, and also lactate, thereby contributing to cancer progression and immunosuppression. Increased aerobic glycolysis has been identified as a key hallmark of cancer. Circular RNAs (circRNAs) are a type of endogenous single-stranded RNAs characterized by covalently circular structures. Accumulating evidence suggests that circRNAs influence the glycolytic phenotype of various cancers. In gastrointestinal (GI) cancers, circRNAs are related to glucose metabolism by regulating specific glycolysis-associated enzymes and transporters as well as some pivotal signaling pathways. Here, we provide a comprehensive review of glucose-metabolism-associated circRNAs in GI cancers. Furthermore, we also discuss the potential clinical prospects of glycolysis-associated circRNAs as diagnostic and prognostic biomarkers and therapeutic targets in GI cancers.
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Phan, Tuan-Nghia, i Robert E. Marquis. "Triclosan inhibition of membrane enzymes and glycolysis of Streptococcus mutans in suspensions and biofilms". Canadian Journal of Microbiology 52, nr 10 (1.10.2006): 977–83. http://dx.doi.org/10.1139/w06-055.
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Triclosan was found to be a potent inhibitor of the F(H+)-ATPase of the oral pathogen Streptococcus mutans and to increase proton permeabilities of intact cells. Moreover, it acted additively with weak-acid transmembrane proton carriers, such as fluoride or sorbate, to sensitize glycolysis to acid inhibition. Even at neutral pH, triclosan could inhibit glycolysis more directly as an irreversible inhibitor of the glycolytic enzymes pyruvate kinase, lactic dehydro genase, aldolase, and the phosphoenolpyruvate:sugar phosphotransferase system (PTS). Cell glycolysis in suspensions or biofilms was inhibited in a pH-dependent manner by triclosan at a concentration of about 0.1 mmol/L at pH 7, approximately the lethal concentration for S. mutans cells in suspensions. Cells in intact biofilms were almost as sensitive to triclosan inhibition of glycolysis as were cells in suspensions but were more resistant to killing. Targets for irreversible inhibition of glycolysis included the PTS and cytoplasmic enzymes, specifically pyruvate kinase, lactic dehydrogenase, and to a lesser extent, aldolase. General conclusions are that triclosan is a multi-target inhibitor for mutans streptococci, which lack a triclosan-sensitive FabI enoyl-ACP reductase, and that inhibition of glycolysis in dental plaque biofilms, in which triclosan is retained after initial or repeated exposure, would reduce cariogenicity.Key words: triclosan, oral streptococci, glycolysis, biofilms, F-ATPase.
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He, Haiqi, Kenneth J. Genovese, Ryan J. Arsenault, Christina L. Swaggerty, Casey N. Johnson, J. Allen Byrd i Michael H. Kogut. "M2 Polarization and Inhibition of Host Cell Glycolysis Contributes Intracellular Survival of Salmonella Strains in Chicken Macrophage HD-11 Cells". Microorganisms 11, nr 7 (19.07.2023): 1838. http://dx.doi.org/10.3390/microorganisms11071838.
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Salmonella enterica is a group of facultative, gram-negative bacteria. Recently, new evidence indicated that Salmonella could reprogram the host metabolism to increase energy or metabolites available for intracellular replication. In this study, using a chicken-specific kinomic immunometabolism peptide array analysis, we found that infection by S. Enteritidis induced significant phosphorylation changes in many key proteins of the glycolytic pathway in chicken macrophage HD-11 cells, indicating a shift in glycolysis caused by Salmonella infection. Nitric oxide production and changes of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) represented by extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively, were measured in chicken macrophages infected with three Salmonella strains (S. Enteritidis, S. Heidelberg, and S. Senftenberg). The infection reduced glycolysis and enhanced OXPHOS in chicken macrophages as indicated by changes of ECAR and OCR. Salmonella strains differentially affected macrophage polarization and glycolysis. Among three strains tested, S. Enteritidis was most effective in downregulating glycolysis and promoting M2 polarization as measured by ECAR, ORC, and NO production; while S. Senftenberg did not alter glycolysis and may promote M1 polarization. Our results suggested that downregulation of host cell glycolysis and increase of M2 polarization of macrophages may contribute to increased intracellular survival of S. Enteritidis.
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Winther, Sally, Marie S. Isidor, Astrid L. Basse, Nina Skjoldborg, Amanda Cheung, Bjørn Quistorff i Jacob B. Hansen. "Restricting glycolysis impairs brown adipocyte glucose and oxygen consumption". American Journal of Physiology-Endocrinology and Metabolism 314, nr 3 (1.03.2018): E214—E223. http://dx.doi.org/10.1152/ajpendo.00218.2017.
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During thermogenic activation, brown adipocytes take up large amounts of glucose. In addition, cold stimulation leads to an upregulation of glycolytic enzymes. Here we have investigated the importance of glycolysis for brown adipocyte glucose consumption and thermogenesis. Using siRNA-mediated knockdown in mature adipocytes, we explored the effect of glucose transporters and glycolytic enzymes on brown adipocyte functions such as consumption of glucose and oxygen. Basal oxygen consumption in brown adipocytes was equally dependent on glucose and fatty acid oxidation, whereas isoproterenol (ISO)-stimulated respiration was fueled mainly by fatty acids, with a significant contribution from glucose oxidation. Knockdown of glucose transporters in brown adipocytes not only impaired ISO-stimulated glycolytic flux but also oxygen consumption. Diminishing glycolytic flux by knockdown of the first and final enzyme of glycolysis, i.e., hexokinase 2 (HK2) and pyruvate kinase M (PKM), respectively, decreased glucose uptake and ISO-stimulated oxygen consumption. HK2 knockdown had a more severe effect, which, in contrast to PKM knockdown, could not be rescued by supplementation with pyruvate. Hence, brown adipocytes rely on glucose consumption and glycolytic flux to achieve maximum thermogenic output, with glycolysis likely supporting thermogenesis not only by pyruvate formation but also by supplying intermediates for efferent metabolic pathways.
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Leong, Hon Sing, Mark Grist, Hannah Parsons, Richard B. Wambolt, Gary D. Lopaschuk, Roger Brownsey i Michael F. Allard. "Accelerated rates of glycolysis in the hypertrophied heart: are they a methodological artifact?" American Journal of Physiology-Endocrinology and Metabolism 282, nr 5 (1.05.2002): E1039—E1045. http://dx.doi.org/10.1152/ajpendo.00507.2001.
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Glycolysis, measured by3H2O production from [5-3H]glucose, is accelerated in isolated working hypertrophied rat hearts. However, nonglycolytic detritiation of [5-3H]glucose via the nonoxidative pentose phosphate pathway (PPP) could potentially lead to an overestimation of true glycolytic rates, especially in hypertrophied hearts where the PPP may be upregulated. To address this concern, we measured glycolysis using [5-3H]glucose and a second, independent method in isolated working hearts from halothane-anesthetized, sham-operated and aortic-constricted rats. Glycolysis was accelerated in hypertrophied hearts compared with control hearts regardless of the method used. There was also excellent concordance in glycolytic rates between the different methods. Moreover, activity of glucose-6-phosphate dehydrogenase and expression of transaldolase, enzymes controlling key steps in the oxidative and nonoxidative PPP, respectively, were not different between control and hypertrophied hearts. Thus nonglycolytic detritiation of [5-3H]glucose in the PPP is insignificant, and 3H2O production from [5-3H]glucose is an accurate means to measure glycolysis in isolated working normal and hypertrophied rat hearts. Furthermore, the PPP does not appear to be increased in cardiac hypertrophy induced by abdominal aortic constriction.
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Willett, Benjamin A. S., Jared Klarquist, Angelo D’Alessandro i Ross M. Kedl. "Exploiting metabolism of vaccine-elicited T cells to enhance tumor immunotherapy". Journal of Immunology 204, nr 1_Supplement (1.05.2020): 91.13. http://dx.doi.org/10.4049/jimmunol.204.supp.91.13.
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Abstract Given the highly glycolytic nature of most cancers, glycolysis inhibition remains a strong potential treatment strategy. However, effective glycolysis blockade may also inhibit the function and survival of infiltrating T cells. Unlike T cells activated by infections and cancer, T cells activated by subunit vaccination do not rely on aerobic glycolysis, either during their initial proliferative burst or thereafter. Instead, these vaccine-elicited T cells primarily rely on mitochondrial metabolism of fatty acids and OXPHOS. Thus, we hypothesize that vaccine-elicited T cells will maintain anti-cancer therapeutic efficacy even under conditions of glycolytic inhibition. Additionally, vaccine-elicited T cells are characterized by robust expression of the transcription factor Tcf1, which has been shown to identify a stem-like pool of T cells capable of sustaining an anti-cancer response. We show that a therapeutic regimen combining subunit vaccination with glycolysis inhibition significantly impairs tumor growth in mice. These effects are further enhanced by the addition of clinically-relevant αPD-1 inhibitors. Collectively, these data show the potential of controlling tumor progression by exploiting the distinct metabolic and transcriptional program of vaccine-elicited T cells through a novel combination immuno/metabolomic therapeutic regimen.
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Warrier, Govind, Lilibeth Lanceta, Yoannis Imbert-Fernandez i Jason Alan Chesney. "Inhibition of glucose metabolism through treatment of BRAF mutated metastatic melanoma with vemurafenib." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): e21005-e21005. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e21005.
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e21005 Background: Increased glucose metabolism is a hallmark of neoplastic cells that allows self-promotion of growth and survival. The enzyme 6-phosphofructo-2-kinase (PFKFB3) is an integral controller of glycolysis by promoting the synthesis of fructose 2,6-bisphosphonate (F2,6BP) which activates 6-phoshofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. Additionally, mitogen-activated protein kinase (MAPK) is a key signaling pathway in a number of cancers with mutations of the BRAF component, described most commonly in melanoma, resulting in constitutive activation of the MAPK pathway. We aim to demonstrate that vemurafenib, a BRAF inhibitor, has antiglycolytic activity in sensitive melanoma cell lines which may help guide development of future therapies with specific attention to PFKFB3 as a potential enzymatic target to decrease glycolytic flux thereby inhibiting tumor growth and survival. Methods: Vemurafenib sensitive and resistant variants of two separate human metastatic melanoma cell lines (451Lu and WM983) were treated with 3 mM Vemurafenib for 24 and 48 hours. Additionally, cells from aforementioned lines were probed for PFKFB3 after 24 hours of treatment with vemurafenib. Glycolysis was measured by incubating cells in complete media containing 1 mCi [5-3H]glucose for 60 minutes. [3H]H2O produced by glycolysis through enolase was measured. Results: A decrease in PFKFB3 protein expression was found in vemurafenib sensitive cells compared to controls but not in resistant cells after 24h treatment with 3 mM vemurafenib in both 451Lu and WM983 metastatic melanoma cell lines (n = 2). Treatment with vemurafenib led to decrease in glycolysis compared to untreated controls in both vemurafenib sensitive metastatic melanoma cell lines but not in resistant cell lines (n = 5). Additionally, there was a significant reduction in glycolysis in vemurafenib resistant WM983 at 48 hours compared to resistant untreated control. Conclusions: BRAF mutated metastatic melanoma cells showed decrease in PFKFB3 protein expression and decreased glycolysis after treatment with BRAF inhibitor vemurafenib. Future studies will focus on assessing metastatic melanoma cell viability and glycolytic activity after treatment with combination BRAF inhibition and PFKFB3 specific inhibition.
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Jimenez-Blasco, Daniel, Jesús Agulla, Rebeca Lapresa, Marina Garcia-Macia, Veronica Bobo-Jimenez, Dario Garcia-Rodriguez, Israel Manjarres-Raza i in. "Weak neuronal glycolysis sustains cognition and organismal fitness". Nature Metabolism, 24.05.2024. http://dx.doi.org/10.1038/s42255-024-01049-0.
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AbstractThe energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis3–6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase–fructose-2,6-bisphosphatase-3 (PFKFB3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD+) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD+ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.
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Rabbani, Naila, i Paul J. Thornalley. "Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications". Frontiers in Endocrinology 14 (16.01.2024). http://dx.doi.org/10.3389/fendo.2023.1268308.
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Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes—unscheduled glycolysis—produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.
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Zhao, Yuanyuan, Louisa S. Chard Dunmall, Zhenguo Cheng, Yaohe Wang i Lingling Si. "Natural products targeting glycolysis in cancer". Frontiers in Pharmacology 13 (1.11.2022). http://dx.doi.org/10.3389/fphar.2022.1036502.
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Many energy metabolism pathways exist in cancer, including glycolysis, amino acid metabolism, fatty acid oxidation, and mitochondrial respiration. Tumor cells mainly generate energy through glycolysis to maintain growth and biosynthesis of tumor cells under aerobic conditions. Natural products regulate many steps in glycolysis and targeting glycolysis using natural products is a promising approach to cancer treatment. In this review, we exemplify the relationship between glycolysis and tumors, demonstrate the natural products that have been discovered to target glycolysis for cancer treatment and clarify the mechanisms involved in their actions. Natural products, such as resveratrol mostly found in red grape skin, licochalcone A derived from root of Glycyrrhiza inflate, and brusatol found in Brucea javanica and Brucea mollis, largely derived from plant or animal material, can affect glycolysis pathways in cancer by targeting glycolytic enzymes and related proteins, oncogenes, and numerous glycolytic signal proteins. Knowledge of how natural products regulate aerobic glycolysis will help illuminate the mechanisms by which these products can be used as therapeutics to inhibit cancer cell growth and regulate cellular metabolism.Systematic Review Registration: https://pubmed.ncbi.nlm.nih.gov/, https://clinicaltrials.gov/, http://lib.zzu.edu.cn/
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Xu, Fangshi, Yibing Guan, Li Xue, Shanlong Huang, Ke Gao, Zhen Yang i Tie Chong. "The effect of a novel glycolysis-related gene signature on progression, prognosis and immune microenvironment of renal cell carcinoma". BMC Cancer 20, nr 1 (grudzień 2020). http://dx.doi.org/10.1186/s12885-020-07702-7.
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Abstract Background Glycolysis is a central metabolic pathway for tumor cells. However, the potential roles of glycolysis-related genes in renal cell carcinoma (RCC) have not been investigated. Methods Seven glycolysis-related gene sets were selected from MSigDB and were analyzed through GSEA. Using TCGA database, the glycolysis-related gene signature was constructed. Prognostic analyses were based on the Kaplan–Meier method. The cBioPortal database was employed to perform the mutation analyses. The CIBERSORT algorithm and TIMER database were used to determine the immunological effect of glycolytic gene signature. The expressions in protein level of eight glycolytic risk genes were determined by HPA database. Finally, qPCR, MTT and Transwell invasion assays were conducted to validate the roles of core glycolytic risk genes (CD44, PLOD1 and PLOD2) in RCC. Results Four glycolysis-related gene sets were significantly enriched in RCC samples. The glycolytic risk signature was constructed (including CD44, PLOD2, KIF20A, IDUA, PLOD1, HMMR, DEPDC1 and ANKZF1) and identified as an independent RCC prognostic factor (HR = 1.204). Moreover, genetic alterations of glycolytic risk genes were uncommon in RCC (10.5%) and glycolytic risk signature can partially affect immune microenvironment of RCC. Six glycolytic risk genes (except for IDUA and HMMR) were over-expression in A498 and 786-O renal cancer cells through qPCR test. MTT and Transwell assays revealed that silencing of CD44, PLOD1 and PLOD2 suppressed the proliferation and invasion of renal cancer cells. Conclusions The glycolysis-related risk signature is closely associated with RCC prognosis, progression and immune microenvironment. CD44, PLOD1 and PLOD2 may serve as RCC oncogenes.
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Kumari, Neeraj, Asmita Das i Anant Narayan Bhatt. "Interleukin-6 confers radio-resistance by inducing Akt mediated glycolysis and reducing mitochondrial damage in cells". Journal of Biochemistry, 31.10.2019. http://dx.doi.org/10.1093/jb/mvz091.
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Abstract Interleukin-6 (IL-6) induced glycolysis and therapeutic resistance is reported in some cell systems; however the mechanism of IL-6 induced glycolysis in radio-resistance is un-explored. Therefore to investigate, we treated Raw264.7 cells with IL-6 (1hr prior to irradiation) and examined the glycolytic flux. Increased expression of mRNA and protein levels of key glycolytic enzymes was observed after IL-6 treatment, which conferred glycolysis dependent resistance from radiation induced cell death. We further established that IL-6 induced glycolysis is activated by Akt signaling and knocking down Akt or inhibition of pan Akt phosphorylation significantly abrogated the IL-6 induced radio-resistance. Moreover, reduction of IL-6 induced pAkt level suppressed the expression of Hexokinase-2 and its translocation to the mitochondria, thereby inhibiting the glycolysis induced resistance to radiation. IL-6 induced glycolysis also minimized the radiation induced mitochondrial damage. These results suggest that IL-6 induced glycolysis observed in cells may be responsible for IL-6 mediated therapeutic radio-resistance in cancer cells, partly by activation of Akt signaling.
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Qian, Yujie, Yeyi Yang, Wenxiang Qing, Chunyun Li, Min Kong, Zhijuan Kang, Yuanbojiao Zuo, Jiping Wu, Meng Yu i Zuocheng Yang. "Coxsackievirus B3 infection induces glycolysis to facilitate viral replication". Frontiers in Microbiology 13 (9.12.2022). http://dx.doi.org/10.3389/fmicb.2022.962766.
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Coxsackievirus B3 (CVB3) is a leading cause of viral myocarditis, but no effective treatment strategy against CVB3 is available. Viruses lack an inherent metabolic system and thus depend on host cellular metabolism for their benefit. In this study, we observed that CVB3 enhanced glycolysis in H9c2 rat cardiomyocytes and HL-1 mouse cardiomyocytes. Therefore, three key glycolytic enzymes, namely, hexokinase 2 (HK2), muscle phosphofructokinase (PFKM), and pyruvate kinase M2 (PKM2), were measured in CVB3-infected H9c2 and HL-1 cells. Expression levels of HK2 and PFKM, but not PKM2, were increased in CVB3-infected H9c2 cells. All three key glycolytic enzymes showed elevated expression in CVB3-infected HL-1 cells. To further investigate this, we used 2 deoxyglucose, sodium citrate, and shikonin as glycolysis inhibitors for HK2, PFKM, and PKM2, respectively. Glycolysis inhibitors significantly reduced CVB3 replication, while the glycolysis enhancer dramatically promoted it. In addition, glycolysis inhibitors decreased autophagy and accelerated autophagosome degradation. The autophagy inducer eliminated partial inhibition effects of glycolysis inhibitors on CVB3 replication. These results demonstrate that CVB3 infection enhances glycolysis and thus benefits viral replication.
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Tan, Chunmei, Lanqing Li, Juanjuan Han, Kang Xu i Xianqiong Liu. "A new strategy for osteoarthritis therapy: Inhibition of glycolysis". Frontiers in Pharmacology 13 (10.11.2022). http://dx.doi.org/10.3389/fphar.2022.1057229.
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Osteoarthritis (OA) is a common degenerative disease of the joints. It is primarily caused by age, obesity, mechanical damage, genetics, and other factors, leading to cartilage degradation, synovial inflammation, and subchondral sclerosis with osteophyte formation. Many recent studies have reported that glycolysis disorders are related lead to OA. There is a close relationship between glycolysis and OA. Because of their hypoxic environment, chondrocytes are highly dependent on glycolysis, their primary energy source for chondrocytes. Glycolysis plays a vital role in OA development. In this paper, we comprehensively summarized the abnormal expression of related glycolytic enzymes in OA, including Hexokinase 2 (HK2), Pyruvate kinase 2 (PKM2), Phosphofructokinase-2/fructose-2, 6-Bisphosphatase 3 (PFKFB3), lactate dehydrogenase A (LDHA), and discussed the potential application of glycolysis in treating OA. Finally, the natural products that can regulate the glycolytic pathway were summarized. Targeting glucose transporters and rate-limiting enzymes to glycolysis may play an essential role in treating OA.
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Zhu, Lei, Fugui Yang, Xinrui Li, Qinchuan Li i Chunlong Zhong. "Glycolysis Changes the Microenvironment and Therapeutic Response Under the Driver of Gene Mutation in Esophageal Adenocarcinoma". Frontiers in Genetics 12 (8.12.2021). http://dx.doi.org/10.3389/fgene.2021.743133.
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Background: Esophageal cancer is one of the most leading and lethal malignancies. Glycolysis and the tumor microenvironment (TME) are responsible for cancer progressions. We aimed to study the relationships between glycolysis, TME, and therapeutic response in esophageal adenocarcinoma (EAC).Materials and Methods: We used the ESTIMATE algorithm to divide EAC patients into ESTIMATE high and ESTIMATE low groups based on the gene expression data downloaded from TCGA. Weighted gene co-expression network analysis (WGCNA) and Gene Set Enrichment Analysis (GSEA) were performed to identify different glycolytic genes in the TME between the two groups. The prognostic gene signature for overall survival (OS) was established through Cox regression analysis. Impacts of glycolytic genes on immune cells were assessed and validated. Next, we conducted the glycolytic gene mutation analysis and drug therapeutic response analysis between the two groups. Finally, the GEO database was employed to validate the impact of glycolysis on TME in patients with EAC.Results: A total of 78 EAC patients with gene expression profiles and clinical information were included for analysis. Functional enrichment results showed that the genes between ESTIMATE high and ESTIMATE low groups (N = 39, respectively) were strongly related with glycolytic and ATP/ADP metabolic pathways. Patients in the low-risk group had probabilities to survive longer than those in the high-risk group (p < 0.001). Glycolytic genes had significant impacts on the components of immune cells in TME, especially on the T-cells and dendritic cells. In the high-risk group, the most common mutant genes were TP53 and TTN, and the most frequent mutation type was missense mutation. Glycolysis significantly influenced drug sensitivity, and high tumor mutation burden (TMB) was associated with better immunotherapeutic response. GEO results confirmed that glycolysis had significant impacts on immune cell contents in TME.Conclusion: We performed a comprehensive study of glycolysis and TME and demonstrated that glycolysis could influence the microenvironment and drug therapeutic response in EAC. Evaluation of the glycolysis pattern could help identify the individualized therapeutic regime.
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Che, Kai, Wenkai Han, Danxia Li, Shuxia Cui, Mingxin Zhang, Xiaokun Yang i Haitao Niu. "Correlations between glycolysis with clinical traits and immune function in bladder urothelial carcinoma". Bioscience Reports 41, nr 2 (luty 2021). http://dx.doi.org/10.1042/bsr20203982.
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Abstract Background: Glycolysis was a representative hallmark in the tumor microenvironment (TME), and we aimed to explore the correlations between glycolysis with immune activity and clinical traits in bladder urothelial carcinoma (BLCA). Methods: Our study obtained glycolysis scores for each BLCA samples from TCGA by a single-sample gene set enrichment analysis (ssGSEA) algorithm, based on a glycolytic gene set. The relationship between glycolysis with prognosis, clinical characteristics, and immune function were investigated subsequently. Results: We found that enhanced glycolysis was associated with poor prognosis and metastasis in BLCA. Moreover, glycolysis had a close correlation with immune function, and enhanced glycolysis increased immune activities. In other words, glycolysis had a positive correlation with immune activities. Immune checkpoints such as IDO1, CD274, were up-regulated in high-glycolysis group as well. Conclusion: We speculated that in BLCA, elevated glycolysis enhanced immune function, which caused tumor cells to overexpress immune checkpoints to evade immune surveillance. Inhibition of glycolysis might be a promising assistant for immunotherapy in bladder cancer.