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Sample records for glycolysis pentose cycle

  1. Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors.

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    Marin-Valencia, Isaac; Cho, Steve K; Rakheja, Dinesh; Hatanpaa, Kimmo J; Kapur, Payal; Mashimo, Tomoyuki; Jindal, Ashish; Vemireddy, Vamsidhara; Good, Levi B; Raisanen, Jack; Sun, Xiankai; Mickey, Bruce; Choi, Changho; Takahashi, Masaya; Togao, Osamu; Pascual, Juan M; Deberardinis, Ralph J; Maher, Elizabeth A; Malloy, Craig R; Bachoo, Robert M

    2012-10-01

    It has been hypothesized that increased flux through the pentose phosphate pathway (PPP) is required to support the metabolic demands of rapid malignant cell growth. Using orthotopic mouse models of human glioblastoma (GBM) and renal cell carcinoma metastatic to brain, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-(13) C(2) ]glucose. The [3-(13) C]lactate/[2,3-(13) C(2) ]lactate ratio was similar for both the GBM and brain metastasis and their respective surrounding brains (GBM, 0.197 ± 0.011 and 0.195 ± 0.033, respectively (p = 1); metastasis: 0.126 and 0.119 ± 0.033, respectively). This suggests that the rate of glycolysis is significantly greater than the PPP flux in these tumors, and that the PPP flux into the lactate pool is similar in both tumors. Remarkably, (13) C-(13) C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrast with GBM, (13) C multiplets of γ-aminobutyric acid (GABA) differed from its precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. In addition, the orthotopic renal tumor, the patient's primary renal mass and brain metastasis were all strongly immunopositive for the 67-kDa isoform of glutamate decarboxylase, as were 84% of tumors on a renal cell carcinoma tissue microarray of the same histology, suggesting that GABA synthesis is cell autonomous in at least a subset of renal cell carcinomas. Taken together, these data demonstrate that (13) C-labeled glucose can be used in orthotopic mouse models to study tumor metabolism in vivo and to ascertain new metabolic targets for cancer diagnosis and therapy. Copyright © 2012 John Wiley & Sons, Ltd.

  2. Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer

    Directory of Open Access Journals (Sweden)

    Ling Li

    2015-04-01

    Full Text Available Inhibition of glycolysis using 2-deoxy-d-glucose (2DG, 20 mM, 24–48 h combined with inhibition of the pentose cycle using dehydroepiandrosterone (DHEA, 300 µM, 24–48 h increased clonogenic cell killing in both human prostate (PC-3 and DU145 and human breast (MDA-MB231 cancer cells via a mechanism involving thiol-mediated oxidative stress. Surprisingly, when 2DG+DHEA treatment was combined with an inhibitor of glutathione (GSH synthesis (l-buthionine sulfoximine; BSO, 1 mM that depleted GSH>90% of control, no further increase in cell killing was observed during 48 h exposures. In contrast, when an inhibitor of thioredoxin reductase (TrxR activity (Auranofin; Au, 1 µM, was combined with 2DG+DHEA or DHEA-alone for 24 h, clonogenic cell killing was significantly increased in all three human cancer cell lines. Furthermore, enhanced clonogenic cell killing seen with the combination of DHEA+Au was nearly completely inhibited using the thiol antioxidant, N-acetylcysteine (NAC, 20 mM. Redox Western blot analysis of PC-3 cells also supported the conclusion that thioredoxin-1 (Trx-1 oxidation was enhanced by treatment DHEA+Au and inhibited by NAC. Importantly, normal human mammary epithelial cells (HMEC were not as sensitive to 2DG, DHEA, and Au combinations as their cancer cell counterparts (MDA-MB-231. Overall, these results support the hypothesis that inhibition of glycolysis and pentose cycle activity, combined with inhibition of Trx metabolism, may provide a promising strategy for selectively sensitizing human cancer cells to oxidative stress-induced cell killing.

  3. Increased metabolite levels of glycolysis and pentose phosphate pathway in rabbit atherosclerotic arteries and hypoxic macrophage.

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    Atsushi Yamashita

    Full Text Available AIMS: Inflammation and possibly hypoxia largely affect glucose utilization in atherosclerotic arteries, which could alter many metabolic systems. However, metabolic changes in atherosclerotic plaques remain unknown. The present study aims to identify changes in metabolic systems relative to glucose uptake and hypoxia in rabbit atherosclerotic arteries and cultured macrophages. METHODS: Macrophage-rich or smooth muscle cell (SMC-rich neointima was created by balloon injury in the iliac-femoral arteries of rabbits fed with a 0.5% cholesterol diet or a conventional diet. THP-1 macrophages stimulated with lipopolysaccharides (LPS and interferon-γ (INFγ were cultured under normoxic and hypoxic conditions. We evaluated comprehensive arterial and macrophage metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using (18F-fluorodeoxyglucose ((18F-FDG and pimonidazole, a marker of hypoxia. RESULTS: The levels of many metabolites increased in the iliac-femoral arteries with macrophage-rich neointima, compared with those that were not injured and those with SMC-rich neointima (glycolysis, 4 of 9; pentose phosphate pathway, 4 of 6; tricarboxylic acid cycle, 4 of 6; nucleotides, 10 of 20. The uptake of (18F-FDG in arterial walls measured by autoradiography positively correlated with macrophage- and pimonidazole-immunopositive areas (r = 0.76, and r = 0.59 respectively; n = 69 for both; p<0.0001. Pimonidazole immunoreactivity was closely localized with the nuclear translocation of hypoxia inducible factor-1α and hexokinase II expression in macrophage-rich neointima. The levels of glycolytic (8 of 8 and pentose phosphate pathway (4 of 6 metabolites increased in LPS and INFγ stimulated macrophages under hypoxic but not normoxic condition. Plasminogen activator inhibitor-1 protein levels in the supernatant were closely

  4. Blocking hexose entry into glycolysis activates alternative metabolic conversion of these sugars and upregulates pentose metabolism in Aspergillus nidulans

    Energy Technology Data Exchange (ETDEWEB)

    Khosravi, Claire; Battaglia, Evy; Kun, Roland S.; Dalhuijsen, Sacha; Visser, Jaap; Aguilar-Pontes, Maria V.; Zhou, Miamiao; Heyman, Heino M.; Kim, Young-Mo; Baker, Scott E.; de Vries, Ronald P.

    2018-03-22

    Background: Plant biomass is the most abundant carbon source for many fungal species. In the biobased industry fungi are used to produce lignocellulolytic enzymes to degrade agricultural waste biomass. Here we evaluated if it would be possible to create an Aspergillus nidulans strain that releases but does not metabolize hexoses from plant biomass. For this purpose, metabolic mutants were generated that were impaired in glycolysis, by using hexokinase (hxkA) and glucokinase (glkA) negative strains. To prevent repression of enzyme production due to the hexose accumulation, strains were generated that combined these mutations with a deletion in creA, the repressor involved in regulating preferential use of different carbon catabolic pathways. Results: Phenotypic analysis revealed reduced growth for the hxkA1 glkA4 mutant on wheat bran. However, hexoses did not accumulate during growth of the mutants on wheat bran, suggesting that glucose metabolism is re-routed towards alternative carbon catabolic pathways. The creAΔ4 mutation in combination with preventing initial phosphorylation in glycolysis resulted in better growth than the hxkA/glkA mutant and an increased expression of pentose catabolic and pentose phosphate pathway genes. This indicates that the reduced ability to use hexoses as carbon sources created a shift towards the pentose fraction of wheat bran as a major carbon source to support growth. Conclusion: Blocking the direct entry of hexoses to glycolysis activates alternative metabolic conversion of these sugars in A. nidulans during growth on plant biomass, but also upregulates conversion of other sugars, such as pentoses.

  5. Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-13C2 glucose

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    Jalloh, Ibrahim; Carpenter, Keri L H; Grice, Peter; Howe, Duncan J; Mason, Andrew; Gallagher, Clare N; Helmy, Adel; Murphy, Michael P; Menon, David K; Carpenter, T Adrian; Pickard, John D; Hutchinson, Peter J

    2015-01-01

    Increased ‘anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-13C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. 13C enrichment for glycolytic 2,3-13C2 lactate was the median 5.4% (interquartile range (IQR) 4.6–7.5%) in TBI brain and 4.2% (2.4–4.4%) in ‘normal' brain (Pbrain and 6.7% (6.3–8.9%) in ‘normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=−0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than ‘normal' brain. Several TBI patients exhibited PPP–lactate elevation above the ‘normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain. PMID:25335801

  6. The Variations of Glycolysis and TCA Cycle Intermediate Levels Grown in Iron and Copper Mediums of Trichoderma harzianum.

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    Tavsan, Zehra; Ayar Kayali, Hulya

    2015-05-01

    The efficiency of optimal metabolic function by microorganism depends on various parameters, especially essential metal supplementation. In the present study, the effects of iron and copper metals on metabolism were investigated by determination of glycolysis and tricarboxylic acid (TCA) cycle metabolites' levels with respect to the metal concentrations and incubation period in Trichoderma harzianum. The pyruvate and citrate levels of T. harzianum increased up to 15 mg/L of copper via redirection of carbon flux though glycolysis by suppression of pentose phosphate pathway (PPP). However, the α-ketoglutarate levels decreased at concentration higher than 5 mg/L of copper to overcome damage of oxidative stress. The fumarate levels correlated with the α-ketoglutarate levels because of substrate limitation. Besides, in T. harzianum cells grown in various concentrations of iron-containing medium, the intracellular pyruvate, citrate, and α-ketoglutarate levels showed positive correlation with iron concentration due to modifying of expression of glycolysis and TCA cycle enzymes via a mechanism involving cofactor or allosteric regulation. However, as a result of consuming of prior substrates required for fumarate production, its levels rose up to 10 mg/L.

  7. HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer.

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    Mondal, Susmita; Roy, Debarshi; Camacho-Pereira, Juliana; Khurana, Ashwani; Chini, Eduardo; Yang, Lifeng; Baddour, Joelle; Stilles, Katherine; Padmabandu, Seth; Leung, Sam; Kalloger, Steve; Gilks, Blake; Lowe, Val; Dierks, Thomas; Hammond, Edward; Dredge, Keith; Nagrath, Deepak; Shridhar, Viji

    2015-10-20

    Warburg effect has emerged as a potential hallmark of many cancers. However, the molecular mechanisms that led to this metabolic state of aerobic glycolysis, particularly in ovarian cancer (OVCA) have not been completely elucidated. HSulf-1 predominantly functions by limiting the bioavailability of heparan binding growth factors and hence their downstream signaling. Here we report that HSulf-1, a known putative tumor suppressor, is a negative regulator of glycolysis. Silencing of HSulf-1 expression in OV202 cell line increased glucose uptake and lactate production by upregulating glycolytic genes such as Glut1, HKII, LDHA, as well as metabolites. Conversely, HSulf-1 overexpression in TOV21G cells resulted in the down regulation of glycolytic enzymes and reduced glycolytic phenotype, supporting the role of HSulf-1 loss in enhanced aerobic glycolysis. HSulf-1 deficiency mediated glycolytic enhancement also resulted in increased inhibitory phosphorylation of pyruvate dehydrogenase (PDH) thus blocking the entry of glucose flux into TCA cycle. Consistent with this, metabolomic and isotope tracer analysis showed reduced glucose flux into TCA cycle. Moreover, HSulf-1 loss is associated with lower oxygen consumption rate (OCR) and impaired mitochondrial function. Mechanistically, lack of HSulf-1 promotes c-Myc induction through HB-EGF-mediated p-ERK activation. Pharmacological inhibition of c-Myc reduced HB-EGF induced glycolytic enzymes implicating a major role of c-Myc in loss of HSulf-1 mediated altered glycolytic pathway in OVCA. Similarly, PG545 treatment, an agent that binds to heparan binding growth factors and sequesters growth factors away from their ligand also blocked HB-EGF signaling and reduced glucose uptake in vivo in HSulf-1 deficient cells.

  8. Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation.

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    Jackson, Laura E; Kulkarni, Sucheta; Wang, Huabo; Lu, Jie; Dolezal, James M; Bharathi, Sivakama S; Ranganathan, Sarangarajan; Patel, Mulchand S; Deshpande, Rahul; Alencastro, Frances; Wendell, Stacy G; Goetzman, Eric S; Duncan, Andrew W; Prochownik, Edward V

    2017-11-01

    Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic, and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC "knockout" (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas was only modestly slowed in the face of 80%-90% reductions in AcCoA and significant alterations in the levels of key tricarboxylic acid (TCA) cycle intermediates and amino acids. Overall, oxphos activity in KO livers and hepatoblastoma was comparable with that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances. Cancer Res; 77(21); 5795-807. ©2017 AACR . ©2017 American Association for Cancer Research.

  9. Quantitative importance of the pentose phosphate pathway determined by incorporation of 13C from [2-13C]- and [3-13C]glucose into TCA cycle intermediates and neurotransmitter amino acids in functionally intact neurons.

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    Brekke, Eva M F; Walls, Anne B; Schousboe, Arne; Waagepetersen, Helle S; Sonnewald, Ursula

    2012-09-01

    The brain is highly susceptible to oxidative injury, and the pentose phosphate pathway (PPP) has been shown to be affected by pathological conditions, such as Alzheimer's disease and traumatic brain injury. While this pathway has been investigated in the intact brain and in astrocytes, little is known about the PPP in neurons. The activity of the PPP was quantified in cultured cerebral cortical and cerebellar neurons after incubation in the presence of [2-(13)C]glucose or [3-(13)C]glucose. The activity of the PPP was several fold lower than glycolysis in both types of neurons. While metabolism of (13)C-labeled glucose via the PPP does not appear to contribute to the production of releasable lactate, it contributes to labeling of tricarboxylic acid (TCA) cycle intermediates and related amino acids. Based on glutamate isotopomers, it was calculated that PPP activity accounts for ~6% of glucose metabolism in cortical neurons and ~4% in cerebellar neurons. This is the first demonstration that pyruvate generated from glucose via the PPP contributes to the synthesis of acetyl CoA for oxidation in the TCA cycle. Moreover, the fact that (13)C labeling from glucose is incorporated into glutamate proves that both the oxidative and the nonoxidative stages of the PPP are active in neurons.

  10. The cellular and compartmental profile of mouse retinal glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and ~P transferring kinases.

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    Rueda, Elda M; Johnson, Jerry E; Giddabasappa, Anand; Swaroop, Anand; Brooks, Matthew J; Sigel, Irena; Chaney, Shawnta Y; Fox, Donald A

    2016-01-01

    The homeostatic regulation of cellular ATP is achieved by the coordinated activity of ATP utilization, synthesis, and buffering. Glucose is the major substrate for ATP synthesis through glycolysis and oxidative phosphorylation (OXPHOS), whereas intermediary metabolism through the tricarboxylic acid (TCA) cycle utilizes non-glucose-derived monocarboxylates, amino acids, and alpha ketoacids to support mitochondrial ATP and GTP synthesis. Cellular ATP is buffered by specialized equilibrium-driven high-energy phosphate (~P) transferring kinases. Our goals were twofold: 1) to characterize the gene expression, protein expression, and activity of key synthesizing and regulating enzymes of energy metabolism in the whole mouse retina, retinal compartments, and/or cells and 2) to provide an integrative analysis of the results related to function. mRNA expression data of energy-related genes were extracted from our whole retinal Affymetrix microarray data. Fixed-frozen retinas from adult C57BL/6N mice were used for immunohistochemistry, laser scanning confocal microscopy, and enzymatic histochemistry. The immunoreactivity levels of well-characterized antibodies, for all major retinal cells and their compartments, were obtained using our established semiquantitative confocal and imaging techniques. Quantitative cytochrome oxidase (COX) and lactate dehydrogenase (LDH) activity was determined histochemically. The Affymetrix data revealed varied gene expression patterns of the ATP synthesizing and regulating enzymes found in the muscle, liver, and brain. Confocal studies showed differential cellular and compartmental distribution of isozymes involved in glucose, glutamate, glutamine, lactate, and creatine metabolism. The pattern and intensity of the antibodies and of the COX and LDH activity showed the high capacity of photoreceptors for aerobic glycolysis and OXPHOS. Competition assays with pyruvate revealed that LDH-5 was localized in the photoreceptor inner segments. The

  11. Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages

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    Sue-jie Koo

    2018-02-01

    Full Text Available Metabolism provides substrates for reactive oxygen species (ROS and nitric oxide (NO generation, which are a part of the macrophage (Mφ anti-microbial response. Mφs infected with Trypanosoma cruzi (Tc produce insufficient levels of oxidative species and lower levels of glycolysis compared to classical Mφs. How Mφs fail to elicit a potent ROS/NO response during infection and its link to glycolysis is unknown. Herein, we evaluated for ROS, NO, and cytokine production in the presence of metabolic modulators of glycolysis and the Krebs cycle. Metabolic status was analyzed by Seahorse Flux Analyzer and mass spectrometry and validated by RNAi. Tc infection of RAW264.7 or bone marrow-derived Mφs elicited a substantial increase in peroxisome proliferator-activated receptor (PPAR-α expression and pro-inflammatory cytokine release, and moderate levels of ROS/NO by 18 h. Interferon (IFN-γ addition enhanced the Tc-induced ROS/NO release and shut down mitochondrial respiration to the levels noted in classical Mφs. Inhibition of PPAR-α attenuated the ROS/NO response and was insufficient for complete metabolic shift. Deprivation of glucose and inhibition of pyruvate transport showed that Krebs cycle and glycolysis support ROS/NO generation in Tc + IFN-γ stimulated Mφs. Metabolic profiling and RNAi studies showed that glycolysis-pentose phosphate pathway (PPP at 6-phosphogluconate dehydrogenase was essential for ROS/NO response and control of parasite replication in Mφ. We conclude that IFN-γ, but not inhibition of PPAR-α, supports metabolic upregulation of glycolytic-PPP for eliciting potent ROS/NO response in Tc-infected Mφs. Chemical analogs enhancing the glucose-PPP will be beneficial in controlling Tc replication and dissemination by Mφs.

  12. Silencing of the pentose phosphate pathway genes influences DNA replication in human fibroblasts.

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    Fornalewicz, Karolina; Wieczorek, Aneta; Węgrzyn, Grzegorz; Łyżeń, Robert

    2017-11-30

    Previous reports and our recently published data indicated that some enzymes of glycolysis and the tricarboxylic acid cycle can affect the genome replication process by changing either the efficiency or timing of DNA synthesis in human normal cells. Both these pathways are connected with the pentose phosphate pathway (PPP pathway). The PPP pathway supports cell growth by generating energy and precursors for nucleotides and amino acids. Therefore, we asked if silencing of genes coding for enzymes involved in the pentose phosphate pathway may also affect the control of DNA replication in human fibroblasts. Particular genes coding for PPP pathway enzymes were partially silenced with specific siRNAs. Such cells remained viable. We found that silencing of the H6PD, PRPS1, RPE genes caused less efficient enterance to the S phase and decrease in efficiency of DNA synthesis. On the other hand, in cells treated with siRNA against G6PD, RBKS and TALDO genes, the fraction of cells entering the S phase was increased. However, only in the case of G6PD and TALDO, the ratio of BrdU incorporation to DNA was significantly changed. The presented results together with our previously published studies illustrate the complexity of the influence of genes coding for central carbon metabolism on the control of DNA replication in human fibroblasts, and indicate which of them are especially important in this process. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. (13)C metabolic flux analysis in neurons utilizing a model that accounts for hexose phosphate recycling within the pentose phosphate pathway.

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    Gebril, Hoda M; Avula, Bharathi; Wang, Yan-Hong; Khan, Ikhlas A; Jekabsons, Mika B

    2016-02-01

    Glycolysis, mitochondrial substrate oxidation, and the pentose phosphate pathway (PPP) are critical for neuronal bioenergetics and oxidation-reduction homeostasis, but quantitating their fluxes remains challenging, especially when processes such as hexose phosphate (i.e., glucose/fructose-6-phosphate) recycling in the PPP are considered. A hexose phosphate recycling model was developed which exploited the rates of glucose consumption, lactate production, and mitochondrial respiration to infer fluxes through the major glucose consuming pathways of adherent cerebellar granule neurons by replicating [(13)C]lactate labeling from metabolism of [1,2-(13)C2]glucose. Flux calculations were predicated on a steady-state system with reactions having known stoichiometries and carbon atom transitions. Non-oxidative PPP activity and consequent hexose phosphate recycling, as well as pyruvate production by cytoplasmic malic enzyme, were optimized by the model and found to account for 28 ± 2% and 7.7 ± 0.2% of hexose phosphate and pyruvate labeling, respectively. From the resulting fluxes, 52 ± 6% of glucose was metabolized by glycolysis, compared to 19 ± 2% by the combined oxidative/non-oxidative pentose cycle that allows for hexose phosphate recycling, and 29 ± 8% by the combined oxidative PPP/de novo nucleotide synthesis reactions. By extension, 62 ± 6% of glucose was converted to pyruvate, the metabolism of which resulted in 16 ± 1% of glucose oxidized by mitochondria and 46 ± 6% exported as lactate. The results indicate a surprisingly high proportion of glucose utilized by the pentose cycle and the reactions synthesizing nucleotides, and exported as lactate. While the in vitro conditions to which the neurons were exposed (high glucose, no lactate or other exogenous substrates) limit extrapolating these results to the in vivo state, the approach provides a means of assessing a number of metabolic fluxes within the context of hexose phosphate recycling in the PPP from a

  14. Pentose pathway in human liver

    International Nuclear Information System (INIS)

    Magnusson, I.; Chandramouli, V.; Schumann, W.C.; Kumaran, K.; Wahren, J.; Landau, B.R.

    1988-01-01

    [1- 14 C]Ribose and [1- 14 C]glucose were given to normal subjects along with glucose loads (1 g per kg of body weight) after administration of diflunisal and acetaminophen, drugs that are excreted in urine as glucuronides. Distributions of 14 C were determined in the carbons of the excreted glucoronides and in the glucose from blood samples drawn from hepatic veins before and after glucagon administration. Eighty percent or more of the 14 C from [1- 14 C]ribose incorporated into the glucuronic acid moiety of the glucuronides was in carbons 1 and 3, with less than 8% in carbon 2. In glucuronic acid from glucuronide excreted when [2- 14 C]glucose was given, 3.5-8.1% of the 14 C was in carbon 1, 2.5-4.3% in carbon 3, and more than 70% in carbon 2. These distributions are in accord with the glucuronides sampling the glucose unit of the glucose 6-phosphate pool that is a component of the pentose pathway and is intermediate in glycogen formation. It is concluded that the glucuronic acid conjugates of the drugs can serve as a noninvasive means of sampling hepatic glucose 6-phosphate. In human liver, as in animal liver, the classical pentose pathway functions, not the L-type pathway, and only a small percentage of the glucose is metabolized via the pathway

  15. Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain.

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    Morken, Tora Sund; Brekke, Eva; Håberg, Asta; Widerøe, Marius; Brubakk, Ann-Mari; Sonnewald, Ursula

    2014-01-01

    Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-(13)C]glucose and were sacrificed 30 min later. Brain extracts were analysed using (1)H- and (13)C-NMR spectroscopy. Numerous differences in metabolism were found between the neonatal and adult brain. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine per mg tissue. Metabolism of [1-(13)C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-(13)C]acetate. The transfer of glutamate from neurons to astrocytes was much lower while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-(13)C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes. Moreover, the ratio of PPP/glucose-metabolism was higher. These findings indicate that only the part of the glutamate-glutamine cycle that transfers glutamine from astrocytes to neurons is operating in the neonatal brain and that compared to adults, relatively more glucose is prioritised to PPP and pyruvate carboxylation. Our results may have implications for the capacity to protect the neonatal brain against excitotoxicity and oxidative stress.

  16. Quantitative importance of the pentose phosphate pathway determined by incorporation of 13C from [2-13C]- and [3-13C]glucose into TCA cycle intermediates and neurotransmitter amino acids in functionally intact neurons

    DEFF Research Database (Denmark)

    Brekke, Eva Marie; Walls, Anne Byriel; Schousboe, Arne

    2012-01-01

    is known about the PPP in neurons. The activity of the PPP was quantified in cultured cerebral cortical and cerebellar neurons after incubation in the presence of [2-(13)C]glucose or [3-(13)C]glucose. The activity of the PPP was several fold lower than glycolysis in both types of neurons. While metabolism...

  17. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway

    Science.gov (United States)

    Stincone, Anna; Prigione, Alessandro; Cramer, Thorsten; Wamelink, Mirjam M. C.; Campbell, Kate; Cheung, Eric; Olin-Sandoval, Viridiana; Grüning, Nana-Maria; Krüger, Antje; Alam, Mohammad Tauqeer; Keller, Markus A.; Breitenbach, Michael; Brindle, Kevin M.; Rabinowitz, Joshua D.; Ralser, Markus

    2015-01-01

    The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares reactions with the Entner–Doudoroff pathway and Calvin cycle and divides into an oxidative and non-oxidative branch. The oxidative branch is highly active in most eukaryotes and converts glucose 6-phosphate into carbon dioxide, ribulose 5-phosphate and NADPH. The latter function is critical to maintain redox balance under stress situations, when cells proliferate rapidly, in ageing, and for the ‘Warburg effect’ of cancer cells. The non-oxidative branch instead is virtually ubiquitous, and metabolizes the glycolytic intermediates fructose 6-phosphate and glyceraldehyde 3-phosphate as well as sedoheptulose sugars, yielding ribose 5-phosphate for the synthesis of nucleic acids and sugar phosphate precursors for the synthesis of amino acids. Whereas the oxidative PPP is considered unidirectional, the non-oxidative branch can supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand. These functions require dynamic regulation of the PPP pathway that is achieved through hierarchical interactions between transcriptome, proteome and metabolome. Consequently, the biochemistry and regulation of this pathway, while still unresolved in many cases, are archetypal for the dynamics of the metabolic network of the cell. In this comprehensive article we review seminal work that led to the discovery and description of the pathway that date back now for 80 years, and address recent results about genetic and metabolic mechanisms that regulate its activity. These biochemical principles are discussed in the context of PPP deficiencies causing metabolic disease and the role of this pathway in biotechnology, bacterial and

  18. Pentose phosphates in nucleoside interconversion and catabolism.

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    Tozzi, Maria G; Camici, Marcella; Mascia, Laura; Sgarrella, Francesco; Ipata, Piero L

    2006-03-01

    Ribose phosphates are either synthesized through the oxidative branch of the pentose phosphate pathway, or are supplied by nucleoside phosphorylases. The two main pentose phosphates, ribose-5-phosphate and ribose-1-phosphate, are readily interconverted by the action of phosphopentomutase. Ribose-5-phosphate is the direct precursor of 5-phosphoribosyl-1-pyrophosphate, for both de novo and 'salvage' synthesis of nucleotides. Phosphorolysis of deoxyribonucleosides is the main source of deoxyribose phosphates, which are interconvertible, through the action of phosphopentomutase. The pentose moiety of all nucleosides can serve as a carbon and energy source. During the past decade, extensive advances have been made in elucidating the pathways by which the pentose phosphates, arising from nucleoside phosphorolysis, are either recycled, without opening of their furanosidic ring, or catabolized as a carbon and energy source. We review herein the experimental knowledge on the molecular mechanisms by which (a) ribose-1-phosphate, produced by purine nucleoside phosphorylase acting catabolically, is either anabolized for pyrimidine salvage and 5-fluorouracil activation, with uridine phosphorylase acting anabolically, or recycled for nucleoside and base interconversion; (b) the nucleosides can be regarded, both in bacteria and in eukaryotic cells, as carriers of sugars, that are made available though the action of nucleoside phosphorylases. In bacteria, catabolism of nucleosides, when suitable carbon and energy sources are not available, is accomplished by a battery of nucleoside transporters and of inducible catabolic enzymes for purine and pyrimidine nucleosides and for pentose phosphates. In eukaryotic cells, the modulation of pentose phosphate production by nucleoside catabolism seems to be affected by developmental and physiological factors on enzyme levels.

  19. The Genetic Requirements for Pentose Fermentation in Budding Yeast

    Directory of Open Access Journals (Sweden)

    Karin Mittelman

    2017-06-01

    Full Text Available Cells grow on a wide range of carbon sources by regulating substrate flow through the metabolic network. Incoming sugar, for example, can be fermented or respired, depending on the carbon identity, cell type, or growth conditions. Despite this genetically-encoded flexibility of carbon metabolism, attempts to exogenously manipulate central carbon flux by rational design have proven difficult, suggesting a robust network structure. To examine this robustness, we characterized the ethanol yield of 411 regulatory and metabolic mutants in budding yeast. The mutants showed little variation in ethanol productivity when grown on glucose or galactose, yet diversity was revealed during growth on xylulose, a rare pentose not widely available in nature. While producing ethanol at high yield, cells grown on xylulose produced ethanol at high yields, yet induced expression of respiratory genes, and were dependent on them. Analysis of mutants that affected ethanol productivity suggested that xylulose fermentation results from metabolic overflow, whereby the flux through glycolysis is higher than the maximal flux that can enter respiration. We suggest that this overflow results from a suboptimal regulatory adjustment of the cells to this unfamiliar carbon source.

  20. Data mining of the transcriptome of Plasmodium falciparum: the pentose phosphate pathway and ancillary processes

    Directory of Open Access Journals (Sweden)

    Ginsburg Hagai

    2005-03-01

    Full Text Available Abstract The general paradigm that emerges from the analysis of the transcriptome of the malaria parasite Plasmodium falciparum is that the expression clusters of genes that code for enzymes engaged in the same cellular function is coordinated. Here the consistency of this perception is examined by analysing specific pathways that metabolically-linked. The pentose phosphate pathway (PPP is a fundamental element of cell biochemistry since it is the major pathway for the recycling of NADP+ to NADPH and for the production of ribose-5-phosphate that is needed for the synthesis of nucleotides. The function of PPP depends on the synthesis of NADP+ and thiamine pyrophosphate, a co-enzyme of the PPP enzyme transketolase. In this essay, the transcription of gene coding for enzymes involved in the PPP, thiamine and NAD(P+ syntheses are analysed. The genes coding for two essential enzymes in these pathways, transaldolase and NAD+ kinase could not be found in the genome of P. falciparum. It is found that the transcription of the genes of each pathway is not always coordinated and there is usually a gene whose transcription sets the latest time for the full deployment of the pathway's activity. The activity of PPP seems to involve only the oxidative arm of PPP that is geared for maximal NADP+ reduction and ribose-5-phosphate production during the early stages of parasite development. The synthesis of thiamine diphosphate is predicted to occur much later than the expression of transketolase. Later in the parasite cycle, the non-oxidative arm of PPP that can use fructose-6-phosphate and glyceraldehyde-3-phosphate supplied by glycolysis, becomes fully deployed allowing to maximize the production of ribose-5-phosphate. These discrepancies require direct biochemical investigations to test the activities of the various enzymes in the developing parasite. Notably, several transcripts of PPP enzyme-coding genes display biphasic pattern of transcription unlike most

  1. Aqueous Extract of Black Maca Prevents Metabolism Disorder via Regulating the Glycolysis/Gluconeogenesis-TCA Cycle and PPARα Signaling Activation in Golden Hamsters Fed a High-Fat, High-Fructose Diet.

    Science.gov (United States)

    Wan, Wenting; Li, Hongxiang; Xiang, Jiamei; Yi, Fan; Xu, Lijia; Jiang, Baoping; Xiao, Peigen

    2018-01-01

    Maca ( Lepidium meyenii Walpers) has been used as a dietary supplement and ethnomedicine for centuries. Recently, maca has become a high profile functional food worldwide because of its multiple biological activities. This study is the first explorative research to investigate the prevention and amelioration capacity of the aqueous extract of black maca (AEM) on high-fat, high-fructose diet (HFD)-induced metabolism disorder in golden hamsters and to identify the potential mechanisms involved in these effects. For 20 weeks, 6-week-old male golden hamsters were fed the following respective diets: (1) a standard diet, (2) HFD, (3) HFD supplemented with metformin, or (4) HFD supplemented with three doses of AEM (300, 600, or 1,200 mg/kg). After 20 weeks, the golden hamsters that received daily AEM supplementation presented with the beneficial effects of improved hyperlipidemia, hyperinsulinemia, insulin resistance, and hepatic steatosis in vivo . Based on the hepatic metabolomic analysis results, alterations in metabolites associated with pathological changes were examined. A total of 194 identified metabolites were mapped to 46 relative metabolic pathways, including those of energy metabolism. In addition, via in silico profiling for secondary maca metabolites by a joint pharmacophore- and structure-based approach, a compound-target-disease network was established. The results revealed that 32 bioactive compounds in maca targeted 16 proteins involved in metabolism disorder. Considering the combined metabolomics and virtual screening results, we employed quantitative real-time PCR assays to verify the gene expression of key enzymes in the relevant pathways. AEM promoted glycolysis and inhibited gluconeogenesis via regulating the expression of key genes such as Gck and Pfkm . Moreover, AEM upregulated tricarboxylic acid (TCA) cycle flux by changing the concentrations of intermediates and increasing the mRNA levels of Aco2 , Fh , and Mdh2 . In addition, the lipid

  2. Aqueous Extract of Black Maca Prevents Metabolism Disorder via Regulating the Glycolysis/Gluconeogenesis-TCA Cycle and PPARα Signaling Activation in Golden Hamsters Fed a High-Fat, High-Fructose Diet

    Directory of Open Access Journals (Sweden)

    Wenting Wan

    2018-04-01

    Full Text Available Maca (Lepidium meyenii Walpers has been used as a dietary supplement and ethnomedicine for centuries. Recently, maca has become a high profile functional food worldwide because of its multiple biological activities. This study is the first explorative research to investigate the prevention and amelioration capacity of the aqueous extract of black maca (AEM on high-fat, high-fructose diet (HFD-induced metabolism disorder in golden hamsters and to identify the potential mechanisms involved in these effects. For 20 weeks, 6-week-old male golden hamsters were fed the following respective diets: (1 a standard diet, (2 HFD, (3 HFD supplemented with metformin, or (4 HFD supplemented with three doses of AEM (300, 600, or 1,200 mg/kg. After 20 weeks, the golden hamsters that received daily AEM supplementation presented with the beneficial effects of improved hyperlipidemia, hyperinsulinemia, insulin resistance, and hepatic steatosis in vivo. Based on the hepatic metabolomic analysis results, alterations in metabolites associated with pathological changes were examined. A total of 194 identified metabolites were mapped to 46 relative metabolic pathways, including those of energy metabolism. In addition, via in silico profiling for secondary maca metabolites by a joint pharmacophore- and structure-based approach, a compound-target-disease network was established. The results revealed that 32 bioactive compounds in maca targeted 16 proteins involved in metabolism disorder. Considering the combined metabolomics and virtual screening results, we employed quantitative real-time PCR assays to verify the gene expression of key enzymes in the relevant pathways. AEM promoted glycolysis and inhibited gluconeogenesis via regulating the expression of key genes such as Gck and Pfkm. Moreover, AEM upregulated tricarboxylic acid (TCA cycle flux by changing the concentrations of intermediates and increasing the mRNA levels of Aco2, Fh, and Mdh2. In addition, the lipid

  3. Mangiferin Accelerates Glycolysis and Enhances Mitochondrial Bioenergetics

    Directory of Open Access Journals (Sweden)

    Zhongbo Liu

    2018-01-01

    Full Text Available One of the main causes of hyperglycemia is inefficient or impaired glucose utilization by skeletal muscle, which can be exacerbated by chronic high caloric intake. Previously, we identified a natural compound, mangiferin (MGF that improved glucose utilization in high fat diet (HFD-induced insulin resistant mice. To further identify the molecular mechanisms of MGF action on glucose metabolism, we conducted targeted metabolomics and transcriptomics studies of glycolyic and mitochondrial bioenergetics pathways in skeletal muscle. These data revealed that MGF increased glycolytic metabolites that were further augmented as glycolysis proceeded from the early to the late steps. Consistent with an MGF-stimulation of glycolytic flux there was a concomitant increase in the expression of enzymes catalyzing glycolysis. MGF also increased important metabolites in the tricarboxylic acid (TCA cycle, such as α-ketoglutarate and fumarate. Interestingly however, there was a reduction in succinate, a metabolite that also feeds into the electron transport chain to produce energy. MGF increased succinate clearance by enhancing the expression and activity of succinate dehydrogenase, leading to increased ATP production. At the transcriptional level, MGF induced mRNAs of mitochondrial genes and their transcriptional factors. Together, these data suggest that MGF upregulates mitochondrial oxidative capacity that likely drives the acceleration of glycolysis flux.

  4. Glycolysis is governed by growth regime and simple enzyme regulation in adherent MDCK cells.

    Science.gov (United States)

    Rehberg, Markus; Ritter, Joachim B; Reichl, Udo

    2014-10-01

    Due to its vital importance in the supply of cellular pathways with energy and precursors, glycolysis has been studied for several decades regarding its capacity and regulation. For a systems-level understanding of the Madin-Darby canine kidney (MDCK) cell metabolism, we couple a segregated cell growth model published earlier with a structured model of glycolysis, which is based on relatively simple kinetics for enzymatic reactions of glycolysis, to explain the pathway dynamics under various cultivation conditions. The structured model takes into account in vitro enzyme activities, and links glycolysis with pentose phosphate pathway and glycogenesis. Using a single parameterization, metabolite pool dynamics during cell cultivation, glucose limitation and glucose pulse experiments can be consistently reproduced by considering the cultivation history of the cells. Growth phase-dependent glucose uptake together with cell-specific volume changes generate high intracellular metabolite pools and flux rates to satisfy the cellular demand during growth. Under glucose limitation, the coordinated control of glycolytic enzymes re-adjusts the glycolytic flux to prevent the depletion of glycolytic intermediates. Finally, the model's predictive power supports the design of more efficient bioprocesses.

  5. Pentose utilization in yeasts: Physiology and biochemistry

    Energy Technology Data Exchange (ETDEWEB)

    Jeppson, H.

    1996-04-01

    The fermentive performance of bacteria, yeasts, and filamentous fungi was investigated in a pentose (xylose)-rich lignocellulosic hydrolyzate. The filamentous fungus Fusarium oxysporum and the xylose-fermenting yeast Pichia stipitis were found to be very sensitive to the inhibiting hydrolyzate. Recombinant xylose-utilizing Saccharomyces cerevisiae showed very poor ethanol formation from xylose; xylitol being the major product formed. The highest ethanol yields were obtained with recombinant Escherichia coli KO11, however, for maximal ethanol yield detoxification of the hydrolyzate was required. The influence of oxygen on the regulation of carbohydrate metabolism in the xylose-fermenting yeast P. stipitis CBS 6054 was investigated. A low and well-controlled level of oxygenation has been found to be required for efficient ethanol formation from xylose by the xylose-fermenting yeasts. The requirement of oxygen is frequently ascribed to the apparent redox imbalance which develops under anaerobic conditions due to the difference in co-factor utilization of the two first enzymes in the xylose metabolism, further reflected in xylitol excretion. However, a low and well controlled level of oxygenation for maximal ethanol production from glucose was also demonstrated, suggesting that the oxygen requirement is not only due to the dual co-factor utilization, but also serves other purposes. Cyanide-insensitive and salicyl hydroxamic acid-sensitive respiration (CIR) was found in P. stipitis. CIR is suggested to act as a redox sink preventing xylitol formation in P. stipitis under oxygen-limited xylose fermentations. Xylitol metabolism by P. stipitis CBS 6054 was strictly respiratory and ethanol was not formed under any conditions. The absence of ethanol formation was not due to a lack of fermentative enzymes, since the addition of glucose to xylitol-pregrown cells resulted in ethanol formation. 277 refs, 5 figs, 7 tabs

  6. Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain

    OpenAIRE

    Morken, Tora Sund; Brekke, Eva Mari Førland; Håberg, Asta; Widerøe, Marius; Brubakk, Ann-Mari; Sonnewald, Ursula

    2014-01-01

    Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-(13)C]glucose and [1,2-(13)C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity duri...

  7. Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism.

    Science.gov (United States)

    Dienel, Gerald A; Cruz, Nancy F

    2016-07-01

    Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific β-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas β-receptor blockade 're-balances' the stoichiometry of oxygen-glucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential non-oxidative glucose utilization and glycogen turnover during brain

  8. High concentrations of H2O2 make aerobic glycolysis energetically more favourable than cellular respiration.

    Directory of Open Access Journals (Sweden)

    Hamid R Molavian

    2016-08-01

    Full Text Available Since the original observation of the Warburg Effect in cancer cells, over eight decades ago, the major question of why aerobic glycolysis is favored over oxidative phosphorylation has remained unresolved. An understanding of this phenomenon may well be the key to the development of more effective cancer therapies. In this paper, we use a semi-empirical method to throw light on this puzzle. We show that aerobic glycolysis is in fact energetically more favorable than oxidative phosphorylation for concentrations of peroxide (H2O2 above some critical threshold value. The fundamental reason for this is the activation and high engagement of the pentose phosphate pathway (PPP in response to the production of reactive oxygen species H2O2 by mitochondria and the high concentration of H2O2 (produced by mitochondria and other sources. This makes oxidative phosphorylation an inefficient source of energy since it leads (despite high levels of ATP production to a concomitant high energy consumption in order to respond to the hazardous waste products resulting from cellular processes associated with this metabolic pathway. We also demonstrate that the high concentration of H2O2 results in an increased glucose consumption, and also increases the lactate production in the case of glycolysis.

  9. Metabolic effect of TAp63α : enhanced glycolysis and pentose phosphate pathway, resulting in increased antioxidant defense

    NARCIS (Netherlands)

    D'Alessandro, Angelo; Amelio, Ivano; Berkers, Celia R; Antonov, Alexey; Vousden, Karen H; Melino, Gerry; Zolla, Lello

    2014-01-01

    TAp63α is a member of the p53 family, which plays a central role in epithelial cancers. Recently, a role has emerged for p53 family members in cancer metabolic modulation. In order to assess whether TAp63α plays a role in cancer metabolism, we exploited p53-null osteosarcoma Tet-On Saos-2 cells, in

  10. Discovery of a novel glucose metabolism in cancer: The role of endoplasmic reticulum beyond glycolysis and pentose phosphate shunt

    Science.gov (United States)

    Marini, Cecilia; Ravera, Silvia; Buschiazzo, Ambra; Bianchi, Giovanna; Orengo, Anna Maria; Bruno, Silvia; Bottoni, Gianluca; Emionite, Laura; Pastorino, Fabio; Monteverde, Elena; Garaboldi, Lucia; Martella, Roberto; Salani, Barbara; Maggi, Davide; Ponzoni, Mirco; Fais, Franco; Raffaghello, Lizzia; Sambuceti, Gianmario

    2016-01-01

    Cancer metabolism is characterized by an accelerated glycolytic rate facing reduced activity of oxidative phosphorylation. This “Warburg effect” represents a standard to diagnose and monitor tumor aggressiveness with 18F-fluorodeoxyglucose whose uptake is currently regarded as an accurate index of total glucose consumption. Studying cancer metabolic response to respiratory chain inhibition by metformin, we repeatedly observed a reduction of tracer uptake facing a marked increase in glucose consumption. This puzzling discordance brought us to discover that 18F-fluorodeoxyglucose preferentially accumulates within endoplasmic reticulum by exploiting the catalytic function of hexose-6-phosphate-dehydrogenase. Silencing enzyme expression and activity decreased both tracer uptake and glucose consumption, caused severe energy depletion and decreased NADPH content without altering mitochondrial function. These data document the existence of an unknown glucose metabolism triggered by hexose-6-phosphate-dehydrogenase within endoplasmic reticulum of cancer cells. Besides its basic relevance, this finding can improve clinical cancer diagnosis and might represent potential target for therapy. PMID:27121192

  11. Competition between pentoses and glucose during uptake and catabolism in recombinant Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Subtil Thorsten

    2012-03-01

    Full Text Available Abstract Background In mixed sugar fermentations with recombinant Saccharomyces cerevisiae strains able to ferment D-xylose and L-arabinose the pentose sugars are normally only utilized after depletion of D-glucose. This has been attributed to competitive inhibition of pentose uptake by D-glucose as pentose sugars are taken up into yeast cells by individual members of the yeast hexose transporter family. We wanted to investigate whether D-glucose inhibits pentose utilization only by blocking its uptake or also by interfering with its further metabolism. Results To distinguish between inhibitory effects of D-glucose on pentose uptake and pentose catabolism, maltose was used as an alternative carbon source in maltose-pentose co-consumption experiments. Maltose is taken up by a specific maltose transport system and hydrolyzed only intracellularly into two D-glucose molecules. Pentose consumption decreased by about 20 - 30% during the simultaneous utilization of maltose indicating that hexose catabolism can impede pentose utilization. To test whether intracellular D-glucose might impair pentose utilization, hexo-/glucokinase deletion mutants were constructed. Those mutants are known to accumulate intracellular D-glucose when incubated with maltose. However, pentose utilization was not effected in the presence of maltose. Addition of increasing concentrations of D-glucose to the hexo-/glucokinase mutants finally completely blocked D-xylose as well as L-arabinose consumption, indicating a pronounced inhibitory effect of D-glucose on pentose uptake. Nevertheless, constitutive overexpression of pentose-transporting hexose transporters like Hxt7 and Gal2 could improve pentose consumption in the presence of D-glucose. Conclusion Our results confirm that D-glucose impairs the simultaneous utilization of pentoses mainly due to inhibition of pentose uptake. Whereas intracellular D-glucose does not seem to have an inhibitory effect on pentose utilization

  12. Methylglyoxal, the dark side of glycolysis

    KAUST Repository

    Allaman, Igor; Bé langer, Mireille; Magistretti, Pierre J.

    2015-01-01

    Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity

  13. Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei.

    Directory of Open Access Journals (Sweden)

    Eduard J Kerkhoven

    Full Text Available Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i including additional enzymatic reactions in the glycosome, or (ii adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.

  14. Oscillations in glycolysis in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Kloster, Antonina; Olsen, Lars Folke

    2012-01-01

    also decreases by stimulating the ATPase activity, e.g. by FCCP or Amphotericin B. Thus, ATPase activity strongly affects the glycolytic oscillations. We discuss these data in relation to a simple autocatalytic model of glycolysis which can reproduce the experimental data and explain the role...... of membrane-bound ATPases . In addition we also studied a recent detailed model of glycolysis and found that, although thismodel faithfully reproduces the oscillations of glycolytic intermediates observed experimentally, it is not able to explain the role of ATPase activity on the oscillations....

  15. Process for the production of furfural from pentoses and/or water soluble pentosans

    NARCIS (Netherlands)

    De Jong, W.; Marcotullio, G.

    2012-01-01

    The invention is directed to a process for the production of furfural from pentoses and/or water soluble pentosans, said process comprising converting the said pentoses and/or water soluble pentosans in aqueous solution in a first step to furfural and in a second step feeding the aqueous solution

  16. Towards integrated biorefinery from dried distillers grains: Selective extraction of pentoses using dilute acid hydrolysis

    International Nuclear Information System (INIS)

    Fonseca, Dania A.; Lupitskyy, Robert; Timmons, David; Gupta, Mayank; Satyavolu, Jagannadh

    2014-01-01

    The abundant availability and high level of hemicellulose content make dried distillers grains (DDG) an attractive feedstock for production of pentoses (C5) and conversion of C5 to bioproducts. One target of this work was to produce a C5 extract (hydrolyzate) with high yield and purity with a low concentration of C5 degradation products. A high selectivity towards pentoses was achieved using dilute acid hydrolysis of DDG in a percolation reactor with liquid recirculation. Pretreatment of starting material using screening and ultrasonication resulted in fractional increase of the pentose yield by 42%. A 94% yield of pentoses on the DDG (280.9 g kg −1 ) was obtained. Selective extraction of individual pentoses has been achieved by using a 2-stage hydrolysis process, resulting in arabinose-rich (arabinose 81.5%) and xylose-rich (xylose 85.2%) streams. A broader impact of this work is towards an Integrated Bio-Refinery based on DDG – for production of biofuels, biochemical intermediates, and other bioproducts. - Highlights: • A process for selective extraction of pentoses from DDG was presented as a part of integrated biorefinery approach. • The selectivity for pentoses was high using dilute acid hydrolysis in a percolation reactor with liquid recirculation. • Pretreatment of DDG using screening and ultrasonication resulted in fractional increase of the pentose yield by 42 %. • A 94% yield in pentoses (280.9 g kg −1 of DDG) was obtained. • A 2-stage hydrolysis process, developed to extract individual pentoses, resulted in arabinose and xylose rich streams

  17. 24-h organization of glycolysis and control by photoperiodism.

    Science.gov (United States)

    Pierre, J N; Celati, C; Queiroz, O

    1985-01-01

    A study of the temporal organization of glycolysis at diverse levels of activity of the pathway showed that consideration of the phases of the 24h oscillations in glycolytic pools affords a means of detecting modifications in regulatory mechanisms according to the level of carbon flow along the pathway. The work utilized Kalanchoe blossfeldiana, a plant with crassulacean acid metabolism (CAM) in which glycolytic activity is under the control of photoperiodism: after transfer from long days to short days carbon flow through the pathway increases drastically. Analysis of the glycolytic pools performed during the day/night cycle showed that: a. 24 h-period variations exist in the content of the glycolytic intermediates; b. time of the acrophase of these rhythms changes as a function of the photoperiodic treatment: in long days the pools of the intermediates preceding the phosphofructokinase (PFK) step oscillate in phase and the same holds for the intermediates after the PFK step but these two sequences of the pathway oscillate out of phase (phase-jump of about 10h); transfer to short days besides producing (after a lag) changes in the mean level and amplitude of the oscillations, modifies their phase: this temporal reorganization of glycolysis results in splitting the pathway into 3 sequences of synchronously-oscillating pools, phase-jumps between successive sequences occurring at the PFK (4h) and at the 3-phosphoglyceraldehyde dehydrogenase (12h) steps.

  18. Glycolysis Is Dynamic and Relates Closely to Respiration Rate in Stored Sugarbeet Roots

    Directory of Open Access Journals (Sweden)

    Clarice A. Megguer

    2017-05-01

    Full Text Available Although respiration is the principal cause of the loss of sucrose in postharvest sugarbeet (Beta vulgaris L., the internal mechanisms that control root respiration rate are unknown. Available evidence, however, indicates that respiration rate is likely to be controlled by the availability of respiratory substrates, and glycolysis has a central role in generating these substrates. To determine glycolytic changes that occur in sugarbeet roots after harvest and to elucidate relationships between glycolysis and respiration, sugarbeet roots were stored for up to 60 days, during which activities of glycolytic enzymes and concentrations of glycolytic substrates, intermediates, cofactors, and products were determined. Respiration rate was also determined, and relationships between respiration rate and glycolytic enzymes and metabolites were evaluated. Glycolysis was highly variable during storage, with 10 of 14 glycolytic activities and 14 of 17 glycolytic metabolites significantly altered during storage. Changes in glycolytic enzyme activities and metabolites occurred throughout the 60 day storage period, but were greatest in the first 4 days after harvest. Positive relationships between changes in glycolytic enzyme activities and root respiration rate were abundant, with 10 of 14 enzyme activities elevated when root respiration was elevated and 9 glycolytic activities static during periods of unchanging respiration rate. Major roles for pyruvate kinase and phosphofructokinase in the regulation of postharvest sugarbeet root glycolysis were indicated based on changes in enzymatic activities and concentrations of their substrates and products. Additionally, a strong positive relationship between respiration rate and pyruvate kinase activity was found indicating that downstream TCA cycle enzymes were unlikely to regulate or restrict root respiration in a major way. Overall, these results establish that glycolysis is not static during sugarbeet root

  19. Glycolysis and the significance of lactate in traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Keri Linda Carpenter

    2015-04-01

    Full Text Available In traumatic brain injury (TBI patients, elevation of the brain extracellular lactate concentration and the lactate/pyruvate ratio are well recognised, and are associated statistically with unfavourable clinical outcome. Brain extracellular lactate was conventionally regarded as a waste product of glucose, when glucose is metabolised via glycolysis (Embden-Meyerhof-Parnas pathway to pyruvate, followed by conversion to lactate by the action of lactate dehydrogenase, and export of lactate into the extracellular fluid. In TBI, glycolytic lactate is ascribed to hypoxia or mitochondrial dysfunction, although the precise nature of the latter is incompletely understood. Seemingly in contrast to lactate’s association with unfavourable outcome is a growing body of evidence that lactate can be beneficial. The idea that the brain can utilise lactate by feeding into the tricarboxylic acid (TCA cycle of neurons, first published two decades ago, has become known as the astrocyte-neuron lactate shuttle hypothesis. Direct evidence of brain utilisation of lactate was first obtained 5 years ago in a cerebral microdialysis study in TBI patients, where administration of 13C-labelled lactate via the microdialysis catheter and simultaneous collection of the emerging microdialysates, with 13C NMR analysis, revealed 13C labelling in glutamine consistent with lactate utilisation via the TCA cycle. This suggests that where neurons are too damaged to utilise the lactate produced from glucose by astrocytes, i.e. uncoupling of neuronal and glial metabolism, high extracellular levels of lactate would accumulate, explaining association between high lactate and poor outcome. An intravenous exogenous lactate supplementation study in TBI patients showed evidence for a beneficial effect judged by surrogate endpoints. Here we review current knowledge about glycolysis and lactate in TBI, how it can be measured in patients, and whether it can be modulated to achieve better

  20. Early reactions of enzymes and metabolites of glycolysis at the myocardium after local irradiation

    International Nuclear Information System (INIS)

    Hoffmeister, N.

    1982-01-01

    The behaviour of enzymes, substrates and metabolites of clycolysis and the pentose-phosphate cycle was chemically investigated in guinea-pig myocardia after applying different radiation doses. The results indicate that already therapeutical doses of radiation result in essential metabolic alterations but also that the organ concerned endeavours to remedy the harmful influence at least partly. The investigations do not permit to define the actual mechanism underlying the modifications; however it is seen that changes in membrane permeability as well as alterations of effectors and inhibitors play an essential part. (orig.) [de

  1. Ethanol production from Dekkera bruxellensis in synthetic media with pentose

    Directory of Open Access Journals (Sweden)

    Carolina B. Codato

    Full Text Available Abstract Ethanol is obtained in Brazil from the fermentation of sugarcane, molasses or a mixture of these. Alternatively, it can also be obtained from products composed of cellulose and hemicellulose, called “second generation ethanol - 2G”. The yeast Saccharomyces cerevisiae, commonly applied in industrial ethanol production, is not efficient in the conversion of pentoses, which is present in high amounts in lignocellulosic materials. This study aimed to evaluate the ability of a yeast strain of Dekkera bruxellensis in producing ethanol from synthetic media, containing xylose or arabinose, xylose and glucose as the sole carbon sources. The results indicated that D. bruxellensis was capable of producing ethanol from xylose and arabinose, with ethanol concentration similar for both carbon sources, 1.9 g L-1. For the fermentations performed with xylose and glucose, there was an increase in the concentration of ethanol to 5.9 g L-1, lower than the standard yeast Pichia stipitis (9.3 g L-1, but with similar maximum yield in ethanol (0.9 g g TOC-1. This proves that the yeast D. bruxellensis produced lower amounts of ethanol when compared with P. stipitis, but showed that is capable of fermenting xylose and can be a promising alternative for ethanol conversion from hydrolysates containing glucose and xylose as carbon source.

  2. Constant Growth Rate Can Be Supported by Decreasing Energy Flux and Increasing Aerobic Glycolysis

    Directory of Open Access Journals (Sweden)

    Nikolai Slavov

    2014-05-01

    Full Text Available Fermenting glucose in the presence of enough oxygen to support respiration, known as aerobic glycolysis, is believed to maximize growth rate. We observed increasing aerobic glycolysis during exponential growth, suggesting additional physiological roles for aerobic glycolysis. We investigated such roles in yeast batch cultures by quantifying O2 consumption, CO2 production, amino acids, mRNAs, proteins, posttranslational modifications, and stress sensitivity in the course of nine doublings at constant rate. During this course, the cells support a constant biomass-production rate with decreasing rates of respiration and ATP production but also decrease their stress resistance. As the respiration rate decreases, so do the levels of enzymes catalyzing rate-determining reactions of the tricarboxylic-acid cycle (providing NADH for respiration and of mitochondrial folate-mediated NADPH production (required for oxidative defense. The findings demonstrate that exponential growth can represent not a single metabolic/physiological state but a continuum of changing states and that aerobic glycolysis can reduce the energy demands associated with respiratory metabolism and stress survival.

  3. Glycolysis-respiration relationships in a neuroblastoma cell line.

    Science.gov (United States)

    Swerdlow, Russell H; E, Lezi; Aires, Daniel; Lu, Jianghua

    2013-04-01

    Although some reciprocal glycolysis-respiration relationships are well recognized, the relationship between reduced glycolysis flux and mitochondrial respiration has not been critically characterized. We concomitantly measured the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of SH-SY5Y neuroblastoma cells under free and restricted glycolysis flux conditions. Under conditions of fixed energy demand ECAR and OCR values showed a reciprocal relationship. In addition to observing an expected Crabtree effect in which increasing glucose availability raised the ECAR and reduced the OCR, a novel reciprocal relationship was documented in which reducing the ECAR via glucose deprivation or glycolysis inhibition increased the OCR. Substituting galactose for glucose, which reduces net glycolysis ATP yield without blocking glycolysis flux, similarly reduced the ECAR and increased the OCR. We further determined how reduced ECAR conditions affect proteins that associate with energy sensing and energy response pathways. ERK phosphorylation, SIRT1, and HIF1a decreased while AKT, p38, and AMPK phosphorylation increased. These data document a novel intracellular glycolysis-respiration effect in which restricting glycolysis flux increases mitochondrial respiration. Since this effect can be used to manipulate cell bioenergetic infrastructures, this particular glycolysis-respiration effect can practically inform the development of new mitochondrial medicine approaches. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle.

    Science.gov (United States)

    Hanover, John A; Chen, Weiping; Bond, Michelle R

    2018-06-01

    Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes. O-GlcNAcylation can thereby alter epigenetics, transcription, signaling, proteostasis, and bioenergetics, key 'hallmarks of cancer'. In this review, we summarize accumulating evidence that many cancer hallmarks are linked to dysregulation of O-GlcNAc cycling on cancer-relevant targets. We argue that onconutrient and oncometabolite-fueled elevation increases HBP flux and triggers O-GlcNAcylation of key regulatory enzymes in glycolysis, Kreb's cycle, pentose-phosphate pathway, and the HBP itself. The resulting rerouting of glucose metabolites leads to elevated O-GlcNAcylation of oncogenes and tumor suppressors further escalating elevation in HBP flux creating a 'vicious cycle'. Downstream, elevated O-GlcNAcylation alters DNA repair and cellular stress pathways which influence oncogenesis. The elevated steady-state levels of O-GlcNAcylated targets found in many cancers may also provide these cells with a selective advantage for sustained growth, enhanced metastatic potential, and immune evasion in the tumor microenvironment.

  5. Combined Treatment of MCF-7 Cells with AICAR and Methotrexate, Arrests Cell Cycle and Reverses Warburg Metabolism through AMP-Activated Protein Kinase (AMPK and FOXO1.

    Directory of Open Access Journals (Sweden)

    Tamás Fodor

    Full Text Available Cancer cells are characterized by metabolic alterations, namely, depressed mitochondrial oxidation, enhanced glycolysis and pentose phosphate shunt flux to support rapid cell growth, which is called the Warburg effect. In our study we assessed the metabolic consequences of a joint treatment of MCF-7 breast cancer cells with AICAR, an inducer of AMP-activated kinase (AMPK jointly with methotrexate (MTX, a folate-analog antimetabolite that blunts de novo nucleotide synthesis. MCF7 cells, a model of breast cancer cells, were resistant to the individual application of AICAR or MTX, however combined treatment of AICAR and MTX reduced cell proliferation. Prolonged joint application of AICAR and MTX induced AMPK and consequently enhanced mitochondrial oxidation and reduced the rate of glycolysis. These metabolic changes suggest an anti-Warburg rearrangement of metabolism that led to the block of the G1/S and the G2/M transition slowing down cell cycle. The slowdown of cell proliferation was abolished when mitotropic transcription factors, PGC-1α, PGC-1β or FOXO1 were silenced. In human breast cancers higher expression of AMPKα and FOXO1 extended survival. AICAR and MTX exerts similar additive antiproliferative effect on other breast cancer cell lines, such as SKBR and 4T1 cells, too. Our data not only underline the importance of Warburg metabolism in breast cancer cells but nominate the AICAR+MTX combination as a potential cytostatic regime blunting Warburg metabolism. Furthermore, we suggest the targeting of AMPK and FOXO1 to combat breast cancer.

  6. Methylglyoxal, the dark side of glycolysis

    KAUST Repository

    Allaman, Igor

    2015-02-09

    Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons. Methylglyoxal, a highly reactive dicarbonyl compound, is inevitably formed as a by-product of glycolysis. Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs), which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. In normal situations, cells are protected against methylglyoxal toxicity by different mechanisms and in particular the glyoxalase system, which represents the most important pathway for the detoxification of methylglyoxal. While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered. Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity. This review focuses on our actual knowledge on the cellular aspects of the glyoxalase system in brain cells, in particular with regard to its activity in astrocytes and neurons. A main emerging concept is that these two neural cell types have different and energetically adapted glyoxalase defense mechanisms which may serve as protective mechanism against methylglyoxal-induced cellular damage.

  7. Methylglyoxal, the dark side of glycolysis

    Directory of Open Access Journals (Sweden)

    Igor eAllaman

    2015-02-01

    Full Text Available Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons. Methylglyoxal, a highly reactive dicarbonyl compound, is inevitably formed as a by-product of glycolysis. Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs, which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. The glyoxalase system is the most important pathway for the detoxification of methylglyoxal, and although the neurotoxic effects of methylglyoxal and AGEs are well characterized, less is known about the glyoxalase system in the brain. Considering the high energy requirements (i.e. glucose of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity. This review focuses on our actual knowledge on the cellular aspects of the glyoxalase system in brain cells, in particular with regards to its activity in astrocytes and neurons. A main emerging concept is that a neuroenergetic specialization is taking place between these two cell types which may serve as a protective mechanism against methylglyoxal-induced toxicity.

  8. Metabolic regulation at the tricarboxylic acid and glyoxylate cycles of the lignin-degrading basidiomycete Phanerochaete chrysosporium against exogenous addition of vanillin.

    Science.gov (United States)

    Shimizu, Motoyuki; Yuda, Naoki; Nakamura, Tomofumi; Tanaka, Hiroo; Wariishi, Hiroyuki

    2005-10-01

    A proteomic differential display technique was utilized to study cellular responses of Phanerochaete chrysosporium exposed to vanillin, one of the key intermediates found during lignin biodegradation. Intracellular proteins were resolved by 2-DE and target protein spots were identified using MALDI-MS after in-gel tryptic digestions. Upon addition of vanillin to P. chrysosporium, up-regulation of homogentisate 1,2-dioxygenase, 1,4-benzoquinone reductases, aldehyde dehydrogenase, and aryl-alcohol dehydrogenase, which seem to play roles in vanillin metabolism, was observed. Furthermore, enzymes involved in glycolysis, the tricarboxylic acid cycle, the pentose-phosphate cycle, and heme biosynthesis were also activated. Up-regulation of extracellular peroxidase was also observed. One of the most unique phenomena against exogenous vanillin was a switch from the glyoxylate cycle to the tricarboxylic acid cycle, where a drastic increase in isocitrate dehydrogenase activity was observed. The exogenous addition of other aromatic compounds also caused an increase in its activity, which in turn triggered NAD(P)H production via the action of dehydrogenases in the tricarboxylic acid cycle, heme biosynthesis via the action of aminolevulinic acid synthase on succinyl-CoA, and energy production via activation of the mitochondrial electron transfer system. These metabolic shifts seem to be required for activating a metabolic system for aromatic compounds.

  9. Reducing the genetic complexity of glycolysis in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Solis Escalante, D.

    2015-01-01

    Glycolysis, a biochemical pathway that oxidizes glucose to pyruvate, is at the core of sugar metabolism in Saccharomyces cerevisiae (bakers’ yeast). Glycolysis is not only a catabolic route involved in energy conservation, but also provides building blocks for anabolism. From an applied perspective,

  10. Lysine Deacetylases and Regulated Glycolysis in Macrophages.

    Science.gov (United States)

    Shakespear, Melanie R; Iyer, Abishek; Cheng, Catherine Youting; Das Gupta, Kaustav; Singhal, Amit; Fairlie, David P; Sweet, Matthew J

    2018-06-01

    Regulated cellular metabolism has emerged as a fundamental process controlling macrophage functions, but there is still much to uncover about the precise signaling mechanisms involved. Lysine acetylation regulates the activity, stability, and/or localization of metabolic enzymes, as well as inflammatory responses, in macrophages. Two protein families, the classical zinc-dependent histone deacetylases (HDACs) and the NAD-dependent HDACs (sirtuins, SIRTs), mediate lysine deacetylation. We describe here mechanisms by which classical HDACs and SIRTs directly regulate specific glycolytic enzymes, as well as evidence that links these protein deacetylases to the regulation of glycolysis-related genes. In these contexts, we discuss HDACs and SIRTs as key control points for regulating immunometabolism and inflammatory outputs from macrophages. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Constant growth rate can be supported by decreasing energy flux and increasing aerobic glycolysis

    NARCIS (Netherlands)

    Slavov, Nikolai; Budnik, Bogdan A; Schwab, David; Airoldi, Edoardo M; van Oudenaarden, Alexander

    2014-01-01

    Fermenting glucose in the presence of enough oxygen to support respiration, known as aerobic glycolysis, is believed to maximize growth rate. We observed increasing aerobic glycolysis during exponential growth, suggesting additional physiological roles for aerobic glycolysis. We investigated such

  12. Functional importance of the astrocytic glycogen-shunt and glycolysis for maintenance of an intact intra/extracellular glutamate gradient

    DEFF Research Database (Denmark)

    Schousboe, Arne; Sickmann, Helle M; Walls, Anne B

    2010-01-01

    It has been proposed that a considerable fraction of glucose metabolism proceeds via the glycogen-shunt consisting of conversion of glucose units to glycogen residues and subsequent production of glucose-1-phosphate to be metabolized in glycolysis after conversion to glucose-6-phosphate. The impo......It has been proposed that a considerable fraction of glucose metabolism proceeds via the glycogen-shunt consisting of conversion of glucose units to glycogen residues and subsequent production of glucose-1-phosphate to be metabolized in glycolysis after conversion to glucose-6-phosphate....... The importance of this as well as the significance of ATP formed in glycolysis versus that formed by the concerted action of the tricarboxylic acid (TCA) cycle processes and oxidative phosphorylation for maintenance of glutamate transport capacity in astrocytes is discussed. It is argued that glycolytically...

  13. Calculation of the pentose phosphate and Embden-Myerhoff pathways from a single incubation with [U-14C]- and [5-3H]glucose

    International Nuclear Information System (INIS)

    O'Fallon, J.V.; Wright, R.W. Jr.

    1987-01-01

    A method that simultaneously determines Embden-Myerhoff pathway and pentose phosphate pathway (PPP) activities from an incubation with [U- 14 C]- and [5- 3 H]glucose is presented. The method relies on the use of unlabeled pyruvate and lactate to dilute out radiolabel entering the tricarboxylic acid cycle. Gluconeogenesis from pyruvate is prevented by the use of an incubation chamber that maintains a CO 2 (and bicarbonate) free environment. The method, which includes the contribution by the recycling steps of the PPP, is especially useful when biological material is limited or developmental timing is critical

  14. Ferroxitosis: A cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma

    Science.gov (United States)

    Lakhter, Alexander J.; Hamilton, James; Dagher, Pierre C.; Mukkamala, Suresh; Hato, Takashi; Dong, X. Charlie; Mayo, Lindsey D.; Harris, Robert A.; Shekhar, Anantha; Ivan, Mircea; Brustovetsky, Nickolay; Naidu, Samisubbu R.

    2014-01-01

    Reliance on glycolysis is a characteristic of malignancy, yet the development of resistance to BRAF inhibitors in melanoma is associated with gain of mitochondrial function. Concurrent attenuation of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis promotes a non-apoptotic, iron- and oxygen-dependent cell death that we term ferroxitosis. The redox cycling agent menadione causes a robust increase in oxygen consumption, accompanied by significant loss of intracellular ATP and rapid cell death. Conversely, either hypoxic adaptation or iron chelation prevents menadione-induced ferroxitosis. Ectopic expression of K213Q HIF-1α mutant blunts the effects of menadione. However, knockdown of HIF-1α or PKM2 restores menadione-induced cytotoxicity in hypoxia. Similarly, exposure of melanoma cells to shikonin, a menadione analog and a potential PKM2 inhibitor, is sufficient to induce ferroxitosis under hypoxic conditions. Collectively, our findings reveal that ferroxitosis curtails metabolic plasticity in melanoma. PMID:25587028

  15. Sensitivity analysis of the noise-induced oscillatory multistability in Higgins model of glycolysis

    Science.gov (United States)

    Ryashko, Lev

    2018-03-01

    A phenomenon of the noise-induced oscillatory multistability in glycolysis is studied. As a basic deterministic skeleton, we consider the two-dimensional Higgins model. The noise-induced generation of mixed-mode stochastic oscillations is studied in various parametric zones. Probabilistic mechanisms of the stochastic excitability of equilibria and noise-induced splitting of randomly forced cycles are analysed by the stochastic sensitivity function technique. A parametric zone of supersensitive Canard-type cycles is localized and studied in detail. It is shown that the generation of mixed-mode stochastic oscillations is accompanied by the noise-induced transitions from order to chaos.

  16. Continuous production of ethanol from hexoses and pentoses using immobilized mixed cultures of Escherichia coli strains

    Science.gov (United States)

    Unrean, Pornkamol; Srienc, Friedrich

    2010-01-01

    We have developed highly efficient ethanologenic E. coli strains that selectively consume pentoses and/or hexoses. Mixed cultures of these strains can be used to selectively adjust the sugar utilization kinetics in ethanol fermentations. Based on the kinetics of sugar utilization, we have designed and implemented an immobilized cell system for the optimized continuous conversion of sugars into ethanol. The results confirm that immobilized mixed cultures support a simultaneous conversion of hexoses and pentoses into ethanol at high yield and at a faster rate than immobilized homogenous cells. Continuous ethanol production has been maintained for several weeks at high productivity with near complete sugar utilization. The control of sugar utilization using immobilized mixed cultures can be adapted to any composition of hexoses and pentoses by adjusting the strain distribution of immobilized cells. The approach, therefore, holds promise for ethanol fermentation from lignocellulosic hydrolysates where the feedstock varies in sugar composition. PMID:20699108

  17. [Intensity of pentose phosphate metabolism of carbohydrates in various brain areas in normal and starved animals].

    Science.gov (United States)

    Kerimov, B F

    2002-01-01

    The activities of key enzymes of pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G-6 PD) and 6-phosphogluconate dehydrogenase (6-PGD), were studied in cytoplasmatic fractions of brain cortical (limbic, orbital, sensorimotor cortex) and subcortical (myelencefalon, mesencefalon, hypothalamus) structures of rats subjected to starvation for 1, 2, 3, 5 and 7 days. Short-term starvation (1-3 days) caused activation of 6-GPD and 6-PGD both in cortical and subcortical structures. Long-term starvation for 5-7 days caused a decrease of activities of the pentose phosphate pathway enzymes in all studied structures. It is suggested that enzymes of pentose phosphate pathway in nervous tissues are functionally and metabolically related to glutathione system and during starvation they indirectly participate in the regulation lipid peroxidation processes.

  18. 13C based proteinogenic amino acid (PAA and metabolic flux ratio analysis of Lactococcus lactis reveals changes in pentose phosphate (PP pathway in response to agitation and temperature related stresses

    Directory of Open Access Journals (Sweden)

    Kamalrul Azlan Azizan

    2017-07-01

    Full Text Available Lactococcus lactis subsp. cremoris MG1363 is an important starter culture for dairy fermentation. During industrial fermentations, L. lactis is constantly exposed to stresses that affect the growth and performance of the bacterium. Although the response of L. lactis to several stresses has been described, the adaptation mechanisms at the level of in vivo fluxes have seldom been described. To gain insights into cellular metabolism, 13C metabolic flux analysis and gas chromatography mass spectrometry (GC-MS were used to measure the flux ratios of active pathways in the central metabolism of L. lactis when subjected to three conditions varying in temperature (30°C, 37°C and agitation (with and without agitation at 150 rpm. Collectively, the concentrations of proteinogenic amino acids (PAAs and free fatty acids (FAAs were compared, and Pearson correlation analysis (r was calculated to measure the pairwise relationship between PAAs. Branched chain and aromatic amino acids, threonine, serine, lysine and histidine were correlated strongly, suggesting changes in flux regulation in glycolysis, the pentose phosphate (PP pathway, malic enzyme and anaplerotic reaction catalysed by pyruvate carboxylase (pycA. Flux ratio analysis revealed that glucose was mainly converted by glycolysis, highlighting the stability of L. lactis’ central carbon metabolism despite different conditions. Higher flux ratios through oxaloacetate (OAA from pyruvate (PYR reaction in all conditions suggested the activation of pyruvate carboxylate (pycA in L. lactis, in response to acid stress during exponential phase. Subsequently, more significant flux ratio differences were seen through the oxidative and non-oxidative pentose phosphate (PP pathways, malic enzyme, and serine and C1 metabolism, suggesting NADPH requirements in response to environmental stimuli. These reactions could play an important role in optimization strategies for metabolic engineering in L. lactis. Overall

  19. 13C based proteinogenic amino acid (PAA) and metabolic flux ratio analysis of Lactococcus lactis reveals changes in pentose phosphate (PP) pathway in response to agitation and temperature related stresses.

    Science.gov (United States)

    Azizan, Kamalrul Azlan; Ressom, Habtom W; Mendoza, Eduardo R; Baharum, Syarul Nataqain

    2017-01-01

    Lactococcus lactis subsp. cremoris MG1363 is an important starter culture for dairy fermentation. During industrial fermentations, L. lactis is constantly exposed to stresses that affect the growth and performance of the bacterium. Although the response of L. lactis to several stresses has been described, the adaptation mechanisms at the level of in vivo fluxes have seldom been described. To gain insights into cellular metabolism, 13 C metabolic flux analysis and gas chromatography mass spectrometry (GC-MS) were used to measure the flux ratios of active pathways in the central metabolism of L. lactis when subjected to three conditions varying in temperature (30°C, 37°C) and agitation (with and without agitation at 150 rpm). Collectively, the concentrations of proteinogenic amino acids (PAAs) and free fatty acids (FAAs) were compared, and Pearson correlation analysis ( r ) was calculated to measure the pairwise relationship between PAAs. Branched chain and aromatic amino acids, threonine, serine, lysine and histidine were correlated strongly, suggesting changes in flux regulation in glycolysis, the pentose phosphate (PP) pathway, malic enzyme and anaplerotic reaction catalysed by pyruvate carboxylase (pycA). Flux ratio analysis revealed that glucose was mainly converted by glycolysis, highlighting the stability of L. lactis' central carbon metabolism despite different conditions. Higher flux ratios through oxaloacetate (OAA) from pyruvate (PYR) reaction in all conditions suggested the activation of pyruvate carboxylate (pycA) in L. lactis , in response to acid stress during exponential phase. Subsequently, more significant flux ratio differences were seen through the oxidative and non-oxidative pentose phosphate (PP) pathways, malic enzyme, and serine and C1 metabolism, suggesting NADPH requirements in response to environmental stimuli. These reactions could play an important role in optimization strategies for metabolic engineering in L. lactis . Overall, the

  20. 13C based proteinogenic amino acid (PAA) and metabolic flux ratio analysis of Lactococcus lactis reveals changes in pentose phosphate (PP) pathway in response to agitation and temperature related stresses

    Science.gov (United States)

    2017-01-01

    Lactococcus lactis subsp. cremoris MG1363 is an important starter culture for dairy fermentation. During industrial fermentations, L. lactis is constantly exposed to stresses that affect the growth and performance of the bacterium. Although the response of L. lactis to several stresses has been described, the adaptation mechanisms at the level of in vivo fluxes have seldom been described. To gain insights into cellular metabolism, 13C metabolic flux analysis and gas chromatography mass spectrometry (GC-MS) were used to measure the flux ratios of active pathways in the central metabolism of L. lactis when subjected to three conditions varying in temperature (30°C, 37°C) and agitation (with and without agitation at 150 rpm). Collectively, the concentrations of proteinogenic amino acids (PAAs) and free fatty acids (FAAs) were compared, and Pearson correlation analysis (r) was calculated to measure the pairwise relationship between PAAs. Branched chain and aromatic amino acids, threonine, serine, lysine and histidine were correlated strongly, suggesting changes in flux regulation in glycolysis, the pentose phosphate (PP) pathway, malic enzyme and anaplerotic reaction catalysed by pyruvate carboxylase (pycA). Flux ratio analysis revealed that glucose was mainly converted by glycolysis, highlighting the stability of L. lactis’ central carbon metabolism despite different conditions. Higher flux ratios through oxaloacetate (OAA) from pyruvate (PYR) reaction in all conditions suggested the activation of pyruvate carboxylate (pycA) in L. lactis, in response to acid stress during exponential phase. Subsequently, more significant flux ratio differences were seen through the oxidative and non-oxidative pentose phosphate (PP) pathways, malic enzyme, and serine and C1 metabolism, suggesting NADPH requirements in response to environmental stimuli. These reactions could play an important role in optimization strategies for metabolic engineering in L. lactis. Overall, the

  1. Genome sequence of the thermophilic strain Bacillus coagulans XZL4, an efficient pentose-utilizing producer of chemicals.

    Science.gov (United States)

    Su, Fei; Xu, Ke; Zhao, Bo; Tai, Cui; Tao, Fei; Tang, Hongzhi; Xu, Ping

    2011-11-01

    Bacillus coagulans XZL4 is an efficient pentose-utilizing producer of important platform compounds, such as l-lactic acid, 2,3-butanediol, and acetoin. Here we present a 2.8-Mb assembly of its genome. Simple and efficient carbohydrate metabolism systems, especially the transketolase/transaldolase pathway, make it possible to convert pentose sugars to products at high levels.

  2. The pentose phosphate pathway in Trypanosoma cruzi: a potential target for the chemotherapy of Chagas disease

    Directory of Open Access Journals (Sweden)

    Mariana Igoillo-Esteve

    2007-12-01

    Full Text Available Trypanosoma cruzi is highly sensitive to oxidative stress caused by reactive oxygen species. Trypanothione, the parasite's major protection against oxidative stress, is kept reduced by trypanothione reductase, using NADPH; the major source of the reduced coenzyme seems to be the pentose phosphate pathway. Its seven enzymes are present in the four major stages in the parasite's biological cycle; we have cloned and expressed them in Escherichia coli as active proteins. Glucose 6-phosphate dehydrogenase, which controls glucose flux through the pathway by its response to the NADP/NADPH ratio, is encoded by a number of genes per haploid genome, and is induced up to 46-fold by hydrogen peroxide in metacyclic trypomastigotes. The genes encoding 6-phosphogluconolactonase, 6-phosphogluconate dehydrogenase, transaldolase and transketolase are present in the CL Brener clone as a single copy per haploid genome. 6-phosphogluconate dehydrogenase is very unstable, but was stabilized introducing two salt bridges by site-directed mutagenesis. Ribose-5-phosphate isomerase belongs to Type B; genes encoding Type A enzymes, present in mammals, are absent. Ribulose-5-phosphate epimerase is encoded by two genes. The enzymes of the pathway have a major cytosolic component, although several of them have a secondary glycosomal localization, and also minor localizations in other organelles.Trypanosoma cruzi é altamente sensível ao estresse oxidativo causado por espécies reativas do oxigênio. Tripanotiona, o principal protetor do parasita contra o estresse oxidativo, é mantido reduzido pela tripanotiona redutase, pela presença deNADPH; a principal fonte da coenzima reduzida parece ser a via da pentose fosfato. As sete enzimas dessa via estão presentes nos quatro principais estágios do ciclo biológico do parasita; nós clonamos e expressamos as enzimas em Escherichia coli como proteínas ativas. Glucose 6-fosfato desidrogenase, que controla o fluxo da glucose da

  3. Sirtuin 1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions.

    Science.gov (United States)

    Pinho, Andreia V; Mawson, Amanda; Gill, Anthony; Arshi, Mehreen; Warmerdam, Max; Giry-Laterriere, Marc; Eling, Nils; Lie, Triyana; Kuster, Evelyne; Camargo, Simone; Biankin, Andrew V; Wu, Jianmin; Rooman, Ilse

    2016-11-15

    Metabolic reprogramming is a feature of neoplasia and tumor growth. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators such as p53. SIRT1 regulates metaplasia in the pancreas. Nevertheless, it is unclear if SIRT1 affects the development of neoplastic lesions and whether metabolic gene expression is altered.To assess neoplastic lesion development, mice with a pancreas-specific loss of Sirt1 (Pdx1-Cre;Sirt1-lox) were bred into a KrasG12D mutant background (KC) that predisposes to the development of pancreatic intra-epithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC). Similar grade PanIN lesions developed in KC and KC;Sirt1-lox mice but specifically early mucinous PanINs occupied 40% less area in the KC;Sirt1-lox line, attributed to reduced proliferation. This was accompanied by reduced expression of proteins in the glycolysis pathway, such as GLUT1 and GAPDH.The stimulatory effect of SIRT1 on proliferation and glycolysis gene expression was confirmed in a human PDAC cell line. In resected PDAC samples, higher proliferation and expression of glycolysis genes correlated with poor patient survival. SIRT1 expression per se was not prognostic but low expression of Cell Cycle and Apoptosis Regulator 2 (CCAR2), a reported SIRT1 inhibitor, corresponded to poor patient survival.These findings open perspectives for novel targeted therapies in pancreatic cancer.

  4. Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway.

    Science.gov (United States)

    Yao, Shihua; Wang, Xiaowei; Li, Chunguang; Zhao, Tiejun; Jin, Hai; Fang, Wentao

    2016-08-01

    Antitumor activity of kaempferol has been studied in various tumor types, but its potency in esophagus squamous cell carcinoma is rarely known. Here, we reported the activity of kaempferol against esophagus squamous cell carcinoma as well as its antitumor mechanisms. Results of cell proliferation and colony formation assay showed that kaempferol substantially inhibited tumor cell proliferation and clone formation in vitro. Flow cytometric analysis demonstrated that tumor cells were induced G0/G1 phase arrest after kaempferol treatment, and the expression of protein involved in cell cycle regulation was dramatically changed. Except the potency on cell proliferation, we also discovered that kaempferol had a significant inhibitory effect against tumor glycolysis. With the downregulation of hexokinase-2, glucose uptake and lactate production in tumor cells were dramatically declined. Mechanism studies revealed kaempferol had a direct effect on epidermal growth factor receptor (EGFR) activity, and along with the inhibition of EGFR, its downstream signaling pathways were also markedly suppressed. Further investigations found that exogenous overexpression of EGFR in tumor cells substantially attenuated glycolysis suppression induced by kaempferol, which implied that EGFR also played an important role in kaempferol-mediated glycolysis inhibition. Finally, the antitumor activity of kaempferol was validated in xenograft model and kaempferol prominently restrained tumor growth in vivo. Meanwhile, dramatic decrease of EGFR activity and hexokinase-2 expression were observed in kaempferol-treated tumor tissue, which confirmed these findings in vitro. Briefly, these studies suggested that kaempferol, or its analogues, may serve as effective candidates for esophagus squamous cell carcinoma management.

  5. Sirtuin 1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions

    Science.gov (United States)

    Pinho, Andreia V.; Mawson, Amanda; Gill, Anthony; Arshi, Mehreen; Warmerdam, Max; Giry-Laterriere, Marc; Eling, Nils; Lie, Triyana; Kuster, Evelyne; Camargo, Simone; Biankin, Andrew V.; Wu, Jianmin; Rooman, Ilse

    2016-01-01

    Metabolic reprogramming is a feature of neoplasia and tumor growth. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators such as p53. SIRT1 regulates metaplasia in the pancreas. Nevertheless, it is unclear if SIRT1 affects the development of neoplastic lesions and whether metabolic gene expression is altered. To assess neoplastic lesion development, mice with a pancreas-specific loss of Sirt1 (Pdx1-Cre;Sirt1-lox) were bred into a KrasG12D mutant background (KC) that predisposes to the development of pancreatic intra-epithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC). Similar grade PanIN lesions developed in KC and KC;Sirt1-lox mice but specifically early mucinous PanINs occupied 40% less area in the KC;Sirt1-lox line, attributed to reduced proliferation. This was accompanied by reduced expression of proteins in the glycolysis pathway, such as GLUT1 and GAPDH. The stimulatory effect of SIRT1 on proliferation and glycolysis gene expression was confirmed in a human PDAC cell line. In resected PDAC samples, higher proliferation and expression of glycolysis genes correlated with poor patient survival. SIRT1 expression per se was not prognostic but low expression of Cell Cycle and Apoptosis Regulator 2 (CCAR2), a reported SIRT1 inhibitor, corresponded to poor patient survival. These findings open perspectives for novel targeted therapies in pancreatic cancer. PMID:27494892

  6. Restricting glycolysis impairs brown adipocyte glucose and oxygen consumption

    DEFF Research Database (Denmark)

    Winther, Sally; Isidor, Marie Sophie; Basse, Astrid Linde

    2018-01-01

    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 kn......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 si...... 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....

  7. Identification of the missing links in prokaryotic pentose oxidation pathways: evidence for enzyme recruitment

    NARCIS (Netherlands)

    Brouns, S.J.J.; Walther, J.; Snijders, A.P.; Werken, van de H.J.G.; Willemen, H.L.D.M.; Worm, P.; Vos, de M.G.; Andersson, A.; Lundgren, M.; Mazon, H.F.; Heuvel, van den R.H.H.; Nilsson, P.; Salmon, L.; Vos, de W.M.; Wright, P.C.; Bernander, R.; Oost, van der J.

    2006-01-01

    The pentose metabolism of Archaea is largely unknown. Here, we have employed an integrated genomics approach including DNA microarray and proteomics analyses to elucidate the catabolic pathway for D-arabinose in Sulfolobus solfataricus. During growth on this sugar, a small set of genes appeared to

  8. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway

    NARCIS (Netherlands)

    Stincone, A.; Prigione, A.; Cramer, T.; Wamelink, M.M.C.; Campbell, K.; Cheung, E.; Olin-Sandoval, V.; Gruning, N.M.; Kruger, A.; Alam, M.T.; Keller, M.A.; Breitenbach, M.; Brindle, K.M.; Rabinowitz, J.D.; Ralser, M.

    2015-01-01

    The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares

  9. On the role of GAPDH isoenzymes during pentose fermentation in engineered Saccharomyces cerevisiae.

    Science.gov (United States)

    Linck, Annabell; Vu, Xuan-Khang; Essl, Christine; Hiesl, Charlotte; Boles, Eckhard; Oreb, Mislav

    2014-05-01

    In the metabolic network of the cell, many intermediary products are shared between different pathways. d-Glyceraldehyde-3-phosphate, a glycolytic intermediate, is a substrate of GAPDH but is also utilized by transaldolase and transketolase in the scrambling reactions of the nonoxidative pentose phosphate pathway. Recent efforts to engineer baker's yeast strains capable of utilizing pentose sugars present in plant biomass rely on increasing the carbon flux through this pathway. However, the competition between transaldolase and GAPDH for d-glyceraldehyde-3-phosphate produced in the first transketolase reaction compromises the carbon balance of the pathway, thereby limiting the product yield. Guided by the hypothesis that reduction in GAPDH activity would increase the availability of d-glyceraldehyde-3-phosphate for transaldolase and thereby improve ethanol production during fermentation of pentoses, we performed a comprehensive characterization of the three GAPDH isoenzymes in baker's yeast, Tdh1, Tdh2, and Tdh3 and analyzed the effect of their deletion on xylose utilization by engineered strains. Our data suggest that overexpression of transaldolase is a more promising strategy than reduction in GAPDH activity to increase the flux through the nonoxidative pentose phosphate pathway. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

  10. Mechanistic and kinetic aspects of pentose dehydration towards furfural in aqueous media employing homogeneous catalysis

    NARCIS (Netherlands)

    Danon, B.; Marcotullio, G.; De Jong, W.

    2013-01-01

    In this paper both the mechanistic and kinetic aspects of furfural formation from pentoses in aqueous acidic media have been reviewed. Based on the reviewed literature, a comprehensive reaction mechanism has been proposed consisting of more than one route, all starting from acyclic xylose, and

  11. Glycolysis of poly(3-hydroxybutyrate) via enzyme catalysis

    International Nuclear Information System (INIS)

    Paula, Everton Luiz de; Campos, Tiago Ferreira; Mano, Valdir

    2014-01-01

    Poly(3-hydroxybutyrate), PHB, is a polymer with broad potential applications because of its biodegradability and biocompatibility. However, its high crystallinity is a limiting factor for many applications. To overcome this drawback, one strategy currently employed involves the reduction of the molecular weight of PHB with the concomitant formation of end-functionalized chains, such as those obtained via glycolysis. The glycolysis of PHB can be catalyzed by acid, base, or organometallic compounds. However, to our knowledge, there are no reports regarding PHB glycolysis catalyzed enzymatically. Among the major types of enzymes used in biocatalysis, the lipases stand out because they have the ability to catalyze reactions in both aqueous and organic media. Thus, in this study, we performed the enzymatic glycolysis of PHB using the lipase Amano PS (Pseudomonas cepacia) with ethane-1,2-diol (ethylene glycol) as the functionalizing agent. The results indicated that the glycolysis was successful and afforded hydroxyl-terminated oligomeric PHB polyols. Nuclear magnetic resonance spectra of the products showed characteristic signals for the terminal hydroxyl groups of the polyols, while thermogravimetric and differential scanning calorimetry analyses confirmed an increase in the thermal stability and a decrease in the crystallinity of the polyols compared with the starting PHB polymer, which were both attributed to the reduction in the molecular weight due to glycolysis. (author)

  12. Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis.

    Science.gov (United States)

    Cisternas, Pedro; Salazar, Paulina; Silva-Álvarez, Carmen; Barros, L Felipe; Inestrosa, Nibaldo C

    2016-12-09

    The Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Boosting the pentose phosphate pathway restores cardiac progenitor cell availability in diabetes.

    Science.gov (United States)

    Katare, Rajesh; Oikawa, Atsuhiko; Cesselli, Daniela; Beltrami, Antonio P; Avolio, Elisa; Muthukrishnan, Deepti; Munasinghe, Pujika Emani; Angelini, Gianni; Emanueli, Costanza; Madeddu, Paolo

    2013-01-01

    Diabetes impinges upon mechanisms of cardiovascular repair. However, the biochemical adaptation of cardiac stem cells to sustained hyperglycaemia remains largely unknown. Here, we investigate the molecular targets of high glucose-induced damage in cardiac progenitor cells (CPCs) from murine and human hearts and attempt safeguarding CPC viability and function through reactivation of the pentose phosphate pathway. Type-1 diabetes was induced by streptozotocin. CPC abundance was determined by flow cytometry. Proliferating CPCs were identified in situ by immunostaining for the proliferation marker Ki67. Diabetic hearts showed marked reduction in CPC abundance and proliferation when compared with controls. Moreover, Sca-1(pos) CPCs isolated from hearts of diabetic mice displayed reduced activity of key enzymes of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD), and transketolase, increased levels of superoxide and advanced glucose end-products (AGE), and inhibition of the Akt/Pim-1/Bcl-2 signalling pathway. Similarly, culture of murine CPCs or human CD105(pos) progenitor cells in high glucose inhibits the pentose phosphate and pro-survival signalling pathways, leading to the activation of apoptosis. In vivo and in vitro supplementation with benfotiamine reactivates the pentose phosphate pathway and rescues CPC availability and function. This benefit is abrogated by either G6PD silencing by small interfering RNA (siRNA) or Akt inhibition by dominant-negative Akt. We provide new evidence of the negative impact of diabetes and high glucose on mechanisms controlling CPC redox state and survival. Boosting the pentose phosphate pathway might represent a novel mechanistic target for protection of CPC integrity.

  14. Importance of glycolysis and oxidative phosphorylation in advanced melanoma

    Directory of Open Access Journals (Sweden)

    Ho Jonhan

    2012-10-01

    Full Text Available Abstract Serum lactate dehydrogenase (LDH is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS, we subsequently determined using tissue microarray (TMA analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy.

  15. Natural Compounds Regulate Glycolysis in Hypoxic Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Jian-Li Gao

    2015-01-01

    Full Text Available In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect. Recently it became a therapeutically interesting strategy and is considered as an emerging hallmark of cancer. Hypoxia inducible factor-1 (HIF-1 is one of the key transcription factors that play major roles in tumor glycolysis and could directly trigger Warburg effect. Thus, how to inhibit HIF-1-depended Warburg effect to assist the cancer therapy is becoming a hot issue in cancer research. In fact, HIF-1 upregulates the glucose transporters (GLUT and induces the expression of glycolytic enzymes, such as hexokinase, pyruvate kinase, and lactate dehydrogenase. So small molecules of natural origin used as GLUT, hexokinase, or pyruvate kinase isoform M2 inhibitors could represent a major challenge in the field of cancer treatment. These compounds aim to suppress tumor hypoxia induced glycolysis process to suppress the cell energy metabolism or enhance the susceptibility of tumor cells to radio- and chemotherapy. In this review, we highlight the role of natural compounds in regulating tumor glycolysis, with a main focus on the glycolysis under hypoxic tumor microenvironment.

  16. Inhibition of glycolysis by misonidazole in hypoxic cells

    International Nuclear Information System (INIS)

    Ling, L.; Sutherland, R.

    1984-01-01

    Inhibition of glycolysis has been postulated to be a mechanism of misonidazole (MISO) toxicity in hypoxic cells. To investigate the effect of MISO on glycolysis, glucose transport and its consumption and lactate formation were measured. Exponential EMT6 cells (10/sup 6/ cells/ml) were made hypoxix by continuous gassing in 3% CO/sub 2/ in N/sub 2/. They were then treated with 5mM MISO for various times, then washed and analysed for their rates of anaerobic glycolysis. Glucose and lactate content were determined enzymatically. The rates of both glucose consumption and lactate formation decreased after 30 min hypoxic incubation with MISO. After 90 min, the rates were not measurable even though the cells still excluded Trypan Blue. There was, however, a parallel decrease in plating efficiency. These data suggest that the inhibition of glycolysis is an important mechanism of hypoxic toxicity of MISO. To locate the site of inhibition, studies were initiated to look at glucose transport by following the uptake of /sup 14/-C-3-0-methyl-glucose, a nonmetabolised glucose analog. Results obtained so far indicate that up to 90 min of hypoxic incubation with MISO, there was no change in the kinetics of the uptake of his analog. Therefore, the results showed that in hypoxic cells treated with MISO, the glucose transport system was unaffected. However, there was a rapid decrease in anaerobic glycolysis

  17. Correlation between TCA cycle flux and glucose uptake rate during respiro-fermentative growth of Saccharomyces cerevisiae.

    Science.gov (United States)

    Heyland, Jan; Fu, Jianan; Blank, Lars M

    2009-12-01

    Glucose repression of the tricarboxylic acid (TCA) cycle in Saccharomyces cerevisiae was investigated under different environmental conditions using (13)C-tracer experiments. Real-time quantification of the volatile metabolites ethanol and CO(2) allowed accurate carbon balancing. In all experiments with the wild-type, a strong correlation between the rates of growth and glucose uptake was observed, indicating a constant yield of biomass. In contrast, glycerol and acetate production rates were less dependent on the rate of glucose uptake, but were affected by environmental conditions. The glycerol production rate was highest during growth in high-osmolarity medium (2.9 mmol g(-1) h(-1)), while the highest acetate production rate of 2.1 mmol g(-1) h(-1) was observed in alkaline medium of pH 6.9. Under standard growth conditions (25 g glucose l(-1) , pH 5.0, 30 degrees C) S. cerevisiae had low fluxes through the pentose phosphate pathway and the TCA cycle. A significant increase in TCA cycle activity from 0.03 mmol g(-1) h(-1) to about 1.7 mmol g(-1) h(-1) was observed when S. cerevisiae grew more slowly as a result of environmental perturbations, including unfavourable pH values and sodium chloride stress. Compared to experiments with high glucose uptake rates, the ratio of CO(2) to ethanol increased more than 50 %, indicating an increase in flux through the TCA cycle. Although glycolysis and the ethanol production pathway still exhibited the highest fluxes, the net flux through the TCA cycle increased significantly with decreasing glucose uptake rates. Results from experiments with single gene deletion mutants partially impaired in glucose repression (hxk2, grr1) indicated that the rate of glucose uptake correlates with this increase in TCA cycle flux. These findings are discussed in the context of regulation of glucose repression.

  18. Glycolysis of poly (3-hydroxybutyrate) catalyzed by an enzyme system

    International Nuclear Information System (INIS)

    Campos, T.F.; Mano, V.

    2010-01-01

    In this work we report the studies of PHB glycolysis catalyzed by lipase Amano PS (Pseudomonas cepacia) in the presence of 1,2-ethanediol (ethylene glycol). The reactions were performed in toluene:dichloroethane 3:1 (v/v) at 60 deg C, varying reaction time and concentration of ethylene glycol. PHB and the products of glycolysis (polyols) were characterized by FTIR, 1 H-NMR, and TG. The FTIR spectra of polyols showed no significant change compared to the spectrum of PHB. The 1 H-NMR spectra of the products of glycolysis showed signs of interest between 3 and 4.7 ppm, related to the ethylene glycol protons inserted in the polymer chain. By analyzing the thermograms we observed that the polyols are more thermally stable than PHB. (author)

  19. Genome-scale consequences of cofactor balancing in engineered pentose utilization pathways in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Amit Ghosh

    Full Text Available Biofuels derived from lignocellulosic biomass offer promising alternative renewable energy sources for transportation fuels. Significant effort has been made to engineer Saccharomyces cerevisiae to efficiently ferment pentose sugars such as D-xylose and L-arabinose into biofuels such as ethanol through heterologous expression of the fungal D-xylose and L-arabinose pathways. However, one of the major bottlenecks in these fungal pathways is that the cofactors are not balanced, which contributes to inefficient utilization of pentose sugars. We utilized a genome-scale model of S. cerevisiae to predict the maximal achievable growth rate for cofactor balanced and imbalanced D-xylose and L-arabinose utilization pathways. Dynamic flux balance analysis (DFBA was used to simulate batch fermentation of glucose, D-xylose, and L-arabinose. The dynamic models and experimental results are in good agreement for the wild type and for the engineered D-xylose utilization pathway. Cofactor balancing the engineered D-xylose and L-arabinose utilization pathways simulated an increase in ethanol batch production of 24.7% while simultaneously reducing the predicted substrate utilization time by 70%. Furthermore, the effects of cofactor balancing the engineered pentose utilization pathways were evaluated throughout the genome-scale metabolic network. This work not only provides new insights to the global network effects of cofactor balancing but also provides useful guidelines for engineering a recombinant yeast strain with cofactor balanced engineered pathways that efficiently co-utilizes pentose and hexose sugars for biofuels production. Experimental switching of cofactor usage in enzymes has been demonstrated, but is a time-consuming effort. Therefore, systems biology models that can predict the likely outcome of such strain engineering efforts are highly useful for motivating which efforts are likely to be worth the significant time investment.

  20. Understanding start-up problems in yeast glycolysis.

    Science.gov (United States)

    Overal, Gosse B; Teusink, Bas; Bruggeman, Frank J; Hulshof, Josephus; Planqué, Robert

    2018-05-01

    Yeast glycolysis has been the focus of research for decades, yet a number of dynamical aspects of yeast glycolysis remain poorly understood at present. If nutrients are scarce, yeast will provide its catabolic and energetic needs with other pathways, but the enzymes catalysing upper glycolytic fluxes are still expressed. We conjecture that this overexpression facilitates the rapid transition to glycolysis in case of a sudden increase in nutrient concentration. However, if starved yeast is presented with abundant glucose, it can enter into an imbalanced state where glycolytic intermediates keep accumulating, leading to arrested growth and cell death. The bistability between regularly functioning and imbalanced phenotypes has been shown to depend on redox balance. We shed new light on these phenomena with a mathematical analysis of an ordinary differential equation model, including NADH to account for the redox balance. In order to gain qualitative insight, most of the analysis is parameter-free, i.e., without assigning a numerical value to any of the parameters. The model has a subtle bifurcation at the switch between an inviable equilibrium state and stable flux through glycolysis. This switch occurs if the ratio between the flux through upper glycolysis and ATP consumption rate of the cell exceeds a fixed threshold. If the enzymes of upper glycolysis would be barely expressed, our model predicts that there will be no glycolytic flux, even if external glucose would be at growth-permissable levels. The existence of the imbalanced state can be found for certain parameter conditions independent of the mentioned bifurcation. The parameter-free analysis proved too complex to directly gain insight into the imbalanced states, but the starting point of a branch of imbalanced states can be shown to exist in detail. Moreover, the analysis offers the key ingredients necessary for successful numerical continuation, which highlight the existence of this bistability and the

  1. Kinetics and mechanism of thermal degradation of pentose- and hexose-based carbohydrate polymers.

    Science.gov (United States)

    Akbar, Jamshed; Iqbal, Mohammad S; Massey, Shazma; Masih, Rashid

    2012-10-15

    This work aims at study of thermal degradation kinetics and mechanism of pentose- and hexose-based carbohydrate polymers isolated from Plantago ovata (PO), Salvia aegyptiaca (SA) and Ocimum basilicum (OB). The analysis was performed by isoconversional method. The materials exhibited mainly two-stage degradation. The weight loss at ambient-115°C characterized by low activation energy corresponds to loss of moisture. The kinetic triplets consisting of E, A and g(α) model of the materials were determined. The major degradation stage represents a loss of high boiling volatile components. This stage is exothermic in nature. Above 340°C complete degradation takes place leaving a residue of 10-15%. The master plots of g(α) function clearly differentiated the degradation mechanism of hexose-based OB and SA polymers and pentose-based PO polymer. The pentose-based carbohydrate polymer showed D(4) type and the hexose-based polymers showed A(4) type degradation mechanism. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Identification of the missing links in prokaryotic pentose oxidation pathways: evidence for enzyme recruitment.

    Science.gov (United States)

    Brouns, Stan J J; Walther, Jasper; Snijders, Ambrosius P L; van de Werken, Harmen J G; Willemen, Hanneke L D M; Worm, Petra; de Vos, Marjon G J; Andersson, Anders; Lundgren, Magnus; Mazon, Hortense F M; van den Heuvel, Robert H H; Nilsson, Peter; Salmon, Laurent; de Vos, Willem M; Wright, Phillip C; Bernander, Rolf; van der Oost, John

    2006-09-15

    The pentose metabolism of Archaea is largely unknown. Here, we have employed an integrated genomics approach including DNA microarray and proteomics analyses to elucidate the catabolic pathway for D-arabinose in Sulfolobus solfataricus. During growth on this sugar, a small set of genes appeared to be differentially expressed compared with growth on D-glucose. These genes were heterologously overexpressed in Escherichia coli, and the recombinant proteins were purified and biochemically studied. This showed that D-arabinose is oxidized to 2-oxoglutarate by the consecutive action of a number of previously uncharacterized enzymes, including a D-arabinose dehydrogenase, a D-arabinonate dehydratase, a novel 2-keto-3-deoxy-D-arabinonate dehydratase, and a 2,5-dioxopentanoate dehydrogenase. Promoter analysis of these genes revealed a palindromic sequence upstream of the TATA box, which is likely to be involved in their concerted transcriptional control. Integration of the obtained biochemical data with genomic context analysis strongly suggests the occurrence of pentose oxidation pathways in both Archaea and Bacteria, and predicts the involvement of additional enzyme components. Moreover, it revealed striking genetic similarities between the catabolic pathways for pentoses, hexaric acids, and hydroxyproline degradation, which support the theory of metabolic pathway genesis by enzyme recruitment.

  3. Nuclear magnetic resonance studies of the regulation of the pentose phosphate pathway

    International Nuclear Information System (INIS)

    Bolo, N.R.

    1991-11-01

    The goal of this work is to investigate the potential for and limitations of in vivo nuclear magnetic resonance (NMR) spectroscopy for quantitation of glucose flux through the pentose phosphate pathway (shunt). Interest in the shunt is motivated by the possibility that its activity may be greatly increased in cancer and in the pathological states of cardiac and cerebral ischemia. The ability to dynamically monitor flux through the pentose shunt can give new knowledge about metabolism in pathological states. 13 C NMR spectroscopy was used to monitor shunt activity by determination of the ratios of [ 13 C-4] to [ 13 C-5]-glutamate, [ 13 C-3] to [ 13 C-2]-alanine or [ 13 C-3] to [ 13 C-2]-lactate produced when [ 13 C-2]-glucose is infused. These methods provide measures of the effect of oxidative stresses on shunt activity in systems ranging from cell free enzyme-substrate preparations to cell suspensions and whole animals. In anaerobic cell free preparations, the fraction of glucose flux through the shunt was monitored with a time resolution of 3 minutes. This work predicts the potential for in vivo human studies of pentose phosphate pathway activity based on the mathematical simulation of the 13 C fractional enrichments of C4 and C5-glutamate as a function of shunt activity and on the signal-to- noise ratio acquired in 13 C NMR human studies from the current literature

  4. Nuclear magnetic resonance studies of the regulation of the pentose phosphate pathway

    Energy Technology Data Exchange (ETDEWEB)

    Bolo, N.R.

    1991-11-01

    The goal of this work is to investigate the potential for and limitations of in vivo nuclear magnetic resonance (NMR) spectroscopy for quantitation of glucose flux through the pentose phosphate pathway (shunt). Interest in the shunt is motivated by the possibility that its activity may be greatly increased in cancer and in the pathological states of cardiac and cerebral ischemia. The ability to dynamically monitor flux through the pentose shunt can give new knowledge about metabolism in pathological states. {sup 13}C NMR spectroscopy was used to monitor shunt activity by determination of the ratios of ({sup 13}C-4) to ({sup 13}C-5)-glutamate, ({sup 13}C-3) to ({sup 13}C-2)-alanine or ({sup 13}C-3) to ({sup 13}C-2)-lactate produced when ({sup 13}C-2)-glucose is infused. These methods provide measures of the effect of oxidative stresses on shunt activity in systems ranging from cell free enzyme-substrate preparations to cell suspensions and whole animals. In anaerobic cell free preparations, the fraction of glucose flux through the shunt was monitored with a time resolution of 3 minutes. This work predicts the potential for in vivo human studies of pentose phosphate pathway activity based on the mathematical simulation of the {sup 13}C fractional enrichments of C4 and C5-glutamate as a function of shunt activity and on the signal-to- noise ratio acquired in {sup 13}C NMR human studies from the current literature.

  5. Experimental determination of control of glycolysis in Lactococcus lactis

    DEFF Research Database (Denmark)

    Købmann, Brian Jensen; Andersen, Heidi Winterberg; Solem, Christian

    2002-01-01

    ), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PYK) and lactate dehydrogenase (LDH) are shown to have no significant control on the glycolytic flux in exponentially growing cells of L. lactis MG1363. Introduction of an uncoupled ATPase activity results in uncoupling of glycolysis from biomass...... production. With MG1363 growing in defined medium supplemented with glucose, the ATP demanding processes do not have a significant control on the glycolytic flux; it appears that glycolysis is running at maximal rate. It is likely that the flux control is distributed over many enzymes in L. lactis...

  6. Trehalose-6-phosphate synthase and stabilization of yeast glycolysis

    DEFF Research Database (Denmark)

    Fraenkel, Dan; Nielsen, Jens

    2016-01-01

    ‘Lost in transition: Startup of glycolysis yields subpopulations of nongrowing cells…’ (‘LIT’, van Heerden et al. 2014) is a massive paper from groups in Amsterdam and Delft, which deals with broad issues in metabolism and cell heterogeneity, as addressed for the predominant metabolic pathway......, glycolysis, in the context of a long studied but incompletely understood yeast mutant which is impaired in use of glucose without evident direct defects in the pathway. The primary approach is the quite original one of predicting, for the mutant, the dynamics of metabolism upon glucose addition, based...

  7. Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

    Science.gov (United States)

    Watanabe, Miki; Muraleedharan, Ranjithmenon; Lambert, Paul F.; Lane, Andrew N.; Romick-Rosendale, Lindsey E.; Wells, Susanne I.

    2017-01-01

    The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth. PMID:28558019

  8. Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis.

    Directory of Open Access Journals (Sweden)

    Marie C Matrka

    Full Text Available The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos. To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth.

  9. Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis

    NARCIS (Netherlands)

    Chang, Chih-Hao; Curtis, Jonathan D.; Maggi, Leonard B.; Faubert, Brandon; Villarino, Alejandro V.; O'Sullivan, David; Huang, Stanley Ching-Cheng; van der Windt, Gerritje J. W.; Blagih, Julianna; Qiu, Jing; Weber, Jason D.; Pearce, Edward J.; Jones, Russell G.; Pearce, Erika L.

    2013-01-01

    A "switch'' from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete

  10. Discrete event simulations for glycolysis pathway and energy balance

    NARCIS (Netherlands)

    Zwieten, van D.A.J.; Rooda, J.E.; Armbruster, H.D.; Nagy, J.D.

    2010-01-01

    In this report, the biological network of the glycolysis pathway has been modeled using discrete event models (DEMs). The most important feature of this pathway is that energy is released. To create a stable steady-state system an energy molecule equilibrating enzyme and metabolic reactions have

  11. Regulation of glycolysis and level of the Crassulacean acid metabolism.

    Science.gov (United States)

    Pierre, J N; Queiroz, O

    1979-01-01

    Glycolysis shows different patterns of operation and different control steps, depending on whether the level of Crassulacean acid metabolism (CAM) is low or high in the leaves of Kalanchoe blossfeldiana v.Poelln., when subjected to appropriate photoperiodic treatments: at a low level of CAM operation all the enzymes of glycolysis and phosphoenol pyruvate (PEP) carboxylase present a 12 h rhythm of capacity, resulting from the superposition of two 24h rhythms out of phase; phosphofructokinase appears to be the main regulation step; attainment of high CAM level involves (1) an increase in the peak of capacity occurring during the night of all the glycolytic enzymes, thus achieving an over-all 24h rhythm, in strict allometric coherence with the increase in PEP carboxylase capacity, (2) the establishment of different phase relationships between the rhythms of enzyme capacity, and (3) the control of three enzymic steps (phosphofructokinase, the group 3-P-glyceraldehyde dehydrogenase - 3-P-glycerate kinase, and PEP carboxylase). Results show that the hypothesis of allosteric regulation of phosphofructokinase (by PEP) and PEP carboxylase (by malate and glucose-6-P) cannot provide a complete explanation for the temporal organization of glycolysis and that changes in the phase relationships between the rhythms of enzyme capacity along the pathway and a strict correlation between the level of PEP carboxylase capacity and the levels of capacity of the glycolytic enzymes are important components of the regulation of glycolysis in relation to CAM.

  12. Tumor cells and memory T cells converge at glycolysis

    Science.gov (United States)

    Karthikeyan, Swathi; Geschwind, Jean-Francois; Ganapathy-Kanniappan, Shanmugasundaram

    2014-01-01

    In the immune system, activation of naïve T (Tn) cells into effector T cells (Teff) involves a metabolic switch to glycolysis to promote rapid proliferation and differentiation. In the October issue of The Journal of Clinical Investigation, Sukumar et al. have demonstrated that in CD8+ memory T (Tems) cells glycolytic phenotype contributes to the shortened lifespan of Tems. Conversely, inhibition of glycolysis in Tems not only extended their viability but also augmented desirable properties. Notably, they also demonstrate that glycolytic inhibition during the ex vivo clonal expansion of tumor-specific Tems enhanced their antitumor function. Overall, the data suggest that an antiglycolytic strategy targeting the Tems could enhance antitumor immune response. On the other hand, cancer cells have long been known to exhibit metabolic reprogramming which involves a shift toward glycolysis (the conversion of glucose into lactate) to facilitate uninterrupted growth. Interestingly, antiglycolytic treatment of cancer cells has been known to trigger antitumor immune response as well. Taken together, it is probable that a strategy involving concurrent inhibition of glycolysis in tumor cells and Tems could promote a dual attack on cancer by inducing an effective antitumor immune response and an immunogenic chemotherapy. PMID:24556820

  13. Nuclear magnetic resonance studies of the regulation of the pentose phosphate pathway

    Energy Technology Data Exchange (ETDEWEB)

    Bolo, Nicolas Robin [Univ. of California, Berkeley, CA (United States)

    1991-11-01

    The goal of this work is to investigate the potential for and limitations of in vivo nuclear magnetic resonance (NMR) spectroscopy for quantitation of glucose flux through the pentose phosphate pathway (shunt). Interest in the shunt is motivated by the possibility that its activity may be greatly increased in cancer and in the pathological states of cardiac and cerebral ischemia. The ability to dynamically monitor flux through the pentose shunt can give new knowledge about metabolism in pathological states. 13C NMR spectroscopy was used to monitor shunt activity by determination of the ratios of [13C-4] to [13C-5]-glutamate, [13C-3] to [13C-2]-alanine or [13C-3] to [13C-2]-lactate produced when [13C-2]-glucose is infused. These methods provide measures of the effect of oxidative stresses on shunt activity in systems ranging from cell free enzyme-substrate preparations to cell suspensions and whole animals. In anaerobic cell free preparations, the fraction of glucose flux through the shunt was monitored with a time resolution of 3 minutes. This work predicts the potential for in vivo human studies of pentose phosphate pathway activity based on the mathematical simulation of the 13C fractional enrichments of C4 and C5-glutamate as a function of shunt activity and on the signal-to- noise ratio acquired in 13C NMR human studies from the current literature.

  14. Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug.

    Science.gov (United States)

    Cardaci, Simone; Desideri, Enrico; Ciriolo, Maria Rosa

    2012-02-01

    The Warburg effect refers to the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions. Although the molecular mechanisms underlying tumor reliance on glycolysis remains not completely clear, its inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have emerged by combinatorial studies exhibiting promising anticancer activity both in vitro and in vivo, as a single agent or in combination with other therapeutic modalities. Therefore, besides reviewing the alterations of glycolysis that occur with malignant transformation, this manuscript aims at recapitulating the most effective pharmacological therapeutics of its targeting. In particular, we describe the principal mechanisms of action and the main targets of 3-bromopyruvate, an alkylating agent with impressive antitumor effects in several models of animal tumors. Moreover, we discuss the chemo-potentiating strategies that would make unparalleled the putative therapeutic efficacy of its use in clinical settings.

  15. Regulation of glycolysis in brown adipocytes by HIF-1α

    DEFF Research Database (Denmark)

    Basse, Astrid L; Isidor, Marie S; Winther, Sally

    2017-01-01

    Brown adipose tissue takes up large amounts of glucose during cold exposure in mice and humans. Here we report an induction of glucose transporter 1 expression and increased expression of several glycolytic enzymes in brown adipose tissue from cold-exposed mice. Accordingly, these genes were also...... with glucose as the only exogenously added fuel. These data suggest that HIF-1α-dependent regulation of glycolysis is necessary for maximum glucose metabolism in brown adipocytes....

  16. Radiation induces aerobic glycolysis through reactive oxygen species

    International Nuclear Information System (INIS)

    Zhong, Jim; Rajaram, Narasimhan; Brizel, David M.; Frees, Amy E.; Ramanujam, Nirmala; Batinic-Haberle, Ines; Dewhirst, Mark W.

    2013-01-01

    Background and purpose: Although radiation induced reoxygenation has been thought to increase radiosensitivity, we have shown that its associated oxidative stress can have radioprotective effects, including stabilization of the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 is known to regulate many of the glycolytic enzymes, thereby promoting aerobic glycolysis, which is known to promote treatment resistance. Thus, we hypothesized that reoxygenation after radiation would increase glycolysis. We previously showed that blockade of oxidative stress using a superoxide dismutase (SOD) mimic during reoxygenation can downregulate HIF-1 activity. Here we tested whether concurrent use of this drug with radiotherapy would reduce the switch to a glycolytic phenotype. Materials and methods: 40 mice with skin fold window chambers implanted with 4T1 mammary carcinomas were randomized into (1) no treatment, (2) radiation alone, (3) SOD mimic alone, and (4) SOD mimic with concurrent radiation. All mice were imaged on the ninth day following tumor implantation (30 h following radiation treatment) following injection of a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Hemoglobin saturation was measured by using hyperspectral imaging to quantify oxygenation state. Results: Mice treated with radiation showed significantly higher 2-NBDG fluorescence compared to controls (p = 0.007). Hemoglobin saturation analysis demonstrated reoxygenation following radiation, coinciding with the observed increase in glycolysis. The concurrent use of the SOD mimic with radiation demonstrated a significant reduction in 2-NBDG fluorescence compared to effects seen after radiation alone, while having no effect on reoxygenation. Conclusions: Radiation induces an increase in tumor glucose demand approximately 30 h following therapy during reoxygenation. The use of an SOD mimic can prevent the increase in aerobic glycolysis when used

  17. Mushroom body glycolysis is required for olfactory memory in Drosophila.

    Science.gov (United States)

    Wu, Chia-Lin; Chang, Ching-Ching; Wu, Jie-Kai; Chiang, Meng-Hsuan; Yang, Chu-Huai; Chiang, Hsueh-Cheng

    2018-04-01

    Glucose catabolism, also known as glycolysis, is important for energy generation and involves a sequence of enzymatic reactions that convert a glucose molecule into two pyruvate molecules. The glycolysis process generates adenosine triphosphate as a byproduct. In this study, we investigated whether glycolysis plays a role in maintaining neuronal functions in the Drosophila mushroom bodies (MBs), which are generally accepted to be an olfactory learning and memory center. Our data showed that individual knockdown of glycolytic enzymes in the MBs, including hexokinase (HexA), phosphofructokinase (Pfk), or pyruvate kinase (PyK), disrupts olfactory memory. Whole-mount brain immunostaining indicated that pyruvate kinase is strongly expressed in the MB αβ, α'β', and γ neuron subsets. We conclude that HexA, Pfk, and PyK are required in each MB neuron subset for olfactory memory formation. Our data therefore indicates that glucose catabolism in the MBs is important for olfactory memory formation in Drosophila. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Inhibition of the pentose phosphate shunt by 2,3-diphosphoglycerate in erythrocyte pyruvate kinase deficiency.

    Science.gov (United States)

    Tomoda, A; Lachant, N A; Noble, N A; Tanaka, K R

    1983-07-01

    Pentose phosphate shunt activity was studied by the release of 14CO2 from 14C-1-glucose and 14C-2-glucose in the red cells of five patients with pyruvate kinase deficiency and found to be significantly decreased after new methylene blue stimulation when compared to high reticulocyte controls. Incubated Heinz body formation was increased and the ascorbate cyanide test was positive in blood from these patients. The activity of glucose-6-phosphate dehydrogenase (G6PD) as well as that of 6-phosphogluconate dehydrogenase (6PGD) was inhibited to 20% of baseline in normal red cell haemolysate by 4 mM 2,3-diphosphoglycerate at pH 7.1. 2,3-Diphosphoglycerate was a competitive inhibitor with 6-phosphogluconate (Ki=1.05 mM) and a noncompetitive inhibitor with NADP (Ki=3.3 mM) for 6PGD. Since the intracellular concentrations of glucose-6-phosphate, 6-phosphogluconate and NADP are below their Kms for G6PD and 6PGD, the kinetic data suggest that increased concentrations of 2,3-diphosphoglycerate in pyruvate kinase deficient red cells are sufficiently high to suppress pentose phosphate shunt activity. This suppression may be an additional factor contributing to the haemolytic anaemia of pyruvate kinase deficiency, particularly during periods of infection or metabolic stress.

  19. Conserved features of cancer cells define their sensitivity of HAMLET-induced death; c-Myc and glycolysis

    Science.gov (United States)

    Storm, Petter; Puthia, Manoj Kumar; Aits, Sonja; Urbano, Alexander; Northen, Trent; Powers, Scott; Bowen, Ben; Chao, Yinxia; Reindl, Wolfgang; Lee, Do Yup; Sullivan, Nancy Liu; Zhang, Jianping; Trulsson, Maria; Yang, Henry; Watson, James; Svanborg, Catharina

    2014-01-01

    HAMLET is the first member of a new family of tumoricidal protein-lipid complexes that kill cancer cells broadly, while sparing healthy, differentiated cells. Many and diverse tumor cell types are sensitive to the lethal effect, suggesting that HAMLET identifies and activates conserved death pathways in cancer cells. Here we investigated the molecular basis for the difference in sensitivity between cancer cells and healthy cells. Using a combination of small hairpin RNA inhibition, proteomic and metabolomic technology we identified the c-Myc oncogene as one essential determinant of HAMLET sensitivity. Increased c-Myc expression levels promoted the sensitivity to HAMLET and shRNA knockdown of c-Myc suppressed the lethal response, suggesting that oncogenic transformation with c-Myc creates a HAMLET-sensitive phenotype. Furthermore, the HAMLET sensitivity was modified by the glycolytic state of the tumor cells. Glucose deprivation sensitized tumor cells to HAMLET-induced cell death and in the shRNA screen Hexokinase 1, PFKFB1 and HIF1α modified HAMLET sensitivity. Hexokinase 1 was shown to bind HAMLET in a protein array containing approximately 8000 targets and Hexokinase activity decreased within 15 minutes of HAMLET treatment, prior to morphological signs of tumor cell death. In parallel, HAMLET triggered rapid metabolic paralysis in carcinoma cells. The glycolytic machinery was modified and glycolysis was shifted towards the pentose phosphate pathway. Tumor cells were also shown to contain large amounts of oleic acid and its derivatives already after 15 minutes. The results identify HAMLET as a novel anti-cancer agent that kills tumor cells by exploiting unifying features of cancer cells such as oncogene-addiction or the Warburg effect. PMID:21643007

  20. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis.

    Science.gov (United States)

    Ding, Hao; Jiang, Lei; Xu, Jing; Bai, Feng; Zhou, Yang; Yuan, Qi; Luo, Jing; Zen, Ke; Yang, Junwei

    2017-09-01

    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. Copyright © 2017 the American Physiological Society.

  1. Fitness of Escherichia coli during urinary tract infection requires gluconeogenesis and the TCA cycle.

    Directory of Open Access Journals (Sweden)

    Christopher J Alteri

    2009-05-01

    Full Text Available Microbial pathogenesis studies traditionally encompass dissection of virulence properties such as the bacterium's ability to elaborate toxins, adhere to and invade host cells, cause tissue damage, or otherwise disrupt normal host immune and cellular functions. In contrast, bacterial metabolism during infection has only been recently appreciated to contribute to persistence as much as their virulence properties. In this study, we used comparative proteomics to investigate the expression of uropathogenic Escherichia coli (UPEC cytoplasmic proteins during growth in the urinary tract environment and systematic disruption of central metabolic pathways to better understand bacterial metabolism during infection. Using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE and tandem mass spectrometry, it was found that UPEC differentially expresses 84 cytoplasmic proteins between growth in LB medium and growth in human urine (P<0.005. Proteins induced during growth in urine included those involved in the import of short peptides and enzymes required for the transport and catabolism of sialic acid, gluconate, and the pentose sugars xylose and arabinose. Proteins required for the biosynthesis of arginine and serine along with the enzyme agmatinase that is used to produce the polyamine putrescine were also up-regulated in urine. To complement these data, we constructed mutants in these genes and created mutants defective in each central metabolic pathway and tested the relative fitness of these UPEC mutants in vivo in an infection model. Import of peptides, gluconeogenesis, and the tricarboxylic acid cycle are required for E. coli fitness during urinary tract infection while glycolysis, both the non-oxidative and oxidative branches of the pentose phosphate pathway, and the Entner-Doudoroff pathway were dispensable in vivo. These findings suggest that peptides and amino acids are the primary carbon source for E. coli during infection of

  2. Isotopomer profiling of Leishmania mexicana promastigotes reveals important roles for succinate fermentation and aspartate uptake in tricarboxylic acid cycle (TCA) anaplerosis, glutamate synthesis, and growth.

    Science.gov (United States)

    Saunders, Eleanor C; Ng, William W; Chambers, Jennifer M; Ng, Milica; Naderer, Thomas; Krömer, Jens O; Likic, Vladimir A; McConville, Malcolm J

    2011-08-05

    Leishmania parasites proliferate within nutritionally complex niches in their sandfly vector and mammalian hosts. However, the extent to which these parasites utilize different carbon sources remains poorly defined. In this study, we have followed the incorporation of various (13)C-labeled carbon sources into the intracellular and secreted metabolites of Leishmania mexicana promastigotes using gas chromatography-mass spectrometry and (13)C NMR. [U-(13)C]Glucose was rapidly incorporated into intermediates in glycolysis, the pentose phosphate pathway, and the cytoplasmic carbohydrate reserve material, mannogen. Enzymes involved in the upper glycolytic pathway are sequestered within glycosomes, and the ATP and NAD(+) consumed by these reactions were primarily regenerated by the fermentation of phosphoenolpyruvate to succinate (glycosomal succinate fermentation). The initiating enzyme in this pathway, phosphoenolpyruvate carboxykinase, was exclusively localized to the glycosome. Although some of the glycosomal succinate was secreted, most of the C4 dicarboxylic acids generated during succinate fermentation were further catabolized in the TCA cycle. A high rate of TCA cycle anaplerosis was further suggested by measurement of [U-(13)C]aspartate and [U-(13)C]alanine uptake and catabolism. TCA cycle anaplerosis is apparently needed to sustain glutamate production under standard culture conditions. Specifically, inhibition of mitochondrial aconitase with sodium fluoroacetate resulted in the rapid depletion of intracellular glutamate pools and growth arrest. Addition of high concentrations of exogenous glutamate alleviated this growth arrest. These findings suggest that glycosomal and mitochondrial metabolism in Leishmania promastigotes is tightly coupled and that, in contrast to the situation in some other trypanosomatid parasites, the TCA cycle has crucial anabolic functions.

  3. Pentose sugars inhibit metabolism and increase expression of an AgrD-type cyclic pentapeptide in Clostridium thermocellum.

    Science.gov (United States)

    Verbeke, Tobin J; Giannone, Richard J; Klingeman, Dawn M; Engle, Nancy L; Rydzak, Thomas; Guss, Adam M; Tschaplinski, Timothy J; Brown, Steven D; Hettich, Robert L; Elkins, James G

    2017-02-23

    Clostridium thermocellum could potentially be used as a microbial biocatalyst to produce renewable fuels directly from lignocellulosic biomass due to its ability to rapidly solubilize plant cell walls. While the organism readily ferments sugars derived from cellulose, pentose sugars from xylan are not metabolized. Here, we show that non-fermentable pentoses inhibit growth and end-product formation during fermentation of cellulose-derived sugars. Metabolomic experiments confirmed that xylose is transported intracellularly and reduced to the dead-end metabolite xylitol. Comparative RNA-seq analysis of xylose-inhibited cultures revealed several up-regulated genes potentially involved in pentose transport and metabolism, which were targeted for disruption. Deletion of the ATP-dependent transporter, CbpD partially alleviated xylose inhibition. A putative xylitol dehydrogenase, encoded by Clo1313_0076, was also deleted resulting in decreased total xylitol production and yield by 41% and 46%, respectively. Finally, xylose-induced inhibition corresponds with the up-regulation and biogenesis of a cyclical AgrD-type, pentapeptide. Medium supplementation with the mature cyclical pentapeptide also inhibits bacterial growth. Together, these findings provide new foundational insights needed for engineering improved pentose utilizing strains of C. thermocellum and reveal the first functional Agr-type cyclic peptide to be produced by a thermophilic member of the Firmicutes.

  4. Modulation of low dose radiation effect on pentose phosphate pathway enzymes by B-multivitamin deficiency

    International Nuclear Information System (INIS)

    Zimatkina, T.I.; Lashak, L.K.; Moiseenok, A.G.

    1997-01-01

    Blood, liver, thymus and spleen of albino rats injected subcutaneously with antivitamins (othythiamine and methotrexate) and subjected to prolonger γ-irradiation in the overall dose of 0.75 Gy were assayed for transketolase and glucose-6-phosphate dehydrogenase after 12h, 1, 2, 5 and 40 days from the last radiation dose. High transketolase sensitivity was found both to radiation (activation) and the combined effects of vitamin deficiency and radiation (potentiation of antivitamin inhibitory action) in all the tissues studied. The activity of glucose-6-phosphate dehydrogenase was little changed under the given experimental manipulations, but the combined effect of the factors considerably inhibited the enzyme activities in the organs of the immune system. Consequently, in B-multivitamin deficiency the effect of low radiation doses was subjected to a considerable modulation resulting in profound inhibition of the oxidation and nonoxidative branches of the pentose phosphate pathway. (author). 9 refs, 2 tabs

  5. Natural Diversity in Pentose Fermentation Is Explained by Variations in Histone Deacetylases

    Directory of Open Access Journals (Sweden)

    Zvi Tamari

    2016-01-01

    Full Text Available The extent to which carbon flux is directed toward fermentation versus respiration differs between cell types and environmental conditions. Understanding the basic cellular processes governing carbon flux is challenged by the complexity of the metabolic and regulatory networks. To reveal the genetic basis for natural diversity in channeling carbon flux, we applied quantitative trait loci analysis by phenotyping and genotyping hundreds of individual F2 segregants of budding yeast that differ in their capacity to ferment the pentose sugar xylulose. Causal alleles were mapped to the RXT3 and PHO23 genes, two components of the large Rpd3 histone deacetylation complex. We show that these allelic variants modulate the expression of SNF1/AMPK-dependent respiratory genes. Our results suggest that over close evolutionary distances, diversification of carbon flow is driven by changes in global regulators, rather than adaptation of specific metabolic nodes. Such regulators may improve the ability to direct metabolic fluxes for biotechnological applications.

  6. A reverse KREBS cycle in photosynthesis: consensus at last

    Science.gov (United States)

    Buchanan, B. B.; Arnon, D. I.

    1990-01-01

    The Krebs cycle (citric acid or tricarboxylic acid cycle), the final common pathway in aerobic metabolism for the oxidation of carbohydrates, fatty acids and amino acids, is known to be irreversible. It liberates CO2 and generates NADH whose aerobic oxidation yields ATP but it does not operate in reverse as a biosynthetic pathway for CO2 assimilation. In 1966, our laboratory described a cyclic pathway for CO2 assimilation (Evans, Buchanan and Arnon 1966) that was unusual in two respects: (i) it provided the first instance of an obligate photoautotroph that assimilated CO2 by a pathway different from Calvin's reductive pentose phosphate cycle (Calvin 1962) and (ii) in its overall effect the new cycle was a reversal of the Krebs cycle. Named the 'reductive carboxylic acid cycle' (sometimes also called the reductive tricarboxylic acid cycle) the new cycle appeared to be the sole CO2 assimilation pathway in Chlorobium thiosulfatophilum (Evans et al. 1966) (now known as Chlorobium limicola forma thiosulfatophilum). Chlorobium is a photosynthetic green sulfur bacterium that grows anaerobically in an inorganic medium with sulfide and thiosulfate as electron donors and CO2 as an obligatory carbon source. In the ensuing years, the new cycle was viewed with skepticism. Not only was it in conflict with the prevailing doctrine that the 'one important property ... shared by all (our emphasis) autotrophic species is the assimilation of CO2 via the Calvin cycle' (McFadden 1973) but also some of its experimental underpinnings were challenged. It is only now that in the words of one of its early skeptics (Tabita 1988) 'a long and tortuous controversy' has ended with general acceptance of the reductive carboxylic acid cycle as a photosynthetic CO2 assimilation pathway distinct from the pentose cycle. (Henceforth, to minimize repetitiveness, the reductive pentose phosphate cycle will often be referred to as the pentose cycle and the reductive carboxylic acid cycle as the carboxylic

  7. Implications of the simultaneous occurrence of glycolysis and gluconeogenesis in hepatocytes from normal and hyperthyroid rats

    International Nuclear Information System (INIS)

    Phillips, J.W.; Berry, M.N.

    2001-01-01

    The mammalian liver has the capability for both glycolysis and gluconeogenesis. In the fasting state, metabolites such as lactate and glycerol, generated in the peripheral tissues, are taken up by the liver and converted to glucose. However, hepatocytes from fasted animals are also capable of substantial rates of glycolysis. It is generally assumed that glycolysis and gluconeogenesis do not occur simultaneously in the same cell, but rather the metabolic conditions that facilitate flux through one pathway impair flow in the opposite direction. The actual direction of flow at any given moment is thought to be determined by regulatory mechanisms that control flux through the enzymatic steps specific to glycolysis and gluconeogenesis. The rates of glycolysis from [6- 3 H]glucose and gluconeogenesis from [U- 14 C]glycerol were determined in isolated hepatocytes from fasted normal and hyperthyroid rats. We observed that glycolysis from glucose and glucose synthesis from glycerol occurred simultaneously at substantial rates in hepatocytes from normal rats and that gluconeogenesis, but not glycolysis, was increased twofold in hepatocytes from thyroid treated rats. In the hyperthyroid state, the rate of glycolysis from glucose was approximately equal to the rate of glucose formation from glycerol. Hence, metabolism and ATP turnover were stimulated without substantially altering steady-state concentrations of glucose. The concomitant operation of hepatic glycolysis and gluconeogenesis may be a mechanism that accounts in part for the calorigenic effect of thyroid hormone. Since hepatocyles are generally impermeable to phosphorylated metabolites, our observations suggest that glycolysis, and phosphorylation of glycerol take place in the same cells, and that the occurrence of simultaneous glycolysis and gluconeogenesis is an indication of channelling within the hepatocyte cytoplasm of individual hepatocytes

  8. Modelling response of glycolysis in S. cerevisiae cells harvested at diauxic shift.

    NARCIS (Netherlands)

    Albers, E.; Bakker, B.M.; Gustafsson, L.

    2002-01-01

    The response of glycolysis to exposure of glucose in non-growing S. cerevisiae cells from diauxic shift was monitored. The result was compared to a kinetic model of glycolysis with branches to glycogen, trehalose, glycerol, and succinate. Experimental data at steady-state concentrations of

  9. Loss of Brain Aerobic Glycolysis in Normal Human Aging.

    Science.gov (United States)

    Goyal, Manu S; Vlassenko, Andrei G; Blazey, Tyler M; Su, Yi; Couture, Lars E; Durbin, Tony J; Bateman, Randall J; Benzinger, Tammie L-S; Morris, John C; Raichle, Marcus E

    2017-08-01

    The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Transient elevation of glycolysis confers radio-resistance by facilitating DNA repair in cells

    International Nuclear Information System (INIS)

    Bhatt, Anant Narayan; Chauhan, Ankit; Khanna, Suchit; Rai, Yogesh; Singh, Saurabh; Soni, Ravi; Kalra, Namita; Dwarakanath, Bilikere S

    2015-01-01

    Cancer cells exhibit increased glycolysis for ATP production (the Warburg effect) and macromolecular biosynthesis; it is also linked with therapeutic resistance that is generally associated with compromised respiratory metabolism. Molecular mechanisms underlying radio-resistance linked to elevated glycolysis remain incompletely understood. We stimulated glycolysis using mitochondrial respiratory modifiers (MRMs viz. di-nitro phenol, DNP; Photosan-3, PS3; Methylene blue, MB) in established human cell lines (HEK293, BMG-1 and OCT-1). Glucose utilization and lactate production, levels of glucose transporters and glycolytic enzymes were investigated as indices of glycolysis. Clonogenic survival, DNA repair and cytogenetic damage were studied as parameters of radiation response. MRMs induced the glycolysis by enhancing the levels of two important regulators of glucose metabolism GLUT-1 and HK-II and resulted in 2 fold increase in glucose consumption and lactate production. This increase in glycolysis resulted in resistance against radiation-induced cell death (clonogenic survival) in different cell lines at an absorbed dose of 5 Gy. Inhibition of glucose uptake and glycolysis (using fasentin, 2-deoxy-D-glucose and 3-bromopyruvate) in DNP treated cells failed to increase the clonogenic survival of irradiated cells, suggesting that radio-resistance linked to inhibition of mitochondrial respiration is glycolysis dependent. Elevated glycolysis also facilitated rejoining of radiation-induced DNA strand breaks by activating both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways of DNA double strand break repair leading to a reduction in radiation-induced cytogenetic damage (micronuclei formation) in these cells. These findings suggest that enhanced glycolysis generally observed in cancer cells may be responsible for the radio-resistance, partly by enhancing the repair of DNA damage

  11. Transformation of oil palm fronds into pentose sugars using copper (II) sulfate pentahydrate with the assistance of chemical additive.

    Science.gov (United States)

    Loow, Yu-Loong; Wu, Ta Yeong

    2018-06-15

    Among the chemical pretreatments available for pretreating biomass, the inorganic salt is considered to be a relatively new but simple reagent that offers comparable pentose (C5) sugar recoveries as the conventional dilute acid hydrolysis. This study investigated the effects of different concentrations (1.5-6.0% (v/v)) of H 2 O 2 or Na 2 S 2 O 8 in facilitating CuSO 4 ·5H 2 O pretreatment for improving pentose sugar recovery from oil palm fronds. The best result was observed when 0.2 mol/L of CuSO 4 ·5H 2 O was integrated with 4.5% (v/v) of Na 2 S 2 O 8 to recover 8.2 and 0.9 g/L of monomeric xylose and arabinose, respectively in the liquid fraction. On the other hand, an addition of 1.5% (v/v) of H 2 O 2 yielded approximately 74% lesser total pentose sugars as compared to using 4.5% (v/v) Na 2 S 2 O 8 . By using CuSO 4 ·5H 2 O alone (control), only 0.8 and 1.0 g/L xylose and arabinose, respectively could be achieved. The results mirrored the importance of using chemical additives together with the inorganic salt pretreatment of oil palm fronds. Thus, an addition of 4.5% (v/v) of Na 2 S 2 O 8 during CuSO 4 ·5H 2 O pretreatment of oil palm fronds at 120 °C and 30 min was able to attain a total pentose sugar yield up to ∼40%. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Reevaluation of the phenol-sulfuric acid reaction for the estimation of hexoses and pentoses.

    Science.gov (United States)

    Rao, P; Pattabiraman, T N

    1989-08-15

    Evidence is provided to show that in the conventional phenol-sulfuric acid reaction procedure, phenol underwent sulfonation in situ and the phenolsulfonic acid formed decreased the color intensity for hydroxymethyl furfural (HMF), furfural, and many hexoses and pentoses tested. A modified method is described to overcome this problem in which phenol was added after the dehydration of carbohydrates by sulfuric acid and after cooling the system. The color intensity around 475-485 nm for different compounds was fairly proportional to the amount of furfural derivatives (absorption at 310-320 nm) formed from the sugars in the modified method unlike in the conventional procedure. The studies also show that for condensation of HMF derivatives with phenol, heat is not necessary. The color intensity in the modified method also increased compared to that in the conventional method. The increase in the modified method compared to that in the conventional method was 6.0-fold for furfural, 9.1-fold for hydroxymethyl furfural, 3.7-fold for fructose, 2.3-fold for xylose, and 2.0-fold for glucose and arabinose. The possible reasons for this differential increase are discussed.

  13. Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Susan J. Gelman

    2018-01-01

    Full Text Available Summary: Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1 occur in multiple types of human cancer. Here, we show that these mutations significantly disrupt NADPH homeostasis by consuming NADPH for 2-hydroxyglutarate (2-HG synthesis. Cells respond to 2-HG synthesis, but not exogenous administration of 2-HG, by increasing pentose phosphate pathway (PPP flux. We show that 2-HG production competes with reductive biosynthesis and the buffering of oxidative stress, processes that also require NADPH. IDH1 mutants have a decreased capacity to synthesize palmitate and an increased sensitivity to oxidative stress. Our results demonstrate that, even when NADPH is limiting, IDH1 mutants continue to synthesize 2-HG at the expense of other NADPH-requiring pathways that are essential for cell viability. Thus, rather than attempting to decrease 2-HG synthesis in the clinic, the consumption of NADPH by mutant IDH1 may be exploited as a metabolic weakness that sensitizes tumor cells to ionizing radiation, a commonly used anti-cancer therapy. : Using liquid chromatography/mass spectrometry (LC/MS and stable isotope tracing, Gelman et al. find that 2-HG production in cells with IDH1 mutations leads to increased pentose phosphate pathway activity to generate NADPH. Production of 2-HG competes with other NADPH-dependent pathways and sensitizes cells to redox stress. Keywords: 2-hydroxyglutarate, cancer metabolism, LC/MS, metabolomcis, pentose phosphate pathway, redox regulation

  14. Improved Xylitol Production from D-Arabitol by Enhancing the Coenzyme Regeneration Efficiency of the Pentose Phosphate Pathway in Gluconobacter oxydans.

    Science.gov (United States)

    Li, Sha; Zhang, Jinliang; Xu, Hong; Feng, Xiaohai

    2016-02-10

    Gluconobacter oxydans is used to produce xylitol from D-arabitol. This study aims to improve xylitol production by increasing the coenzyme regeneration efficiency of the pentose phosphate pathway in G. oxydans. Glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) were overexpressed in G. oxydans. Real-time PCR and enzyme activity assays revealed that G6PDH/6PGDH activity and coenzyme regeneration efficiency increased in the recombinant G. oxydans strains. Approximately 29.3 g/L xylitol was obtained, with a yield of 73.2%, from 40 g/L d-arabitol in the batch biotransformation with the G. oxydans PZ strain. Moreover, the xylitol productivity (0.62 g/L/h) was 3.26-fold of the wild type strain (0.19 g/L/h). In repetitive batch biotransformation, the G. oxydans PZ cells were used for five cycles without incurring a significant loss in productivity. These results indicate that the recombinant G. oxydans PZ strain is economically feasible for xylitol production in industrial bioconversion.

  15. Glycolysis-induced discordance between glucose metabolic rates measured with radiolabeled fluorodeoxyglucose and glucose

    International Nuclear Information System (INIS)

    Ackermann, R.F.; Lear, J.L.

    1989-01-01

    We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered [ 18 F]fluorodeoxyglucose (FDG) and [ 14 C]-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic (GMg) and oxidative (GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the 14 C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the 14 C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt. If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum

  16. Global ablation of the mitochondrial calcium uniporter increases glycolysis in cortical neurons subjected to energetic stressors.

    Science.gov (United States)

    Nichols, Matthew; Elustondo, Pia A; Warford, Jordan; Thirumaran, Aruloli; Pavlov, Evgeny V; Robertson, George S

    2017-08-01

    The effects of global mitochondrial calcium (Ca 2+ ) uniporter (MCU) deficiency on hypoxic-ischemic (HI) brain injury, neuronal Ca 2+ handling, bioenergetics and hypoxic preconditioning (HPC) were examined. Forebrain mitochondria isolated from global MCU nulls displayed markedly reduced Ca 2+ uptake and Ca 2+ -induced opening of the membrane permeability transition pore. Despite evidence that these effects should be neuroprotective, global MCU nulls and wild-type (WT) mice suffered comparable HI brain damage. Energetic stress enhanced glycolysis and depressed Complex I activity in global MCU null, relative to WT, cortical neurons. HI reduced forebrain NADH levels more in global MCU nulls than WT mice suggesting that increased glycolytic consumption of NADH suppressed Complex I activity. Compared to WT neurons, pyruvate dehydrogenase (PDH) was hyper-phosphorylated in MCU nulls at several sites that lower the supply of substrates for the tricarboxylic acid cycle. Elevation of cytosolic Ca 2+ with glutamate or ionomycin decreased PDH phosphorylation in MCU null neurons suggesting the use of alternative mitochondrial Ca 2+ transport. Under basal conditions, global MCU nulls showed similar increases of Ca 2+ handling genes in the hippocampus as WT mice subjected to HPC. We propose that long-term adaptations, common to HPC, in global MCU nulls compromise resistance to HI brain injury and disrupt HPC.

  17. Astroglial Pentose Phosphate Pathway Rates in Response to High-Glucose Environments

    Directory of Open Access Journals (Sweden)

    Shinichi Takahashi

    2012-02-01

    Full Text Available ROS (reactive oxygen species play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of 14CO2 production from [1-14C]glucose and [6-14C]glucose. ROS production, mainly H2O2, and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum stress (presumably through increased hexosamine biosynthetic pathway flux. Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2, which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke.

  18. Fluorescence resonance energy transfer sensors for quantitative monitoring of pentose and disaccharide accumulation in bacteria

    Directory of Open Access Journals (Sweden)

    Looger Loren L

    2008-06-01

    Full Text Available Abstract Background Engineering microorganisms to improve metabolite flux requires detailed knowledge of the concentrations and flux rates of metabolites and metabolic intermediates in vivo. Fluorescence resonance energy transfer sensors represent a promising technology for measuring metabolite levels and corresponding rate changes in live cells. These sensors have been applied successfully in mammalian and plant cells but potentially could also be used to monitor steady-state levels of metabolites in microorganisms using fluorimetric assays. Sensors for hexose and pentose carbohydrates could help in the development of fermentative microorganisms, for example, for biofuels applications. Arabinose is one of the carbohydrates to be monitored during biofuels production from lignocellulose, while maltose is an important degradation product of starch that is relevant for starch-derived biofuels production. Results An Escherichia coli expression vector compatible with phage λ recombination technology was constructed to facilitate sensor construction and was used to generate a novel fluorescence resonance energy transfer sensor for arabinose. In parallel, a strategy for improving the sensor signal was applied to construct an improved maltose sensor. Both sensors were expressed in the cytosol of E. coli and sugar accumulation was monitored using a simple fluorimetric assay of E. coli cultures in microtiter plates. In the case of both nanosensors, the addition of the respective ligand led to concentration-dependent fluorescence resonance energy transfer responses allowing quantitative analysis of the intracellular sugar levels at given extracellular supply levels as well as accumulation rates. Conclusion The nanosensor destination vector combined with the optimization strategy for sensor responses should help to accelerate the development of metabolite sensors. The new carbohydrate fluorescence resonance energy transfer sensors can be used for in vivo

  19. Astroglial pentose phosphate pathway rates in response to high-glucose environments

    Science.gov (United States)

    Takahashi, Shinichi; Izawa, Yoshikane; Suzuki, Norihiro

    2012-01-01

    ROS (reactive oxygen species) play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway) and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of 14CO2 production from [1-14C]glucose and [6-14C]glucose. ROS production, mainly H2O2, and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum) stress (presumably through increased hexosamine biosynthetic pathway flux). Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase) by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein) expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke. PMID:22300409

  20. Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes

    Directory of Open Access Journals (Sweden)

    Johann eSteiner

    2014-11-01

    Full Text Available Clozapine has stronger systemic metabolic side effects than haloperidol and it was hypothesized that therapeutic antipsychotic and adverse metabolic effects might be related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production.Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT and monocarboxylate (MCT transporters was determined after 6h and 24h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed.Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside.Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.

  1. Metabolism: Part II. The Tricarboxylic Acid (TCA), Citric Acid, or Krebs Cycle.

    Science.gov (United States)

    Bodner, George M.

    1986-01-01

    Differentiates the tricarboxylic acid (TCA) cycle (or Krebs cycle) from glycolysis, and describes the bridge between the two as being the conversion of pyruvate into acetyl coenzyme A. Discusses the eight steps in the TCA cycle, the results of isotopic labeling experiments, and the net effects of the TCA cycle. (TW)

  2. 3-bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth.

    Science.gov (United States)

    Wang, Ting-An; Zhang, Xiao-Dong; Guo, Xing-Yu; Xian, Shu-Lin; Lu, Yun-Fei

    2016-03-01

    Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.

  3. Linking tumor glycolysis and immune evasion in cancer: Emerging concepts and therapeutic opportunities.

    Science.gov (United States)

    Ganapathy-Kanniappan, Shanmugasundaram

    2017-08-01

    Metabolic reprogramming and immune evasion are two hallmarks of cancer. Metabolic reprogramming is exemplified by cancer's propensity to utilize glucose at an exponential rate which in turn is linked with "aerobic glycolysis", popularly known as the "Warburg effect". Tumor glycolysis is pivotal for the efficient management of cellular bioenergetics and uninterrupted cancer growth. Mounting evidence suggests that tumor glycolysis also plays a key role in instigating immunosuppressive networks that are critical for cancer cells to escape immune surveillance ("immune evasion"). Recent data show that induction of cellular stress or metabolic dysregulation sensitize cancer cells to antitumor immune cells implying that metabolic reprogramming and immune evasion harmonize during cancer progression. However, the molecular link between these two hallmarks of cancer remains obscure. In this review the molecular intricacies of tumor glycolysis that facilitate immune evasion has been discussed in the light of recent research to explore immunotherapeutic potential of targeting cancer metabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Glycolysis in contracting rat skeletal muscle is controlled by factors related to energy state

    DEFF Research Database (Denmark)

    Ørtenblad, Niels; Macdonald, Will A; Sahlin, Kent

    2009-01-01

    The control of glycolysis in contracting muscle is not fully understood. The aim of the present study was to examine whether activation of glycolysis is mediated by factors related to the energy state or by a direct effect of Ca2+ on the regulating enzymes. Extensor digitorum longus muscles from...... and 58% of those in Con respectively. Glycolytic rate in BTS was only 51% of that in Con but the relative contribution of ATP derived from PCr (phosphocreatine) and glycolysis and the relation between muscle contents of PCr and Lac (lactate) were not different. Prolonged cyanide incubation of quiescent...... contribution of energy delivered from PCr and glycolysis during both conditions suggests that the glycolytic rate is controlled by factors related to energy state....

  5. Tissue Respiration and Glycolysis in the Development of Acute Radiation Sickness

    National Research Council Canada - National Science Library

    Golubentsev, D

    1960-01-01

    The condition of tissue respiration and glycolysis in the development of acute radiation sickness has been insufficiently studied, and the factual data and opinions of various investigators are frequently contradictory...

  6. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

    NARCIS (Netherlands)

    Everts, Bart; Amiel, Eyal; van der Windt, Gerritje J. W.; Freitas, Tori C.; Chott, Robert; Yarasheski, Kevin E.; Pearce, Erika L.; Pearce, Edward J.

    2012-01-01

    TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents

  7. Glyphosate-induced oxidative stress in Arabidopsis thaliana affecting peroxisomal metabolism and triggers activity in the oxidative phase of the pentose phosphate pathway (OxPPP) involved in NADPH generation.

    Science.gov (United States)

    de Freitas-Silva, Larisse; Rodríguez-Ruiz, Marta; Houmani, Hayet; da Silva, Luzimar Campos; Palma, José M; Corpas, Francisco J

    2017-11-01

    Glyphosate is a broad-spectrum systemic herbicide used worldwide. In susceptible plants, glyphosate affects the shikimate pathway and reduces aromatic amino acid synthesis. Using Arabidopsis seedlings grown in the presence of 20μM glyphosate, we analyzed H 2 O 2 , ascorbate, glutathione (GSH) and protein oxidation content as well as antioxidant catalase, superoxide dismutase (SOD) and ascorbate-glutathione cycle enzyme activity. We also examined the principal NADPH-generating system components, including glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), NADP-malic enzyme (NADP-ME) and NADP-isocitrate dehydrogenase (NADP-ICDH). Glyphosate caused a drastic reduction in growth parameters and an increase in protein oxidation. The herbicide also resulted in an overall increase in GSH content, antioxidant enzyme activity (catalase and all enzymatic components of the ascorbate-glutathione cycle) in addition to the two oxidative phase enzymes, G6PDH and 6PGDH, in the pentose phosphate pathway involved in NADPH generation. In this study, we provide new evidence on the participation of G6PDH and 6PGDH in the response to oxidative stress induced by glyphosate in Arabidopsis, in which peroxisomal enzymes, such as catalase and glycolate oxidase, are positively affected. We suggest that the NADPH provided by the oxidative phase of the pentose phosphate pathway (OxPPP) should serve to maintain glutathione reductase (GR) activity, thus preserving and regenerating the intracellular GSH pool under glyphosate-induced stress. It is particularly remarkable that the 6PGDH activity was unaffected by pro-oxidant and nitrating molecules such as H 2 0 2 , nitric oxide or peroxynitrite. Copyright © 2017 Elsevier GmbH. All rights reserved.

  8. Inhaled Beta2-agonist increases power output and glycolysis during sprinting in men

    DEFF Research Database (Denmark)

    Kalsen, Anders; Hostrup, Morten; Söderlund, Karin

    2016-01-01

    . Moreover, net rate of glycogenolysis (6.5±0.8 vs. 3.1±0.7 mmol glucosyl units kg dw s) and glycolysis (2.4±0.2 vs. 1.6±0.2 mmol glucosyl units kg dw s) were higher (P... and glycolysis in skeletal muscles. Furthermore, as terbutaline counteracted a reduction in ATP in type II fibers, terbutaline may postpone fatigue development in these fibers....

  9. Tumor cells and memory T cells converge at glycolysis: Therapeutic implications

    OpenAIRE

    Karthikeyan, Swathi; Geschwind, Jean-Francois; Ganapathy-Kanniappan, Shanmugasundaram

    2014-01-01

    In the immune system, activation of naïve T (Tn) cells into effector T cells (Teff) involves a metabolic switch to glycolysis to promote rapid proliferation and differentiation. In the October issue of The Journal of Clinical Investigation, Sukumar et al. have demonstrated that in CD8+ memory T (Tems) cells glycolytic phenotype contributes to the shortened lifespan of Tems. Conversely, inhibition of glycolysis in Tems not only extended their viability but also augmented desirable properties. ...

  10. Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells.

    Directory of Open Access Journals (Sweden)

    Ayako Nakano

    Full Text Available Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2, KG-1 (ABCB1 and HepG2 cells (ABCB1 and ABCG2. Interestingly, although side population (SP cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.

  11. Glycolysis of poly(3-hydroxybutyrate) via enzyme catalysis; Glicolise do poli(3-hidroxibutirato) por via enzimatica

    Energy Technology Data Exchange (ETDEWEB)

    Paula, Everton Luiz de, E-mail: everton2804@gmail.com [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Departamento de Quimica; Campos, Tiago Ferreira; Mano, Valdir [Universidade Federal de Sao Joao del-Rei (UFSJ), MG (Brazil). Departamento de Ciencias Naturais

    2014-05-15

    Poly(3-hydroxybutyrate), PHB, is a polymer with broad potential applications because of its biodegradability and biocompatibility. However, its high crystallinity is a limiting factor for many applications. To overcome this drawback, one strategy currently employed involves the reduction of the molecular weight of PHB with the concomitant formation of end-functionalized chains, such as those obtained via glycolysis. The glycolysis of PHB can be catalyzed by acid, base, or organometallic compounds. However, to our knowledge, there are no reports regarding PHB glycolysis catalyzed enzymatically. Among the major types of enzymes used in biocatalysis, the lipases stand out because they have the ability to catalyze reactions in both aqueous and organic media. Thus, in this study, we performed the enzymatic glycolysis of PHB using the lipase Amano PS (Pseudomonas cepacia) with ethane-1,2-diol (ethylene glycol) as the functionalizing agent. The results indicated that the glycolysis was successful and afforded hydroxyl-terminated oligomeric PHB polyols. Nuclear magnetic resonance spectra of the products showed characteristic signals for the terminal hydroxyl groups of the polyols, while thermogravimetric and differential scanning calorimetry analyses confirmed an increase in the thermal stability and a decrease in the crystallinity of the polyols compared with the starting PHB polymer, which were both attributed to the reduction in the molecular weight due to glycolysis. (author)

  12. The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns.

    Science.gov (United States)

    Noguchi, Rei; Kubota, Hiroyuki; Yugi, Katsuyuki; Toyoshima, Yu; Komori, Yasunori; Soga, Tomoyoshi; Kuroda, Shinya

    2013-05-14

    Insulin governs systemic glucose metabolism, including glycolysis, gluconeogenesis and glycogenesis, through temporal change and absolute concentration. However, how insulin-signalling pathway selectively regulates glycolysis, gluconeogenesis and glycogenesis remains to be elucidated. To address this issue, we experimentally measured metabolites in glucose metabolism in response to insulin. Step stimulation of insulin induced transient response of glycolysis and glycogenesis, and sustained response of gluconeogenesis and extracellular glucose concentration (GLC(ex)). Based on the experimental results, we constructed a simple computational model that characterises response of insulin-signalling-dependent glucose metabolism. The model revealed that the network motifs of glycolysis and glycogenesis pathways constitute a feedforward (FF) with substrate depletion and incoherent feedforward loop (iFFL), respectively, enabling glycolysis and glycogenesis responsive to temporal changes of insulin rather than its absolute concentration. In contrast, the network motifs of gluconeogenesis pathway constituted a FF inhibition, enabling gluconeogenesis responsive to absolute concentration of insulin regardless of its temporal patterns. GLC(ex) was regulated by gluconeogenesis and glycolysis. These results demonstrate the selective control mechanism of glucose metabolism by temporal patterns of insulin.

  13. Aerobic Glycolysis Is Essential for Normal Rod Function and Controls Secondary Cone Death in Retinitis Pigmentosa.

    Science.gov (United States)

    Petit, Lolita; Ma, Shan; Cipi, Joris; Cheng, Shun-Yun; Zieger, Marina; Hay, Nissim; Punzo, Claudio

    2018-05-29

    Aerobic glycolysis accounts for ∼80%-90% of glucose used by adult photoreceptors (PRs); yet, the importance of aerobic glycolysis for PR function or survival remains unclear. Here, we further established the role of aerobic glycolysis in murine rod and cone PRs. We show that loss of hexokinase-2 (HK2), a key aerobic glycolysis enzyme, does not affect PR survival or structure but is required for normal rod function. Rods with HK2 loss increase their mitochondrial number, suggesting an adaptation to the inhibition of aerobic glycolysis. In contrast, cones adapt without increased mitochondrial number but require HK2 to adapt to metabolic stress conditions such as those encountered in retinitis pigmentosa, where the loss of rods causes a nutrient shortage in cones. The data support a model where aerobic glycolysis in PRs is not a necessity but rather a metabolic choice that maximizes PR function and adaptability to nutrient stress conditions. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  14. Glycolysis and mitochondrial respiration in mouse LDHC-null sperm.

    Science.gov (United States)

    Odet, Fanny; Gabel, Scott; London, Robert E; Goldberg, Erwin; Eddy, Edward M

    2013-04-01

    We demonstrated previously that a knockout (KO) of the lactate dehydrogenase type C (Ldhc) gene disrupted male fertility and caused a considerable reduction in sperm glucose consumption, ATP production, and motility. While that study used mice with a mixed genetic background, the present study used C57BL/6 (B6) and 129S6 (129) Ldhc KO mice. We found that B6 KO males were subfertile and 129 KO males were infertile. Sperm from 129 wild-type (WT) mice have a lower glycolytic rate than sperm from B6 WT mice, resulting in a greater reduction in ATP production in 129 KO sperm than in B6 KO sperm. The lower glycolytic rate in 129 sperm offered a novel opportunity to examine the role of mitochondrial respiration in sperm ATP production and motility. We observed that in media containing a mitochondrial substrate (pyruvate or lactate) as the sole energy source, ATP levels and progressive motility in 129 KO sperm were similar to those in 129 WT sperm. However, when glucose was added, lactate was unable to maintain ATP levels or progressive motility in 129 KO sperm. The rate of respiration (ZO2) was high when 129 KO or WT sperm were incubated with lactate alone, but addition of glucose caused a reduction in ZO2. These results indicate that in the absence of glucose, 129 sperm can produce ATP via oxidative phosphorylation, but in the presence of glucose, oxidative phosphorylation is suppressed and the sperm utilize aerobic glycolysis, a phenomenon known as the Crabtree effect.

  15. Histone acetyltransferase inhibitors antagonize AMP-activated protein kinase in postmortem glycolysis

    Directory of Open Access Journals (Sweden)

    Qiong Li

    2017-06-01

    Full Text Available Objective The purpose of this study was to investigate the influence of AMP-activated protein kinase (AMPK activation on protein acetylation and glycolysis in postmortem muscle to better understand the mechanism by which AMPK regulates postmortem glycolysis and meat quality. Methods A total of 32 mice were randomly assigned to four groups and intraperitoneally injected with 5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR, a specific activator of AMPK, AICAR and histone acetyltransferase inhibitor II, or AICAR, Trichostatin A (TSA, an inhibitor of histone deacetylase I and II and Nicotinamide (NAM, an inhibitor of the Sirt family deacetylases. After mice were euthanized, the Longissimus dorsi muscle was collected at 0 h, 45 min, and 24 h postmortem. AMPK activity, protein acetylation and glycolysis in postmortem muscle were measured. Results Activation of AMPK by AICAR significantly increased glycolysis in postmortem muscle. At the same time, it increased the total acetylated proteins in muscle 45 min postmortem. Inhibition of protein acetylation by histone acetyltransferase inhibitors reduced AMPK activation induced increase in the total acetylated proteins and glycolytic rate in muscle early postmortem, while histone deacetylase inhibitors further promoted protein acetylation and glycolysis. Several bands of proteins were detected to be differentially acetylated in muscle with different glycolytic rates. Conclusion Protein acetylation plays an important regulatory role in postmortem glycolysis. As AMPK mediates the effects of pre-slaughter stress on postmortem glycolysis, protein acetylation is likely a mechanism by which antemortem stress influenced postmortem metabolism and meat quality though the exact mechanism is to be elucidated.

  16. Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

    International Nuclear Information System (INIS)

    Lim, Yoojoo; Lee, Kyung-Hun; Bang, Ji-In; Paeng, Jin Chul; Han, Sae-Won; Kim, Jee Hyun; Kang, Gyeong Hoon; Jeong, Seung-Yong; Park, Kyu Joo; Kim, Tae-You

    2017-01-01

    This study was performed to evaluate whether fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) could predict treatment outcome of regorafenib in metastatic colorectal cancer (mCRC). Previously treated refractory mCRC patients were enrolled into a prospective biomarker study of regorafenib. For this sub-study, the results of FDG PET/CT scans at baseline and after two cycles of treatment were analyzed. Various metabolic parameters obtained from PET images were analyzed in relation to treatment outcome. A total of 40 patients were evaluable for PET image analysis. Among various PET parameters, total lesion glycolysis (TLG) measured in the same target lesions for RECIST 1.1 analysis were the most significant in predicting prognosis, with the lowest p-value observed in TLG calculated using the margin threshold of 40 % (TLG 40 % ). Further analysis using TLG 40 % showed significantly longer overall survival (OS) in patients with lower baseline TLG 40 % (<151.8) (p = 0.003, median 14.2 vs. 9.1 months in <151.8 and ≥151.8, respectively). Patients showing higher decrease in TLG 40 % after treatment showed significantly longer progression-free survival (PFS) (p = 0.001, median 8.0 vs. 2.4 months in % ΔTLG 40 % < -9.6 % and ≥ -9.6 %, respectively) and OS (p = 0.002, median 16.4 vs. 9.1 months in % ΔTLG 40 % < -9.6 % and ≥ -9.6 %, respectively). The same cutoff could discriminate patients with longer survival among the patients who were under the stable disease category according to RECIST 1.1 (median PFS 8.4 vs. 6.8 months, p = 0.020; median OS 18.3 vs. 11.5 months, p = 0.049). Measurement of TLG can predict treatment outcome of regorafenib in mCRC. (orig.)

  17. Astrocyte Elevated Gene-1 Mediates Glycolysis and Tumorigenesis in Colorectal Carcinoma Cells via AMPK Signaling

    Directory of Open Access Journals (Sweden)

    Hong-tao Song

    2014-01-01

    Full Text Available To investigate the role of AEG-1 in glycolysis and tumorigenesis, we construct myc-AEG-1 expression vector and demonstrate a novel mechanism that AEG-1 may increase the activity of AMPK by Thr172 phosphorylation. The higher expression levels of AEG-1 in colorectal carcinoma cells were found but showed significant difference in different cell lines. To study the role of AEG-1 in colorectal cells, myc-AEG-1 vector was constructed and transfected into NCM460 colonic epithelial cells. We observed consistent increasing of glucose consumption and lactate production, typical features of anaerobic glycolysis, suggesting that AEG-1 may promote anaerobic glycolysis. Moreover, we noted that AMPK phosphorylation at Thr172 as well as pPFK2 (Ser466 was increased in NCM460 cells overexpressing AEG-1. Compound C may block AMPK and PFK2 phosphorylation in both control and AEG-1-overexpressed cells and decrease the glucose consumption and lactate production. The present findings indicated that reduced AEG-1 protein levels by RNAi may decrease the glucose consumption and lactate production in HCT116 colorectal carcinoma cells. The present identified AEG-1/AMPK/PFK2 glycolysis cascade may be essential to cell proliferation and tumor growth. The present results may provide us with a mechanistic insight into novel targets controlled by AEG-1, and the components in the AEG-1/AMPK/PFK2 glycolysis process may be targeted for the clinical treatment of cancer.

  18. Cancer cells recovering from damage exhibit mitochondrial restructuring and increased aerobic glycolysis

    Energy Technology Data Exchange (ETDEWEB)

    Akakura, Shin; Ostrakhovitch, Elena; Sanokawa-Akakura, Reiko [Frontiers in Bioscience Research Institute in Aging and Cancer, University of California, Irvine, CA (United States); Tabibzadeh, Siamak, E-mail: fbs@bioscience.org [Frontiers in Bioscience Research Institute in Aging and Cancer, University of California, Irvine, CA (United States); Dept of Oncologic Radiology, University of California, Irvine, CA (United States)

    2014-06-13

    Highlights: • Some cancer cells recover from severe damage that causes cell death in majority of cells. • Damage-Recovered (DR) cancer cells show reduced mitochondria, mDNA and mitochondrial enzymes. • DR cells show increased aerobic glycolysis, ATP, cell proliferation, and resistance to damage. • DR cells recovered from in vivo damage also show increased glycolysis and proliferation rate. - Abstract: Instead of relying on mitochondrial oxidative phosphorylation, most cancer cells rely heavily on aerobic glycolysis, a phenomenon termed as “the Warburg effect”. We considered that this effect is a direct consequence of damage which persists in cancer cells that recover from damage. To this end, we studied glycolysis and rate of cell proliferation in cancer cells that recovered from severe damage. We show that in vitro Damage-Recovered (DR) cells exhibit mitochondrial structural remodeling, display Warburg effect, and show increased in vitro and in vivo proliferation and tolerance to damage. To test whether cancer cells derived from tumor microenvironment can show similar properties, we isolated Damage-Recovered (T{sup DR}) cells from tumors. We demonstrate that T{sup DR} cells also show increased aerobic glycolysis and a high proliferation rate. These findings show that Warburg effect and its consequences are induced in cancer cells that survive severe damage.

  19. Cellular Glycolysis and The Differential Survival of Lung Fibroblast and Lung Carcinoma Cell Lines.

    Science.gov (United States)

    Farah, Ibrahim O

    2016-04-01

    Tumor growth and abnormal cell survival were shown to be associated with a number of cellular metabolic abnormalities revealed by impaired oral glucose tolerance, depressed lipoprotein lipase activity leading to hypertriglyceridemia, and changes in amino acid profile as evidenced by increased plasma free tryptophan levels in patients with breast, lung, colon, stomach, and other cancers from various origins. The above findings seem to relate to or indicate a shift to non-oxidative metabolic pathways in cancer. In contrast to normal cells, cancer cells may lose the ability to utilize aerobic respiration due to either defective mitochondria or hypoxia within the tumor microenvironments. Glucose was shown to be the major energy source in cancer cells where it utilizes aerobic /anaerobic glycolysis with the resultant lactic acid formation. The role of energetic modulations and use of glycolytic inhibitors on cancer/normal cell survival is not clearly established in the literature. We hypothesize that natural intermediates of glycolysis and the citric acid cycle will differentially and negatively impact the cancer phenotype in contrast to their no effects on the normal cell phenotype. Therefore, the purpose of this study was to evaluate six potential glycolytic modulators namely, Pyruvic acid, oxalic acid, Zn acetate, sodium citrate, fructose diphosphate (FDP) and sodium bicarbonate at μM concentrations on growing A549 (lung cancer) and MRC-5 (normal; human lung fibroblast) cell lines with the objective of determining their influence on visual impact, cell metabolic activity, cell viability and end-point cell survival. Exposed and non-exposed cells were tested with phase-contrast micro-scanning, survival/death and metabolic activity trends through MTT-assays, as well as death end-point determinations by testing re-growth on complete media and T4 cellometer counts. Results showed that oxalic acid and Zn acetate both influenced the pH of the medium and resulted in

  20. Hydrothermal pentose to furfural conversion and simultaneous extraction with SC-CO2--kinetics and application to biomass hydrolysates.

    Science.gov (United States)

    Gairola, Krishan; Smirnova, Irina

    2012-11-01

    This work explores hydrothermal d-xylose and hemicellulose to furfural conversion coupled with simultaneous furfural extraction by SC-CO(2) and the underlying reaction pathway. A maximum furfural yield of 68% was attained from d-xylose at 230°C and 12MPa. Additionally missing kinetic data for l-arabinose to furfural conversion was provided, showing close similarity to d-xylose. Furfural yields from straw and brewery waste hydrolysates were significantly lower than those obtained from model compounds, indicating side reactions with other hydrolysate components. Simultaneous furfural extraction by SC-CO(2) significantly increased extraction yield in all cases. The results indicate that furfural reacts with intermediates of pentose dehydration. The proposed processing route can be well integrated into existing lignocellulose biorefinery concepts. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Anaerobic glycolysis as a property of malignant cells and its application aspects

    International Nuclear Information System (INIS)

    Shmakova, N.L.; Korogodin, V.I.

    1996-01-01

    Under hypoxia excess glucose causes fast death of malignant cells without affecting viability of benign tumor and normal tissue cells. Laws and mechanisms of this phenomenon are described. Relationship between glycolysis activation and malignant degeneration of normal cells, application of artificial hyperglycemia to cancer therapy are discussed. 21 refs., 5 figs., 2 tabs

  2. Recycling of PUR scrap from car seats-glycolysis of flexible PUR foam

    Czech Academy of Sciences Publication Activity Database

    Beneš, Hynek; Holler, Petr; Schmidt, Pavel; Horák, Zdeněk; Rösner, J.

    2005-01-01

    Roč. 99, - (2005), s. 29 ISSN 0009-2770. [International Conference on Polymeric Materials in Automotive , Slovak Rubber Conference /17./. 10.5.2005-12.5.2005, Bratislava] Institutional research plan: CEZ:AV0Z40500505 Keywords : chemical recycling * flexible polyurethane foam * glycolysis Subject RIV: CD - Macromolecular Chemistry

  3. Limits to sustainable muscle performance: interaction between glycolysis and oxidative phosphorylation.

    Science.gov (United States)

    Conley, K E; Kemper, W F; Crowther, G J

    2001-09-01

    This paper proposes a mechanism responsible for setting the sustainable level of muscle performance. Our contentions are that the sustainable work rate is determined (i) at the muscle level, (ii) by the ability to maintain ATP supply and (iii) by the products of glycolysis that may inhibit the signal for oxidative phosphorylation. We argue below that no single factor 'limits' sustainable performance, but rather that the flux through and the interaction between glycolysis and oxidative phosphorylation set the level of sustainable ATP supply. This argument is based on magnetic resonance spectroscopy measurements of the sources and sinks for energy in vivo in human muscle and rattlesnake tailshaker muscle during sustained contractions. These measurements show that glycolysis provides between 20% (human muscle) and 40% (tailshaker muscle) of the ATP supply during sustained contractions in these muscles. We cite evidence showing that this high glycolytic flux does not reflect an O(2) limitation or mitochondria operating at their capacity. Instead, this flux reflects a pathway independent of oxidative phosphorylation for ATP supply during aerobic exercise. The consequence of this high glycolytic flux is accumulation of H(+), which we argue inhibits the rise in the signal activating oxidative phosphorylation, thereby restricting oxidative ATP supply to below the oxidative capacity. Thus, both glycolysis and oxidative phosphorylation play important roles in setting the highest steady-state ATP synthesis flux and thereby determine the sustainable level of work by exercising muscle.

  4. Glycolysis and ATP degradation in cod ( Gadus morhua ) at subzero temperatures in relation to thaw rigor

    DEFF Research Database (Denmark)

    Cappeln, Gertrud; Jessen, Flemming

    2001-01-01

    Glycolysis was shown to occur during freezing of cod of decrease in glycogen and an increase in lactate. In addition, the ATP content decreased during freezing. Synthesis of ATP was measured as degradation of glycogen. During storage at -9 and - 12 degreesC it was found that degradation of ATP...

  5. Control of Glycolysis by Glyceraldehyde-3-Phosphate Dehydrogenase in Streptococcus cremoris and Streptococcus lactis

    NARCIS (Netherlands)

    POOLMAN, B; BOSMAN, B; KONINGS, WN

    1987-01-01

    The decreased response of the energy metabolism of lactose-starved Streptococcus cremoris upon readdition of lactose is caused by a decrease of the glycolytic activity. The decrease in glycolysis is accompanied by a decrease in the activities of glyceraldehyde-3-phosphate dehydrogenase and

  6. AKT-mediated enhanced aerobic glycolysis causes acquired radioresistance by human tumor cells

    International Nuclear Information System (INIS)

    Shimura, Tsutomu; Noma, Naoto; Sano, Yui; Ochiai, Yasushi; Oikawa, Toshiyuki; Fukumoto, Manabu; Kunugita, Naoki

    2014-01-01

    Background and purpose: Cellular radioresistance is a major impediment to effective radiotherapy. Here, we demonstrated that long-term exposure to fractionated radiation conferred acquired radioresistance to tumor cells due to AKT-mediated enhanced aerobic glycolysis. Material and methods: Two human tumor cell lines with acquired radioresistance were established by long-term exposure to fractionated radiation with 0.5 Gy of X-rays. Glucose uptake was inhibited using 2-deoxy-D-glucose, a non-metabolizable glucose analog. Aerobic glycolysis was assessed by measuring lactate concentrations. Cells were then used for assays of ROS generation, survival, and cell death as assessed by annexin V staining. Results: Enhanced aerobic glycolysis was shown by increased glucose transporter Glut1 expression and a high lactate production rate in acquired radioresistant cells compared with parental cells. Inhibiting the AKT pathway using the AKT inhibitor API-2 abrogated these phenomena. Moreover, we found that inhibiting glycolysis with 2-deoxy-D-glucose suppressed acquired tumor cell radioresistance. Conclusions: Long-term fractionated radiation confers acquired radioresistance to tumor cells by AKT-mediated alterations in their glucose metabolic pathway. Thus, tumor cell metabolic pathway is an attractive target to eliminate radioresistant cells and improve radiotherapy efficacy

  7. Fatal attraction in glycolysis: how Saccharomyces cerevisiae manages sudden transitions to high glucose

    Science.gov (United States)

    Heerden, Johan H. v.; Wortel, Meike T.; Bruggeman, Frank J.; Heijnen, Joseph J.; Bollen, Yves J.; Planqué, Robert; Hulshof, Josephus; O’Toole, Tom G.; Wahl, S. A.; Teusink, Bas

    2014-01-01

    In the model eukaryote Saccharomyces cerevisiae, it has long been known that a functional trehalose pathway is indispensable for transitions to high glucose conditions. Upon addition of glucose, cells with a defect in trehalose 6-phosphate synthase (Tps1), the first committed step in the trehalose pathway, display what we have termed an imbalanced glycolytic state; in this state the flux through the upper part of glycolysis outpaces that through the lower part of glycolysis. As a consequence, the intermediate fructose 1,6-bisphosphate (FBP) accumulates at low concentrations of ATP and inorganic phosphate (Pi). Despite significant research efforts, a satisfactory understanding of the regulatory role that trehalose metabolism plays during such transitions has remained infamously unresolved. In a recent study, we demonstrate that the startup of glycolysis exhibits two dynamic fates: a proper, functional, steady state or the imbalanced state described above. Both states are stable, attracting states, and the probability distribution of initial states determines the fate of a yeast cell exposed to glucose. Trehalose metabolism steers the dynamics of glycolysis towards the proper functional state through its ATP hydrolysis activity; a mechanism that ensures that the demand and supply of ATP is balanced with Pi availability under dynamic conditions. [van Heerden et al. Science (2014), DOI: 10.1126/science.1245114.] PMID:28357229

  8. Fatal attraction in glycolysis: how Saccharomyces cerevisiae manages sudden transitions to high glucose

    Directory of Open Access Journals (Sweden)

    Johan H. van Heerden

    2015-02-01

    Full Text Available In the model eukaryote Saccharomyces cerevisiae, it has long been known that a functional trehalose pathway is indispensable for transitions to high glucose conditions. Upon addition of glucose, cells with a defect in trehalose 6-phosphate synthase (Tps1, the first committed step in the trehalose pathway, display what we have termed an imbalanced glycolytic state; in this state the flux through the upper part of glycolysis outpaces that through the lower part of glycolysis. As a consequence, the intermediate fructose 1,6-bisphosphate (FBP accumulates at low concentrations of ATP and inorganic phosphate (Pi. Despite significant research efforts, a satisfactory understanding of the regulatory role that trehalose metabolism plays during such transitions has remained infamously unresolved. In a recent study, we demonstrate that the startup of glycolysis exhibits two dynamic fates: a proper, functional, steady state or the imbalanced state described above. Both states are stable, attracting states, and the probability distribution of initial states determines the fate of a yeast cell exposed to glucose. Trehalose metabolism steers the dynamics of glycolysis towards the proper functional state through its ATP hydrolysis activity; a mechanism that ensures that the demand and supply of ATP is balanced with Pi availability under dynamic conditions. [van Heerden et al. Science (2014, DOI: 10.1126/science.1245114.

  9. Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal.

    Science.gov (United States)

    Kanatsu-Shinohara, Mito; Tanaka, Takashi; Ogonuki, Narumi; Ogura, Atsuo; Morimoto, Hiroko; Cheng, Pei Feng; Eisenman, Robert N; Trumpp, Andreas; Shinohara, Takashi

    2016-12-01

    Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max, a Myc-binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1, whose deficiency impairs SSC self-renewal. Myc/Mycn-deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc-mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division. © 2016 Kanatsu-Shinohara et al.; Published by Cold Spring Harbor Laboratory Press.

  10. Tumor cells and memory T cells converge at glycolysis: therapeutic implications.

    Science.gov (United States)

    Karthikeyan, Swathi; Geschwind, Jean-Francois; Ganapathy-Kanniappan, Shanmugasundaram

    2014-05-01

    In the immune system, activation of naïve T (Tn) cells into effector T cells (Teff) involves a metabolic switch to glycolysis to promote rapid proliferation and differentiation. In the October issue of The Journal of Clinical Investigation, Sukumar et al. have demonstrated that in CD8(+) memory T (Tems) cells glycolytic phenotype contributes to the shortened lifespan of Tems. Conversely, inhibition of glycolysis in Tems not only extended their viability but also augmented desirable properties. Notably, they also demonstrate that glycolytic inhibition during the ex vivo clonal expansion of tumor-specific Tems enhanced their antitumor function. Overall, the data suggest that an antiglycolytic strategy targeting the Tems could enhance antitumor immune response. On the other hand, cancer cells have long been known to exhibit metabolic reprogramming which involves a shift toward glycolysis (the conversion of glucose into lactate) to facilitate uninterrupted growth. Interestingly, antiglycolytic treatment of cancer cells has been known to trigger antitumor immune response as well. Taken together, it is probable that a strategy involving concurrent inhibition of glycolysis in tumor cells and Tems could promote a dual attack on cancer by inducing an effective antitumor immune response and an immunogenic chemotherapy.

  11. Increasing the radiosensitivity of tumours in an hypoxic environment using inhibitors of the pentose phosphate pathway

    International Nuclear Information System (INIS)

    Sahasrabudhe, M.B.; Bhonsle, S.R.; Krishnamurti, K.; Tilak, B.D.

    1977-01-01

    Rapidly growing tumours contain few blood vessels in the tumour mass. Cells in such tumours obtain nutrients and oxygen from the periphery by diffusion, resulting in a diminishing oxygen and nutrient gradient from the periphery to centre of the tumour mass. In normal tissues, oxygen is utilized via a tricarboxylic acid (TCA) cycle; in tumour cells oxygen is utilized via a hexose monophosphate (HMP) pathway and through the TCA cycle at a 30% reduced level. Interference with the HMP pathway selectively inhibits the utilization of oxygen by tumour cells, thus increasing the availability of oxygen to hypoxic cells situated deeper in the tumour mass. This effect has been exploited for increasing the radiosensitivity of tumour cells situated in an hypoxic environment. The influence of sixteen potential antimetabolites on the HMP pathway has been studied. Of these, six compounds, namely, (1) 2-carboxy 5-hydroxymethyl thiophene, (2) the sodium salt of 2:5 dicarbethoxy 3:4 dihydroxy thiophene, (3) the dihydrazide of 2:5 dicarboxy thiophene, (4) the dihydrazide of 3:4 dimethoxy 2:5 dicarboxy thiophene, (5) trithiocyanuric acid, and (6) cyanuric trithioglycollic acid showed an inhibiting effect on the HMP pathway without any influence on the TCA cycle. Influence of administration of compounds (1), (2) and (4) prior to radiation on the growth of transplanted fibrosarcomas in mice has been studied and is reported here. These three compounds showed marked potentiation of radiosensitivity of tumours. (author)

  12. Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with regorafenib

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Yoojoo; Lee, Kyung-Hun [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Bang, Ji-In; Paeng, Jin Chul [Seoul National University Hospital, Department of Nuclear Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Han, Sae-Won [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Cancer Research Institute, Seoul (Korea, Republic of); Kim, Jee Hyun [Seoul National University Bundang Hospital, Department of Internal Medicine, Geyonggi-do (Korea, Republic of); Kang, Gyeong Hoon [Seoul National University Hospital, Department of Pathology, Seoul (Korea, Republic of); Jeong, Seung-Yong; Park, Kyu Joo [Seoul National University Hospital, Department of Surgery, Seoul (Korea, Republic of); Kim, Tae-You [Seoul National University Hospital, Department of Internal Medicine, 101 Daehang-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University College of Medicine, Cancer Research Institute, Seoul (Korea, Republic of); Seoul National University, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of)

    2017-05-15

    This study was performed to evaluate whether fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) could predict treatment outcome of regorafenib in metastatic colorectal cancer (mCRC). Previously treated refractory mCRC patients were enrolled into a prospective biomarker study of regorafenib. For this sub-study, the results of FDG PET/CT scans at baseline and after two cycles of treatment were analyzed. Various metabolic parameters obtained from PET images were analyzed in relation to treatment outcome. A total of 40 patients were evaluable for PET image analysis. Among various PET parameters, total lesion glycolysis (TLG) measured in the same target lesions for RECIST 1.1 analysis were the most significant in predicting prognosis, with the lowest p-value observed in TLG calculated using the margin threshold of 40 % (TLG{sub 40} {sub %}). Further analysis using TLG{sub 40} {sub %} showed significantly longer overall survival (OS) in patients with lower baseline TLG{sub 40} {sub %} (<151.8) (p = 0.003, median 14.2 vs. 9.1 months in <151.8 and ≥151.8, respectively). Patients showing higher decrease in TLG{sub 40} {sub %} after treatment showed significantly longer progression-free survival (PFS) (p = 0.001, median 8.0 vs. 2.4 months in % ΔTLG{sub 40} {sub %} < -9.6 % and ≥ -9.6 %, respectively) and OS (p = 0.002, median 16.4 vs. 9.1 months in % ΔTLG{sub 40} {sub %} < -9.6 % and ≥ -9.6 %, respectively). The same cutoff could discriminate patients with longer survival among the patients who were under the stable disease category according to RECIST 1.1 (median PFS 8.4 vs. 6.8 months, p = 0.020; median OS 18.3 vs. 11.5 months, p = 0.049). Measurement of TLG can predict treatment outcome of regorafenib in mCRC. (orig.)

  13. Waste Not, Want Not: Lactate Oxidation Fuels the TCA Cycle.

    Science.gov (United States)

    Martínez-Reyes, Inmaculada; Chandel, Navdeep S

    2017-12-05

    Previous studies have demonstrated that mitochondrial respiration is essential for tumorigenesis. Hui et al. (2017) and Faubert et al. (2017) demonstrate that lactate, traditionally viewed as a waste product of anaerobic and aerobic glycolysis, is a major carbon source to fuel the mitochondrial TCA cycle in normal tissue and in tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Succinyl-proteome profiling of Dendrobium officinale, an important traditional Chinese orchid herb, revealed involvement of succinylation in the glycolysis pathway.

    Science.gov (United States)

    Feng, Shangguo; Jiao, Kaili; Guo, Hong; Jiang, Mengyi; Hao, Juan; Wang, Huizhong; Shen, Chenjia

    2017-08-10

    Lysine succinylation is a ubiquitous and important protein post-translational modification in various eukaryotic and prokaryotic cells. However, its functions in Dendrobium officinale, an important traditional Chinese orchid herb with high polysaccharide contents, are largely unknown. In our study, LC-MS/MS was used to identify the peptides that were enriched by immune-purification with a high-efficiency succinyl-lysine antibody. In total, 314 lysine succinylation sites in 207 proteins were identified. A gene ontology analysis showed that these proteins are associated with a wide range of cellular functions, from metabolic processes to stimuli responses. Moreover, two types of conserved succinylation motifs, '***K suc ******K**' and '****EK suc ***', were identified. Our data showed that lysine succinylation occurred on five key enzymes in the glycolysis pathway. The numbers of average succinylation sites on these five enzymes in plants were lower than those in bacteria and mammals. Interestingly, two active site amino acids residues, K103 and K225, could be succinylated in fructose-bisphosphate aldolase, indicating a potential function of lysine succinylation in the regulation of glycolytic enzyme activities. Furthermore, the protein-protein interaction network for the succinylated proteins showed that several functional terms, such as glycolysis, TCA cycle, oxidative phosphorylation and ribosome, are consisted. Our results provide the first comprehensive view of the succinylome of D. officinale and may accelerate future biological investigations of succinylation in the synthesis of polysaccharides, which are major active ingredients.

  15. The axon-protective WLD(S) protein partially rescues mitochondrial respiration and glycolysis after axonal injury.

    Science.gov (United States)

    Godzik, Katharina; Coleman, Michael P

    2015-04-01

    The axon-protective Wallerian degeneration slow (WLD(S)) protein can ameliorate the decline in axonal ATP levels after neurite transection. Here, we tested the hypothesis that this effect is associated with maintenance of mitochondrial respiration and/or glycolysis. We used isolated neurites of superior cervical ganglion (SCG) cultures in the Seahorse XF-24 Metabolic Flux Analyser to determine mitochondrial respiration and glycolysis under different conditions. We observed that both mitochondrial respiration and glycolysis declined significantly during the latent phase of Wallerian degeneration. WLD(S) partially reduced the decline both in glycolysis and in mitochondrial respiration. In addition, we found that depleting NAD levels in uncut cultures led to changes in mitochondrial respiration and glycolysis similar to those rescued by WLD(S) after cut, suggesting that the maintenance of NAD levels in Wld(S) neurites after axonal injury at least partially underlies the maintenance of ATP levels. However, by using another axon-protective mutation (Sarm1(-/-)), we could demonstrate that rescue of basal ECAR (and hence probably glycolysis) rather than basal OCR (mitochondrial respiration) may be part of the protective phenotype to delay Wallerian degeneration. These findings open new routes to study glycolysis and the connection between NAD and ATP levels in axon degeneration, which may help to eventually develop therapeutic strategies to treat neurodegenerative diseases.

  16. Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis.

    Directory of Open Access Journals (Sweden)

    Weiling Xu

    Full Text Available Asthma, a chronic inflammatory airway disease, is typified by high levels of TH2-cytokines and excessive generation of reactive nitrogen and oxygen species, which contribute to bronchial epithelial injury and airway remodeling. While immune function plays a major role in the pathogenesis of the disease, accumulating evidence suggests that altered cellular metabolism is a key determinant in the predisposition and disease progression of asthma. Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic. However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients. Platelets are easily accessible blood cells that are known to propagate airway inflammation in asthma. Here we perform a bioenergetic screen of platelets from asthmatic and healthy individuals and demonstrate that asthmatic platelets show a decreased reliance on glycolytic processes and have increased tricarboxylic acid cycle activity. These data demonstrate a systemic alteration in asthma and are consistent with prior reports suggesting that oxidative phosphorylation is more efficient asthmatic individuals. The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients. Further, these data suggest that platelets are potentially a good model for the monitoring of bioenergetic changes in asthma.

  17. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene

    DEFF Research Database (Denmark)

    Hall, Arnaldur; Meyle, Kathrine Damm; Lange, Marina Krarup

    2013-01-01

    basis for this addiction is largely unknown. Here we provide evidence for a metabolic rationale behind the addiction to (V600E)BRAF in two malignant melanoma cell lines. Both cell lines display a striking addiction to glycolysis due to underlying dysfunction of oxidative phosphorylation (OXPHOS......). Notably, even minor reductions in glycolytic activity lead to increased OXPHOS activity (reversed Warburg effect), however the mitochondria are unable to sustain ATP production. We show that (V600E)BRAF upholds the activity of glycolysis and therefore the addiction to glycolysis de facto becomes...

  18. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the V600EBRAF oncogene

    DEFF Research Database (Denmark)

    Hall, Arnaldur; Meyle, Kathrine Damm; Lange, Marina Krarup

    2013-01-01

    basis for this addiction is largely unknown. Here we provide evidence for a metabolic rationale behind the addiction to V600EBRAF in two malignant melanoma cell lines. Both cell lines display a striking addiction to glycolysis due to underlying dysfunction of oxidative phosphorylation (OXPHOS). Notably......, even minor reductions in glycolytic activity lead to increased OXPHOS activity (reversed Warburg effect), however the mitochondria are unable to sustain ATP production. We show that V600EBRAF upholds the activity of glycolysis and therefore the addiction to glycolysis de facto becomes an addiction to V...

  19. Glucose Regulates Cyclin D2 Expression in Quiescent and Replicating Pancreatic β-Cells Through Glycolysis and Calcium Channels

    Science.gov (United States)

    Salpeter, Seth J.; Klochendler, Agnes; Weinberg-Corem, Noa; Porat, Shay; Granot, Zvi; Shapiro, A. M. James; Magnuson, Mark A.; Eden, Amir; Grimsby, Joseph; Glaser, Benjamin

    2011-01-01

    Understanding the molecular triggers of pancreatic β-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in β-cell proliferation and mass homeostasis, but its specific function in β-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent β-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the β-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G2-M phases of each β-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent β-cells and modulates the down-regulation of cyclin D2 in replicating β-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and β-cell replication. PMID:21521747

  20. Thiol Redox Sensitivity of Two Key Enzymes of Heme Biosynthesis and Pentose Phosphate Pathways: Uroporphyrinogen Decarboxylase and Transketolase

    Directory of Open Access Journals (Sweden)

    Brian McDonagh

    2013-01-01

    Full Text Available Uroporphyrinogen decarboxylase (Hem12p and transketolase (Tkl1p are key mediators of two critical processes within the cell, heme biosynthesis, and the nonoxidative part of the pentose phosphate pathway (PPP. The redox properties of both Hem12p and Tkl1p from Saccharomyces cerevisiae were investigated using proteomic techniques (SRM and label-free quantification and biochemical assays in cell extracts and in vitro with recombinant proteins. The in vivo analysis revealed an increase in oxidized Cys-peptides in the absence of Grx2p, and also after treatment with H2O2 in the case of Tkl1p, without corresponding changes in total protein, demonstrating a true redox response. Out of three detectable Cys residues in Hem12p, only the conserved residue Cys52 could be modified by glutathione and efficiently deglutathionylated by Grx2p, suggesting a possible redox control mechanism for heme biosynthesis. On the other hand, Tkl1p activity was sensitive to thiol redox modification and although Cys622 could be glutathionylated to a limited extent, it was not a natural substrate of Grx2p. The human orthologues of both enzymes have been involved in certain cancers and possess Cys residues equivalent to those identified as redox sensitive in yeast. The possible implication for redox regulation in the context of tumour progression is put forward.

  1. Fermentation of hexoses and pentoses from hydrolyzed soybean hull into ethanol and xylitol by Candida guilliermondii BL 13

    Directory of Open Access Journals (Sweden)

    F. da Cunha-Pereira

    Full Text Available Abstract This work investigated the ability of a recently isolated strain of Candida guilliermondii to convert hexoses and pentoses obtained from acid-enzymatic soybean hull hydrolysates into ethanol and, in smaller amounts, into xylitol. Operational conditions and media formulation were optimized concerning ethanol production using experimental designs (Plackett-Burman and Central Composite Design. Results showed that C. guilliermondii BL 13 was capable of growing in non-supplemented, non-detoxified biomass hydrolysates, and the best culture conditions were determined to be 28 °C, pH 5.0, and 109 CFU mL-1 of inoculum size. Ethanol productivity reached 1.4 g L-1 h-1, and maximal yields of 0.41 g g-1 were obtained, representing 80.4 % of the expected theoretical yields, whereas small amounts of xylitol were also produced. These results suggest that C. guilliermondii BL13 is a potentially useful yeast strain to be applied in second-generation ethanol production from lignocellulosic biomass based on its natural capacity to metabolize C-5 and C-6 sugars.

  2. Metabolic engineering of the pentose phosphate pathway for enhanced limonene production in the cyanobacterium Synechocysti s sp. PCC 6803.

    Science.gov (United States)

    Lin, Po-Cheng; Saha, Rajib; Zhang, Fuzhong; Pakrasi, Himadri B

    2017-12-13

    Isoprenoids are diverse natural compounds, which have various applications as pharmaceuticals, fragrances, and solvents. The low yield of isoprenoids in plants makes them difficult for cost-effective production, and chemical synthesis of complex isoprenoids is impractical. Microbial production of isoprenoids has been considered as a promising approach to increase the yield. In this study, we engineered the model cyanobacterium Synechocystis sp. PCC 6803 for sustainable production of a commercially valuable isoprenoid, limonene. Limonene synthases from the plants Mentha spicata and Citrus limon were expressed in cyanobacteria for limonene production. Production of limonene was two-fold higher with limonene synthase from M. spicata than that from C. limon. To enhance isoprenoid production, computational strain design was conducted by applying the OptForce strain design algorithm on Synechocystis 6803. Based on the metabolic interventions suggested by this algorithm, genes (ribose 5-phosphate isomerase and ribulose 5-phosphate 3-epimerase) in the pentose phosphate pathway were overexpressed, and a geranyl diphosphate synthase from the plant Abies grandis was expressed to optimize the limonene biosynthetic pathway. The optimized strain produced 6.7 mg/L of limonene, a 2.3-fold improvement in productivity. Thus, this study presents a feasible strategy to engineer cyanobacteria for photosynthetic production of isoprenoids.

  3. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat.

    Science.gov (United States)

    Park, Thomas J; Reznick, Jane; Peterson, Bethany L; Blass, Gregory; Omerbašić, Damir; Bennett, Nigel C; Kuich, P Henning J L; Zasada, Christin; Browe, Brigitte M; Hamann, Wiebke; Applegate, Daniel T; Radke, Michael H; Kosten, Tetiana; Lutermann, Heike; Gavaghan, Victoria; Eigenbrod, Ole; Bégay, Valérie; Amoroso, Vince G; Govind, Vidya; Minshall, Richard D; Smith, Ewan St J; Larson, John; Gotthardt, Michael; Kempa, Stefan; Lewin, Gary R

    2017-04-21

    The African naked mole-rat's ( Heterocephalus glaber ) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease. Copyright © 2017, American Association for the Advancement of Science.

  4. Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis

    Directory of Open Access Journals (Sweden)

    Franziska Paech

    2017-06-01

    Full Text Available Tyrosine kinase inhibitors (TKIs are anticancer drugs with a lesser toxicity than classical chemotherapeutic agents but still with a narrow therapeutic window. While hepatotoxicity is known for most TKIs, underlying mechanisms remain mostly unclear. We therefore aimed at investigating mechanisms of hepatotoxicity for imatinib, sunitinib, lapatinib and erlotinib in vitro. We treated HepG2 cells, HepaRG cells and mouse liver mitochondria with TKIs (concentrations 1–100 μM for different periods of time and assessed toxicity. In HepG2 cells maintained with glucose (favoring glycolysis, all TKIs showed a time- and concentration-dependent cytotoxicity and, except erlotinib, a drop in intracellular ATP. In the presence of galactose (favoring mitochondrial metabolism, imatinib, sunitinib and erlotinib showed a similar toxicity profile as for glucose whereas lapatinib was less toxic. For imatinib, lapatinib and sunitinib, cytotoxicity increased in HepaRG cells induced with rifampicin, suggesting formation of toxic metabolites. In contrast, erlotinib was more toxic in HepaRG cells under basal than CYP-induced conditions. Imatinib, sunitinib and lapatinib reduced the mitochondrial membrane potential in HepG2 cells and in mouse liver mitochondria. In HepG2 cells, these compounds increased reactive oxygen species production, impaired glycolysis, and induced apoptosis. In addition, imatinib and sunitinib impaired oxygen consumption and activities of complex I and III (only imatinib, and reduced the cellular GSH pool. In conclusion, imatinib and sunitinib are mitochondrial toxicants after acute and long-term exposure and inhibit glycolysis. Lapatinib affected mitochondria only weakly and inhibited glycolysis, whereas the cytotoxicity of erlotinib could not be explained by a mitochondrial mechanism.

  5. Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment

    Directory of Open Access Journals (Sweden)

    Bo Jiang

    2017-03-01

    Full Text Available Metabolic abnormalities is a hallmark of cancer. About 100 years ago, Nobel laureate Otto Heinrich Warburg first described high rate of glycolysis in cancer cells. Recently more and more novel opinions about cancer metabolism supplement to this hypothesis, consist of glucose uptake, lactic acid generation and secretion, acidification of the microenvironment and cancer immune evasion. Here we briefly review metabolic pathways generating lactate, and discuss the function of higher lactic acid in cancer microenvironments.

  6. Astrocytic energetics during excitatory neurotransmission: What are contributions of glutamate oxidation and glycolysis?

    OpenAIRE

    Dienel, Gerald A.

    2013-01-01

    Astrocytic energetics of excitatory neurotransmission is controversial due to discrepant findings in different experimental systems in vitro and in vivo. The energy requirements of glutamate uptake are believed by some researchers to be satisfied by glycolysis coupled with shuttling of lactate to neurons for oxidation. However, astrocytes increase glycogenolysis and oxidative metabolism during sensory stimulation in vivo, indicating that other sources of energy are used by astrocytes during b...

  7. Neuron-derived transthyretin modulates astrocytic glycolysis in hormone-independent manner

    OpenAIRE

    Zawiślak, Alina; Jakimowicz, Piotr; McCubrey, James A.; Rakus, Dariusz

    2017-01-01

    It has been shown that neurons alter the expression of astrocytic metabolic enzymes by secretion of until now unknown molecule(s) into extracellular fluid. Here, we present evidence that neuron-derived transthyretin (TTR) stimulates expression of glycolytic enzymes in astrocytes which is reflected by an increased synthesis of ATP. The action of TTR is restricted to regulatory enzymes of glycolysis: phosphofructokinase P (PFKP) and pyruvate kinase M1/M2 isoforms (PKM1/2). The regulation of PFK...

  8. Overexpression of mitochondrial sirtuins alters glycolysis and mitochondrial function in HEK293 cells.

    Directory of Open Access Journals (Sweden)

    Michelle Barbi de Moura

    Full Text Available SIRT3, SIRT4, and SIRT5 are mitochondrial deacylases that impact multiple facets of energy metabolism and mitochondrial function. SIRT3 activates several mitochondrial enzymes, SIRT4 represses its targets, and SIRT5 has been shown to both activate and repress mitochondrial enzymes. To gain insight into the relative effects of the mitochondrial sirtuins in governing mitochondrial energy metabolism, SIRT3, SIRT4, and SIRT5 overexpressing HEK293 cells were directly compared. When grown under standard cell culture conditions (25 mM glucose all three sirtuins induced increases in mitochondrial respiration, glycolysis, and glucose oxidation, but with no change in growth rate or in steady-state ATP concentration. Increased proton leak, as evidenced by oxygen consumption in the presence of oligomycin, appeared to explain much of the increase in basal oxygen utilization. Growth in 5 mM glucose normalized the elevations in basal oxygen consumption, proton leak, and glycolysis in all sirtuin over-expressing cells. While the above effects were common to all three mitochondrial sirtuins, some differences between the SIRT3, SIRT4, and SIRT5 expressing cells were noted. Only SIRT3 overexpression affected fatty acid metabolism, and only SIRT4 overexpression altered superoxide levels and mitochondrial membrane potential. We conclude that all three mitochondrial sirtuins can promote increased mitochondrial respiration and cellular metabolism. SIRT3, SIRT4, and SIRT5 appear to respond to excess glucose by inducing a coordinated increase of glycolysis and respiration, with the excess energy dissipated via proton leak.

  9. Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

    Directory of Open Access Journals (Sweden)

    Cara J. Valvona

    2018-03-01

    Full Text Available Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4, which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C may be more appropriate than LDHA inhibition alone.

  10. Necessity of glycolysis for recovery from ultraviolet killing of Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Atsuta, J.; Okajima, S.

    1976-01-01

    An inverse relationship was found between uv (2537 A) survival and preirradiation respiratory rate of diploid yeast: Survival was consistently high in cells grown in anaerobic complete medium where only glycolysis was operating, while it was low in cells grown in aerobic glycerin medium where only oxidative phosphorylation was operating; these observations are consistent with the observed shift from the high resistance in logarithmic phase to the lesser resistance in stationary phase in cells grown in aerobic complete medium. Immediate recovery, which was determined by the ratio between split-dose survival and no recovery survival, occurred only in cells having a low respiratory rate and not in cells having a high respiratory rate. Severe suppression of aerobic ATP synthesis during the first hour after irradiation was found only in cells having a high respiratory rate. Otherwise, delayed recovery, which was determined by immediate plating on glycerin medium, was not related to the respiratory rate. These results indicate a low resistance to uv of oxidative phosphorylation in mitochondria existing at the time of irradiation and a high resistance to uv of both glycolysis and oxidative phosphorylation in new mitochondria produced after irradiation. Survival therefore may be dependent on whether irradiated cells can recover from sublethal damage by utilizing ATP produced by glycolysis immediately after irradiation

  11. Understanding bistability in yeast glycolysis using general properties of metabolic pathways.

    Science.gov (United States)

    Planqué, Robert; Bruggeman, Frank J; Teusink, Bas; Hulshof, Josephus

    2014-09-01

    Glycolysis is the central pathway in energy metabolism in the majority of organisms. In a recent paper, van Heerden et al. showed experimentally and computationally that glycolysis can exist in two states, a global steady state and a so-called imbalanced state. In the imbalanced state, intermediary metabolites accumulate at low levels of ATP and inorganic phosphate. It was shown that Baker's yeast uses a peculiar regulatory mechanism--via trehalose metabolism--to ensure that most yeast cells reach the steady state and not the imbalanced state. Here we explore the apparent bistable behaviour in a core model of glycolysis that is based on a well-established detailed model, and study in great detail the bifurcation behaviour of solutions, without using any numerical information on parameter values. We uncover a rich suite of solutions, including so-called imbalanced states, bistability, and oscillatory behaviour. The techniques employed are generic, directly suitable for a wide class of biochemical pathways, and could lead to better analytical treatments of more detailed models. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer.

    Science.gov (United States)

    Yeung, S J; Pan, J; Lee, M-H

    2008-12-01

    Despite diversity in genetic events in oncogenesis, cancer cells exhibit a common set of functional characteristics. Otto Warburg discovered that cancer cells have consistently higher rates of glycolysis than normal cells. The underlying mechanisms leading to the Warburg phenomenon include mitochondrial changes, upregulation of rate-limiting enzymes/proteins in glycolysis and intracellular pH regulation, hypoxia-induced switch to anaerobic metabolism, and metabolic reprogramming after loss of p53 function. The regulation of energy metabolism can be traced to a "triad" of transcription factors: c-MYC, HIF-1 and p53. Oncogenetic changes involve a nonrandom set of gene deletions, amplifications and mutations, and many oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53. Glycolysis in cancer cells has clinical implications in cancer diagnosis, treatment and interaction with diabetes mellitus. Many drugs targeting energy metabolism are in development. Future advances in technology may bring about transcriptome and metabolome-guided chemotherapy.

  13. Long-term stability of glucose: glycolysis inhibitor vs. gel barrier tubes.

    Science.gov (United States)

    Winter, Theresa; Hannemann, Anke; Suchsland, Juliane; Nauck, Matthias; Petersmann, Astrid

    2018-03-12

    Measuring the glucose concentration in whole blood samples is critical due to unsatisfactory glycolysis inhibition. Previous studies showed that Terumo tubes were superior, but they were taken off the European market in 2016 and alternatives were required. This initiated the present evaluation of glucose stability in five available tube types. Venous blood samples were collected from 61 healthy volunteers to test tubes supplied by Terumo (two sets), Greiner FC-Mix, BD FX-Mixture and BD serum. After sampling, the contents were thoroughly mixed and centrifuged within an hour. The glucose concentrations were determined and the samples resuspended except for BD serum tubes (gel barrier). The first 30 samples were stored at room temperature and the remaining 31 at 4°C. After 24, 48, 72 and 96 h, all tubes were (re)centrifuged, and glucose concentration measurements were repeated. Changes in glucose concentrations over time differed significantly between the investigated tube types and to a certain extent between the two storing conditions. Glycolysis was most evident in the BD FX-mixture tubes. Good glucose stability was observed in samples retrieved form BD serum and Greiner tubes. The stability in both Terumo tubes was comparable to that in other studies. Although Greiner and both Terumo tubes are supposed to contain the same glycolysis inhibitor, glucose stability differed between these tubes. We showed that Greiner is an acceptable alternative to Terumo and that glucose in serum that was rapidly separated from corpuscles by a gel barrier is stable for an extended time.

  14. Simultaneous overexpression of enzymes of the lower part of glycolysis can enhance the fermentative capacity of Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Smits, H. P.; Hauf, J.; Muller, S.

    2000-01-01

    Recombinant S. cerevisiae strains, with elevated levels of the enzymes of lower glycolysis (glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate mutase, phosphoglycerate kinase, enolase, pyruvate kinase, pyruvate decarboxylase and alcohol dehydrogenase) were physiologically characterized...

  15. Mesurements of intracellular ATP provide new insight into the regulation of glycolysis in the yeast Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Ytting, Cecilie Karkov; Fuglsang, Anja Thoe; Hiltunen, J. Kalervo

    2012-01-01

    Glycolysis in the yeast Saccharomyces cerevisiae exhibits temporal oscillation under anaerobic or semianaerobic conditions. Previous evidence indicated that at least two membrane-bound ATPases, the mitochondrial F0F1 ATPase and the plasma membrane P-type ATPase (Pma1p), were important in regulating...... of the temporal behaviour of intracellular ATP in a yeast strain with oscillating glycolysis showed that, in addition to oscillation in intracellular ATP, there is an overall slow decrease in intracellular ATP because the ATP consumption rate exceeds the ATP production in glycolysis. Measurements of the temporal...... activity is under strict control. In the absence of glucose ATPase activity is switched off, and the intracellular ATP concentration is high. When glucose is added to the cells the ATP concentration starts to decrease, because ATP consumption exceeds ATP production by glycolysis. Finally, when glucose...

  16. Dynamics and regulation of glycolysis-tricarboxylic acid metabolism in the midgut of Spodoptera litura during metamorphosis.

    Science.gov (United States)

    Hu, D; Luo, W; Fan, L F; Liu, F L; Gu, J; Deng, H M; Zhang, C; Huang, L H; Feng, Q L

    2016-04-01

    Significant changes usually take place in the internal metabolism of insects during metamorphosis. The glycolysis-tricarboxylic acid (glycolysis-TCA) pathway is important for energy metabolism. To elucidate its dynamics, the mRNA levels of genes involved in this pathway were examined in the midgut of Spodoptera litura during metamorphosis, and the pyruvate content was quantified. The expression patterns of these genes in response to starvation were examined, and the interaction between protein phosphatase 1 (PP1) and phosphofructokinase (PFK) was studied. The results revealed that the expression or activities of most glycolytic enzymes was down-regulated in prepupae and then recovered in some degree in pupae, and all TCA-related genes were remarkably suppressed in both the prepupae and pupae. Pyruvate was enriched in the pupal midgut. Taken together, these results suggest that insects decrease both glycolysis and TCA in prepupae to save energy and then up-regulate glycolysis but down-regulate TCA in pupae to increase the supply of intermediates for construction of new organs. The expression of all these genes were down-regulated by starvation, indicating that non-feeding during metamorphosis may be a regulator of glycolysis-TCA pathway in the midgut. Importantly, interaction between PP1 and PFK was identified and is suggested to be involved in the regulation of glycolysis. © 2015 The Royal Entomological Society.

  17. Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells.

    Science.gov (United States)

    Zhou, Fang; Du, Jin; Wang, Jianjun

    2017-04-01

    Albendazole (ABZ) has an anti-tumor ability and inhibits HIF-1α activity. HIF-1α is associated with glycolysis and vascular endothelial cell growth factor (VEGF) expression, which plays an important role in cancer progression. These clues indicate that ABZ exerts an anti-cancer effect by regulating glycolysis and VEGF expression. The aim of this study is to clarify the effects of ABZ on non-small cell lung cancer (NSCLC) cells and explore the underlying molecular mechanisms. The expression levels of HIF-1α and VEGF were detected using western blot analysis, and the effect of ABZ on glycolysis was evaluated by measuring the relative activities of hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) and detecting the production of lactate in A549 and H1299 cells. The results showed that ABZ decreased the expression levels of HIF-1α and VEGF and suppressed glycolysis in under hypoxia, but not normoxic condition. Inhibiting HIF-1α also suppressed glycolysis and VEGF expression. Additionally, ABZ inhibited the volume and weight, decreased the relative activities of HK, PK, and LDH, and reduced the levels of HIF-1α and VEGF of A549 xenografts in mouse models. In conclusion, ABZ inhibited growth of NSCLC cells by suppressing HIF-1α-dependent glycolysis and VEGF expression.

  18. The miR-383-LDHA axis regulates cell proliferation, invasion and glycolysis in hepatocellular cancer

    Directory of Open Access Journals (Sweden)

    Zhixiong Fang

    2017-02-01

    Full Text Available Objective(s: To explore the correlation between expression patterns and functions of miR-383 and LDHA in hepatocellular cancer (HCC. Materials and Methods: We detected the expression of miR-383 and LDHA in 30 HCC tissues and their matched adjacent normal tissues using qRT-PCR. Then we performed MTT assay, foci formation assay, transwell migration assay, glucose uptake assay and lactate production assay to explore the function of miR-383 in cell proliferation, invasion and glycolysis in HCC cell lines. Luciferase reporter assay was used to explore whether LDHA was a target gene of miR-383. Western blot and qRT-PCR were used to further confirm LDHA was targeted by miR-383. Then the above functional experiments were repeated to see whether the function of LDHA could be inhibited by miR-383. Results: The results of qRT-PCR showed that miR-383 was down-regulated in HCC tissues compared with their matched adjacent normal tissues. Functional experiments showed that overexpression of miR-383 significantly suppressed cell proliferation, invasion and glycolysis. Luciferase reporter assay showed LDHA was a target gene of miR-383 and expression of LDHA was inversely correlated with that of miR-383 in HCC. Besides, increased cell proliferation, invasion and glycolysis triggered by LDHA could be inhibited by overexpression of miR-383 in HCC cell lines. Conclusion: Our study proved that miR-383 is down-regulated in HCC and acts as a tumor suppressor through targeting LDHA. Targeting the miR-383-LDHA axis might be a promising strategy in HCC treatment.

  19. The nutritional status of Methanosarcina acetivorans regulates glycogen metabolism and gluconeogenesis and glycolysis fluxes.

    Science.gov (United States)

    Santiago-Martínez, Michel Geovanni; Encalada, Rusely; Lira-Silva, Elizabeth; Pineda, Erika; Gallardo-Pérez, Juan Carlos; Reyes-García, Marco Antonio; Saavedra, Emma; Moreno-Sánchez, Rafael; Marín-Hernández, Alvaro; Jasso-Chávez, Ricardo

    2016-05-01

    Gluconeogenesis is an essential pathway in methanogens because they are unable to use exogenous hexoses as carbon source for cell growth. With the aim of understanding the regulatory mechanisms of central carbon metabolism in Methanosarcina acetivorans, the present study investigated gene expression, the activities and metabolic regulation of key enzymes, metabolite contents and fluxes of gluconeogenesis, as well as glycolysis and glycogen synthesis/degradation pathways. Cells were grown with methanol as a carbon source. Key enzymes were kinetically characterized at physiological pH/temperature. Active consumption of methanol during exponential cell growth correlated with significant methanogenesis, gluconeogenic flux and steady glycogen synthesis. After methanol exhaustion, cells reached the stationary growth phase, which correlated with the rise in glycogen consumption and glycolytic flux, decreased methanogenesis, negligible acetate production and an absence of gluconeogenesis. Elevated activities of carbon monoxide dehydrogenase/acetyl-CoA synthetase complex and pyruvate: ferredoxin oxidoreductase suggested the generation of acetyl-CoA and pyruvate for glycogen synthesis. In the early stationary growth phase, the transcript contents and activities of pyruvate phosphate dikinase, fructose 1,6-bisphosphatase and glycogen synthase decreased, whereas those of glycogen phosphorylase, ADP-phosphofructokinase and pyruvate kinase increased. Therefore, glycogen and gluconeogenic metabolites were synthesized when an external carbon source was provided. Once such a carbon source became depleted, glycolysis and methanogenesis fed by glycogen degradation provided the ATP supply. Weak inhibition of key enzymes by metabolites suggested that the pathways evaluated were mainly transcriptionally regulated. Because glycogen metabolism and glycolysis/gluconeogenesis are not present in all methanogens, the overall data suggest that glycogen storage might represent an environmental

  20. Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease.

    Directory of Open Access Journals (Sweden)

    Meliana Riwanto

    Full Text Available Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD. Here we tested whether metabolic reprogramming towards aerobic glycolysis ("Warburg effect" plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+, a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1 in cystic kidneys of Cy/+ rats compared with wild-type (+/+ rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day for 5 weeks resulted in significantly lower kidney weights (-27% and 2-kidney/total-body-weight ratios (-20% and decreased renal cyst index (-48% compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98±0.67 vs 1.41±0.37 ml/min, BUN (0.69±0.26 vs 0.40±0.10 ml/min and uric acid (0.38±0.20 vs 0.21±0.10 ml/min, and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-α, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD.

  1. Activation of glycolysis and inhibition of glucose transport into leaves by fluoride

    Energy Technology Data Exchange (ETDEWEB)

    Lustinec, J; Pokorna, V; Ruzicka, J

    1962-01-01

    During stimulation of wheat leaf respiration by fluoride at 100 to 200 ppM fluorine in dry tissue the ratio of radioactivities of /sup 14/CO/sub 2/ released from glucose-6-/sup 14/C and that released from glucose-1-/sup 14/C (C/sub 6//C/sub 1/) increases due especially to an increased output of 6-/sup 14/CO/sub 2/ which suggests an activation of glycolysis. The absolute values of radioactivity of /sup 14/CO/sub 2/, however, are decreased by the action of fluoride due to its inhibition of the transport of glucose into leaves. 15 references, 2 figures, 2 tables.

  2. EPR oxygen imaging and hyperpolarized (13) C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate

    DEFF Research Database (Denmark)

    Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu

    2013-01-01

    The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has...... the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under...

  3. Large Intergenic Non-coding RNA-RoR Inhibits Aerobic Glycolysis of Glioblastoma Cells via Akt Pathway

    Science.gov (United States)

    Li, Yong; He, Zhi-Cheng; Liu, Qing; Zhou, Kai; Shi, Yu; Yao, Xiao-Hong; Zhang, Xia; Kung, Hsiang-Fu; Ping, Yi-Fang; Bian, Xiu-Wu

    2018-01-01

    Reprogramming energy metabolism is a hallmark of malignant tumors, including glioblastoma (GBM). Aerobic glycolysis is often utilized by tumor cells to maintain survival and proliferation. However, the underlying mechanisms of aerobic glycolysis in GBM remain elusive. Herein, we demonstrated that large intergenic non-coding RNA-RoR (LincRNA-RoR) functioned as a critical suppressor to inhibit the aerobic glycolysis and viability of GBM cells. We found that LincRNA-RoR was markedly reduced in GBM tissues compared with adjacent non-tumor tissues from 10 cases of GBM patients. Consistently, LincRNA-RoR expression in GBM cells was significantly lower than that in normal glial cells. The aerobic glycolysis of GBM cells, as determined by the measurement of glucose uptake and lactate production, was impaired by LincRNA-RoR overexpression. Mechanistically, LincRNA-RoR inhibited the expression of Rictor, the key component of mTORC2 (mammalian target of rapamycin complex 2), to suppress the activity of Akt pathway and impair the expression of glycolytic effectors, including Glut1, HK2, PKM2 and LDHA. Finally, enforced expression of LincRNA-RoR reduced the proliferation of GBM cells in vitro, restrained tumor growth in vivo, and repressed the expression of glycolytic molecules in GBM xenografts. Collectively, our results underscore LincRNA-RoR as a new suppressor of GBM aerobic glycolysis with therapeutic potential. PMID:29581766

  4. Glycolysis of carbon fiber-epoxy unidirectional mat catalysed by sodium hydroxide

    Science.gov (United States)

    Zaini, Mariana Binti Mohd; Badri, Khairiah Haji

    2014-09-01

    This study was conducted to recycle carbon fibre-epoxy (CFRP) composite in woven sheet/ mat form. The CFRP was recycled through glycolysis with polyethlyene glycol (PEG 200) as the solvent. The CFRP was loaded into the solvent at a ratio of 4:1 (w/w). PEG200 was diluted with water to a ratio of 80:20 (v/v). This reaction was catalysed by sodium hydroxide (NaOH) solution with varying concentrations at 1.5, 1.7 and 1.9% (w/v). The glycolysis was conducted at 180-190 °C. The recovered CF (rCF) was analysed using Fourier Transform Infrared (FTIR), Scanning Electron Microscopy (SEM) and Energy Dispersive X-Ray (EDX) while the degraded solution was analysed using FTIR and the epoxy content was determined. The FTIR spectrum of the rCF exhibited the disappearance of the COC peak belonged to epoxy and supported by the SEM micrographs that showed clear rCF. On the other hand, the analysed filtrate detected the disappearance of oxygen peak element in the EDX spectrum for all rCF samples. This gave an indication that the epoxy resin has been removed from the surface of the carbon fiber.

  5. LMP1-mediated glycolysis induces myeloid-derived suppressor cell expansion in nasopharyngeal carcinoma.

    Directory of Open Access Journals (Sweden)

    Ting-Ting Cai

    2017-07-01

    Full Text Available Myeloid-derived suppressor cells (MDSCs are expanded in tumor microenvironments, including that of Epstein-Barr virus (EBV-associated nasopharyngeal carcinoma (NPC. The link between MDSC expansion and EBV infection in NPC is unclear. Here, we show that EBV latent membrane protein 1 (LMP1 promotes MDSC expansion in the tumor microenvironment by promoting extra-mitochondrial glycolysis in malignant cells, which is a scenario for immune escape initially suggested by the frequent, concomitant detection of abundant LMP1, glucose transporter 1 (GLUT1 and CD33+ MDSCs in tumor sections. The full process has been reconstituted in vitro. LMP1 promotes the expression of multiple glycolytic genes, including GLUT1. This metabolic reprogramming results in increased expression of the Nod-like receptor family protein 3 (NLRP3 inflammasome, COX-2 and P-p65 and, consequently, increased production of IL-1β, IL-6 and GM-CSF. Finally, these changes in the environment of malignant cells result in enhanced NPC-derived MDSC induction. One key step is the physical interaction of LMP1 with GLUT1 to stabilize the GLUT1 protein by blocking its K48-ubiquitination and p62-dependent autolysosomal degradation. This work indicates that LMP1-mediated glycolysis regulates IL-1β, IL-6 and GM-CSF production through the NLRP3 inflammasome, COX-2 and P-p65 signaling pathways to enhance tumor-associated MDSC expansion, which leads to tumor immunosuppression in NPC.

  6. 3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

    Science.gov (United States)

    Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

    2015-02-01

    Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro . However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

  7. Glycolysis in Panc-1 human pancreatic cancer cells is inhibited by everolimus.

    Science.gov (United States)

    Liu, Ling; Gong, Liansheng; Zhang, Yangde; Li, Nianfeng

    2013-01-01

    The aim of this study was to evaluate the effects and molecular mechanisms of everolimus on Panc-1 human pancreatic cancer cells. Panc-1 human pancreatic cancer cells were treated with everolimus (10 μg/ml) at selected time points (6, 12 and 24 h). Cell proliferation and apoptosis were evaluated by MTT and flow cytometric analyses. The glycolytic activity was determined by measuring the activity of the key enzyme lactate dehydrogenase (LDH) and lactate production. The activity of mammalian target of rapamycin (mTOR) signaling was measured by western blotting. The expression of genes, including hexokinase 2 (HK2) and microRNA-143 (miR-143), was evaluated by real-time polymerase chain reaction (PCR). The administration of everolimus time-dependently inhibited proliferation and glycolysis and induced apoptosis in the Panc-1 human pancreatic cancer cells. As the time of treatment with everolimus increased, the mTOR signaling activity decreased, indicated by lower phosphorylation levels of S6 kinase; however, the phosphorylation levels of mTOR barely changed. Moreover, our data showed an everolimus-induced increase in miR-143 and decrease in HK2 in Panc-1 cells in a time-dependent manner. In conclusion, the current study indicates a novel role of everolimus in its antitumor effect as an inhibitor of glycolysis in Panc-1 human pancreatic cancer cells. Furthermore, our data highlights the significance of exploring the mechanisms of everolimus and miR-143 in malignant tumors.

  8. Glycolysis of carbon fiber-epoxy unidirectional mat catalysed by sodium hydroxide

    Energy Technology Data Exchange (ETDEWEB)

    Zaini, Mariana Binti Mohd [School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor (Malaysia); Badri, Khairiah Haji [School of Chemical Sciences and Food Technology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia and Polymer Research Center, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43 (Malaysia)

    2014-09-03

    This study was conducted to recycle carbon fibre-epoxy (CFRP) composite in woven sheet/ mat form. The CFRP was recycled through glycolysis with polyethlyene glycol (PEG 200) as the solvent. The CFRP was loaded into the solvent at a ratio of 4:1 (w/w). PEG200 was diluted with water to a ratio of 80:20 (v/v). This reaction was catalysed by sodium hydroxide (NaOH) solution with varying concentrations at 1.5, 1.7 and 1.9% (w/v). The glycolysis was conducted at 180-190 °C. The recovered CF (rCF) was analysed using Fourier Transform Infrared (FTIR), Scanning Electron Microscopy (SEM) and Energy Dispersive X-Ray (EDX) while the degraded solution was analysed using FTIR and the epoxy content was determined. The FTIR spectrum of the rCF exhibited the disappearance of the COC peak belonged to epoxy and supported by the SEM micrographs that showed clear rCF. On the other hand, the analysed filtrate detected the disappearance of oxygen peak element in the EDX spectrum for all rCF samples. This gave an indication that the epoxy resin has been removed from the surface of the carbon fiber.

  9. Influence of Cooling on the Glycolysis Rate and Development of PSE (Pale, Soft, Exudative Meat

    Directory of Open Access Journals (Sweden)

    Mayka Reghiany Pedrão

    2015-04-01

    Full Text Available The aim of this work was to evaluate pH values fall rate in chicken breast meat under commercial refrigeration processing conditions and the development of PSE (pale, soft, exudative meat. Broiler breast samples from the Cobb breed, both genders, at 47 days of age (n = 100 were taken from refrigerated carcasses (RS immersed in water and ice in a tank chilled at 0°C (±2. pH and temperature (T values were recorded at several periods throughout refrigeration in comparison to samples left at room T as control (CS. The ultimate pH (pHu value of 5.86 for RS carcasses were only reached at 11°C after 8.35 h post mortem (PM while, for CS samples, pHu value was 5.94 at 22°C after 4.08 h PM. Thus, under commercial refrigeration conditions, the glycolysis rate was retarded by over 4.0 h PM and the breast meat color was affected. At 24.02 h PM, PSE meat incidence was 30% while for CS, meat remained dark and PSE meat was not detected. Results show retardation in the glycolysis rate and PSE meat development was promoted by the refrigeration treatment when compared with samples stored at processing room temperature.

  10. Emerging Glycolysis Targeting and Drug Discovery from Chinese Medicine in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Zhiyu Wang

    2012-01-01

    Full Text Available Molecular-targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells have different metabolic properties from normal cells. Normal cells mostly rely upon the process of mitochondrial oxidative phosphorylation to produce energy whereas cancer cells have developed an altered metabolism that allows them to sustain higher proliferation rates. Cancer cells could predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic characteristic is known as the “Warburg Effect.” Although the exact mechanisms underlying the Warburg effect are unclear, recent progress indicates that glycolytic pathway of cancer cells could be a critical target for drug discovery. With a long history in cancer treatment, traditional Chinese medicine (TCM is recognized as a valuable source for seeking bioactive anticancer compounds. A great progress has been made to identify active compounds from herbal medicine targeting on glycolysis for cancer treatment. Herein, we provide an overall picture of the current understanding of the molecular targets in the cancer glycolytic pathway and reviewed active compounds from Chinese herbal medicine with the potentials to inhibit the metabolic targets for cancer treatment. Combination of TCM with conventional therapies will provide an attractive strategy for improving clinical outcome in cancer treatment.

  11. Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation.

    Science.gov (United States)

    Zheng, Xinde; Boyer, Leah; Jin, Mingji; Mertens, Jerome; Kim, Yongsung; Ma, Li; Ma, Li; Hamm, Michael; Gage, Fred H; Hunter, Tony

    2016-06-10

    How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.

  12. From Position-Specific Labeling to Environmental Fluxomics: Elucidating Biogeochemical Cycles from the Metabolic Perspective (BG Division Outstanding ECS Award Lecture)

    Science.gov (United States)

    Dippold, Michaela; Apostel, Carolin; Dijkstra, Paul; Kuzyakov, Yakov

    2017-04-01

    Understanding soil and sedimentary organic matter (SOM) dynamics is one of the most important challenges in biogeoscience. To disentangle the fluxes and transformations of C in soils a detailed knowledge on the biochemical pathways and its controlling factors is required. Biogeochemists' view on the C transformation of microorganisms in soil has rarely exceed a strongly simplified concept assuming that C gets either oxidized to CO2 via the microbial catabolism or incorporated into biomass via the microbial anabolism. Biochemists, however, thoroughly identified in the past decades the individual reactions of glycolysis, pentose-phosphate pathway and citric acid cycle underlying the microbial catabolism. At various points within that metabolic network the anabolic fluxes feeding biomass formation branch off. Recent studies on metabolic flux tracing by position-specific isotope labeling allowed tracing these C transformations in soils in situ, an approach which is qunatitatively complemented by metabolic flux modeling. This approach has reached new impact by the cutting-edge combination of position-specific 13C labeling with compound-specific isotope analysis of microbial biomarkers and metabolites which allows 1) tracing specific anabolic pathways in diverse microbial communities in soils and 2) identification of specific pathways of individual functional microbial groups. Thus, the combination of position-specific labeling, compound-specific isotope incorporation in biomarkers and quantitative metabolic flux modelling provide the toolbox for quantitative soil fluxomics. Our studies combining position-specific labeled glucose with amino sugar 13C analysis showed that up to 55% of glucose, incorporated into the glucose derivative glucosamine, first passed glycolysis before allocated back via gluconeogenesis. Similarly, glutamate-derived C is allocated via anaplerotic pathways towards fatty acid synthesis and in parallel to its oxidation in citric acid cycle. Thus

  13. Glycolysis of poly (3-hydroxybutyrate) catalyzed by an enzyme system; Glicolise do poli(3-hidroxibutirato) por via enzimatica

    Energy Technology Data Exchange (ETDEWEB)

    Campos, T.F.; Mano, V., E-mail: mano@ufsj.edu.b [Universidade Federal de Sao Joao del Rei (UFSJ), MG (Brazil). Dept. de Ciencias Naturais

    2010-07-01

    In this work we report the studies of PHB glycolysis catalyzed by lipase Amano PS (Pseudomonas cepacia) in the presence of 1,2-ethanediol (ethylene glycol). The reactions were performed in toluene:dichloroethane 3:1 (v/v) at 60 deg C, varying reaction time and concentration of ethylene glycol. PHB and the products of glycolysis (polyols) were characterized by FTIR, {sup 1}H-NMR, and TG. The FTIR spectra of polyols showed no significant change compared to the spectrum of PHB. The {sup 1}H-NMR spectra of the products of glycolysis showed signs of interest between 3 and 4.7 ppm, related to the ethylene glycol protons inserted in the polymer chain. By analyzing the thermograms we observed that the polyols are more thermally stable than PHB. (author)

  14. miR-4458 suppresses glycolysis and lactate production by directly targeting hexokinase2 in colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Qin, Yaguang; Cheng, Chuanyao; Lu, Hong, E-mail: honglu6512@163.com; Wang, Yaqiu

    2016-01-01

    miR-4458, a new tumor-suppressor, was reported to down-regulated in human hepatocellular carcinoma. The expression status, roles and inhibitory mechanisms of miR-4458 in other tumors still need to be clarified. The aim of this study is to investigate the effects of miR-4458 and to elucidate the potential mechanism in colon cancer cells. Using bioinformatic databases, we predicted that hexokinase2 (HK2), a rate-limiting enzyme in the glycolytic pathway, was a target of miR-4458, so the effects of miR-4458 on glycolysis and lactate production was assessed in colon cancer cells. We found that miR-4458 was down-regulated and HK2 was up-regulated in colon cancer cells. Overexpression of miR-4458 inhibited proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. Luciferase activity assays showed that HK2 was a direct target of miR-4458. Moreover, knockdown of HK2 by specific RNAi also suppressed proliferation, glycolysis, and lactate production under both normoxic and hypoxic conditions. In conclusion, our findings suggested that miR-4458 inhibited the progression of colon cancer cells by inhibition of glycolysis and lactate production via directly targeting HK2 mRNA. - Highlights: • miR-4458 is down-regulated in colon cancer cells. • miR-4458 suppresses proliferation, glycolysis, and lactate production. • HK2 is a target of miR-4458. • HK2 knockdown inhibits proliferation, glycolysis, and lactate production.

  15. Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Shanshan Sun

    2017-04-01

    Full Text Available Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury. In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD, a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen–glucose-deprivation/reperfusion (OGD/R model in a mouse hippocampal neuronal cell line. CBD supplementation during reperfusion rescued OGD/R-induced cell death, attenuated intracellular ROS generation and lipid peroxidation, and simultaneously reversed the abnormal changes in antioxidant biomarkers. Using the Seahorse XFe24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons. The activation of glucose 6-phosphate dehydrogenase and the preservation of the NADPH/NADP+ ratio implies that the pentose-phosphate pathway is stimulated by CBD, thus protecting hippocampal neurons from OGD/R injury. This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance.

  16. Exploring the potential of lactic acid production from lignocellulosic hydrolysates with various ratios of hexose versus pentose by Bacillus coagulans IPE22.

    Science.gov (United States)

    Wang, Yujue; Cao, Weifeng; Luo, Jianquan; Wan, Yinhua

    2018-08-01

    The aim of this study was to investigate the feasibility of utilizing different lignocellulosic hydrolysates with various hexose versus pentose (H:P) ratios to produce lactic acid (LA) from Bacillus coagulans IPE22 by fermentations with single and mixed sugar. In single sugar utilization, glucose tended to promote LA production, and xylose preferred to enhance cell growth. In mixed sugar utilization, glucose and pentose were consumed simultaneously when glucose concentration was lower than 20 g/L, and almost the same concentration of LA (50 g/L) was obtained regardless of the differences of H:P values. Finally, LA production from corn cob hydrolysates (CCH) contained 60 g/L mixed sugar verified the mechanisms found in the fermentations with simulated sugar mixture. Comparing with single glucose utilization, CCH utilization was faster and the yield of LA was not significantly affected. Therefore, the great potential of producing LA with lignocellulosic materials by B. coagulans was proved. Copyright © 2018. Published by Elsevier Ltd.

  17. Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons.

    Science.gov (United States)

    Sun, Shanshan; Hu, Fangyuan; Wu, Jihong; Zhang, Shenghai

    2017-04-01

    Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury. In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD), a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen-glucose-deprivation/reperfusion (OGD/R) model in a mouse hippocampal neuronal cell line. CBD supplementation during reperfusion rescued OGD/R-induced cell death, attenuated intracellular ROS generation and lipid peroxidation, and simultaneously reversed the abnormal changes in antioxidant biomarkers. Using the Seahorse XF e 24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons. The activation of glucose 6-phosphate dehydrogenase and the preservation of the NADPH/NADP + ratio implies that the pentose-phosphate pathway is stimulated by CBD, thus protecting hippocampal neurons from OGD/R injury. This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  18. Expression of genes encoding F-1-ATPase results in uncoupling of glycolysis from biomass production in Lactococcus lactis

    DEFF Research Database (Denmark)

    Købmann, Brian Jensen; Solem, Christian; Pedersen, M.B.

    2002-01-01

    of the genes encoding F-1-ATPase was found to decrease the intracellular energy level and resulted in a decrease in the growth rate. The yield of biomass also decreased, which showed that the incorporated F-1-ATPase activity caused glycolysis to be uncoupled from biomass production. The increase in ATPase...... threefold in nongrowing cells resuspended in buffer, but in steadily growing cells no increase in flux was observed. The latter result shows that glycolysis occurs close to its maximal capacity and indicates that control of the glycolytic flux under these conditions resides in the glycolytic reactions...

  19. Uptake of 13C-glucose by cell suspensions of carrot (Daucus carota) measured by in vivo NMR: Cycling of triose, pentose- and hexose-phosphates

    NARCIS (Netherlands)

    Krook, J.; Vreugdenhil, D.; Dijkema, C.; Plas, van der L.H.W.

    2000-01-01

    After a lag phase of 2 days, batch-grown cells of carrot (Daucus carota L.) cv. Flakkese entered the exponential growth phase and started to accumulate sucrose and hexoses. Short-term feeding 13C-glucose in this period resulted in only minor labelling of sucrose or fructose. CO2 production from

  20. Notch stimulates growth by direct regulation of genes involved in the control of glycolysis and the tricarboxylic acid cycle

    Czech Academy of Sciences Publication Activity Database

    Slaninová, Věra; Krafčíková, M.; Perez-Gomez, R.; Steffal, P.; Trantírek, L.; Bray, S. J.; Krejčí, Alena

    2016-01-01

    Roč. 6, Feb 15 (2016), s. 150155 ISSN 2046-2441 R&D Projects: GA ČR(CZ) GAP305/11/0126; GA ČR(CZ) GA14-08583S Grant - others:EU program (FP7/2007-20013)(CZ) 316304; POSTDOC2(CZ) CZ.1.07/2.3.00/30.0049 Program:FP7 Institutional support: RVO:60077344 Keywords : metabolism * Notch targets * Warburg effect Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.481, year: 2016 http://rsob.royalsocietypublishing.org/content/royopenbio/6/2/150155.full.pdf

  1. E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Jennifer L Major

    Full Text Available The E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme β-hydroxybutyrate dehydrogenase I (BDH1 is a potential biomarker.To define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM with a focus on BDH1.We previously developed transgenic (Tg mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43 levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70% in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone β-hydroxybutyrate (β-OHB showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to β-OHB.The data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We

  2. The transcriptional co-repressor myeloid translocation gene 16 inhibits glycolysis and stimulates mitochondrial respiration.

    Directory of Open Access Journals (Sweden)

    Parveen Kumar

    Full Text Available The myeloid translocation gene 16 product MTG16 is found in multiple transcription factor-containing complexes as a regulator of gene expression implicated in development and tumorigenesis. A stable Tet-On system for doxycycline-dependent expression of MTG16 was established in B-lymphoblastoid Raji cells to unravel its molecular functions in transformed cells. A noticeable finding was that expression of certain genes involved in tumor cell metabolism including 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4 (PFKFB3 and PFKFB4, and pyruvate dehydrogenase kinase isoenzyme 1 (PDK1 was rapidly diminished when MTG16 was expressed. Furthermore, hypoxia-stimulated production of PFKFB3, PFKFB4 and PDK1 was inhibited by MTG16 expression. The genes in question encode key regulators of glycolysis and its coupling to mitochondrial metabolism and are commonly found to be overexpressed in transformed cells. The MTG16 Nervy Homology Region 2 (NHR2 oligomerization domain and the NHR3 protein-protein interaction domain were required intact for inhibition of PFKFB3, PFKFB4 and PDK1 expression to occur. Expression of MTG16 reduced glycolytic metabolism while mitochondrial respiration and formation of reactive oxygen species increased. The metabolic changes were paralleled by increased phosphorylation of mitogen-activated protein kinases, reduced levels of amino acids and inhibition of proliferation with a decreased fraction of cells in S-phase. Overall, our findings show that MTG16 can serve as a brake on glycolysis, a stimulator of mitochondrial respiration and an inhibitor of cell proliferation. Hence, elevation of MTG16 might have anti-tumor effect.

  3. Quantitative elementary mode analysis of metabolic pathways: the example of yeast glycolysis

    Directory of Open Access Journals (Sweden)

    Kanehisa Minoru

    2006-04-01

    Full Text Available Abstract Background Elementary mode analysis of metabolic pathways has proven to be a valuable tool for assessing the properties and functions of biochemical systems. However, little comprehension of how individual elementary modes are used in real cellular states has been achieved so far. A quantitative measure of fluxes carried by individual elementary modes is of great help to identify dominant metabolic processes, and to understand how these processes are redistributed in biological cells in response to changes in environmental conditions, enzyme kinetics, or chemical concentrations. Results Selecting a valid decomposition of a flux distribution onto a set of elementary modes is not straightforward, since there is usually an infinite number of possible such decompositions. We first show that two recently introduced decompositions are very closely related and assign the same fluxes to reversible elementary modes. Then, we show how such decompositions can be used in combination with kinetic modelling to assess the effects of changes in enzyme kinetics on the usage of individual metabolic routes, and to analyse the range of attainable states in a metabolic system. This approach is illustrated by the example of yeast glycolysis. Our results indicate that only a small subset of the space of stoichiometrically feasible steady states is actually reached by the glycolysis system, even when large variation intervals are allowed for all kinetic parameters of the model. Among eight possible elementary modes, the standard glycolytic route remains dominant in all cases, and only one other elementary mode is able to gain significant flux values in steady state. Conclusion These results indicate that a combination of structural and kinetic modelling significantly constrains the range of possible behaviours of a metabolic system. All elementary modes are not equal contributors to physiological cellular states, and this approach may open a direction toward a

  4. Quantitative analysis of glycerol accumulation, glycolysis and growth under hyper osmotic stress.

    Directory of Open Access Journals (Sweden)

    Elzbieta Petelenz-Kurdziel

    Full Text Available We provide an integrated dynamic view on a eukaryotic osmolyte system, linking signaling with regulation of gene expression, metabolic control and growth. Adaptation to osmotic changes enables cells to adjust cellular activity and turgor pressure to an altered environment. The yeast Saccharomyces cerevisiae adapts to hyperosmotic stress by activating the HOG signaling cascade, which controls glycerol accumulation. The Hog1 kinase stimulates transcription of genes encoding enzymes required for glycerol production (Gpd1, Gpp2 and glycerol import (Stl1 and activates a regulatory enzyme in glycolysis (Pfk26/27. In addition, glycerol outflow is prevented by closure of the Fps1 glycerol facilitator. In order to better understand the contributions to glycerol accumulation of these different mechanisms and how redox and energy metabolism as well as biomass production are maintained under such conditions we collected an extensive dataset. Over a period of 180 min after hyperosmotic shock we monitored in wild type and different mutant cells the concentrations of key metabolites and proteins relevant for osmoadaptation. The dataset was used to parameterize an ODE model that reproduces the generated data very well. A detailed computational analysis using time-dependent response coefficients showed that Pfk26/27 contributes to rerouting glycolytic flux towards lower glycolysis. The transient growth arrest following hyperosmotic shock further adds to redirecting almost all glycolytic flux from biomass towards glycerol production. Osmoadaptation is robust to loss of individual adaptation pathways because of the existence and upregulation of alternative routes of glycerol accumulation. For instance, the Stl1 glycerol importer contributes to glycerol accumulation in a mutant with diminished glycerol production capacity. In addition, our observations suggest a role for trehalose accumulation in osmoadaptation and that Hog1 probably directly contributes to the

  5. Can yeast glycolysis be understood in terms of in vitro kinetics of the constituent enxymes? Testing biochemistry.

    NARCIS (Netherlands)

    Teusink, B.; Passarge, J.R.; Reijenga, C.A.; Esgalhado, M.E.L.M.; van der Weijden, C.C.; Schepper, M.; Walsh, M.C.; Bakker, B.M.; van Dam, K.; Westerhoff, H.V.; Snoep, J.L.

    2000-01-01

    This paper examines whether the in vivo behavior of yeast glycolysis can be understood in terms of the in vitro kinetic properties of the constituent enzymes. In nongrowing, anaerobic, compressed Saccharomyces cerevisiae the values of the kinetic parameters of most glycolytic enzymes were

  6. Preslaughter Transport Effect on Broiler Meat Quality and Post-mortem Glycolysis Metabolism of Muscles with Different Fiber Types.

    Science.gov (United States)

    Wang, Xiaofei; Li, Jiaolong; Cong, Jiahui; Chen, Xiangxing; Zhu, Xudong; Zhang, Lin; Gao, Feng; Zhou, Guanghong

    2017-11-29

    Preslaughter transport has been reported to decrease the quality of breast meat but not thigh meat of broilers. However, tissue-specific difference in glycogen metabolism between breast and thigh muscles of transported broilers has not been well studied. We thus investigated the differences in meat quality, adenosine phosphates, glycolysis, and bound key enzymes associated with glycolysis metabolism in skeletal muscles with different fiber types of preslaughter transported broilers during summer. Compared to a 0.5 h transport, a 3 h transport during summer decreased ATP content, increased AMP content and AMP/ATP ratio, and accelerated glycolysis metabolism via the upregulation of glycogen phosphorylase expression accompanied by increased activities of bound glycolytic enzymes (hexokinase, pyruvate kinase, and lactate dehydrogenase) in pectoralis major muscle, which subsequently increased the likelihood of pale, soft, and exudative-like breast meat. On the other hand, a 3 h transport induced only a moderate glycolysis metabolism in tibialis anterior muscle, which did not cause any noticeable changes in the quality traits of the thigh meat.

  7. Resveratrol Inhibits ROS-Promoted Activation and Glycolysis of Pancreatic Stellate Cells via Suppression of miR-21

    Directory of Open Access Journals (Sweden)

    Bin Yan

    2018-01-01

    Full Text Available Activation of pancreatic stellate cells (PSCs initiates pancreatic fibrosis in chronic pancreatitis and furnishes a niche that enhances the malignancy of pancreatic cancer cells (PCCs in pancreatic ductal adenocarcinoma (PDAC. Resveratrol (RSV, a natural polyphenol, exhibits potent antioxidant and anticancer effects. However, whether and how RSV influences the biological properties of activated PSCs and the effects of these changes on tumor remain unknown. In the present study, we found that RSV impeded hydrogen peroxide-driven reactive oxygen species- (ROS- induced activation, invasion, migration, and glycolysis of PSCs. In addition, miR-21 expression in activated PSCs was downregulated after RSV treatment, whereas the PTEN protein level increased. miR-21 silencing attenuated ROS-induced activation, invasion, migration, and glycolysis of PSCs, whereas the overexpression of miR-21 rescued the responses of PSCs treated with RSV. Moreover, RSV or N-acetyl-L-cysteine (NAC administration or miR-21 knockdown in PSCs reduced the invasion and migration of PCCs in coculture, and the effects of RSV were partly reversed by miR-21 upregulation. Collectively, RSV inhibits PCC invasion and migration through suppression of ROS/miR-21-mediated activation and glycolysis in PSCs. Therefore, targeting miR-21-mediated glycolysis by RSV in tumor stroma may serve as a new strategy for clinical PDAC prevention or treatment.

  8. BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.

    Science.gov (United States)

    An, Ming-Xin; Li, Si; Yao, Han-Bing; Li, Chao; Wang, Jia-Mei; Sun, Jia; Li, Xin-Yu; Meng, Xiao-Na; Wang, Hua-Qin

    2017-12-04

    Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents. © 2017 An et al.

  9. Separation of metabolic supply and demand: aerobic glycolysis as a normal physiological response to fluctuating energetic demands in the membrane.

    Science.gov (United States)

    Epstein, Tamir; Xu, Liping; Gillies, Robert J; Gatenby, Robert A

    2014-01-01

    Cancer cells, and a variety of normal cells, exhibit aerobic glycolysis, high rates of glucose fermentation in the presence of normal oxygen concentrations, also known as the Warburg effect. This metabolism is considered abnormal because it violates the standard model of cellular energy production that assumes glucose metabolism is predominantly governed by oxygen concentrations and, therefore, fermentative glycolysis is an emergency back-up for periods of hypoxia. Though several hypotheses have been proposed for the origin of aerobic glycolysis, its biological basis in cancer and normal cells is still not well understood. We examined changes in glucose metabolism following perturbations in membrane activity in different normal and tumor cell lines and found that inhibition or activation of pumps on the cell membrane led to reduction or increase in glycolysis, respectively, while oxidative phosphorylation remained unchanged. Computational simulations demonstrated that these findings are consistent with a new model of normal physiological cellular metabolism in which efficient mitochondrial oxidative phosphorylation supplies chronic energy demand primarily for macromolecule synthesis and glycolysis is necessary to supply rapid energy demands primarily to support membrane pumps. A specific model prediction was that the spatial distribution of ATP-producing enzymes in the glycolytic pathway must be primarily localized adjacent to the cell membrane, while mitochondria should be predominantly peri-nuclear. The predictions were confirmed experimentally. Our results show that glycolytic metabolism serves a critical physiological function under normoxic conditions by responding to rapid energetic demand, mainly from membrane transport activities, even in the presence of oxygen. This supports a new model for glucose metabolism in which glycolysis and oxidative phosphorylation supply different types of energy demand. Cells use efficient but slow-responding aerobic metabolism

  10. Inhibition of Non-flux-Controlling Enzymes Deters Cancer Glycolysis by Accumulation of Regulatory Metabolites of Controlling Steps.

    Science.gov (United States)

    Marín-Hernández, Álvaro; Rodríguez-Zavala, José S; Del Mazo-Monsalvo, Isis; Rodríguez-Enríquez, Sara; Moreno-Sánchez, Rafael; Saavedra, Emma

    2016-01-01

    Glycolysis provides precursors for the synthesis of macromolecules and may contribute to the ATP supply required for the constant and accelerated cellular duplication in cancer cells. In consequence, inhibition of glycolysis has been reiteratively considered as an anti-cancer therapeutic option. In previous studies, kinetic modeling of glycolysis in cancer cells allowed the identification of the main steps that control the glycolytic flux: glucose transporter, hexokinase (HK), hexose phosphate isomerase (HPI), and glycogen degradation in human cervix HeLa cancer cells and rat AS-30D ascites hepatocarcinoma. It was also previously experimentally determined that simultaneous inhibition of the non-controlling enzymes lactate dehydrogenase (LDH), pyruvate kinase (PYK), and enolase (ENO) brings about significant decrease in the glycolytic flux of cancer cells and accumulation of intermediate metabolites, mainly fructose-1,6-bisphosphate (Fru1,6BP), and dihydroxyacetone phosphate (DHAP), which are inhibitors of HK and HPI, respectively. Here it was found by kinetic modeling that inhibition of cancer glycolysis can be attained by blocking downstream non flux-controlling steps as long as Fru1,6BP and DHAP, regulatory metabolites of flux-controlling enzymes, are accumulated. Furthermore, experimental results and further modeling showed that oxamate and iodoacetate inhibitions of PYK, ENO, and glyceraldehyde3-phosphate dehydrogenase (GAPDH), but not of LDH and phosphoglycerate kinase, induced accumulation of Fru1,6BP and DHAP in AS-30D hepatoma cells. Indeed, PYK, ENO, and GAPDH exerted the highest control on the Fru1,6BP and DHAP concentrations. The high levels of these metabolites inhibited HK and HPI and led to glycolytic flux inhibition, ATP diminution, and accumulation of toxic methylglyoxal. Hence, the anticancer effects of downstream glycolytic inhibitors are very likely mediated by this mechanism. In parallel, it was also found that uncompetitive inhibition of the

  11. Improving L-arabinose utilization of pentose fermenting Saccharomyces cerevisiae cells by heterologous expression of L-arabinose transporting sugar transporters

    Directory of Open Access Journals (Sweden)

    Boles Eckhard

    2011-10-01

    Full Text Available Abstract Background Hydrolysates of plant biomass used for the production of lignocellulosic biofuels typically contain sugar mixtures consisting mainly of D-glucose and D-xylose, and minor amounts of L-arabinose. The yeast Saccharomyces cerevisiae is the preferred microorganism for the fermentative production of ethanol but is not able to ferment pentose sugars. Although D-xylose and L-arabinose fermenting S. cerevisiae strains have been constructed recently, pentose uptake is still a limiting step in mixed sugar fermentations. Results Here we described the cloning and characterization of two sugar transporters, AraT from the yeast Scheffersomyces stipitis and Stp2 from the plant Arabidopsis thaliana, which mediate the uptake of L-arabinose but not of D-glucose into S. cerevisiae cells. A yeast strain lacking all of its endogenous hexose transporter genes and expressing a bacterial L-arabinose utilization pathway could no longer take up and grow with L-arabinose as the only carbon source. Expression of the heterologous transporters supported uptake and utilization of L-arabinose especially at low L-arabinose concentrations but did not, or only very weakly, support D-glucose uptake and utilization. In contrast, the S. cerevisiae D-galactose transporter, Gal2, mediated uptake of both L-arabinose and D-glucose, especially at high concentrations. Conclusions Using a newly developed screening system we have identified two heterologous sugar transporters from a yeast and a plant which can support uptake and utilization of L-arabinose in L-arabinose fermenting S. cerevisiae cells, especially at low L-arabinose concentrations.

  12. 3-bromopyruvate inhibits glycolysis, depletes cellular glutathione, and compromises the viability of cultured primary rat astrocytes.

    Science.gov (United States)

    Ehrke, Eric; Arend, Christian; Dringen, Ralf

    2015-07-01

    The pyruvate analogue 3-bromopyruvate (3-BP) is an electrophilic alkylator that is considered a promising anticancer drug because it has been shown to kill cancer cells efficiently while having little toxic effect on nontumor cells. To test for potential adverse effects of 3-BP on brain cells, we exposed cultured primary rat astrocytes to 3-BP and investigated the effects of this compound on cell viability, glucose metabolism, and glutathione (GSH) content. The presence of 3-BP severely compromised cell viability and slowed cellular glucose consumption and lactate production in a time- and concentration-dependent manner, with half-maximal effects observed at about 100 µM 3-BP after 4 hr of incubation. The cellular hexokinase activity was not affected in 3-BP-treated astrocytes, whereas within 30 min after application of 3-BP the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was inhibited, and cellular GSH content was depleted in a concentration-dependent manner, with half-maximal effects observed at about 30 µM 3-BP. The depletion of cellular GSH after exposure to 100 µM 3-BP was not prevented by the presence of 10 mM of the monocarboxylates lactate or pyruvate, suggesting that 3-BP is not taken up into astrocytes predominantly by monocarboxylate transporters. The data suggest that inhibition of glycolysis by inactivation of GAPDH and GSH depletion contributes to the toxicity that was observed for 3-BP-treated cultured astrocytes. © 2014 Wiley Periodicals, Inc.

  13. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

    Science.gov (United States)

    Koppe, Laetitia; Nyam, Elsa; Vivot, Kevin; Manning Fox, Jocelyn E.; Dai, Xiao-Qing; Nguyen, Bich N.; Attané, Camille; Moullé, Valentine S.; MacDonald, Patrick E.; Ghislain, Julien

    2016-01-01

    Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis. PMID:27525435

  14. Aerobic Glycolysis as a Marker of Tumor Aggressiveness: Preliminary Data in High Grade Human Brain Tumors

    Directory of Open Access Journals (Sweden)

    Andrei G. Vlassenko

    2015-01-01

    Full Text Available Objectives. Glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG, is a hallmark of active cancer cells that is not directly measured with standard 18F-fluorodeoxyglucose (FDG positron emission tomography (PET. In this study, we characterized tumor regions with elevated AG defined based on PET measurements of glucose and oxygen metabolism. Methods. Fourteen individuals with high-grade brain tumors underwent structural MR scans and PET measurements of cerebral blood flow (CBF, oxygen (CMRO2 and glucose (CMRGlu metabolism, and AG, using 15O-labeled CO, O2 and H2O, and FDG, and were compared to a normative cohort of 20 age-matched individuals. Results. Elevated AG was observed in most high-grade brain tumors and it was associated with decreased CMRO2 and CBF, but not with significant changes in CMRGlu. Elevated AG was a dramatic and early sign of tumor growth associated with decreased survival. AG changes associated with tumor growth were differentiated from the effects of nonneoplastic processes such as epileptic seizures. Conclusions. Our findings demonstrate that high-grade brain tumors exhibit elevated AG as a marker of tumor growth and aggressiveness. AG may detect areas of active tumor growth that are not evident on conventional FDG PET.

  15. ARTD1/PARP1 Negatively Regulates Glycolysis by Inhibiting Hexokinase 1 Independent of NAD+ Depletion

    Directory of Open Access Journals (Sweden)

    Elise Fouquerel

    2014-09-01

    Full Text Available ARTD1 (PARP1 is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose (PAR in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD+ depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD+ depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD+ depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1 as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.

  16. Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis.

    Science.gov (United States)

    Ruprecht, Benjamin; Zaal, Esther A; Zecha, Jana; Wu, Wei; Berkers, Celia R; Kuster, Bernhard; Lemeer, Simone

    2017-04-15

    HER2/ERBB2-overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases, and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an extensive and exclusively phosphorylation-mediated reprogramming of glycolytic activity, supported additionally by widespread changes of corresponding metabolites and an increased sensitivity towards glycolysis inhibition. Collectively, our multi-omic analysis offers deeper perspectives on cancer drug resistance and suggests new biomarkers and treatment options for lapatinib-resistant cancers. Cancer Res; 77(8); 1842-53. ©2017 AACR . ©2017 American Association for Cancer Research.

  17. An engineered non-oxidative glycolysis pathway for acetone production in Escherichia coli.

    Science.gov (United States)

    Yang, Xiaoyan; Yuan, Qianqian; Zheng, Yangyang; Ma, Hongwu; Chen, Tao; Zhao, Xueming

    2016-08-01

    To find new metabolic engineering strategies to improve the yield of acetone in Escherichia coli. Results of flux balance analysis from a modified Escherichia coli genome-scale metabolic network suggested that the introduction of a non-oxidative glycolysis (NOG) pathway would improve the theoretical acetone yield from 1 to 1.5 mol acetone/mol glucose. By inserting the fxpk gene encoding phosphoketolase from Bifidobacterium adolescentis into the genome, we constructed a NOG pathway in E.coli. The resulting strain produced 47 mM acetone from glucose under aerobic conditions in shake-flasks. The yield of acetone was improved from 0.38 to 0.47 mol acetone/mol glucose which is a significant over the parent strain. Guided by computational analysis of metabolic networks, we introduced a NOG pathway into E. coli and increased the yield of acetone, which demonstrates the importance of modeling analysis for the novel metabolic engineering strategies.

  18. Longevity of U cells of differentiated yeast colonies grown on respiratory medium depends on active glycolysis.

    Science.gov (United States)

    Čáp, Michal; Váchová, Libuše; Palková, Zdena

    2015-01-01

    Colonies of Saccharomyces cerevisiae laboratory strains pass through specific developmental phases when growing on solid respiratory medium. During entry into the so-called alkali phase, in which ammonia signaling is initiated, 2 prominent cell types are formed within the colonies: U cells in upper colony regions, which have a longevity phenotype and activate the expression of a large number of metabolic genes, and L cells in lower regions, which die more quickly and exhibit a starvation phenotype. Here, we performed a detailed analysis of the activities of enzymes of central carbon metabolism in lysates of both cell types and determined several fermentation end products, showing that previously reported expression differences are reflected in the different enzymatic capabilities of each cell type. Hence, U cells, despite being grown on respiratory medium, behave as fermenting cells, whereas L cells rely on respiratory metabolism and possess active gluconeogenesis. Using a spectrum of different inhibitors, we showed that glycolysis is essential for the formation, and particularly, the survival of U cells. We also showed that β-1,3-glucans that are released from the cell walls of L cells are the most likely source of carbohydrates for U cells.

  19. Mitochondrial Sirtuin 4 Resolves Immune Tolerance in Monocytes by Rebalancing Glycolysis and Glucose Oxidation Homeostasis

    Directory of Open Access Journals (Sweden)

    Jie Tao

    2018-03-01

    Full Text Available The goal of this investigation was to define the molecular mechanism underlying physiologic conversion of immune tolerance to resolution of the acute inflammatory response, which is unknown. An example of this knowledge gap and its clinical importance is the broad-based energy deficit and immunometabolic paralysis in blood monocytes from non-survivors of human and mouse sepsis that precludes sepsis resolution. This immunometabolic dysregulation is biomarked by ex vivo endotoxin tolerance to increased glycolysis and TNF-α expression. To investigate how tolerance switches to resolution, we adapted our previously documented models associated with acute inflammatory, immune, and metabolic reprogramming that induces endotoxin tolerance as a model of sepsis in human monocytes. We report here that mitochondrial sirtuin 4 (SIRT4 physiologically breaks tolerance and resolves acute inflammation in human monocytes by coordinately reprogramming of metabolism and bioenergetics. We find that increased SIRT4 mRNA and protein expression during immune tolerance counters the increase in pyruvate dehydrogenase kinase 1 (PDK1 and SIRT1 that promote tolerance by switching glucose-dependent support of immune resistance to fatty acid oxidation support of immune tolerance. By decreasing PDK1, pyruvate dehydrogenase complex reactivation rebalances mitochondrial respiration, and by decreasing SIRT1, SIRT4 represses fatty acid oxidation. The precise mechanism for the mitochondrial SIRT4 nuclear feedback is unclear. Our findings are consistent with a new concept in which mitochondrial SIRT4 directs the axis that controls anabolic and catabolic energy sources.

  20. Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma.

    Science.gov (United States)

    Lin, Yang-Hsiang; Wu, Meng-Han; Huang, Ya-Hui; Yeh, Chau-Ting; Cheng, Mei-Ling; Chi, Hsiang-Cheng; Tsai, Chung-Ying; Chung, I-Hsiao; Chen, Ching-Ying; Lin, Kwang-Huei

    2018-01-01

    Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR-455-3p/AMPKβ2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKβ2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203). © 2017 by the American Association for the Study of Liver Diseases.

  1. Oleic acid stimulates glucagon-like peptide-1 release from enteroendocrine cells by modulating cell respiration and glycolysis.

    Science.gov (United States)

    Clara, Rosmarie; Langhans, Wolfgang; Mansouri, Abdelhak

    2016-03-01

    Glucagon-like peptide-1 (GLP-1) is a potent satiating and incretin hormone released by enteroendocrine L-cells in response to eating. Dietary fat, in particular monounsaturated fatty acids, such as oleic acid (OA), potently stimulates GLP-1 secretion from L-cells. It is, however, unclear whether the intracellular metabolic handling of OA is involved in this effect. First we determined the optimal medium for the bioenergetics measurements. Then we examined the effect of OA on the metabolism of the immortalized enteroendocrine GLUTag cell model and assessed GLP-1 release in parallel. We measured oxygen consumption rate and extracellular acidification rate in response to OA and to different metabolic inhibitors with the Seahorse extracellular flux analyzer. OA increased cellular respiration and potently stimulated GLP-1 release. The fatty acid oxidation inhibitor etomoxir did neither reduce OA-induced respiration nor affect the OA-induced GLP-1 release. In contrast, inhibition of the respiratory chain or of downstream steps of aerobic glycolysis reduced the OA-induced GLP-1 release, and an inhibition of the first step of glycolysis by addition of 2-deoxy-d-glucose even abolished it. These findings indicate that an indirect stimulation of glycolysis is crucial for the OA-induced release of GLP-1. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. A shift to glycolysis accompanies the inflammatory changes in PBMCs from individuals with an IQ-discrepant memory.

    Science.gov (United States)

    Wolfe, Hannah; Hannigan, Caoimhe; O'Sullivan, Michael; Carroll, Liam Barry; Brennan, Sabina; Lawlor, Brian; Robertson, Ian H; Lynch, Marina

    2018-04-15

    Identification of a blood-based biomarker that can detect early cognitive decline presents a significant healthcare challenge. We prepared peripheral blood mononuclear cells (PBMCs) from individuals who had a poorer than predicted performance in their delayed recall performance on the Logical Memory II Subtest of the Wechsler Memory Scale (WMS) relative to their IQ estimated by the National Adult Reading Test (NART); we described these individuals as IQ-discrepant, compared with IQ-consistent, individuals. Stimulation with Aβ + LPS increased production of TNFα to a greater extent in cells from IQ-discrepant, compared with IQ-consistent, individuals. This was associated with a shift towards glycolysis and the evidence indicates that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3 plays a role in driving glycolysis. A similar shift towards glycolysis was observed in MDMs prepared from IQ-discrepant, compared with IQ-consistent, individuals. The important finding here is that we have established an increased sensitivity to Aβ + LPS stimulation in PBMCs from individuals that under-perform on a memory task, relative to their estimated premorbid IQ, which may be an indicator of early cognitive decline. This may be a useful tool in determining the presence of early cognitive dysfunction. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Use of Molecular Imaging Markers of Glycolysis, Hypoxia and Proliferation (18F-FDG, 64Cu-ATSM and 18F-FLT) in a Dog with Fibrosarcoma

    DEFF Research Database (Denmark)

    Zornhagen, Kamilla; Clausen, Malene; Hansen, Anders Elias

    2015-01-01

    Glycolysis, hypoxia, and proliferation are important factors in the tumor microenvironment contributing to treatment-resistant aggressiveness. Imaging these factors using combined functional positron emission tomography and computed tomography can potentially guide diagnosis and management...

  4. Cellular targets of the myeloperoxidase-derived oxidant hypothiocyanous acid (HOSCN) and its role in the inhibition of glycolysis in macrophages

    DEFF Research Database (Denmark)

    Love, D; Barrett, T.J.; White, M.Y.

    2016-01-01

    the cellular targets of HOSCN in macrophages (J774A.1). We report that multiple thiol-containing proteins involved in metabolism and glycolysis; fructose bisphosphate aldolase, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and creatine kinase, together with a number of chaperone......, antioxidant and structural proteins, were modified in a reversible manner in macrophages treated with HOSCN. The modification of the metabolic enzymes was associated with a decrease in basal glycolysis, glycolytic reserve, glycolytic capacity and lactate release, which was only partly reversible on further...... incubation in the absence of HOSCN. Inhibition of glycolysis preceded cell death and was seen in cells exposed to low concentrations (r25 mM) of HOSCN. The ability of HOSCN to inhibit glycolysis and perturb energy production is likely to contribute to the cell death seen in macrophages on further incubation...

  5. Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation

    International Nuclear Information System (INIS)

    Ge, Xin; Lyu, Pengwei; Gu, Yuanting; Li, Lin; Li, Jingruo; Wang, Yan; Zhang, Linfeng; Fu, Chao; Cao, Zhang

    2015-01-01

    Sonic hesgehog (Shh) signaling has been reported to play an essential role in cancer progression. The mechanism of Shh involved in breast cancer carcinogenesis remains unclear. The present study sought to explore whether Shh signaling could regulate the glycolytic metabolism in breast cancers. Overexpression of the smoothed (Smo) and Gli-1 was found in human primary breast cancers. The expressions of Shh and Gli-1 correlated significantly with tumor size and tumor stage. In vitro, human recombinant Shh (rShh) triggered Smo and Gli-1 expression, promoted glucose utilization and lactate production, and accelerated cell proliferation in MCF-7 and MDA-MB-231 cells. Notably, rShh did not alter 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) expression but augmented PFKFB3 phosphorylation on ser 461 , along with elevated fructose-2,6-bisphosphate (F2,6BP) generation by MCF-7 and MDA-MB-231 cells. This effect could be dampened by Smo siRNA but not by Gli-1 siRNA. In addition, our data showed the upregulated expressions of MAPK by rShh and elevatory PFKFB3 phosphorylation by p38/MAPK activated kinase (MK2). In conclusion, our study characterized a novel role of Shh in promoting glycolysis and proliferation of breast cancer cells via PFKFB3 phosphorylation, which was mediated by Smo and p38/MK2. - Highlights: • Overexpression of Smo and Gli-1 was found in human primary breast cancers. • Shh promoted glucose utilization, lactate production, and cell proliferation. • Shh did not alter PFKFB3 expression but augmented PFKFB3 phosphorylation on ser461. • Shh acts on PFKFB3 phosphorylation via Smo and p38 MAPK/MK2

  6. Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Xin; Lyu, Pengwei; Gu, Yuanting; Li, Lin; Li, Jingruo; Wang, Yan; Zhang, Linfeng [Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Fu, Chao [Department of Ultrasonography, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China); Cao, Zhang, E-mail: zzzhangcao@126.com [Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan (China)

    2015-08-28

    Sonic hesgehog (Shh) signaling has been reported to play an essential role in cancer progression. The mechanism of Shh involved in breast cancer carcinogenesis remains unclear. The present study sought to explore whether Shh signaling could regulate the glycolytic metabolism in breast cancers. Overexpression of the smoothed (Smo) and Gli-1 was found in human primary breast cancers. The expressions of Shh and Gli-1 correlated significantly with tumor size and tumor stage. In vitro, human recombinant Shh (rShh) triggered Smo and Gli-1 expression, promoted glucose utilization and lactate production, and accelerated cell proliferation in MCF-7 and MDA-MB-231 cells. Notably, rShh did not alter 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) expression but augmented PFKFB3 phosphorylation on ser{sup 461}, along with elevated fructose-2,6-bisphosphate (F2,6BP) generation by MCF-7 and MDA-MB-231 cells. This effect could be dampened by Smo siRNA but not by Gli-1 siRNA. In addition, our data showed the upregulated expressions of MAPK by rShh and elevatory PFKFB3 phosphorylation by p38/MAPK activated kinase (MK2). In conclusion, our study characterized a novel role of Shh in promoting glycolysis and proliferation of breast cancer cells via PFKFB3 phosphorylation, which was mediated by Smo and p38/MK2. - Highlights: • Overexpression of Smo and Gli-1 was found in human primary breast cancers. • Shh promoted glucose utilization, lactate production, and cell proliferation. • Shh did not alter PFKFB3 expression but augmented PFKFB3 phosphorylation on ser461. • Shh acts on PFKFB3 phosphorylation via Smo and p38 MAPK/MK2.

  7. Regulatory properties of 6-phosphofructokinase and control of glycolysis in boar spermatozoa.

    Science.gov (United States)

    Kamp, G; Schmidt, H; Stypa, H; Feiden, S; Mahling, C; Wegener, G

    2007-01-01

    Glycolysis is crucial for sperm functions (motility and fertilization), but how this pathway is regulated in spermatozoa is not clear. This prompted to study the location and the regulatory properties of 6-phosphofructokinase (PFK, EC 2.7.1.11), the most important element for control of glycolytic flux. Unlike some other glycolytic enzymes, PFK showed no tight binding to sperm structures. It could readily be extracted from ejaculated boar spermatozoa by sonication and was then chromatographically purified. At physiological pH, the enzyme was allosterically inhibited by near-physiological concentrations of its co-substrate ATP, which induced co-operativity, i.e. reduced the affinity for the substrate fructose 6-phosphate. Inhibition by ATP was reinforced by citrate and H+. Above pH 8, PFK lost all its regulatory properties and showed maximum activity. However, in the physiological pH range, PFK activity was very sensitive to small changes in effectors. At near-physiological substrate concentrations, PFK activity requires activators (de-inhibitors) of which the combination of AMP and fructose 2,6-bisphosphate (F2,6P2) was most efficient as a result of synergistic effects. The kinetics of PFK suggest AMP, F2,6P2, H+, and citrate as allosteric effectors controlling PFK activity in boar spermatozoa. Using immunogold labeling, PFK was localized in the mid-piece and principal piece of the flagellum as well as in the acrosomal area at the top of the head and in the cytoplasmic droplets released from the mid-piece after ejaculation.

  8. Single and combined effects of acetic acid, furfural, and sugars on the growth of the pentose-fermenting yeast Meyerozyma guilliermondii.

    Science.gov (United States)

    Perna, Michelle Dos Santos Cordeiro; Bastos, Reinaldo Gaspar; Ceccato-Antonini, Sandra Regina

    2018-02-01

    The tolerance of the pentose-fermenting yeast Meyerozyma guilliermondii to the inhibitors released after the biomass hydrolysis, such as acetic acid and furfural, was surveyed. We first verified the effects of acetic acid and cell concentrations and initial pH on the growth of a M. guilliermondii strain in a semi-synthetic medium containing acetic acid as the sole carbon source. Second, the single and combined effects of furfural, acetic acid, and sugars (xylose, arabinose, and glucose) on the sugar uptake, cell growth, and ethanol production were also analysed. Growth inhibition occurred in concentrations higher than 10.5 g l -1 acetic acid and initial pH 3.5. The maximum specific growth rate (µ) was 0.023 h -1 and the saturation constant (ks) was 0.75 g l -1 acetic acid. Initial cell concentration also influenced µ. Acetic acid (initial concentration 5 g l -1 ) was co-consumed with sugars even in the presence of 20 mg l -1 furfural without inhibition to the yeast growth. The yeast grew and fermented sugars in a sugar-based medium with acetic acid and furfural in concentrations much higher than those usually found in hemicellulosic hydrolysates.

  9. Further increased production of free fatty acids by overexpressing a predicted transketolase gene of the pentose phosphate pathway in Aspergillus oryzae faaA disruptant.

    Science.gov (United States)

    Tamano, Koichi; Miura, Ai

    2016-09-01

    Free fatty acids are useful as source materials for the production of biodiesel fuel and various chemicals such as pharmaceuticals and dietary supplements. Previously, we attained a 9.2-fold increase in free fatty acid productivity by disrupting a predicted acyl-CoA synthetase gene (faaA, AO090011000642) in Aspergillus oryzae. In this study, we achieved further increase in the productivity by overexpressing a predicted transketolase gene of the pentose phosphate pathway in the faaA disruptant. The A. oryzae genome is predicted to have three transketolase genes and overexpression of AO090023000345, one of the three genes, resulted in phenotypic change and further increase (corresponding to an increased production of 0.38 mmol/g dry cell weight) in free fatty acids at 1.4-fold compared to the faaA disruptant. Additionally, the biomass of hyphae increased at 1.2-fold by the overexpression. As a result, free fatty acid production yield per liter of liquid culture increased at 1.7-fold by the overexpression.

  10. Sulfur cycle

    Digital Repository Service at National Institute of Oceanography (India)

    LokaBharathi, P.A.

    Microbes, especially bacteria, play an important role in oxidative and reductive cycle of sulfur. The oxidative part of the cycle is mediated by photosynthetic bacteria in the presence of light energy and chemosynthetic forms in the absence of light...

  11. SDHB downregulation facilitates the proliferation and invasion of colorectal cancer through AMPK functions excluding those involved in the modulation of aerobic glycolysis.

    Science.gov (United States)

    Xiao, Zhiming; Liu, Shaojun; Ai, Feiyan; Chen, Xiong; Li, Xiayu; Liu, Rui; Ren, Weiguo; Zhang, Xuemei; Shu, Peng; Zhang, Decai

    2018-01-01

    Loss-of-function of succinate dehydrogenase-B (SDHB) is a predisposing factor of aerobic glycolysis and cancer progression. Adenosine monophosphate activated protein kinase (AMPK) is involved in the regulation of aerobic glycolysis and the diverse hallmarks of cancer. The present study investigated whether AMPK mediated the regulatory effects of SDHB in aerobic glycolysis and cancer growth. The expression of SDHB and AMPK in colorectal cancer (CRC) and normal tissues was assessed by western blotting. HT-29 CRC cells were used to establish in vitro models of ectopic overexpression and knockdown of SDHB. SDHB was downregulated, while AMPK and phosphorylated-AMPK (Thr172) were upregulated in CRC tissues. Experiments involving the loss- or gain-of-function of SDHB, revealed that this protein negatively regulated AMPK by influencing its expression and activity. However, SDHB and AMPK were identified to suppress lactic acid production in CRC cells, indicating that each had an inhibitory effect on aerobic glycolysis. Therefore, the regulation of aerobic glycolysis by SDHB is unlikely to be mediated via AMPK. SDHB knockdown promoted the viability, migration and invasion of HT-29 cells, whereas inhibition of AMPK demonstrated the opposite effect. SDHB overexpression impaired cell migration and invasion, and this effect was reversed following AMPK activation. These results indicate that AMPK may mediate the effects of SDHB in CRC cell proliferation and migration. In conclusion, SDHB downregulation in CRC cells may increase AMPK activity, which may subsequently facilitate the proliferation and invasion of these cancer cells. However, the regulation of aerobic glycolysis by SDHB may be independent of AMPK. Further studies are warranted to elucidate the mechanism by which SDHB regulates aerobic glycolysis.

  12. 3-Bromopyruvate reverses hypoxia-induced pulmonary arterial hypertension through inhibiting glycolysis: In vitro and in vivo studies.

    Science.gov (United States)

    Chen, Fangzheng; Wang, Heng; Lai, Jiadan; Cai, Shujing; Yuan, Linbo

    2018-05-04

    Pulmonary arterial smooth muscle cell (PASMC) proliferation is vital to pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) pathogenesis, and inhibiting PASMC metabolism could serve as a new possible therapy to reverse the process. 3-Bromopyruvate (3-BrPA) is an effective glycolysis inhibitor with its effect in PAH remains unclear. Our study aims to assess the therapeutic effect of 3-BrPA in PAH rats and investigate the possible mechanism of 3-BrPA in PASMC proliferation and apoptosis. 27 healthy SD rats were grouped and treated with hypoxia/normoxia and administration of 3-BrPA/physiological saline. Mean pulmonary artery pressure (mPAP) and cardiac output (CO) were measured and pulmonary vascular resistance (PVR) was calculated. Right ventricular hypertrophy index (RVHI) was calculated to evaluate the right ventricular hypertrophy degree. The percentage of medial wall area (WA%) and medial wall thickness (WT%) were measured by image analysis. PASMCs groups received hypoxia/normoxia treatments and 3-BrPA/physiological saline. PASMC proliferation and migration were respectively detected by CCK-8 and cell wound scratch assay. Hexokinase II (HK-2) expression and lactate level were respectively measured by Western Blotting and lactate test kit to detect glycolysis. mPAP, PVR, PVHI, WA% and WT% in rats increased after the hypoxia treatment, but were lower compared to rats received 3-BrPA in hypoxia environment. HK-2 expression, lactate concentration, OD value and scratch areas in PASMCs increased after the hypoxia treatment, but were decreased after the administration of 3-BrPA. 3-BrPA can inhibit PASMC proliferation and migration by inhibiting glycolysis, and is effective in reversing the vascular remodeling in hypoxia-induced PAH rats. Copyright © 2017. Published by Elsevier B.V.

  13. Time and temperature affect glycolysis in blood samples regardless of fluoride-based preservatives: a potential underestimation of diabetes.

    Science.gov (United States)

    Stapleton, Mary; Daly, Niamh; O'Kelly, Ruth; Turner, Michael J

    2017-11-01

    Background The inhibition of glycolysis prior to glucose measurement is an important consideration when interpreting glucose tolerance tests. This is particularly important in gestational diabetes mellitus where prompt diagnosis and treatment is essential. A study was planned to investigate the effect of preservatives and temperature on glycolysis. Methods Blood samples for glucose were obtained from consented females. Lithium heparin and fluoride-EDTA samples transported rapidly in ice slurry to the laboratory were analysed for glucose concentration and then held either in ice slurry or at room temperature for varying time intervals. Paired fluoride-citrate samples were received at room temperature and held at room temperature, with analysis at similar time intervals. Results No significant difference was noted between mean glucose concentrations when comparing different sample types received in ice slurry. The mean glucose concentrations decreased significantly for both sets of samples when held at room temperature (0.4 mmol/L) and in ice slurry (0.2 mmol/L). A review of patient glucose tolerance tests reported in our hospital indicated that 17.8% exceeded the recommended diagnostic criteria for gestational diabetes mellitus. It was predicted that if the results of fasting samples were revised to reflect the effect of glycolysis at room temperature, the adjusted diagnostic rate could increase to 35.3%. Conclusion Preanalytical handling of blood samples for glucose analysis is vital. Fluoride-EDTA is an imperfect antiglycolytic, even when the samples are transported and analysed rapidly provides such optimal conditions. The use of fluoride-citrate tubes may offer a viable alternative in the diagnosis of diabetes mellitus.

  14. Jolkinolide B inhibits glycolysis by downregulating hexokinase 2 expression through inactivating the Akt/mTOR pathway in non-small cell lung cancer cells.

    Science.gov (United States)

    Gao, Xiang; Han, Han

    2018-06-01

    Jolkinolide B (JB), a bioactive compound isolated from herbal medicine, has been found to inhibit tumor growth by altering glycolysis. However, whether glycolysis is influenced by JB in non-small cell lung cancer (NSCLC) cells and the mechanism remain unknown. The aim of the present study was to evaluate the effect of JB on the glycolysis in NSCLC cells and the underlying molecular mechanism. The results showed that JB treatment inhibited cell viability of A549 and H1299 cells in a concentration-dependent manner. JB reduced the glucose consumption, lactate production, and HK2 expression. The expressions of p-Akt and p-mTOR were also decreased by JB treatment. Knockdown of HK2 reduced glucose consumption and lactate production. Inhibition of the Akt/mTOR pathway decreased HK2 expression and inhibited glycolysis. In conclusion, the results indicated that JB inhibits glycolysis by down-regulating HK2 expression through inactivating the Akt/mTOR pathway in NSCLC cells, suggesting that JB might be a potential therapeutic agent for the treatment of NSCLC. © 2018 Wiley Periodicals, Inc.

  15. Role of glycolysis inhibition and poly(ADP-ribose) polymerase activation in necrotic-like cell death caused by ascorbate/menadione-induced oxidative stress in K562 human chronic myelogenous leukemic cells.

    Science.gov (United States)

    Verrax, Julien; Vanbever, Stéphanie; Stockis, Julie; Taper, Henryk; Calderon, Pedro Buc

    2007-03-15

    Among different features of cancer cells, two of them have retained our interest: their nearly universal glycolytic phenotype and their sensitivity towards an oxidative stress. Therefore, we took advantage of these features to develop an experimental approach by selectively exposing cancer cells to an oxidant insult induced by the combination of menadione (vitamin K(3)) and ascorbate (vitamin C). Ascorbate enhances the menadione redox cycling, increases the formation of reactive oxygen species and kills K562 cells as shown by more than 65% of LDH leakage after 24 hr of incubation. Since both lactate formation and ATP content are depressed by about 80% following ascorbate/menadione exposure, we suggest that the major intracellular event involved in such a cytotoxicity is related to the impairment of glycolysis. Indeed, NAD(+) is rapidly and severely depleted, a fact most probably related to a strong Poly(ADP-ribose) polymerase (PARP) activation, as shown by the high amount of poly-ADP-ribosylated proteins. The addition of N-acetylcysteine (NAC) restores most of the ATP content and the production of lactate as well. The PARP inhibitor dihydroxyisoquinoline (DiQ) was able to partially restore both parameters as well as cell death induced by ascorbate/menadione. These results suggest that the PARP activation induced by the oxidative stress is a major but not the only intracellular event involved in cell death by ascorbate/menadione. Due to the high energetic dependence of cancer cells on glycolysis, the impairment of such an essential pathway may explain the effectiveness of this combination to kill cancer cells. (c) 2006 Wiley-Liss, Inc.

  16. The pentose moiety of adenosine and inosine is an important energy source for the fermented-meat starter culture Lactobacillus sakei CTC 494.

    Science.gov (United States)

    Rimaux, T; Vrancken, G; Vuylsteke, B; De Vuyst, L; Leroy, F

    2011-09-01

    The genome sequence of Lactobacillus sakei 23K has revealed that the species L. sakei harbors several genes involved in the catabolism of energy sources other than glucose in meat, such as glycerol, arginine, and nucleosides. In this study, a screening of 15 L. sakei strains revealed that arginine, inosine, and adenosine could be used as energy sources by all strains. However, no glycerol catabolism occurred in any of the L. sakei strains tested. A detailed kinetic analysis of inosine and adenosine catabolism in the presence of arginine by L. sakei CTC 494, a fermented-meat starter culture, was performed. It showed that nucleoside catabolism occurred as a mixed-acid fermentation in a pH range (pH 5.0 to 6.5) relevant for sausage fermentation. This resulted in the production of a mixture of acetic acid, formic acid, and ethanol from ribose, while the nucleobase (hypoxanthine and adenine in the case of fermentations with inosine and adenosine, respectively) was excreted into the medium stoichiometrically. This indicates that adenosine deaminase activity did not take place. The ratios of the different fermentation end products did not vary with environmental pH, except for the fermentation with inosine at pH 5.0, where lactic acid was produced too. In all cases, no other carbon-containing metabolites were found; carbon dioxide was derived only from arginine catabolism. Arginine was cometabolized in all cases and resulted in the production of both citrulline and ornithine. Based on these results, a pathway for inosine and adenosine catabolism in L. sakei CTC 494 was presented, whereby both nucleosides are directly converted into their nucleobase and ribose, the latter entering the heterolactate pathway. The present study revealed that the pentose moiety (ribose) of the nucleosides inosine and adenosine is an effective fermentable substrate for L. sakei. Thus, the ability to use these energy sources offers a competitive advantage for this species in a meat environment.

  17. Exposure to high glutamate concentration activates aerobic glycolysis but inhibits ATP-linked respiration in cultured cortical astrocytes.

    Science.gov (United States)

    Shen, Yao; Tian, Yueyang; Shi, Xiaojie; Yang, Jianbo; Ouyang, Li; Gao, Jieqiong; Lu, Jianxin

    2014-08-01

    Astrocytes play a key role in removing the synaptically released glutamate from the extracellular space and maintaining the glutamate below neurotoxic level in the brain. However, high concentration of glutamate leads to toxicity in astrocytes, and the underlying mechanisms are unclear. The purpose of this study was to investigate whether energy metabolism disorder, especially impairment of mitochondrial respiration, is involved in the glutamate-induced gliotoxicity. Exposure to 10-mM glutamate for 48 h stimulated glycolysis and respiration in astrocytes. However, the increased oxygen consumption was used for proton leak and non-mitochondrial respiration, but not for oxidative phosphorylation and ATP generation. When the exposure time extended to 72 h, glycolysis was still activated for ATP generation, but the mitochondrial ATP-linked respiration of astrocytes was reduced. The glutamate-induced astrocyte damage can be mimicked by the non-metabolized substrate d-aspartate but reversed by the non-selective glutamate transporter inhibitor TBOA. In addition, the glutamate toxicity can be partially reversed by vitamin E. These findings demonstrate that changes of bioenergetic profile occur in cultured cortical astrocytes exposed to high concentration of glutamate and highlight the role of mitochondria respiration in glutamate-induced gliotoxicity in cortical astrocytes. Copyright © 2014 John Wiley & Sons, Ltd.

  18. Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat.

    Science.gov (United States)

    Dimitriadis, G D; Leighton, B; Parry-Billings, M; West, D; Newsholme, E A

    1989-01-01

    1. The effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin were investigated in the isolated, incubated soleus muscle of the rat. 2. Hypothyroidism, which was induced by administration of propylthiouracil to the rats, decreased fasting plasma levels of free fatty acids and increased plasma levels of glucose but did not significantly change plasma levels of insulin. 3. The sensitivity of the rates of glycogen synthesis to insulin was increased at physiological, but decreased at supraphysiological, concentrations of insulin. 4. The rates of glycolysis in the hypothyroid muscles were decreased at all insulin concentrations studied and the EC50 for insulin was increased more than 8-fold; the latter indicates decreased sensitivity of this process to insulin. However, at physiological concentrations of insulin, the rates of glucose phosphorylation in the soleus muscles of hypothyroid rats were not different from controls. This suggests that hypothyroidism affects glucose metabolism in muscle not by affecting glucose transport but by decreasing the rate of glucose 6-phosphate conversion to lactate and increasing the rate of conversion of glucose 6-phosphate to glycogen. 5. The rates of glucose oxidation were decreased in the hypothyroid muscles at all insulin concentrations. PMID:2649073

  19. Glycolysis-related gene induction and ATP reduction during fractionated irradiation. Markers for radiation responsiveness of human tumor xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Goetze, K.; Meyer, S.S.; Mueller-Klieser, W. [University Medical Center Mainz Univ. (Germany). Inst. of Physiology and Pathophysiology; Yaromina, A. [Technical Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; Zips, D. [University Hospital Tuebingen (Germany). Dept. of Radiation Oncology; Baumann, M. [Technical Univ. Dresden (Germany). OncoRay - National Center for Radiation Research in Oncology; University Hospital Dresden Technical Univ. Dresden (Germany). Dept. of Radiation Oncology

    2013-09-15

    Background and purpose: Lactate was previously shown to be a prognostic but not a predictive pre-therapeutic marker for radiation response of tumor xenografts. We hypothesize that metabolic changes during fractionated irradiation may restrict the predictiveness of lactate regarding tumor radiosensitivity. Materials and methods: Tumor xenografts were generated in nude mice by implanting 4 head and neck squamous cell carcinoma lines with different sensitivities to fractionated irradiation. Tumors were irradiated with up to 15 fractions of 2 Gy over a period of 3 weeks, and ATP and lactate levels were measured in vital tumor areas with induced metabolic bioluminescence imaging. Corresponding changes in mRNA expression of glycolysis-related genes were determined by quantitative RT-PCR. Results: Lactate content decreased significantly in 3 out of 4 cell lines in the course of irradiation showing no correlation with cell line-specific radiosensitivity. Radiation-induced changes in ATP levels and glycolysis-related mRNA expression, however, only occurred in radiosensitive or intermediately radioresistant xenografts, whereas these parameters remained unchanged in radioresistant tumors. Conclusion: Sensitivity-related differences in the transcriptional response of tumors to radiotherapy may be exploited in the clinic for better individualization of tumor treatment. (orig.)

  20. HK2 Recruitment to Phospho-BAD Prevents Its Degradation, Promoting Warburg Glycolysis by Theileria-Transformed Leukocytes.

    Science.gov (United States)

    Haidar, Malak; Lombès, Anne; Bouillaud, Frédéric; Kennedy, Eileen J; Langsley, Gordon

    2017-03-10

    Theileria annulata infects bovine leukocytes, transforming them into invasive, cancer-like cells that cause the widespread disease called tropical theileriosis. We report that in Theileria-transformed leukocytes hexokinase-2 (HK2) binds to B cell lymphoma-2-associated death promoter (BAD) only when serine (S) 155 in BAD is phosphorylated. We show that HK2 recruitment to BAD is abolished by a cell-penetrating peptide that acts as a nonphosphorylatable BAD substrate that inhibits endogenous S155 phosphorylation, leading to complex dissociation and ubiquitination and degradation of HK2 by the proteasome. As HK2 is a critical enzyme involved in Warburg glycolysis, its loss forces Theileria-transformed macrophages to switch back to HK1-dependent oxidative glycolysis that down-regulates macrophage proliferation only when they are growing on glucose. When growing on galactose, degradation of HK2 has no effect on Theileria-infected leukocyte proliferation, because metabolism of this sugar is independent of hexokinases. Thus, targeted disruption of the phosphorylation-dependent HK2/BAD complex may represent a novel approach to control Theileria-transformed leukocyte proliferation.

  1. Regulation of the insulin-Akt signaling pathway and glycolysis during dehydration stress in the African clawed frog Xenopus laevis.

    Science.gov (United States)

    Wu, Cheng-Wei; Tessier, Shannon N; Storey, Kenneth B

    2017-12-01

    Estivation is an adaptive stress response utilized by some amphibians during periods of drought in the summer season. In this study, we examine the regulation of the insulin signaling cascade and glycolysis pathway in the African clawed frog Xenopus laevis during the dehydration stress induced state of estivation. We show that in the brain and heart of X. laevis, dehydration reduces the phosphorylation of the insulin growth factor-1 receptor (IGF-1R), and this is followed by similar reductions in the phosphorylation of the Akt and mechanistic target of rapamycin (mTOR) kinase. Interestingly, phosphorylation levels of IGF-1R and mTOR were not affected in the kidney, and phosphorylation levels of P70S6K and the ribosomal S6 protein were elevated during dehydration stress. Animals under estivation are also susceptible to periods of hypoxia, suggesting that glycolysis may also be affected. We observed that protein levels of many glycolytic enzymes remained unchanged during dehydration; however, the hypoxia response factor-1 alpha (HIF-1α) protein was elevated by greater than twofold in the heart during dehydration. Overall, we provide evidence that shows that the insulin signaling pathway in X. laevis is regulated in a tissue-specific manner during dehydration stress and suggests an important role for this signaling cascade in mediating the estivation response.

  2. Carnosine inhibits the proliferation of human gastric cancer SGC-7901 cells through both of the mitochondrial respiration and glycolysis pathways.

    Directory of Open Access Journals (Sweden)

    Yao Shen

    Full Text Available Carnosine, a naturally occurring dipeptide, has been recently demonstrated to possess anti-tumor activity. However, its underlying mechanism is unclear. In this study, we investigated the effect and mechanism of carnosine on the cell viability and proliferation of the cultured human gastric cancer SGC-7901 cells. Carnosine treatment did not induce cell apoptosis or necrosis, but reduced the proliferative capacity of SGC-7901 cells. Seahorse analysis showed SGC-7901 cells cultured with pyruvate have active mitochondria, and depend on mitochondrial oxidative phosphorylation more than glycolysis pathway for generation of ATP. Carnosine markedly decreased the absolute value of mitochondrial ATP-linked respiration, and reduced the maximal oxygen consumption and spare respiratory capacity, which may reduce mitochondrial function correlated with proliferative potential. Simultaneously, carnosine also reduced the extracellular acidification rate and glycolysis of SGC-7901 cells. Our results suggested that carnosine is a potential regulator of energy metabolism of SGC-7901 cells both in the anaerobic and aerobic pathways, and provided a clue for preclinical and clinical evaluation of carnosine for gastric cancer therapy.

  3. The post-transcriptional regulatory system CSR controls the balance of metabolic pools in upper glycolysis of Escherichia coli.

    Science.gov (United States)

    Morin, Manon; Ropers, Delphine; Letisse, Fabien; Laguerre, Sandrine; Portais, Jean-Charles; Cocaign-Bousquet, Muriel; Enjalbert, Brice

    2016-05-01

    Metabolic control in Escherichia coli is a complex process involving multilevel regulatory systems but the involvement of post-transcriptional regulation is uncertain. The post-transcriptional factor CsrA is stated as being the only regulator essential for the use of glycolytic substrates. A dozen enzymes in the central carbon metabolism (CCM) have been reported as potentially controlled by CsrA, but its impact on the CCM functioning has not been demonstrated. Here, a multiscale analysis was performed in a wild-type strain and its isogenic mutant attenuated for CsrA (including growth parameters, gene expression levels, metabolite pools, abundance of enzymes and fluxes). Data integration and regulation analysis showed a coordinated control of the expression of glycolytic enzymes. This also revealed the imbalance of metabolite pools in the csrA mutant upper glycolysis, before the phosphofructokinase PfkA step. This imbalance is associated with a glucose-phosphate stress. Restoring PfkA activity in the csrA mutant strain suppressed this stress and increased the mutant growth rate on glucose. Thus, the carbon storage regulator system is essential for the effective functioning of the upper glycolysis mainly through its control of PfkA. This work demonstrates the pivotal role of post-transcriptional regulation to shape the carbon metabolism. © 2016 John Wiley & Sons Ltd.

  4. The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity

    DEFF Research Database (Denmark)

    Lund, Trine Meldgaard; Ploug, K.B.; Iversen, Anne

    2015-01-01

    -hydroxybutyrate might change neuronal function as there is a known coupling between metabolism and neurotransmission. The purpose of this study was to shed light on the effects of the ketone body β-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown...... an effect of β-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when β-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of β...... to a combination of glucose and R-β-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release....

  5. 3-Bromopyruvate and sodium citrate induce apoptosis in human gastric cancer cell line MGC-803 by inhibiting glycolysis and promoting mitochondria-regulated apoptosis pathway

    International Nuclear Information System (INIS)

    Guo, Xingyu; Zhang, Xiaodong; Wang, Tingan; Xian, Shulin; Lu, Yunfei

    2016-01-01

    Cancer cells are mainly dependent on glycolysis to generate adenosine triphosphate (ATP) and intermediates required for cell growth and proliferation. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Our previously studies had found that both 3-bromopyruvate (BP) and sodium citrate (SCT) can inhibit tumor growth and proliferation in vitro and in vivo. However, the mechanism involved in the BP and SCT mediated antitumor activity is not entirely clear. In this work, it is demonstrated that BP inhibits the enzyme hexokinase (HK) activity and SCT suppresses the phosphofructokinase (PFK) activity respectively, both the two agents decrease viability, ATP generation and lactate content in the human gastric cancer cell line MGC-803. These effects are directly correlated with blockage of glycolysis. Furthermore, BP and SCT can induce the characteristic manifestations of mitochondria-regulated apoptosis, such as down-regulation of anti-apoptosis proteins Bcl-2 and Survivin, up-regulation of pro-apoptosis protein Bax, activation of caspase-3, as well as leakage of cytochrome c (Cyt-c). In summary, our results provided evidences that BP and SCT inhibit the MGC-803 cells growth and proliferation might be correlated with inhibiting glycolysis and promoting mitochondria-regulated apoptosis. -- Highlights: •Blockage of glycolysis might be a novel way to anticancer. •Both 3-bromopyruvate and sodium citrate could inhibit glycolysis and regulate mitochondrial pathway in cancer cells. •Both 3-bromopyruvate and sodium citrate would be the novel agents on treatment of gastric cancer.

  6. 3-Bromopyruvate and sodium citrate induce apoptosis in human gastric cancer cell line MGC-803 by inhibiting glycolysis and promoting mitochondria-regulated apoptosis pathway

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Xingyu; Zhang, Xiaodong; Wang, Tingan, E-mail: moonsonlife@yahoo.com; Xian, Shulin; Lu, Yunfei, E-mail: doctorlife@126.com

    2016-06-17

    Cancer cells are mainly dependent on glycolysis to generate adenosine triphosphate (ATP) and intermediates required for cell growth and proliferation. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Our previously studies had found that both 3-bromopyruvate (BP) and sodium citrate (SCT) can inhibit tumor growth and proliferation in vitro and in vivo. However, the mechanism involved in the BP and SCT mediated antitumor activity is not entirely clear. In this work, it is demonstrated that BP inhibits the enzyme hexokinase (HK) activity and SCT suppresses the phosphofructokinase (PFK) activity respectively, both the two agents decrease viability, ATP generation and lactate content in the human gastric cancer cell line MGC-803. These effects are directly correlated with blockage of glycolysis. Furthermore, BP and SCT can induce the characteristic manifestations of mitochondria-regulated apoptosis, such as down-regulation of anti-apoptosis proteins Bcl-2 and Survivin, up-regulation of pro-apoptosis protein Bax, activation of caspase-3, as well as leakage of cytochrome c (Cyt-c). In summary, our results provided evidences that BP and SCT inhibit the MGC-803 cells growth and proliferation might be correlated with inhibiting glycolysis and promoting mitochondria-regulated apoptosis. -- Highlights: •Blockage of glycolysis might be a novel way to anticancer. •Both 3-bromopyruvate and sodium citrate could inhibit glycolysis and regulate mitochondrial pathway in cancer cells. •Both 3-bromopyruvate and sodium citrate would be the novel agents on treatment of gastric cancer.

  7. Decreased hepatic response to glucagon, adrenergic agonists, and cAMP in glycogenolysis, gluconeogenesis, and glycolysis in tumor-bearing rats.

    Science.gov (United States)

    Biazi, Giuliana R; Frasson, Isabele G; Miksza, Daniele R; de Morais, Hely; de Fatima Silva, Flaviane; Bertolini, Gisele L; de Souza, Helenir M

    2018-05-15

    The response to glucagon and adrenaline in cancer cachexia is poorly known. The aim of this study was to investigate the response to glucagon, adrenergic agonists (α and β) and cyclic adenosine monophosphate (cAMP) on glycogenolysis, gluconeogenesis, and glycolysis in liver perfusion of Walker-256 tumor-bearing rats with advanced cachexia. Liver ATP content was also investigated. Rats without tumor (healthy) were used as controls. Agonists α (phenylephrine) and β (isoproterenol) adrenergic, instead of adrenaline, and cAMP, the second messenger of glucagon and isoproterenol, were used in an attempt to identify mechanisms involved in the responses. Glucagon (1 nM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in the liver of healthy and tumor-bearing rats, but their effects were lower in tumor-bearing rats. Isoproterenol (20 µM) stimulated glycogenolysis, gluconeogenesis, and glycolysis in healthy rats and had virtually no effect in tumor-bearing rats. cAMP (9 µM) also stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in healthy rats but had practically no effect in tumor-bearing rats. Phenylephrine (2 µM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis and these effects were also lower in tumor-bearing rats than in healthy. Liver ATP content was lower in tumor-bearing rats. In conclusion, tumor-bearing rats with advanced cachexia showed a decreased hepatic response to glucagon, adrenergic agonists (α and β), and cAMP in glycogenolysis, gluconeogenesis, and glycolysis, which may be due to a reduced rate of regulatory enzyme phosphorylation caused by the low ATP levels in the liver. © 2018 Wiley Periodicals, Inc.

  8. Combined Hyperpolarized 13C-pyruvate MRS and 18F-FDG PET (HyperPET) Estimates of Glycolysis in Canine Cancer Patients

    DEFF Research Database (Denmark)

    Hansen, Adam E.; Gutte, Henrik; Holst, Pernille

    2018-01-01

    13C Magnetic Resonance Spectroscopy (MRS) using hyperpolarized 13C-labeled pyruvate as a substrate offers a measure of pyruvate-lactate interconversion and is thereby a marker of the elevated aerobic glycolysis (Warburg effect) generally exhibited by cancer cells. Here, we aim to compare hyperpol......13C Magnetic Resonance Spectroscopy (MRS) using hyperpolarized 13C-labeled pyruvate as a substrate offers a measure of pyruvate-lactate interconversion and is thereby a marker of the elevated aerobic glycolysis (Warburg effect) generally exhibited by cancer cells. Here, we aim to compare...

  9. [Mechanism of changes in the rate of glycolysis and levels of ATP and 2,3-diphosphoglycerate in human erythrocytes during aging].

    Science.gov (United States)

    Bogatskaia, L N; Pisaruk, A V

    1987-01-01

    Reasons which have induced changes in the glycolysis rate, ATP and 2,3-diphosphoglycerate content in human erythrocytes with ageing are studied. A fall of the hexokinase activity is shown to be one of the reasons of a significant decrease in the glycolysis rate. The total ATPase activity in erythrocytes does not change with the age. At the same time the decay rate of 2,3-diphosphoglycerate increases, that, evidently, is one of the reasons of the 2,3-diphosphoglycerate content decrease in erythrocytes with ageing.

  10. Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis.

    Science.gov (United States)

    Harris, Richard A; Tindale, Lauren; Lone, Asad; Singh, Olivia; Macauley, Shannon L; Stanley, Molly; Holtzman, David M; Bartha, Robert; Cumming, Robert C

    2016-02-10

    Aerobic glycolysis and lactate production in the brain plays a key role in memory, yet the role of this metabolism in the cognitive decline associated with Alzheimer's disease (AD) remains poorly understood. Here we examined the relationship between cerebral lactate levels and memory performance in an APP/PS1 mouse model of AD, which progressively accumulates amyloid-β. In vivo (1)H-magnetic resonance spectroscopy revealed an age-dependent decline in lactate levels within the frontal cortex of control mice, whereas lactate levels remained unaltered in APP/PS1 mice from 3 to 12 months of age. Analysis of hippocampal interstitial fluid by in vivo microdialysis revealed a significant elevation in lactate levels in APP/PS1 mice relative to control mice at 12 months of age. An age-dependent decline in the levels of key aerobic glycolysis enzymes and a concomitant increase in lactate transporter expression was detected in control mice. Increased expression of lactate-producing enzymes correlated with improved memory in control mice. Interestingly, in APP/PS1 mice the opposite effect was detected. In these mice, increased expression of lactate producing enzymes correlated with poorer memory performance. Immunofluorescent staining revealed localization of the aerobic glycolysis enzymes pyruvate dehydrogenase kinase and lactate dehydrogenase A within cortical and hippocampal neurons in control mice, as well as within astrocytes surrounding amyloid plaques in APP/PS1 mice. These observations collectively indicate that production of lactate, via aerobic glycolysis, is beneficial for memory function during normal aging. However, elevated lactate levels in APP/PS1 mice indicate perturbed lactate processing, a factor that may contribute to cognitive decline in AD. Lactate has recently emerged as a key metabolite necessary for memory consolidation. Lactate is the end product of aerobic glycolysis, a unique form of metabolism that occurs within certain regions of the brain. Here

  11. Reassessment of FDG uptake in tumor cells: High FDG uptake as a reflection of oxygen-independent glycolysis dominant energy production

    Energy Technology Data Exchange (ETDEWEB)

    Waki, A.; Fujibayashi, Y.; Yonekura, Y.; Sadato, N.; Ishii, Y.; Yokoyama, A

    1997-10-01

    To determine appropriate use of 2-[{sup 18}F]-fluoro-2-deoxy-D-glucose (FDG) in the diagnosis of malignant tumors, the mechanism of enhanced FDG uptake in tumor cells was reassessed using in vitro cultured cell lines and {sup 3}H-deoxyglucose (DG), in combination with possible parameters of aerobic and anaerobic energy production. The high DG uptake in the tumor cells reflected the dependency of energy production on anaerobic glycolysis, and paradoxically on low levels of aerobic oxidative phosphorylation in mitochondria. We discuss here factors underlying anaerobic glycolysis in tumor cells.

  12. Differential effects of safflower oil versus fish oil feeding on insulin-stimulated glycogen synthesis, glycolysis, and pyruvate dehydrogenase flux in skeletal muscle: a 13C nuclear magnetic resonance study.

    Science.gov (United States)

    Jucker, B M; Cline, G W; Barucci, N; Shulman, G I

    1999-01-01

    To examine the effects of safflower oil versus fish oil feeding on in vivo intramuscular glucose metabolism and relative pyruvate dehydrogenase (PDH) versus tricarboxylic acid (TCA) cycle flux, rats were pair-fed on diets consisting of 1) 59% safflower oil, 2) 59% menhaden fish oil, or 3) 59% carbohydrate (control) in calories. Rates of glycolysis and glycogen synthesis were assessed by monitoring [1-(13)C]glucose label incorporation into [1-(13)C]glycogen, [3-(13)C]lactate, and [3-(13)C]alanine in the hindlimb of awake rats via 13C nuclear magnetic resonance (NMR) spectroscopy during a euglycemic (approximately 6 mmol/l) hyperinsulinemic (approximately 180 microU/ml) clamp. A steady-state isotopic analysis of lactate, alanine, and glutamate was used to determine the relative PDH versus TCA cycle flux present in muscle under these conditions. The safflower oil-fed rats were insulin resistant compared with control and fish oil-fed rats, as reflected by a markedly reduced glucose infusion rate (Ginf) during the clamp (21.4 +/- 2.3 vs. 31.6 +/- 2.8 and 31.7 +/- 1.9 mg x kg(-1) x min(-1) in safflower oil versus control and fish oil groups, respectively, P safflower oil group was associated with a lower rate of glycolysis (21.7 +/- 2.2 nmol x g(-1) x min(-1)) versus control (62.1 +/- 10.3 nmol x g(-1) x min(-1), P safflower oil, fish oil, and control, respectively) was detected. The intramuscular triglyceride (TG) content was increased in the safflower oil group (7.3 +/- 0.8 micromol/g) compared with the control group (5.2 +/- 0.8 micromol/g, P safflower oil (43 +/- 8%) versus the control (73 +/- 8%, P safflower oil feeding was a consequence of reduced glycolytic flux associated with an increase in relative free fatty acid/ketone oxidation versus TCA cycle flux, whereas fish oil feeding did not alter glucose metabolism and may in part be protective of insulin-stimulated glucose disposal by limiting intramuscular TG deposition.

  13. Analysis of l-glutamic acid fermentation by using a dynamic metabolic simulation model of Escherichia coli

    OpenAIRE

    Nishio, Yousuke; Ogishima, Soichi; Ichikawa, Masao; Yamada, Yohei; Usuda, Yoshihiro; Masuda, Tadashi; Tanaka, Hiroshi

    2013-01-01

    Background Understanding the process of amino acid fermentation as a comprehensive system is a challenging task. Previously, we developed a literature-based dynamic simulation model, which included transcriptional regulation, transcription, translation, and enzymatic reactions related to glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and the anaplerotic pathway of Escherichia coli. During simulation, cell growth was defined such as to reproduce the experimental...

  14. The effect of isoproterenol on some aspects of the anaerobic metabolism of carbohydrates in mouse submandibular gland.

    Science.gov (United States)

    Sassaki, K T; Nicolau, J

    1982-01-01

    1. The effect of isoproterenol, a beta-adrenergic drug, on some aspects of the anaerobic metabolism of carbohydrates in the submandibular salivary glands of mice was studied. 2. Alterations in enzymatic activities and in the concentrations of some metabolites were observed in groups of animals killed at various times after the stimulation. 3. The potential capacity of the pentose phosphate cycle was greater than that of glycolysis up to 20 hr after the stimulation.

  15. Purification and characterization of xylitol dehydrogenase with l-arabitol dehydrogenase activity from the newly isolated pentose-fermenting yeast Meyerozyma caribbica 5XY2.

    Science.gov (United States)

    Sukpipat, Wiphat; Komeda, Hidenobu; Prasertsan, Poonsuk; Asano, Yasuhisa

    2017-01-01

    Meyerozyma caribbica strain 5XY2, which was isolated from an alcohol fermentation starter in Thailand, was found to catabolize l-arabinose as well as d-glucose and d-xylose. The highest production amounts of ethanol from d-glucose, xylitol from d-xylose, and l-arabitol from l-arabinose were 0.45 g/g d-glucose, 0.60 g/g d-xylose, and 0.61 g/g l-arabinose with 21.7 g/L ethanol, 20.2 g/L xylitol, and 30.3 g/l l-arabitol, respectively. The enzyme with l-arabitol dehydrogenase (LAD) activity was purified from the strain and found to exhibit broad specificity to polyols, such as xylitol, d-sorbitol, ribitol, and l-arabitol. Xylitol was the preferred substrate with K m =16.1 mM and k cat /K m =67.0 min -1 mM -1 , while l-arabitol was also a substrate for the enzyme with K m =31.1 mM and k cat /K m =6.5 min -1  mM -1 . Therefore, this enzyme from M. caribbica was named xylitol dehydrogenase (McXDH). McXDH had an optimum temperature and pH at 40°C and 9.5, respectively. The McXDH gene included a coding sequence of 1086 bp encoding a putative 362 amino acid protein of 39 kDa with an apparent homopentamer structure. Native McXDH and recombinant McXDH exhibited relative activities toward l-arabitol of approximately 20% that toward xylitol, suggesting the applicability of this enzyme with the functions of XDH and LAD to the development of pentose-fermenting Saccharomyces cerevisiae. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  16. Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP+-dependent dehydrogenases of the pentose phosphate pathway

    International Nuclear Information System (INIS)

    Rodrigues, Juan; Branco, Vasco; Lu, Jun; Holmgren, Arne; Carvalho, Cristina

    2015-01-01

    Mercury (Hg) is a strong toxicant affecting mainly the central nervous, renal, cardiovascular and immune systems. Thiomersal (TM) is still in use in medical practice as a topical antiseptic and as a preservative in multiple dose vaccines, routinely given to young children in some developing countries, while other forms of mercury such as methylmercury represent an environmental and food hazard. The aim of the present study was to determine the effects of thiomersal (TM) and its breakdown product ethylmercury (EtHg) on the thioredoxin system and NADP + -dependent dehydrogenases of the pentose phosphate pathway. Results show that TM and EtHg inhibited the thioredoxin system enzymes in purified suspensions, being EtHg comparable to methylmercury (MeHg). Also, treatment of neuroblastoma and liver cells with TM or EtHg decreased cell viability (GI 50 : 1.5 to 20 μM) and caused a significant (p < 0.05) decrease in the overall activities of thioredoxin (Trx) and thioredoxin reductase (TrxR) in a concentration- and time-dependent manner in cell lysates. Compared to control, the activities of Trx and TrxR in neuroblastoma cells after EtHg incubation were reduced up to 60% and 80% respectively, whereas in hepatoma cells the reduction was almost 100%. In addition, the activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were also significantly inhibited by all mercurials, with inhibition intensity of Hg 2+ > MeHg ≈ EtHg > TM (p < 0.05). Cell incubation with sodium selenite alleviated the inhibitory effects on TrxR and glucose-6-phosphate dehydrogenase. Thus, the molecular mechanism of toxicity of TM and especially of its metabolite EtHg encompasses the blockage of the electrons from NADPH via the thioredoxin system. - Highlights: • TM and EtHg inhibit Trx and TrxR both in purified suspensions and cell lysates. • TM and EtHg also inhibit the activities of G6PDH and 6PGDH in cell lysates, • Co-exposure to selenite alleviates the

  17. Toxicological effects of thiomersal and ethylmercury: Inhibition of the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway

    Energy Technology Data Exchange (ETDEWEB)

    Rodrigues, Juan, E-mail: juanricardorodrigues@gmail.com [Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa (Portugal); Laboratory of Biochemistry, Faculty of Pharmacy, Central University of Venezuela (Venezuela, Bolivarian Republic of); Branco, Vasco [Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa (Portugal); Lu, Jun; Holmgren, Arne [Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet (Sweden); Carvalho, Cristina, E-mail: cristina.carvalho@ff.ulisboa.pt [Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa (Portugal)

    2015-08-01

    Mercury (Hg) is a strong toxicant affecting mainly the central nervous, renal, cardiovascular and immune systems. Thiomersal (TM) is still in use in medical practice as a topical antiseptic and as a preservative in multiple dose vaccines, routinely given to young children in some developing countries, while other forms of mercury such as methylmercury represent an environmental and food hazard. The aim of the present study was to determine the effects of thiomersal (TM) and its breakdown product ethylmercury (EtHg) on the thioredoxin system and NADP{sup +}-dependent dehydrogenases of the pentose phosphate pathway. Results show that TM and EtHg inhibited the thioredoxin system enzymes in purified suspensions, being EtHg comparable to methylmercury (MeHg). Also, treatment of neuroblastoma and liver cells with TM or EtHg decreased cell viability (GI{sub 50}: 1.5 to 20 μM) and caused a significant (p < 0.05) decrease in the overall activities of thioredoxin (Trx) and thioredoxin reductase (TrxR) in a concentration- and time-dependent manner in cell lysates. Compared to control, the activities of Trx and TrxR in neuroblastoma cells after EtHg incubation were reduced up to 60% and 80% respectively, whereas in hepatoma cells the reduction was almost 100%. In addition, the activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were also significantly inhibited by all mercurials, with inhibition intensity of Hg{sup 2+} > MeHg ≈ EtHg > TM (p < 0.05). Cell incubation with sodium selenite alleviated the inhibitory effects on TrxR and glucose-6-phosphate dehydrogenase. Thus, the molecular mechanism of toxicity of TM and especially of its metabolite EtHg encompasses the blockage of the electrons from NADPH via the thioredoxin system. - Highlights: • TM and EtHg inhibit Trx and TrxR both in purified suspensions and cell lysates. • TM and EtHg also inhibit the activities of G6PDH and 6PGDH in cell lysates, • Co-exposure to selenite alleviates

  18. Glucose feeds the TCA cycle via circulating lactate.

    Science.gov (United States)

    Hui, Sheng; Ghergurovich, Jonathan M; Morscher, Raphael J; Jang, Cholsoon; Teng, Xin; Lu, Wenyun; Esparza, Lourdes A; Reya, Tannishtha; Le Zhan; Yanxiang Guo, Jessie; White, Eileen; Rabinowitz, Joshua D

    2017-11-02

    Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues and tumours. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13 C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13 C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.

  19. NaCl stress impact on the key enzymes in glycolysis from Lactobacillus bulgaricus during freeze-drying.

    Science.gov (United States)

    Li, Chun; Sun, Jinwei; Qi, Xiaoxi; Liu, Libo

    2015-01-01

    The viability of Lactobacillus bulgaricus in freeze-drying is of significant commercial interest to dairy industries. In the study, L.bulgaricus demonstrated a significantly improved (p enzymes in glycolysis during 2% NaCl stress were studied. NaCl stress significantly enhanced (p enzymes (phosphofructokinase, pyruvate kinase, and lactate dehydrogenase) decreased during freeze-drying, and NaCl stress were found to improve activities of these enzymes before and after freeze-drying. However, a transcriptional analysis of the corresponding genes suggested that the effect of NaCl stress on the expression of the pfk2 gene was not obvious. The increased survival of freeze-dried cells of L. bulgaricus under NaCl stress might be due to changes in only the activity or translation level of these enzymes in different environmental conditions but have no relation to their mRNA transcription level.

  20. The early asthmatic response is associated with glycolysis, calcium binding and mitochondria activity as revealed by proteomic analysis in rats

    Directory of Open Access Journals (Sweden)

    Xu Yu-Dong

    2010-08-01

    Full Text Available Abstract Background The inhalation of allergens by allergic asthmatics results in the early asthmatic response (EAR, which is characterized by acute airway obstruction beginning within a few minutes. The EAR is the earliest indicator of the pathological progression of allergic asthma. Because the molecular mechanism underlying the EAR is not fully defined, this study will contribute to a better understanding of asthma. Methods In order to gain insight into the molecular basis of the EAR, we examined changes in protein expression patterns in the lung tissue of asthmatic rats during the EAR using 2-DE/MS-based proteomic techniques. Bioinformatic analysis of the proteomic data was then performed using PPI Spider and KEGG Spider to investigate the underlying molecular mechanism. Results In total, 44 differentially expressed protein spots were detected in the 2-DE gels. Of these 44 protein spots, 42 corresponded to 36 unique proteins successfully identified using mass spectrometry. During subsequent bioinformatic analysis, the gene ontology classification, the protein-protein interaction networking and the biological pathway exploration demonstrated that the identified proteins were mainly involved in glycolysis, calcium binding and mitochondrial activity. Using western blot and semi-quantitative RT-PCR, we confirmed the changes in expression of five selected proteins, which further supports our proteomic and bioinformatic analyses. Conclusions Our results reveal that the allergen-induced EAR in asthmatic rats is associated with glycolysis, calcium binding and mitochondrial activity, which could establish a functional network in which calcium binding may play a central role in promoting the progression of asthma.

  1. Simultaneous stimulation of glycolysis and gluconeogenesis by feeding in the anterior intestine of the omnivorous GIFT tilapia, Oreochromis niloticus

    Directory of Open Access Journals (Sweden)

    Yong-Jun Chen

    2017-06-01

    Full Text Available The present study was performed to investigate the roles of anterior intestine in the postprandial glucose homeostasis of the omnivorous Genetically Improved Farmed Tilapia (GIFT. Sub-adult fish (about 173 g were sampled at 0, 1, 3, 8 and 24 h post feeding (HPF after 36 h of food deprivation, and the time course of changes in intestinal glucose transport, glycolysis, glycogenesis and gluconeogenesis at the transcription and enzyme activity level, as well as plasma glucose contents, were analyzed. Compared with 0 HPF (fasting for 36 h, the mRNA levels of both ATP-dependent sodium/glucose cotransporter 1 and facilitated glucose transporter 2 increased during 1-3 HPF, decreased at 8 HPF and then leveled off. These results indicated that intestinal uptake of glucose and its transport across the intestine to blood mainly occurred during 1-3 HPF, which subsequently resulted in the increase of plasma glucose level at the same time. Intestinal glycolysis was stimulated during 1-3 HPF, while glucose storage as glycogen was induced during 3-8 HPF. Unexpectedly, intestinal gluconeogenesis (IGNG was also strongly induced during 1-3 HPF at the state of nutrient assimilation. The mRNA abundance and enzyme activities of glutamic-pyruvic and glutamic-oxaloacetic transaminases increased during 1-3 HPF, suggesting that the precursors of IGNG might originate from some amino acids. Taken together, it was concluded that the anterior intestine played an important role in the regulation of postprandial glucose homeostasis in omnivorous tilapia, as it represented significant glycolytic potential and glucose storage. It was interesting that postprandial IGNG was stimulated by feeding temporarily, and its biological significance remains to be elucidated in fish.

  2. Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms.

    Directory of Open Access Journals (Sweden)

    Colleen Marie Bartman

    Full Text Available A wide search for ischemic preconditioning (IPC mechanisms of cardioprotection identified the light elicited circadian rhythm protein Period 2 (Per2 to be cardioprotective. Studies on cardiac metabolism found a key role for light elicited Per2 in mediating metabolic dependence on carbohydrate metabolism. To profile Per2 mediated pathways following IPC of the mouse heart, we performed a genome array and identified 352 abundantly expressed and well-characterized Per2 dependent micro RNAs. One prominent result of our in silico analysis for cardiac Per2 dependent micro RNAs revealed a selective role for miR-21 in the regulation of hypoxia and metabolic pathways. Based on this Per2 dependency, we subsequently found a diurnal expression pattern for miR-21 with higher miR-21 expression levels at Zeitgeber time (ZT 15 compared to ZT3. Gain or loss of function studies for miR-21 using miRNA mimics or miRNA inhibitors and a Seahorse Bioanalyzer uncovered a critical role of miR-21 for cellular glycolysis, glycolytic capacity, and glycolytic reserve. Exposing mice to intense light, a strategy to induce Per2, led to a robust induction of cardiac miR-21 tissue levels and decreased infarct sizes, which was abolished in miR-21-/- mice. Similarly, first translational studies in humans using intense blue light exposure for 5 days in healthy volunteers resulted in increased plasma miR-21 levels which was associated with increased phosphofructokinase activity, the rate-limiting enzyme in glycolysis. Together, we identified miR-21 as cardioprotective downstream target of Per2 and suggest intense light therapy as a potential strategy to enhance miR-21 activity and subsequent carbohydrate metabolism in humans.

  3. Simultaneous stimulation of glycolysis and gluconeogenesis by feeding in the anterior intestine of the omnivorous GIFT tilapia, Oreochromis niloticus.

    Science.gov (United States)

    Chen, Yong-Jun; Zhang, Ti-Yin; Chen, Hai-Yan; Lin, Shi-Mei; Luo, Li; Wang, De-Shou

    2017-06-15

    The present study was performed to investigate the roles of anterior intestine in the postprandial glucose homeostasis of the omnivorous Genetically Improved Farmed Tilapia (GIFT). Sub-adult fish (about 173 g) were sampled at 0, 1, 3, 8 and 24 h post feeding (HPF) after 36 h of food deprivation, and the time course of changes in intestinal glucose transport, glycolysis, glycogenesis and gluconeogenesis at the transcription and enzyme activity level, as well as plasma glucose contents, were analyzed. Compared with 0 HPF (fasting for 36 h), the mRNA levels of both ATP-dependent sodium/glucose cotransporter 1 and facilitated glucose transporter 2 increased during 1-3 HPF, decreased at 8 HPF and then leveled off. These results indicated that intestinal uptake of glucose and its transport across the intestine to blood mainly occurred during 1-3 HPF, which subsequently resulted in the increase of plasma glucose level at the same time. Intestinal glycolysis was stimulated during 1-3 HPF, while glucose storage as glycogen was induced during 3-8 HPF. Unexpectedly, intestinal gluconeogenesis (IGNG) was also strongly induced during 1-3 HPF at the state of nutrient assimilation. The mRNA abundance and enzyme activities of glutamic-pyruvic and glutamic-oxaloacetic transaminases increased during 1-3 HPF, suggesting that the precursors of IGNG might originate from some amino acids. Taken together, it was concluded that the anterior intestine played an important role in the regulation of postprandial glucose homeostasis in omnivorous tilapia, as it represented significant glycolytic potential and glucose storage. It was interesting that postprandial IGNG was stimulated by feeding temporarily, and its biological significance remains to be elucidated in fish. © 2017. Published by The Company of Biologists Ltd.

  4. Glacial cycles

    DEFF Research Database (Denmark)

    Kaufmann, R. K.; Juselius, Katarina

    We use a statistical model, the cointegrated vector autoregressive model, to assess the degree to which variations in Earth's orbit and endogenous climate dynamics can be used to simulate glacial cycles during the late Quaternary (390 kyr-present). To do so, we estimate models of varying complexity...... and compare the accuracy of their in-sample simulations. Results indicate that strong statistical associations between endogenous climate variables are not enough for statistical models to reproduce glacial cycles. Rather, changes in solar insolation associated with changes in Earth's orbit are needed...... to simulate glacial cycles accurately. Also, results suggest that non-linear 10 dynamics, threshold effects, and/or free oscillations may not play an overriding role in glacial cycles....

  5. Fuel cycles

    International Nuclear Information System (INIS)

    Hawley, N.J.

    1983-05-01

    AECL publications, from the open literature, on fuels and fuel cycles used in CANDU reactors are listed in this bibliography. The accompanying index is by subject. The bibliography will be brought up to date periodically

  6. 3-Bromopyruvate and sodium citrate induce apoptosis in human gastric cancer cell line MGC-803 by inhibiting glycolysis and promoting mitochondria-regulated apoptosis pathway.

    Science.gov (United States)

    Guo, Xingyu; Zhang, Xiaodong; Wang, Tingan; Xian, Shulin; Lu, Yunfei

    2016-06-17

    Cancer cells are mainly dependent on glycolysis to generate adenosine triphosphate (ATP) and intermediates required for cell growth and proliferation. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Our previously studies had found that both 3-bromopyruvate (BP) and sodium citrate (SCT) can inhibit tumor growth and proliferation in vitro and in vivo. However, the mechanism involved in the BP and SCT mediated antitumor activity is not entirely clear. In this work, it is demonstrated that BP inhibits the enzyme hexokinase (HK) activity and SCT suppresses the phosphofructokinase (PFK) activity respectively, both the two agents decrease viability, ATP generation and lactate content in the human gastric cancer cell line MGC-803. These effects are directly correlated with blockage of glycolysis. Furthermore, BP and SCT can induce the characteristic manifestations of mitochondria-regulated apoptosis, such as down-regulation of anti-apoptosis proteins Bcl-2 and Survivin, up-regulation of pro-apoptosis protein Bax, activation of caspase-3, as well as leakage of cytochrome c (Cyt-c). In summary, our results provided evidences that BP and SCT inhibit the MGC-803 cells growth and proliferation might be correlated with inhibiting glycolysis and promoting mitochondria-regulated apoptosis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Adaptation to the coupling of glycolysis to toxic methylglyoxal production in tpiA deletion strains of Escherichia coli requires synchronized and counterintuitive genetic changes

    DEFF Research Database (Denmark)

    McCloskey, Douglas; Xu, Sibei; Sandberg, Troy E.

    2018-01-01

    -talk between carbon starvation and inorganic phosphate signalling was revealed in the tpiA deletion strain that required mutations in inorganic phosphate signalling mechanisms to alleviate; and 3) The split flux through lower glycolysis depleted glycolytic intermediates requiring a host of synchronized...

  8. The inhibition of lactate dehydrogenase A hinders the transcription of histone 2B gene independently from the block of aerobic glycolysis

    International Nuclear Information System (INIS)

    Brighenti, Elisa; Carnicelli, Domenica; Brigotti, Maurizio; Fiume, Luigi

    2017-01-01

    Most cancer cells use aerobic glycolysis to fuel their growth and many efforts are made to selectively block this metabolic pathway in cancer cells by inhibiting lactate dehydrogenase A (LDHA). However, LDHA is a moonlighting protein which exerts functions also in the nucleus as a factor associated to transcriptional complexes. Here we found that two small molecules which inhibit the enzymatic activity of LDHA hinder the transcription of histone 2B gene independently from the block of aerobic glycolysis. Moreover, we observed that silencing this gene reduces cell replication, hence suggesting that the inhibition of LDHA can also affect the proliferation of normal non-glycolysing dividing cells. - Highlights: • Blocking aerobic glycolysis is an approach to impair proliferation of cancer cells. • Small inhibitors of LDHA block aerobic glycolysis. • LDHA is also involved in the transcription of histone 2B gene. • LDHA inhibitors block histone 2B transcription. • LDHA inhibitors can hinder the proliferation also of non-glycolysing normal cells.

  9. Creatine Monohydrate Enhances Energy Status and Reduces Glycolysis via Inhibition of AMPK Pathway in Pectoralis Major Muscle of Transport-Stressed Broilers.

    Science.gov (United States)

    Zhang, Lin; Wang, Xiaofei; Li, Jiaolong; Zhu, Xudong; Gao, Feng; Zhou, Guanghong

    2017-08-16

    Creatine monohydrate (CMH) contributes to reduce transport-induced muscle rapid glycolysis and improve meat quality of broilers, but the underlying mechanism is still unknown. Therefore, this study aimed to investigate the molecular mechanisms underlying the ameliorative effects of CMH on muscle glycolysis metabolism of transported broilers during summer. The results showed that 3 h transport during summer elevated chicken live weight loss and plasma corticosterone concentration; decreased muscle concentrations of ATP, creatine, and energy charge value; increased muscle AMP concentration and AMP/ATP ratio; and upregulated muscle mRNA expression of LKB1 and AMPKα2, as well as protein expression of p-LKB1 Thr189 and p-AMPKα Thr172 , which subsequently resulted in rapid glycolysis in the pectoralis major muscle and consequent reduction of meat quality. Dietary addition of CMH at 1200 mg/kg ameliorated transport-induced rapid muscle glycolysis and reduction of meat quality via enhancement of the energy-buffering capacity of intramuscular phosphocreatine/creatine system and inhibition of AMPK pathway.

  10. Hypoxia-inducible transcription factor-1α promotes hypoxia-induced A549 apoptosis via a mechanism that involves the glycolysis pathway

    International Nuclear Information System (INIS)

    Luo, FengMing; Liu, XiaoJing; Yan, NaiHong; Li, ShuangQing; Cao, GuiQun; Cheng, QingYing; Xia, QingJie; Wang, HongJing

    2006-01-01

    Hypoxia-inducible transcription factor-1α (HIF-1α), which plays an important role in controlling the hypoxia-induced glycolysis pathway, is a 'master' gene in the tissue hypoxia response during tumor development. However, its role in the apoptosis of non-small cell lung cancer remains unknown. Here, we have studied the effects of HIF-1α on apoptosis by modulating HIF-1α gene expression in A549 cells through both siRNA knock-down and over-expression. A549 cells were transfected with a HIF-1α siRNA plasmid or a HIF-1α expression vector. Transfected cells were exposed to a normoxic or hypoxic environment in the presence or absence of 25 mM HEPES and 2-deoxyglucose (2-DG) (5 mM). The expression of three key genes of the glycolysis pathway, glucose transporter type 1(GLUT1), phosphoglycerate kinase 1(PGK1), and hexokinase 1(HK1), were measured using real-time RT-PCR. Glycolysis was monitored by measuring changes of pH and lactate concentration in the culture medium. Apoptosis was detected by TUNEL assay and flow cytometry. Knocking down expression of HIF-1α inhibited the glycolysis pathway, increased the pH of the culture medium, and protected the cells from hypoxia-induced apoptosis. In contrast, over-expression of HIF-1α accelerated glycolysis in A549 cells, decreased the pH of the culture medium, and enhanced hypoxia-induced apoptosis. These effects of HIF-1α on glycolysis, pH of the medium, and apoptosis were reversed by treatment with the glycolytic inhibitor, 2-DG. Apoptosis induced by HIF-1α over-expression was partially inhibited by increasing the buffering capacity of the culture medium by adding HEPES. During hypoxia in A549 cells, HIF-1α promotes activity of the glycolysis pathway and decreases the pH of the culture medium, resulting in increased cellular apoptosis

  11. RNA interference targeting CD147 inhibits the proliferation, invasiveness, and metastatic activity of thyroid carcinoma cells by down-regulating glycolysis

    Science.gov (United States)

    Huang, Peng; Chang, Shi; Jiang, Xiaolin; Su, Juan; Dong, Chao; Liu, Xu; Yuan, Zhengtai; Zhang, Zhipeng; Liao, Huijun

    2015-01-01

    A high rate of glycolytic flux, even in the presence of oxygen, is a key metabolic hallmark of cancer cells. Lactate, the end product of glycolysis, decreases the extracellular pH and contributes to the proliferation, invasiveness and metastasis of tumor cells. CD147 play a crucial role in tumorigenicity, invasion and metastasis; and CD147 also interacts strongly and specifically with monocarboxylate transporter1 (MCT1) that mediates the transport of lactate. The objective of this study was to determine whether CD147 is involved, via its association with MCT1 to transport lactate, in glycolysis, contributing to the progression of thyroid carcinoma. The expression levels of CD147 in surgical specimens of normal thyroid, nodular goiter (NG), well-differentiated thyroid carcinoma (WDTC), and undifferentiated thyroid carcinoma (UDTC) were determined using immunohistochemical techniques. The effects of CD147 silencing on cell proliferation, invasiveness, metastasis, co-localization with MCT1, glycolysis rate and extracellular pH of thyroid cancer cells (WRO and FRO cell lines) were measured after CD147 was knocked-down using siRNA targeting CD147. Immunohistochemical analysis of thyroid carcinoma (TC) tissues revealed significant increases in signal for CD147 compared with normal tissue or NG, while UDTC expressed remarkably higher levels of CD147 compared with WDTC. Furthermore, silencing of CD147 in TC cells clearly abrogated the expression of MCT1 and its co-localization with CD147 and dramatically decreased both the glycolysis rate and extracellular pH. Thus, cell proliferation, invasiveness, and metastasis were all significantly decreased by siRNA. These results demonstrate in vitro that the expression of CD147 correlates with the degree of dedifferentiation of thyroid cancer, and show that CD147 interacts with MCT1 to regulate tumor cell glycolysis, resulting in the progression of thyroid carcinoma. PMID:25755717

  12. Glucose metabolism and astrocyte-neuron interactions in the neonatal brain.

    Science.gov (United States)

    Brekke, Eva; Morken, Tora Sund; Sonnewald, Ursula

    2015-03-01

    Glucose is essentially the sole fuel for the adult brain and the mapping of its metabolism has been extensive in the adult but not in the neonatal brain, which is believed to rely mainly on ketone bodies for energy supply. However, glucose is absolutely indispensable for normal development and recent studies have shed light on glycolysis, the pentose phosphate pathway and metabolic interactions between astrocytes and neurons in the 7-day-old rat brain. Appropriately (13)C labeled glucose was used to distinguish between glycolysis and the pentose phosphate pathway during development. Experiments using (13)C labeled acetate provided insight into the GABA-glutamate-glutamine cycle between astrocytes and neurons. It could be shown that in the neonatal brain the part of this cycle that transfers glutamine from astrocytes to neurons is operating efficiently while, in contrast, little glutamate is shuttled from neurons to astrocytes. This lack of glutamate for glutamine synthesis is compensated for by anaplerosis via increased pyruvate carboxylation relative to that in the adult brain. Furthermore, compared to adults, relatively more glucose is prioritized to the pentose phosphate pathway than glycolysis and pyruvate dehydrogenase activity. The reported developmental differences in glucose metabolism and neurotransmitter synthesis may determine the ability of the brain at various ages to resist excitotoxic insults such as hypoxia-ischemia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Protective effects of a wheat germ rich diet against the toxic influence of profenofos on rat tissue lipids and oxidative pentose phosphate shunt enzymes

    Directory of Open Access Journals (Sweden)

    Abdel-Rahim, G. A.

    2011-09-01

    Full Text Available The effects of technical and formulated forms of profenofos on the metabolic lipid fractions of the liver, brain and kidneys as well as the activity of glucose-6-phosphate dehydrogenase (G6PD and 6-phosphogluconate dehydrogenase (6PGD, which consider lipid related enzymes, were studied. The two forms of profenofos were given separately either orally or by dermal at doses of 1/20 LD50 for 3 months (one dose every 48 h. Total lipids and lipid fractions (cholesterol, triglycerides and phospholipid contents decreased in the three studied organ tissues either in technical or formulated profenofos-induced rats compared with normal control animals. The highest effect was observed in the case of orally formulated profenofo induction, and the lowest was detected for the dermal technical one. The same trend was found in the activities of G6PD and 6PGD associated with lipid metabolism in the liver, brain and kidney tissues under the same conditions. On other hand, the treatment of profenofos-induced animals by feeding a wheat germ rich diet (as antioxidant agent produced significant improvements in both lipid fraction content and enzyme activity. In addition, the effects of the wheat germ rich diet (α-tocopherol rich source readjusted and improved the disturbed metabolic fractions of the lipid profiles in the profenofos-induced rats as well as their related enzyme activities (G6PD and 6PGD: oxidative pentose phosphate shunt.

    El efecto de formas técnicas o formuladas de profenofós en la fracción lipídica metabólica de hígado, cerebro y riñones así como la actividad de la glucosa-6-fosfato deshidrogenasa (G6PD y 6-fosfogluconato deshidrogenasa (6PGD, que son consideradas enzimas relacionadas con los lípidos, fueron estudiadas. Ambas formas de profenofós fueron suministradas separadamente tanto por vía oral como cutánea a una dosis de 1/20 LD50 durante 3 meses (una dosis cada 48 horas. Los lípidos totales y

  14. Coordination cycles

    Czech Academy of Sciences Publication Activity Database

    Steiner, Jakub

    -, č. 274 (2005), s. 1-26 ISSN 1211-3298 Institutional research plan: CEZ:AV0Z70850503 Keywords : coordination * crises * cycles and fluctuations Subject RIV: AH - Economics http://www.cerge-ei.cz/pdf/wp/Wp274.pdf

  15. Happy Cycling

    DEFF Research Database (Denmark)

    Geert Jensen, Birgitte; Nielsen, Tom

    2013-01-01

    og Interaktions Design, Aarhus Universitet under opgave teamet: ”Happy Cycling City – Aarhus”. Udfordringen i studieopgaven var at vise nye attraktive løsningsmuligheder i forhold til cyklens og cyklismens integration i byrum samt at påpege relationen mellem design og overordnede diskussioner af...

  16. Coordination cycles

    Czech Academy of Sciences Publication Activity Database

    Steiner, Jakub

    2008-01-01

    Roč. 63, č. 1 (2008), s. 308-327 ISSN 0899-8256 Institutional research plan: CEZ:AV0Z70850503 Keywords : global games * coordination * crises * cycles and fluctuations Subject RIV: AH - Economics Impact factor: 1.333, year: 2008

  17. Flux Analysis of the Trypanosoma brucei Glycolysis Based on a Multiobjective-Criteria Bioinformatic Approach

    Directory of Open Access Journals (Sweden)

    Amine Ghozlane

    2012-01-01

    Full Text Available Trypanosoma brucei is a protozoan parasite of major of interest in discovering new genes for drug targets. This parasite alternates its life cycle between the mammal host(s (bloodstream form and the insect vector (procyclic form, with two divergent glucose metabolism amenable to in vitro culture. While the metabolic network of the bloodstream forms has been well characterized, the flux distribution between the different branches of the glucose metabolic network in the procyclic form has not been addressed so far. We present a computational analysis (called Metaboflux that exploits the metabolic topology of the procyclic form, and allows the incorporation of multipurpose experimental data to increase the biological relevance of the model. The alternatives resulting from the structural complexity of networks are formulated as an optimization problem solved by a metaheuristic where experimental data are modeled in a multiobjective function. Our results show that the current metabolic model is in agreement with experimental data and confirms the observed high metabolic flexibility of glucose metabolism. In addition, Metaboflux offers a rational explanation for the high flexibility in the ratio between final products from glucose metabolism, thsat is, flux redistribution through the malic enzyme steps.

  18. Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis

    Directory of Open Access Journals (Sweden)

    Gandham SK

    2015-07-01

    for both 10 µM and 25 µM concentrations. Conclusion: SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer cells. Encapsulation of 3-BPA in a liposomal formulation improved permeability, HK2 inhibition, and cytotoxicity in the multicellular spheroid model.Keywords: ovarian cancer, aerobic glycolysis, hexokinase-2, 3-bromopyruvate, epidermal growth factor receptor-targeted liposomes

  19. Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Saleha B Vuyyuri

    Full Text Available Ascorbic acid (AA exhibits significant anticancer activity at pharmacologic doses achievable by parenteral administration that have minimal effects on normal cells. Thus, AA has potential uses as a chemotherapeutic agent alone or in combination with other therapeutics that specifically target cancer-cell metabolism. We compared the effects of AA and combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3-PO on the viability of three non-small cell lung cancer (NSCLC cell lines to the effects on an immortalized lung epithelial cell line. AA concentrations of 0.5 to 5 mM caused a complete loss of viability in all NSCLC lines compared to a <10% loss of viability in the lung epithelial cell line. Combinations of AA and 3-PO synergistically enhanced cell death in all NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone. A synergistic interaction was not observed in combination treatments of lung epithelial cells and combination treatments that caused a complete loss of viability in NSCLC cells had modest effects on normal lung cell viability and reactive oxygen species (ROS levels. Combination treatments induced dramatically higher ROS levels compared to treatment with AA and 3-PO alone in NSCLC cells and combination-induced cell death was inhibited by addition of catalase to the medium. Analyses of DNA fragmentation, poly (ADP-ribose polymerase cleavage, annexin V-binding, and caspase activity demonstrated that AA-induced cell death is caused via the activation of apoptosis and that the combination treatments caused a synergistic induction of apoptosis. These results demonstrate the effectiveness of AA against NSCLC cells and that combinations of AA with 3-PO synergistically induce apoptosis via a ROS-dependent mechanism. These results support further evaluation of pharmacologic concentrations of AA as an adjuvant treatment for NSCLC and that combination of AA with

  20. Fuel cycle

    International Nuclear Information System (INIS)

    Bahm, W.

    1989-01-01

    The situation of the nuclear fuel cycle for LWR type reactors in France and in the Federal Republic of Germany was presented in 14 lectures with the aim to compare the state-of-the-art in both countries. In addition to the momentarily changing fuilds of fuel element development and fueling strategies, the situation of reprocessing, made interesting by some recent developmnts, was portrayed and differences in ultimate waste disposal elucidated. (orig.) [de

  1. An anthocyanin rich strawberry extract induces apoptosis and ROS while decreases glycolysis and fibrosis in human uterine leiomyoma cells.

    Science.gov (United States)

    Islam, Md Soriful; Giampieri, Francesca; Janjusevic, Milijana; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Y; Mazzoni, Luca; Greco, Stefania; Giannubilo, Stefano Raffaele; Ciavattini, Andrea; Mezzetti, Bruno; Capocasa, Franco; Castellucci, Mario; Battino, Maurizio; Ciarmela, Pasquapina

    2017-04-04

    Uterine leiomyomas are highly prevalent benign tumors in reproductive aged women. Unfortunately, medical treatments are still limited and no preventive therapies have been developed. In the present study, we investigated the therapeutic effects of strawberry extract on uterine leiomyoma cells. Leiomyoma and myometrial cells were treated with strawberry (cultivar Alba) extract (250 μg/ml) for 48 h to measure apoptosis, reactive oxygen species (ROS), oxidative phosphorylation (OCR, oxygen consumption rate) and glycolysis (ECAR, extracellular acidification rate) as well as fibrosis associated gene and/or protein expression. In leiomyoma cells, strawberry increased the percentage of apoptotic and dead cells. Strawberry significantly increased ROS concentration in leiomyoma cells, while decreased it in myometrial cells. After strawberry treatment, leiomyoma cells showed a significant decreased rate of ECAR, while OCR was unchanged in both myometrial and leiomyoma cells. Strawberry significantly decreased collagen1A1, fibronectin and versican mRNA expression in leiomyoma cells. The reduced protein expression of fibronectin was observed by strawberry extract in leiomyoma cells as well. Furthermore, strawberry was able to reduce activin A induced fibronectin, collagen1A1, and versican as well as activin A and PAI-1 mRNA expression in leiomyoma cells. This study suggests that strawberry can be developed as therapeutic and/or preventive agent for uterine leiomyomas.

  2. Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

    Science.gov (United States)

    Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

    2017-11-18

    Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Engineered Trx2p industrial yeast strain protects glycolysis and fermentation proteins from oxidative carbonylation during biomass propagation

    Directory of Open Access Journals (Sweden)

    Gómez-Pastor Rocío

    2012-01-01

    Full Text Available Abstract Background In the yeast biomass production process, protein carbonylation has severe adverse effects since it diminishes biomass yield and profitability of industrial production plants. However, this significant detriment of yeast performance can be alleviated by increasing thioredoxins levels. Thioredoxins are important antioxidant defenses implicated in many functions in cells, and their primordial functions include scavenging of reactive oxygen species that produce dramatic and irreversible alterations such as protein carbonylation. Results In this work we have found several proteins specifically protected by yeast Thioredoxin 2 (Trx2p. Bidimensional electrophoresis and carbonylated protein identification from TRX-deficient and TRX-overexpressing cells revealed that glycolysis and fermentation-related proteins are specific targets of Trx2p protection. Indeed, the TRX2 overexpressing strain presented increased activity of the central carbon metabolism enzymes. Interestingly, Trx2p specifically preserved alcohol dehydrogenase I (Adh1p from carbonylation, decreased oligomer aggregates and increased its enzymatic activity. Conclusions The identified proteins suggest that the fermentative capacity detriment observed under industrial conditions in T73 wine commercial strain results from the oxidative carbonylation of specific glycolytic and fermentation enzymes. Indeed, increased thioredoxin levels enhance the performance of key fermentation enzymes such as Adh1p, which consequently increases fermentative capacity.

  4. Reactive oxygen species-driven HIF1α triggers accelerated glycolysis in endothelial cells exposed to low oxygen tension

    International Nuclear Information System (INIS)

    Paik, Jin-Young; Jung, Kyung-Ho; Lee, Jin-Hee; Park, Jin-Won; Lee, Kyung-Han

    2017-01-01

    Endothelial cells and their metabolic state regulate glucose transport into underlying tissues. Here, we show that low oxygen tension stimulates human umbilical vein endothelial cell 18 F–fluorodeoxyglucose ( 18 F–FDG) uptake and lactate production. This was accompanied by augmented hexokinase activity and membrane Glut-1, and increased accumulation of hypoxia-inducible factor-1α (HIF1α). Restoration of oxygen reversed the metabolic effect, but this was blocked by HIF1α stabilization. Hypoxia-stimulated 18 F–FDG uptake was completely abrogated by silencing of HIF1α expression or by a specific inhibitor. There was a rapid and marked increase of reactive oxygen species (ROS) by hypoxia, and ROS scavenging or NADPH oxidase inhibition completely abolished hypoxia-stimulated HIF1α and 18 F–FDG accumulation, placing ROS production upstream of HIF1α signaling. Hypoxia-stimulated HIF1α and 18 F–FDG accumulation was blocked by the protein kinase C (PKC) inhibitor, staurosporine. The phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, blocked hypoxia-stimulated 18 F–FDG uptake and attenuated hypoxia-responsive element binding of HIF1α without influencing its accumulation. Thus, ROS-driven HIF1α accumulation, along with PKC and PI3K signaling, play a key role in triggering accelerated glycolysis in endothelial cells under hypoxia, thereby contributing to 18 F–FDG transport.

  5. The Glycerate and Phosphorylated Pathways of Serine Synthesis in Plants: The Branches of Plant Glycolysis Linking Carbon and Nitrogen Metabolism.

    Science.gov (United States)

    Igamberdiev, Abir U; Kleczkowski, Leszek A

    2018-01-01

    Serine metabolism in plants has been studied mostly in relation to photorespiration where serine is formed from two molecules of glycine. However, two other pathways of serine formation operate in plants and represent the branches of glycolysis diverging at the level of 3-phosphoglyceric acid. One branch (the glycerate - serine pathway) is initiated in the cytosol and involves glycerate formation from 3-phosphoglycerate, while the other (the phosphorylated serine pathway) operates in plastids and forms phosphohydroxypyruvate as an intermediate. Serine formed in these pathways becomes a precursor of glycine, formate and glycolate accumulating in stress conditions. The pathways can be linked to GABA shunt via transamination reactions and via participation of the same reductase for both glyoxylate and succinic semialdehyde. In this review paper we present a hypothesis of the regulation of redox balance in stressed plant cells via participation of the reactions associated with glycerate and phosphorylated serine pathways. We consider these pathways as important processes linking carbon and nitrogen metabolism and maintaining cellular redox and energy levels in stress conditions.

  6. High USP6NL levels in breast cancer sustain chronic AKT phosphorylation and GLUT1 stability fueling aerobic glycolysis.

    Science.gov (United States)

    Avanzato, Daniele; Pupo, Emanuela; Ducano, Nadia; Isella, Claudio; Bertalot, Giovanni; Luise, Chiara; Pece, Salvatore; Bruna, Alejandra; Rueda, Oscar M; Caldas, Carlos; Di Fiore, Pier Paolo; Sapino, Anna; Lanzetti, Letizia

    2018-04-24

    USP6NL, also named RN-tre, is a GTPase activating protein (GAP) involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer (BC), mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in BC cells delayed endocytosis and degradation of the epidermal growth factor receptor (EGFR), causing chronic AKT activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized BC cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in BC cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of BC cells and promote their proliferation. Copyright ©2018, American Association for Cancer Research.

  7. Comparative Metabolomic Profiling Reveals That Dysregulated Glycolysis Stemming from Lack of Salvage NAD+ Biosynthesis Impairs Reproductive Development in Caenorhabditis elegans.

    Science.gov (United States)

    Wang, Wenqing; McReynolds, Melanie R; Goncalves, Jimmy F; Shu, Muya; Dhondt, Ineke; Braeckman, Bart P; Lange, Stephanie E; Kho, Kelvin; Detwiler, Ariana C; Pacella, Marisa J; Hanna-Rose, Wendy

    2015-10-23

    Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD(+) consumers to resynthesize NAD(+), resulting in a reduction in global NAD(+) bioavailability. We manipulate NAD(+) levels to demonstrate that a minor deficit in NAD(+) availability is incompatible with a normal pace of gonad development. The NAD(+) deficit compromises NAD(+) consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal widespread metabolic perturbations, and using complementary pharmacological and genetic approaches, we demonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD(+) biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD(+) salvage biosynthesis for the purposes of inhibiting tumor growth. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Comparative Metabolomic Profiling Reveals That Dysregulated Glycolysis Stemming from Lack of Salvage NAD+ Biosynthesis Impairs Reproductive Development in Caenorhabditis elegans*

    Science.gov (United States)

    Wang, Wenqing; McReynolds, Melanie R.; Goncalves, Jimmy F.; Shu, Muya; Dhondt, Ineke; Braeckman, Bart P.; Lange, Stephanie E.; Kho, Kelvin; Detwiler, Ariana C.; Pacella, Marisa J.; Hanna-Rose, Wendy

    2015-01-01

    Temporal developmental progression is highly coordinated in Caenorhabditis elegans. However, loss of nicotinamidase PNC-1 activity slows reproductive development, uncoupling it from its typical progression relative to the soma. Using LC/MS we demonstrate that pnc-1 mutants do not salvage the nicotinamide released by NAD+ consumers to resynthesize NAD+, resulting in a reduction in global NAD+ bioavailability. We manipulate NAD+ levels to demonstrate that a minor deficit in NAD+ availability is incompatible with a normal pace of gonad development. The NAD+ deficit compromises NAD+ consumer activity, but we surprisingly found no functional link between consumer activity and reproductive development. As a result we turned to a comparative metabolomics approach to identify the cause of the developmental phenotype. We reveal widespread metabolic perturbations, and using complementary pharmacological and genetic approaches, we demonstrate that a glycolytic block accounts for the slow pace of reproductive development. Interestingly, mitochondria are protected from both the deficiency in NAD+ biosynthesis and the effects of reduced glycolytic output. We suggest that compensatory metabolic processes that maintain mitochondrial activity in the absence of efficient glycolysis are incompatible with the requirements for reproductive development, which requires high levels of cell division. In addition to demonstrating metabolic requirements for reproductive development, this work also has implications for understanding the mechanisms behind therapeutic interventions that target NAD+ salvage biosynthesis for the purposes of inhibiting tumor growth. PMID:26350462

  9. Total Lesion Glycolysis and Sequential (90)Y-Selective Internal Radiation Therapy in Breast Cancer Liver Metastases: Preliminary Results.

    Science.gov (United States)

    Bagni, Oreste; Filippi, Luca; Pelle, Giuseppe; Cianni, Roberto; Schillaci, Orazio

    2015-12-01

    To assess the prognostic role of total lesion glycolysis (TLG) in patients with breast cancer liver metastases (BCLM) after sequential lobar (90)Y-radioembolization ((90)Y-RE). Seventeen patients with bilobar BCLM underwent FDG PET/CT and TLG calculation before (90)Y-RE. The hepatic lobe with the highest TLG was treated in the first session. PET was performed 6 weeks postprocedure and decrease in TLG (ΔTLG) in the treated lobe was calculated before the second (90)Y administration. Subjects were divided in two groups (group 1: ΔTLG >50%, group 2: ΔTLG 50% and seven had a ΔTLG value 50% and ΔTLG <50% had a mean OS of 16.4 ± 0.6 and 10.3 ± 0.4 months, respectively (p < 0.001). Cox regression analysis demonstrated hepatic tumor load (p = 0.048) and ΔTLG as the only significant (p = 0.005) predictors of survival. ΔTLG after the first (90)Y administration agrees with final outcome in BCLM patients after separate sequential lobar (90)Y-RE.

  10. Inihibition of Glycolysis by Using a Micro/Nano-Lipid Bromopyruvic Chitosan Carrier as a Promising Tool to Improve Treatment of Hepatocellular Carcinoma

    Science.gov (United States)

    Dini, Luciana; Citti, Cinzia; Cannazza, Giuseppe

    2018-01-01

    Glucose consumption in many types of cancer cells, in particular hepatocellular carcinoma (HCC), was followed completely by over-expression of type II hexokinase (HKII). This evidence has been used in modern pharmacotherapy to discover therapeutic target against glycolysis in cancer cells. Bromopyruvate (BrPA) exhibits antagonist property against HKII and can be used to inhibit glycolysis. However, the clinical application of BrPA is mostly combined with inhibition effect for healthy cells particularly erythrocytes. Our strategy is to encapsulate BrPA in a selected vehicle, without any leakage of BrPA out of vehicle in blood stream. This structure has been constructed from chitosan embedded into oleic acid layer and then coated by dual combination of folic acid (FA) and bovine serum albumin (BSA). With FA as specific ligand for cancer folate receptor and BSA that can be an easy binding for hepatocytes, they can raise the potential selection of carrier system. PMID:29320411

  11. Inihibition of Glycolysis by Using a Micro/Nano-Lipid Bromopyruvic Chitosan Carrier as a Promising Tool to Improve Treatment of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Nemany A. Hanafy

    2018-01-01

    Full Text Available Glucose consumption in many types of cancer cells, in particular hepatocellular carcinoma (HCC, was followed completely by over-expression of type II hexokinase (HKII. This evidence has been used in modern pharmacotherapy to discover therapeutic target against glycolysis in cancer cells. Bromopyruvate (BrPA exhibits antagonist property against HKII and can be used to inhibit glycolysis. However, the clinical application of BrPA is mostly combined with inhibition effect for healthy cells particularly erythrocytes. Our strategy is to encapsulate BrPA in a selected vehicle, without any leakage of BrPA out of vehicle in blood stream. This structure has been constructed from chitosan embedded into oleic acid layer and then coated by dual combination of folic acid (FA and bovine serum albumin (BSA. With FA as specific ligand for cancer folate receptor and BSA that can be an easy binding for hepatocytes, they can raise the potential selection of carrier system.

  12. Real-Time DNP NMR Observations of Acetic Acid Uptake, Intracellular Acidification, and of Consequences for Glycolysis and Alcoholic Fermentation in Yeast

    DEFF Research Database (Denmark)

    Jensen, Pernille Rose; Karlsson, Magnus; Lerche, Mathilde Hauge

    2013-01-01

    Uptake and upshot in vivo: Straightforward methods that permit the real-time observation of organic acid influx, intracellular acidification, and concomitant effects on cellular-reaction networks are crucial for improved bioprocess monitoring and control (see scheme). Herein, dynamic nuclear pola...... polarization (DNP) NMR is used to observe acetate influx, ensuing intracellular acidification and the metabolic consequences on alcoholic fermentation and glycolysis in living cells....

  13. EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as non-invasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate

    Science.gov (United States)

    Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu; Morris, H. Douglas; Munasinghe, Jeeva P.; Lizak, Martin; Merkle, Hellmut; Ardenkjaer-Larsen, Jan Henrik; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Koretsky, Alan P.; Mitchell, James B.; Krishna, Murali C.

    2012-01-01

    The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation, and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate (3-BP) blocks glycolysis pathway by inhibiting hypoxia inducible enzymes, and enhanced cytotoxicity of 3-BP under hypoxic conditions has been reported in vitro. However, the efficacy of 3-BP was substantially attenuated in hypoxic tumor regions (pO2 < 10 mmHg) in vivo using squamous cell carcinoma (SCCVII)-bearing mouse model. Metabolic MRI studies using hyperpolarized 13C-labeled pyruvate showed that monocarboxylate transporter-1 (MCT1) is the major transporter for pyruvate and the analog 3-BP in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of MCT1 in vivo. Expression of MCT1 was enhanced in moderately hypoxic (8–15 mmHg) tumor regions, but down regulated in severely hypoxic (< 5 mmHg) tumor regions. These results emphasize the importance of non-invasive imaging biomarkers to confirm the action of hypoxia-activated drugs. PMID:22692861

  14. EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate.

    Science.gov (United States)

    Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu; Morris, H Douglas; Munasinghe, Jeeva P; Lizak, Martin; Merkle, Hellmut; Ardenkjaer-Larsen, Jan Henrik; Choudhuri, Rajani; Devasahayam, Nallathamby; Subramanian, Sankaran; Koretsky, Alan P; Mitchell, James B; Krishna, Murali C

    2013-05-01

    The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under hypoxic conditions has been reported in vitro. However, the efficacy of 3-bromopyruvate was substantially attenuated in hypoxic tumor regions (pO23-bromopyruvate in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of monocarboxylate transporter-1 in vivo. Expression of monocarboxylate transporter-1 was enhanced in moderately hypoxic (8-15 mmHg) tumor regions but down regulated in severely hypoxic (<5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia-activated drugs. Copyright © 2012 Wiley Periodicals, Inc.

  15. Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis.

    Science.gov (United States)

    Hyder, Fahmeed; Herman, Peter; Bailey, Christopher J; Møller, Arne; Globinsky, Ronen; Fulbright, Robert K; Rothman, Douglas L; Gjedde, Albert

    2016-05-01

    Regionally variable rates of aerobic glycolysis in brain networks identified by resting-state functional magnetic resonance imaging (R-fMRI) imply regionally variable adenosine triphosphate (ATP) regeneration. When regional glucose utilization is not matched to oxygen delivery, affected regions have correspondingly variable rates of ATP and lactate production. We tested the extent to which aerobic glycolysis and oxidative phosphorylation power R-fMRI networks by measuring quantitative differences between the oxygen to glucose index (OGI) and the oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) in normal human brain (resting awake, eyes closed). Regionally uniform and correlated OEF and OGI estimates prevailed, with network values that matched the gray matter means, regardless of size, location, and origin. The spatial agreement between oxygen delivery (OEF≈0.4) and glucose oxidation (OGI ≈ 5.3) suggests that no specific regions have preferentially high aerobic glycolysis and low oxidative phosphorylation rates, with globally optimal maximum ATP turnover rates (VATP ≈ 9.4 µmol/g/min), in good agreement with (31)P and (13)C magnetic resonance spectroscopy measurements. These results imply that the intrinsic network activity in healthy human brain powers the entire gray matter with ubiquitously high rates of glucose oxidation. Reports of departures from normal brain-wide homogeny of oxygen extraction fraction and oxygen to glucose index may be due to normalization artefacts from relative PET measurements. © The Author(s) 2016.

  16. Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells.

    Science.gov (United States)

    Gong, Yuanqi; Lan, Haibing; Yu, Zhihong; Wang, Meng; Wang, Shu; Chen, Yu; Rao, Haiwei; Li, Jingying; Sheng, Zhiyong; Shao, Jianghua

    2017-09-16

    Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate-induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Safe cycling!

    CERN Multimedia

    Anaïs Schaeffer

    2012-01-01

    The HSE Unit will be running a cycling safety campaign at the entrances to CERN's restaurants on 14, 15 and 16 May. Pop along to see if they can persuade you to get back in the saddle!   With summer on its way, you might feel like getting your bike out of winter storage. Well, the HSE Unit has come up with some original ideas to remind you of some of the most basic safety rules. This year, the prevention campaign will be focussing on three themes: "Cyclists and their equipment", "The bicycle on the road", and "Other road users". This is an opportunity to think about the condition of your bike as well as how you ride it. From 14 to 16 May, representatives of the Swiss Office of Accident Prevention and the Touring Club Suisse will join members of the HSE Unit at the entrances to CERN's restaurants to give you advice on safe cycling (see box). They will also be organising three activity stands where you can test your knowle...

  18. Cycle 22

    International Nuclear Information System (INIS)

    Kappernman, J.G.; Albertson, V.D.

    1991-01-01

    This paper reports that for many electric utility systems, Solar Cycle 22 has been the first introduction to the phenomena of Geomagnetic Disturbances and the disrupting and damaging effects that they can have upon modern power systems. For all intents and purposes, Power Industry awareness of Cycle 22 started with a bang during the Great Geomagnetic Storm of March 13, 1989. This storm caused a blackout to the entire Province of Quebec, permanently damaged a large nuclear plant GSU transformer in New Jersey, and created enough havoc across the entire North American power grid to create the plausible threat of a massive power system blackout. The flurry of activity and investigation that followed has led many engineers to realize that their power systems are indeed vulnerable to this phenomena and if anything are becoming ever more vulnerable as the system grows to meet future requirements. As a result some organizations such as Hydro Quebec, PSE and G, and the PJM Pool now implement strategic measures as a remedial response to detection of geomagnetic storm conditions. Many more companies pay particularly close attention to storm forecasts and alerts, and the industry in general has accelerated research and monitoring activities through their own means of in concert with the Electric Power Research Institute (EPRI)

  19. Effects of glucose metabolism pathways on sperm motility and oxidative status during long-term liquid storage of goat semen.

    Science.gov (United States)

    Qiu, Jian-Hua; Li, You-Wei; Xie, Hong-Li; Li, Qing; Dong, Hai-Bo; Sun, Ming-Ju; Gao, Wei-Qiang; Tan, Jing-He

    2016-08-01

    Although great efforts were made to prolong the fertility of liquid-stored semen, limited improvements have been achieved in different species. Although it is expected that energy supply and the redox potential will play an essential role in sperm function, there are few reports on the impact of specific energy substrates on spermatozoa during liquid semen storage. Furthermore, although it is accepted that glucose metabolism through glycolysis provides energy, roles of pentose phosphate pathway (PPP) and tricarboxylic acid cycle remain to be unequivocally found in spermatozoa. We have studied the pathways by which spermatozoa metabolize glucose during long-term liquid storage of goat semen. The results indicated that among the substrates tested, glucose and pyruvate were better than lactate in maintaining goat sperm motility. Although both glycolysis and PPP were essential, PPP was more important than glycolysis to maintain sperm motility. Pentose phosphate pathway reduced oxidative stress and provided glycolysis with more intermediate products such as fructose-6-phosphate. Pyruvate entered goat spermatozoa through monocarboxylate transporters and was oxidized by the tricarboxylic acid cycle and electron transfer to sustain sperm motility. Long-term liquid semen storage can be used as a good model to study sperm glucose metabolism. The data are important for an optimal control of sperm survival during semen handling and preservation not only in the goat but also in other species. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Defective glycolysis and the use of 2-deoxy-D-glucose in polycystic kidney disease: from animal models to humans.

    Science.gov (United States)

    Magistroni, Riccardo; Boletta, Alessandra

    2017-08-01

    Autosomal dominant polycystic kidney disease (ADPKD) is an inherited renal disease characterized by bilateral renal cyst formation. ADPKD is one of the most common rare disorders, accounting for ~10% of all patients with end-stage renal disease (ESRD). ADPKD is a chronic disorder in which the gradual expansion of cysts that form in a minority of nephrons eventually causes loss of renal function due to the compression and degeneration of the surrounding normal parenchyma. Numerous deranged pathways have been identified in the cyst-lining epithelia, prompting the design of potential therapies. Several of these potential treatments have proved effective in slowing down disease progression in pre-clinical animal studies, while only one has subsequently been proven to effectively slow down disease progression in patients, and it has recently been approved for therapy in Europe, Canada and Japan. Among the affected cellular functions and pathways, recent investigations have described metabolic derangement in ADPKD as a major trait offering additional opportunities for targeted therapies. In particular, increased aerobic glycolysis (the Warburg effect) has been described as a prominent feature of ADPKD kidneys and its inhibition using the glucose analogue 2-deoxy-D-glucose (2DG) proved effective in slowing down disease progression in preclinical models of the disease. At the same time, previous clinical experiences have been reported with 2DG, showing that this compound is well tolerated in humans with minimal and reversible side effects. In this work, we review the literature and speculate that 2DG could be a good candidate for a clinical trial in humans affected by ADPKD.

  1. Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Xin; Lyu, Pengwei; Cao, Zhang; Li, Jingruo; Guo, Guangcheng; Xia, Wanjun; Gu, Yuanting, E-mail: zzyuantinggu@126.com

    2015-08-07

    miRNAs, sorting as non-coding RNAs, are differentially expressed in breast tumor and act as tumor promoters or suppressors. miR-206 could suppress the progression of breast cancer, the mechanism of which remains unclear. The study here was aimed to investigate the effect of miR-206 on human breast cancers. We found that miR-206 was down-regulated while one of its predicted targets, 6-Phosphofructo-2-kinase (PFKFB3) was up-regulated in human breast carcinomas. 17β-estradiol dose-dependently decreased miR-206 expression as well as enhanced PFKFB3 mRNA and protein expression in estrogen receptor α (ERα) positive breast cancer cells. Furthermore, we identified that miR-206 directly interacted with 3′-untranslated region (UTR) of PFKFB3 mRNA. miR-206 modulated PFKFB3 expression in MCF-7, T47D and SUM159 cells, which was influenced by 17β-estradiol depending on ERα expression. In addition, miR-206 overexpression impeded fructose-2,6-bisphosphate (F2,6BP) production, diminished lactate generation and reduced cell proliferation and migration in breast cancer cells. In conclusion, our study demonstrated that miR-206 regulated PFKFB3 expression in breast cancer cells, thereby stunting glycolysis, cell proliferation and migration. - Highlights: • miR-206 was down-regulated and PFKFB3 was up-regulated in human breast carcinomas. • 17β-estradiol regulated miR-206 and PFKFB3 expression in ERα+ cancer cells. • miR-206directly interacted with 3′-UTR of PFKFB3 mRNA. • miR-206 fructose-2,6-bisphosphate (F2,6BP) impeded production and lactate generation. • miR-206 reduced cell proliferation and migration in breast cancer cells.

  2. Prognostic significance of total lesion glycolysis in patients with advanced non-small cell lung cancer receiving chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Zaizen, Yoshiaki [Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume (Japan); Azuma, Koichi, E-mail: azuma@med.kurume-u.ac.jp [Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume (Japan); Kurata, Seiji [Department of Radiology, Kurume University School of Medicine, Kurume (Japan); Sadashima, Eiji; Hattori, Satoshi [Biostatistics Center, Kurume University, Kurume (Japan); Sasada, Tetsuro [Department of Immunology and Immunotherapy, Kurume University School of Medicine, Kurume (Japan); Imamura, Yohei [Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume (Japan); Kaida, Hayato [Department of Radiology, Kurume University School of Medicine, Kurume (Japan); Kawahara, Akihiko [Department of Pathology, Kurume University School of Medicine, Kurume (Japan); Kinoshita, Takashi [Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume (Japan); Ishibashi, Masatoshi [Department of Radiology, Kurume University School of Medicine, Kurume (Japan); Hoshino, Tomoaki [Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume (Japan)

    2012-12-15

    Background: [{sup 18}F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging has been employed as a non-invasive diagnostic tool for malignant tumors. Total lesion glycolysis (TLG) on FDG-PET is calculated by multiplying the mean standardized uptake value (SUVmean) by the tumor volume. Unlike the maximum standardized uptake value (SUVmax), which represents the point of greatest metabolic activity within tumors, TLG has been suggested to reflect global metabolic activity in whole tumors. Methods: We retrospectively examined whether or not FDG-PET measurements, including SUVmean, SUVmax, and TLG, could predict progression-free survival (PFS) or overall survival (OS) in patients with non-small cell lung cancer (NSCLC) receiving chemotherapy. Results: This study involved 81 consecutive patients with NSCLC who received chemotherapy. All of the patients underwent FDG-PET examination before treatment. SUVmean, SUVmax, and TLG on FDG-PET were significantly associated with gender, smoking status, and tumor histology. With adjustment for several other variables, Cox regression analysis showed that TLG was significantly prognostic for both PFS [hazard ratio = 2.34; 95% confidence interval, 1.18–4.64; P = 0.015] and OS (hazard ratio = 2.80; 95% confidence interval, 1.12–6.96; P = 0.003), whereas SUVmean and SUVmax had no significant association with PFS (P = 0.693 and P = 0.322, respectively) or OS (P = 0.587 and P = 0.214, respectively). Conclusions: Our findings suggest that TLG may be more useful than SUVmean and SUVmax for predicting PFS and OS in NSCLC patients receiving chemotherapy. The TLG measurement on FDG-PET imaging could be routinely recommended to advanced NSCLC patients.

  3. The role of glycolysis and gluconeogenesis in the cytoprotection of neuroblastoma cells against 1-methyl 4-phenylpyridinium ion toxicity.

    Science.gov (United States)

    Mazzio, Elizabeth; Soliman, Karam F A

    2003-01-01

    concluded from these studies that several metabolic intermediates are effective in fueling anaerobic glycolysis during mitochondrial inhibition by MPP+.

  4. Carbon cycle

    Energy Technology Data Exchange (ETDEWEB)

    Jaeger, J; Halbritter, G; Neumann-Hauf, G

    1982-05-01

    This report contains a review of literature on the subjects of the carbon cycle, the increase of the atmospheric CO/sub 2/ concentration and the possible impacts of an increased CO/sub 2/ concentration on the climate. In addition to this survey, the report discusses the questions that are still open and the resulting research needs. During the last twenty years a continual increase of the atmospheric carbon dioxide concentration by about 1-2 ppm per years has been observed. In 1958 the concentration was 315 ppm and this increased to 336 ppm in 1978. A rough estimate shows that the increase of the atmospheric carbon dioxide concentration is about half of the amount of carbon dioxide added to the atmosphere by the combustion of fossil fuels. Two possible sinks for the CO/sub 2/ released into the atmosphere are known: the ocean and the biota. The role of the biota is, however, unclear, since it can act both as a sink and as a source. Most models of the carbon cycle are one-dimensional and cannot be used for accurate predictions. Calculations with climate models have shown that an increased atmospheric CO/sub 2/ concentration leads to a warming of the earth's surface and lower atmosphere. Calculations show that a doubling of the atmospheric CO/sub 2/-concentration would lead to a net heating of the lower atmosphere and earth's surface by a global average of about 4 W m/sup -2/. Greater uncertainties arise in estimating the change in surface temperature resulting from this change in heating rate. It is estimated that the global average annual surface temperature would change between 1.5 and 4.5 K. There are, however, latitudinal and seasonal variations of the impact of increased CO/sub 2/ concentration. Other meteorological variables (e.g. precipitation, wind speed etc.) would also be changed. It appears that the impacts of the other products of fossil fuel combustion are unlikely to counteract the impacts of CO/sub 2/ on the climate.

  5. Your Menstrual Cycle

    Science.gov (United States)

    ... your menstrual cycle What happens during your menstrual cycle The menstrual cycle includes not just your period, but the rise ... that take place over the weeks in your cycle. Want to know what happens on each day ...

  6. Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.

    Science.gov (United States)

    Gandham, Srujan Kumar; Talekar, Meghna; Singh, Amit; Amiji, Mansoor M

    2015-01-01

    The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA). Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 µm by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions (P<0.0001, Student's t-test, unpaired and two-tailed). Liposomal formulations (both non-targeted and targeted) of 3-BPA showed a more potent inhibitory effect (P<0.001, Student's t-test, unpaired and two-tailed) at a dose of 50 µM than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 µM-100 µM) showed that the liposomal formulations had an enhanced cytotoxic effect of 2-5-fold (P<0.0001, Student's t-test, unpaired and two-tailed) when compared to the aqueous solution form for both 10 µM and 25 µM concentrations. SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer

  7. MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia

    Science.gov (United States)

    Guest, Paul C.; Iwata, Keiko; Kato, Takahiro A.; Steiner, Johann; Schmitt, Andrea; Turck, Christoph W.; Martins-de-Souza, Daniel

    2015-01-01

    Schizophrenia is a debilitating mental disorder, affecting more than 30 million people worldwide. As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte, and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK), and phosphoglycerate mutase 1 after acute MK-801 treatment (8 h), and HK1, ENO2, PGK, and triosephosphate isomerase (TPI) following long term treatment (72 h). Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that

  8. The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity.

    Science.gov (United States)

    Lund, Trine M; Ploug, Kenneth B; Iversen, Anne; Jensen, Anders A; Jansen-Olesen, Inger

    2015-03-01

    Glucose is the main energy substrate for neurons, and ketone bodies are known to be alternative substrates. However, the capacity of ketone bodies to support different neuronal functions is still unknown. Thus, a change in energy substrate from glucose alone to a combination of glucose and β-hydroxybutyrate might change neuronal function as there is a known coupling between metabolism and neurotransmission. The purpose of this study was to shed light on the effects of the ketone body β-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown an effect of β-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when β-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of β-hydroxybutyrate, whereas a direct effect of the ketone body on transmitter release was absent. However, the presence of β-hydroxybutyrate augmented transmitter release induced by the KATP channel blocker glibenclamide, thus giving an indirect indication of the involvement of KATP channels in the effects of ketone bodies on transmitter release. Energy metabolism and neurotransmission are linked and involve ATP-sensitive potassium (KATP ) channels. However, it is still unclear how and to what degree available energy substrate affects this link. We investigated the effect of changing energy substrate from only glucose to a combination of glucose and R-β-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release. © 2014 International Society for Neurochemistry.

  9. Role of Akt/PKB and PFKFB isoenzymes in the control of glycolysis, cell proliferation and protein synthesis in mitogen-stimulated thymocytes.

    Science.gov (United States)

    Houddane, Amina; Bultot, Laurent; Novellasdemunt, Laura; Johanns, Manuel; Gueuning, Marie-Agnès; Vertommen, Didier; Coulie, Pierre G; Bartrons, Ramon; Hue, Louis; Rider, Mark H

    2017-06-01

    Proliferating cells depend on glycolysis mainly to supply precursors for macromolecular synthesis. Fructose 2,6-bisphosphate (Fru-2,6-P 2 ) is the most potent positive allosteric effector of 6-phosphofructo-1-kinase (PFK-1), and hence of glycolysis. Mitogen stimulation of rat thymocytes with concanavalin A (ConA) led to time-dependent increases in lactate accumulation (6-fold), Fru-2,6-P 2 content (4-fold), 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase isoenzyme 3 and 4 (PFKFB3 and PFKFB4) protein levels (~2-fold and ~15-fold, respectively) and rates of cell proliferation (~40-fold) and protein synthesis (10-fold) after 68h of incubation compared with resting cells. After 54h of ConA stimulation, PFKFB3 mRNA levels were 45-fold higher than those of PFKFB4 mRNA. Although PFKFB3 could be phosphorylated at Ser461 by protein kinase B (PKB) in vitro leading to PFK-2 activation, PFKFB3 Ser461 phosphorylation was barely detectable in resting cells and only increased slightly in ConA-stimulated cells. On the other hand, PFKFB3 and PFKFB4 mRNA levels were decreased (90% and 70%, respectively) by exposure of ConA-stimulated cells to low doses of PKB inhibitor (MK-2206), suggesting control of expression of the two PFKFB isoenzymes by PKB. Incubation of thymocytes with ConA resulted in increased expression and phosphorylation of the translation factors eukaryotic initiation factor-4E-binding protein-1 (4E-BP1) and ribosomal protein S6 (rpS6). Treatment of ConA-stimulated thymocytes with PFK-2 inhibitor (3PO) or MK-2206 led to significant decreases in Fru-2,6-P 2 content, medium lactate accumulation and rates of cell proliferation and protein synthesis. These data were confirmed by using siRNA knockdown of PFKFB3, PFKFB4 and PKB α/β in the more easily transfectable Jurkat E6-1 cell line. The findings suggest that increased PFKFB3 and PFKFB4 expression, but not increased PFKFB3 Ser461 phosphorylation, plays a role in increasing glycolysis in mitogen

  10. The emerging role and targetability of the TCA cycle in cancer metabolism

    Directory of Open Access Journals (Sweden)

    Nicole M. Anderson

    2017-07-01

    Full Text Available ABSTRACT The tricarboxylic acid (TCA cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

  11. The emerging role and targetability of the TCA cycle in cancer metabolism.

    Science.gov (United States)

    Anderson, Nicole M; Mucka, Patrick; Kern, Joseph G; Feng, Hui

    2018-02-01

    The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

  12. Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer.

    Science.gov (United States)

    Cervantes-Madrid, Diana; Dominguez-Gomez, Guadalupe; Gonzalez-Fierro, Aurora; Perez-Cardenas, Enrique; Taja-Chayeb, Lucia; Trejo-Becerril, Catalina; Duenas-Gonzalez, Alfonso

    2017-03-01

    The aim of the present study was to investigate in vivo the feasibility and efficacy of the combination of lonidamine (LND), 6-diazo-5-oxo-L-norleucine (DON) and orlistat to simultaneously target glycolysis, glutaminolysis and de novo synthesis of fatty acids, respectively. The doses of LND and DON used in humans were translated to mouse doses (77.7 mg/kg and 145.5 mg/kg, respectively) and orlistat was used at 240 mg/kg. Three schedules of LND, DON and orlistat at different doses were administered by intraperitoneal injection to BALB/c mice in a 21-day cycle (schedule 1: LND, 0.5 mg/day; DON, 0.25 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 2: LND, 0.1 mg/day; DON, 0.5 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 3: LND, 0.5 mg/day; DON, 0.08 mg/day 1, 5 and 9; orlistat, 360 mg/kg/day) to assess tolerability. To determine the antitumor efficacy, a syngeneic tumor model in BALB/c mice was created using colon cancer CT26.WT cells, and a xenogeneic tumor model was created in nude mice using the human colon cancer SW480 cell line. Mice were treated with schedule 1. Animals were weighed, clinically inspected during the experiment and the tumor volume was measured at day 21. The 3 schedules assessed in the tolerability experiments were well tolerated, as mice maintained their weight and no evident clinical signs of toxicity were observed. Combination treatment with schedule 1 significantly decreased tumor growth in each mouse model. No evident signs of toxicity were observed and mice maintained their weight during treatment. The triple metabolic blockade of the malignant phenotype appears feasible and promising for cancer therapy.

  13. The cultural divide: exponential growth in classical 2D and metabolic equilibrium in 3D environments

    DEFF Research Database (Denmark)

    Carvalho, Vasco Botelho

    Cellular metabolism can be considered to have two extremes: one is characterized by exponential growth (in 2D cultures) and the other by a dynamic equilibrium (in 3D cultures). We have analysed the proteome and cellular architecture at these two extremes and found that they are dramatically...... different. Ultrastructurally, actin organization is changed, microtubules are increased and keratins 8 and 18 decreased. Metabolically, glycolysis, fatty acid metabolism and the pentose phosphate cycle are increased while Krebs cycle and oxidative phosphorylation is unchanged. Enzymes involved...

  14. Impaired mitochondrial Ca2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels

    International Nuclear Information System (INIS)

    Kleist-Retzow, Juergen-Christoph von; Hue-Tran Hornig-Do; Schauen, Matthias; Eckertz, Sabrina; Tuan Anh Duong Dinh; Stassen, Frank; Lottmann, Nadine; Bust, Maria; Galunska, Bistra; Wielckens, Klaus; Hein, Wolfgang; Beuth, Joseph; Braun, Jan-Matthias; Fischer, Juergen H.; Ganitkevich, Vladimir Y.; Maniura-Weber, Katharina; Wiesner, Rudolf J.

    2007-01-01

    Energy-producing pathways, adenine nucleotide levels, oxidative stress response and Ca 2+ homeostasis were investigated in cybrid cells incorporating two pathogenic mitochondrial DNA point mutations, 3243A > G and 3302A > G in tRNA Leu(UUR) , as well as Rho 0 cells and compared to their parental 143B osteosarcoma cell line. All cells suffering from a severe respiratory chain deficiency were able to proliferate as fast as controls. The major defect in oxidative phosphorylation was efficiently compensated by a rise in anaerobic glycolysis, so that the total ATP production rate was preserved. This enhancement of glycolysis was enabled by a considerable decrease of cellular total adenine nucleotide pools and a concomitant shift in the AMP + ADP/ATP ratios, while the energy charge potential was still in the normal range. Further important consequences were an increased production of superoxide which, however, was neither escorted by major changes in the antioxidative defence systems nor was it leading to substantial oxidative damage. Most interestingly, the lowered mitochondrial membrane potential led to a disturbed intramitochondrial calcium homeostasis, which most likely is a major pathomechanism in mitochondrial diseases

  15. Gallic Acid Alleviates Hypertriglyceridemia and Fat Accumulation via Modulating Glycolysis and Lipolysis Pathways in Perirenal Adipose Tissues of Rats Fed a High-Fructose Diet

    Directory of Open Access Journals (Sweden)

    Da-Wei Huang

    2018-01-01

    Full Text Available This study investigated the ameliorative effect of gallic acid (GA on hypertriglyceridemia and fat accumulation in perirenal adipose tissues of high-fructose diet (HFD-induced diabetic rats. The previous results showed that orally administered GA (30 mg/kg body weight for four weeks significantly reduced the levels of plasma glucose and triglyceride (TG in HFD rats. GA also markedly decreased the perirenal adipose tissues weight of HFD rats in present study (p < 0.05. Western blot assay indicated that GA restored expression of insulin signaling-related proteins, such as insulin receptor (IR, protein kinase C-zeta (PKC-ζ, and glucose transporter-4 (GLUT4 in the perirenal adipose tissues of HFD rats. Moreover, GA enhanced expression of glycolysis-related proteins, such as phosphofructokinase (PFK and pyruvate kinase (PK, and increased the expression of lipolysis-related proteins, such as adipose triglyceride lipase (ATGL, which is involved in lipolysis in the perirenal adipose tissues of HFD rats. This study revealed that GA may alleviate hypertriglyceridemia and fat accumulation through enhancing glycolysis and lipolysis pathways in perirenal adipose tissues of HFD rats. These findings also suggest the potential of GA in preventing the progression of diabetes mellitus (DM complications.

  16. Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells

    Directory of Open Access Journals (Sweden)

    An S

    2018-04-01

    Full Text Available Shuxian An,1,* Liangqian Huang,2,3,* Ping Miao,1 Liang Shi,1 Mengqin Shen,1 Xiaoping Zhao,1 Jianjun Liu,1 Gang Huang1,3,4 1Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 2Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; 3Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; 4Shanghai University of Medicine and Health Sciences, Shanghai, China *These authors contributed equally to this work Objective: Lung cancer is the leading cause of cancer-related death worldwide. Aerobic glycolysis is considered the seventh hallmark of cancer. The M2 isoform of pyruvate kinase (PKM2 is an important rate-limiting enzyme in glycolytic pathway, and is strongly expressed in several types of cancer. Thus, understanding the underlying mechanisms of regulation of PKM2 is of great value for targeted therapy for lung cancer.Patients and methods: Seventy-three lung adenocarcinoma patients were analyzed in our study. The expression levels of PKM2 were analyzed by immunohistochemistry on tissues. The effect of small ubiquitin-like modifier 1 (SUMO1 on PKM2 expression was investigated using Western blot assay and quantitative polymerase chain reaction. PKM2 SUMO1 modification was determined by in vitro and in vivo SUMOylation assays. 18F-deoxyglucose uptake and lactate production measurements were conducted to research the levels of glycolysis. The level of oxidative phosphorylation in cells was determined by cellular oxygen consumption rate measurements. Cell proliferation assays were carried out to confirm the growth ability of tumor cells.Results: PKM2 was overexpressed in lung adenocarcinoma patients based on immunohistochemical staining. Patients with high PKM2 expression had reduced

  17. Bipolar mood cycles and lunar tidal cycles.

    Science.gov (United States)

    Wehr, T A

    2018-04-01

    In 17 patients with rapid cycling bipolar disorder, time-series analyses detected synchronies between mood cycles and three lunar cycles that modulate the amplitude of the moon's semi-diurnal gravimetric tides: the 14.8-day spring-neap cycle, the 13.7-day declination cycle and the 206-day cycle of perigee-syzygies ('supermoons'). The analyses also revealed shifts among 1:2, 1:3, 2:3 and other modes of coupling of mood cycles to the two bi-weekly lunar cycles. These shifts appear to be responses to the conflicting demands of the mood cycles' being entrained simultaneously to two different bi-weekly lunar cycles with slightly different periods. Measurements of circadian rhythms in body temperature suggest a biological mechanism through which transits of one of the moon's semi-diurnal gravimetric tides might have driven the patients' bipolar cycles, by periodically entraining the circadian pacemaker to its 24.84-h rhythm and altering the pacemaker's phase-relationship to sleep in a manner that is known to cause switches from depression to mania.

  18. Importance of glutamine metabolism in leukemia cells by energy production through TCA cycle and by redox homeostasis.

    Science.gov (United States)

    Goto, Mineaki; Miwa, Hiroshi; Shikami, Masato; Tsunekawa-Imai, Norikazu; Suganuma, Kazuto; Mizuno, Shohei; Takahashi, Miyuki; Mizutani, Motonori; Hanamura, Ichiro; Nitta, Masakazu

    2014-07-01

    Some cancer cells depend on glutamine despite of pronounced glycolysis. We examined the glutamine metabolism in leukemia cells, and found that HL-60 cells most depended on glutamine in the 4 acute myelogenous leukemia (AML) cell lines examined: growth of HL-60 cells was most suppressed by glutamine deprivation and by inhibition of glutaminolysis, which was rescued by tricarboxylic acid (TCA) cycle intermediate, oxaloacetic acid. Glutamine is also involved in antioxidant defense function by increasing glutathione. Glutamine deprivation suppressed the glutathione content and elevated reactive oxygen species most evidently in HL-60 cells. Glutamine metabolism might be a therapeutic target in some leukemia.

  19. Essays on economic cycles

    NARCIS (Netherlands)

    Groot, de E.A. (Bert)

    2006-01-01

    Schumpeter’s line of thought of multiple economic cycles is further investigated. The existence of multiple cycles in economic variables is demonstrated. In basic innovations five different cycles are found. Multiple cycle structures are shown in various macro-economic variables from the United

  20. Hormone resistance in two MCF-7 breast cancer cell lines is associated with reduced mTOR signaling, decreased glycolysis and increased sensitivity to cytotoxic drugs

    Directory of Open Access Journals (Sweden)

    Euphemia Yee Leung

    2014-09-01

    Full Text Available The mTOR pathway is a key regulator of multiple cellular signaling pathways and is a potential target for therapy. We have previously developed two hormone-resistant sub-lines of the MCF-7 human breast cancer line, designated TamC3 and TamR3, which were characterized by reduced mTOR signaling, reduced cell volume and resistance to mTOR inhibition. Here we show that these lines exhibit increased sensitivity to carboplatin, oxaliplatin, 5-fluorouracil, camptothecin, doxorubicin, paclitaxel, docetaxel and hydrogen peroxide. The mechanisms underlying these changes have not yet been characterized but may include a shift from glycolysis to mitochondrial respiration. If this phenotype is found in clinical hormone-resistant breast cancers, conventional cytotoxic therapy may be a preferred option for treatment.

  1. Use of Molecular Imaging Markers of Glycolysis, Hypoxia and Proliferation (18F-FDG, 64Cu-ATSM and 18F-FLT) in a Dog with Fibrosarcoma

    DEFF Research Database (Denmark)

    Zornhagen, Kamilla; Clausen, Malene; Hansen, Anders Elias

    2015-01-01

    of cancer patients. A dog with fibrosarcoma was imaged using 18F-FDG, 64Cu-ATSM, and 18F-FLT before, during, and after 10 fractions of 4.5 Gy radiotherapy. Uptake of all tracers decreased during treatment. Fluctuations in 18F-FDG and 18F-FLT PET uptakes and a heterogeneous spatial distribution of the three......Glycolysis, hypoxia, and proliferation are important factors in the tumor microenvironment contributing to treatment-resistant aggressiveness. Imaging these factors using combined functional positron emission tomography and computed tomography can potentially guide diagnosis and management...... tracers were seen. Tracer distributions partially overlapped. It appears that each tracer provides distinct information about tumor heterogeneity and treatment response....

  2. Protection to glycolysis by a combination of 5-hydroxy-L-tryptophan and 2-aminoethylisothiuronium bromide hydrobromide in lethally irradiated rats

    International Nuclear Information System (INIS)

    Basu, S.K.; Srinivasan, M.N.; Chuttani, K.; George, S.

    1992-01-01

    Rate of glycolysis in vivo at different time intervals following 8 Gy[LDsub(100(30)] whole body gamma radiation (WBGR) was evaluated by estimating liver glycogen, blood sugar, serum lactic dehydrogenase (LDH) and lactic acid concentration in adult male Sprague Dawley rats. Within 1 hr of radiation exposure, a significant fall in liver glycogen was observed in rats fed food and water ad libitum. The glycogen content increased after 24 hr and had returned to control level on 7th day after radiation exposure. Blood sugar, serum LDH and blood lactate levels increased significantly as compared to non irradiated controls. Pretreatment with 5-hydroxy-L-tryptophan (5-HTP;100 mg/kg) + 2-aminoethylisothiuronium bromide hydrobromide (AET;20 mg/kg)ip 30 min before 8 Gy WBGR, modified these values and restored them to normal level on 7th day post-irradiation. (author). 24 refs

  3. Nuclear power fuel cycle

    International Nuclear Information System (INIS)

    Havelka, S.; Jakesova, L.

    1982-01-01

    Economic problems are discussed of the fuel cycle (cost of the individual parts of the fuel cycle and the share of the fuel cycle in the price of 1 kWh), the technological problems of the fuel cycle (uranium ore mining and processing, uranium isotope enrichment, the manufacture of fuel elements, the building of long-term storage sites for spent fuel, spent fuel reprocessing, liquid and gaseous waste processing), and the ecologic aspects of the fuel cycle. (H.S.)

  4. Feasibility study of FDG PET/CT-derived primary tumour glycolysis as a prognostic indicator of survival in patients with non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Mehta, G.; Chander, A.; Huang, C.; Kelly, M.; Fielding, P.

    2014-01-01

    Aim: To assess the feasibility and prognostic value of measuring total lesion glycolysis of the primary tumour (TLG primary ) using combined 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography/computed tomography (PET/CT) in patients with proven or suspected non-small-cell lung cancer (NSCLC) in the routine diagnostic setting. Materials and methods: At the All wales Research and Diagnostic Positron Emission Tomography Centre in Cardiff (PETIC), in the calendar year 2011, 288 consecutive patients were identified with a single pulmonary mass in whom NSCLC was confirmed or clinically diagnosed following multidisciplinary team review. In a retrospective analysis, for each patient the PET-derived volume of the primary tumour and SUV MEAN was calculated using adaptive thresholds of 40% and 50% of the SUV MAX of the primary tumour. The TLG primary (calculated by volume x SUV MEAN ) was calculated at these two thresholds and was used to predict survival in a multivariate analysis with TNM (tumour, node, metastasis) stage, age, sex, and SUV MAX . The primary endpoint was overall survival over a minimum follow-up of at least 7 months. Results: In virtually every case, the primary tumour could be measured using the automated software with minimal use of manual adjustments. In multivariate analysis, TNM clinical stage, log(TLG primary ) and sex were independent predictors of overall survival. Conclusion: Measurements of primary tumour total lesion glycolysis are simple to perform and provide additional prognostic information over and above that provided by TNM staging

  5. The Phosphatidylinositol 3,5-Bisphosphate (PI(3,5)P2)-dependent Tup1 Conversion (PIPTC) Regulates Metabolic Reprogramming from Glycolysis to Gluconeogenesis*

    Science.gov (United States)

    Han, Bong-Kwan; Emr, Scott D.

    2013-01-01

    Glucose/carbon metabolism is a fundamental cellular process in living cells. In response to varying environments, eukaryotic cells reprogram their glucose/carbon metabolism between aerobic or anaerobic glycolysis, oxidative phosphorylation, and/or gluconeogenesis. The distinct type of glucose/carbon metabolism that a cell carries out has significant effects on the cell's proliferation and differentiation. However, it is poorly understood how the reprogramming of glucose/carbon metabolism is regulated. Here, we report a novel endosomal PI(3,5)P2 lipid-dependent regulatory mechanism that is required for metabolic reprogramming from glycolysis to gluconeogenesis in Saccharomyces cerevisiae. Certain gluconeogenesis genes, such as FBP1 (encoding fructose-1,6-bisphosphatase 1) and ICL1 (encoding isocitrate lyase 1) are under control of the Mig1 repressor and Cyc8-Tup1 corepressor complex. We previously identified the PI(3,5)P2-dependent Tup1 conversion (PIPTC), a mechanism to convert Cyc8-Tup1 corepressor to Cti6-Cyc8-Tup1 coactivator. We demonstrate that the PIPTC plays a critical role for transcriptional activation of FBP1 and ICL1. Furthermore, without the PIPTC, the Cat8 and Sip4 transcriptional activators cannot be efficiently recruited to the promoters of FBP1 and ICL1, suggesting a key role for the PIPTC in remodulating the chromatin architecture at the promoters. Our findings expand our understanding of the regulatory mechanisms for metabolic reprogramming in eukaryotes to include key regulation steps outside the nucleus. Given that Tup1 and the metabolic enzymes that control PI(3,5)P2 are highly conserved among eukaryotes, our findings may provide important insights toward understanding glucose/carbon metabolic reprogramming in other eukaryotes, including humans. PMID:23733183

  6. The phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-dependent Tup1 conversion (PIPTC) regulates metabolic reprogramming from glycolysis to gluconeogenesis.

    Science.gov (United States)

    Han, Bong-Kwan; Emr, Scott D

    2013-07-12

    Glucose/carbon metabolism is a fundamental cellular process in living cells. In response to varying environments, eukaryotic cells reprogram their glucose/carbon metabolism between aerobic or anaerobic glycolysis, oxidative phosphorylation, and/or gluconeogenesis. The distinct type of glucose/carbon metabolism that a cell carries out has significant effects on the cell's proliferation and differentiation. However, it is poorly understood how the reprogramming of glucose/carbon metabolism is regulated. Here, we report a novel endosomal PI(3,5)P2 lipid-dependent regulatory mechanism that is required for metabolic reprogramming from glycolysis to gluconeogenesis in Saccharomyces cerevisiae. Certain gluconeogenesis genes, such as FBP1 (encoding fructose-1,6-bisphosphatase 1) and ICL1 (encoding isocitrate lyase 1) are under control of the Mig1 repressor and Cyc8-Tup1 corepressor complex. We previously identified the PI(3,5)P2-dependent Tup1 conversion (PIPTC), a mechanism to convert Cyc8-Tup1 corepressor to Cti6-Cyc8-Tup1 coactivator. We demonstrate that the PIPTC plays a critical role for transcriptional activation of FBP1 and ICL1. Furthermore, without the PIPTC, the Cat8 and Sip4 transcriptional activators cannot be efficiently recruited to the promoters of FBP1 and ICL1, suggesting a key role for the PIPTC in remodulating the chromatin architecture at the promoters. Our findings expand our understanding of the regulatory mechanisms for metabolic reprogramming in eukaryotes to include key regulation steps outside the nucleus. Given that Tup1 and the metabolic enzymes that control PI(3,5)P2 are highly conserved among eukaryotes, our findings may provide important insights toward understanding glucose/carbon metabolic reprogramming in other eukaryotes, including humans.

  7. Soluble Sugars as the Carbohydrate Reserve for CAM in Pineapple Leaves : Implications for the Role of Pyrophosphate:6-Phosphofructokinase in Glycolysis.

    Science.gov (United States)

    Carnal, N W; Black, C C

    1989-05-01

    Neutral ethanol-soluble sugar pools serve as carbohydrate reserves for Crassulacean acid metabolism (CAM) in pineapple (Ananas comosus (L.) Merr.) leaves. Levels of neutral soluble sugars and glucans fluctuated reciprocally with concentrations of malic acid. Hexose loss from neutral soluble-sugar pools was sufficient to account for malic acid accumulation with about 95% of the required hexose accounted for by turnover of fructose and glucose pools. Hexose loss from starch or starch plus lower molecular weight glucan pools was insufficient to account for nocturnal accumulation of malic acid. The apparent maximum catalytic capacity of pyrophosphate:6-phosphofructokinase (PPi-PFK) at 15 degrees C was about 16 times higher than the mean maximum rate of glycolysis that occurred to support malic acid accumulation in pineapple leaves at night and 12 times higher than the mean maximum rate of hexose turnover from all carbohydrate pools. The apparent maximum catalytic capacity of ATP-PFK at 15 degrees C was about 70% of the activity required to account for the mean maximal rate of hexose turnover from all carbohydrate pools if turnover were completely via glycolysis, and marginally sufficient to account for mean maximal rates of acidification. Therefore, at low night temperatures conducive to CAM and under subsaturating substrate concentrations, PPi-PFK activity, but not ATP-PFK activity, would be sufficient to support the rate of glycolytic carbohydrate processing required for acid accumulation. These data for pineapple establish that there are at least two types of CAM plants with respect to the nature of the carbohydrate reserve utilized to support nighttime CO(2) accumulation. The data further indicate that the glycolytic carbohydrate processing that supports acidification proceeds in different subcellular compartments in plants utilizing different carbohydrate reserves.

  8. [Importance of binding of 2,3-diphosphoglycerate and ATP to hemoglobin for erythrocyte glycolysis: activation by 2,3-diphosphoglycerate of hexokinase at intracellular conditions].

    Science.gov (United States)

    Geier, T; Glende, M; Reich, J G

    1978-01-01

    In a theoretical study the influence of hemoglobin and Mg-ions as binding partners of red cell 2,3-diphosphoglycerate and ATP was investigated. Free hemoglobin may be an efficient competitor of Mg2+ for the ligand ATP. At conditions which favour hemoglobin as binding partner (i.e. desoxygenation, low medium pH and incubation temperature, as in blood preservation) up to 95% of the whole cellular ATP (ca. 2mM in cell water) may be bound to hemoglobin (ca. 7 mM). This binding is largely prevented in the presence of physiological amounts of diphosphoglycerate (ca. 7 mM) which is in excess and has a higher binding affinity to hemoglobin. Therefore, diphosphoglycerate keeps ATP (MgATP) in cell water solution at conditions in which Hb would trop it in the presence of Mg2+ (ca. 3mM). It can be calculated that, by lack of free MgATP, the activity of hexokinase within the cell drops by a factor of greater than 10 when diphosphoglycerate is metabolized. This indirect activation by diphosphoglycerate of hexokinase is operative at free concentrations of DPG far below those which exert the well known excess inhibitory effect on hexokinase and phosphofructokinase. In a model study, the activation by diphosphoglycerate of the initial two-kinase stage was introduced into a simplified kinetic model of glycolysis. A pronounced hysteresis loop of the stationary concentrations of ATP and diphosphoglycerate was produced indicating the existence of several stationary states, one with high ATP and high diphosphoglycerate, the other one with low values. It is demonstrated that diphosphoglycerate, being a protector of glycolysis at physiological concentrations, triggers an autocatalytic breakdown of the energy state when permitted to drop to low values.

  9. Inhibition of glycolysis and growth of colon cancer cells by 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO in combination with butyrate, 2-deoxy glucose, 3-bromopyruvate or biguanides

    Directory of Open Access Journals (Sweden)

    Lea MA

    2015-09-01

    Full Text Available Introduction: Glycolysis shows a positive correlation with growth of human colon cancer cells. PFKFB3 is an important enzyme regulating glycolysis in many tumor cells and presents a target for cancer chemotherapy. We studied the action of an inhibitor of PFKFB3, 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO, as a single agent and in combination with other molecules that affect glycolysis. Materials and methods: Effects on growth were studied in four human colon cancer cell lines. Glucose metabolism was monitored by uptake from the incubation medium and lactic acid production was judged by acidification of the medium. Induction of alkaline phosphatase served as a marker of differentiation. Results: Growth of colon cancer cells was inhibited by 3PO and butyrate but only butyrate induced activation of alkaline phosphatase. Although metformin and phenformin can increase glucose metabolism, they inhibit colon cancer cell growth and can exert additive inhibitory effects in combination with 3PO. Additive growth inhibitory effects with 3PO were also observed with two compounds that inhibit glycolysis: 2-deoxyglucose and 3-bromopyruvate. Conclusion: 3PO was an inhibitor of growth of colon cancer cells and may be a useful agent in combination with other drugs that inhibit colon cancer cell proliferation.

  10. Proliferation in cycle

    Energy Technology Data Exchange (ETDEWEB)

    Piao Yunsong [College of Physical Sciences, Graduate School of Chinese Academy of Sciences, Beijing 100049 (China)], E-mail: yspiao@gucas.ac.cn

    2009-06-15

    In the contracting phase with w{approx_equal}0, the scale invariant spectrum of curvature perturbation is given by the increasing mode of metric perturbation. In this Letter, it is found that if the contracting phase with w{approx_equal}0 is included in each cycle of a cycle universe, since the metric perturbation is amplified on super horizon scale cycle by cycle, after each cycle the universe will be inevitably separated into many parts independent of one another, each of which corresponds to a new universe and evolves up to next cycle, and then is separated again. In this sense, a cyclic multiverse scenario is actually presented, in which the universe proliferates cycle by cycle. We estimate the number of new universes proliferated in each cycle, and discuss the implications of this result.

  11. Proliferation in cycle

    International Nuclear Information System (INIS)

    Piao Yunsong

    2009-01-01

    In the contracting phase with w≅0, the scale invariant spectrum of curvature perturbation is given by the increasing mode of metric perturbation. In this Letter, it is found that if the contracting phase with w≅0 is included in each cycle of a cycle universe, since the metric perturbation is amplified on super horizon scale cycle by cycle, after each cycle the universe will be inevitably separated into many parts independent of one another, each of which corresponds to a new universe and evolves up to next cycle, and then is separated again. In this sense, a cyclic multiverse scenario is actually presented, in which the universe proliferates cycle by cycle. We estimate the number of new universes proliferated in each cycle, and discuss the implications of this result.

  12. Updates to a 13C metabolic flux analysis model for evaluating energy metabolism in cultured cerebellar granule neurons from neonatal rats.

    Science.gov (United States)

    Jekabsons, Mika B; Gebril, Hoda M; Wang, Yan-Hong; Avula, Bharathi; Khan, Ikhlas A

    2017-10-01

    A hexose phosphate recycling model previously developed to infer fluxes through the major glucose consuming pathways in cultured cerebellar granule neurons (CGNs) from neonatal rats metabolizing [1,2- 13 C 2 ]glucose was revised by considering reverse flux through the non-oxidative pentose phosphate pathway (PPP) and symmetrical succinate oxidation within the tricarboxylic acid (TCA) cycle. The model adjusts three flux ratios to effect 13 C distribution in the hexose, pentose, and triose phosphate pools, and in TCA cycle malate to minimize the error between predicted and measured 13 C labeling in exported lactate (i.e., unlabeled, single-, double-, and triple-labeled; M, M1, M2, and M3, respectively). Inclusion of reverse non-oxidative PPP flux substantially increased the number of calculations but ultimately had relatively minor effects on the labeling of glycolytic metabolites. From the error-minimized solution in which the predicted M-M3 lactate differed by 0.49% from that measured by liquid chromatography-triple quadrupole mass spectrometry, the neurons exhibited negligible forward non-oxidative PPP flux. Thus, no glucose was used by the pentose cycle despite explicit consideration of hexose phosphate recycling. Mitochondria consumed only 16% of glucose while 45% was exported as lactate by aerobic glycolysis. The remaining 39% of glucose was shunted to pentose phosphates presumably for de novo nucleotide synthesis, but the proportion metabolized through the oxidative PPP vs. the reverse non-oxidative PPP could not be determined. The lactate exported as M1 (2.5%) and M3 (1.2%) was attributed to malic enzyme, which was responsible for 7.8% of pyruvate production (vs. 92.2% by glycolysis). The updated model is more broadly applicable to different cell types by considering bi-directional flux through the non-oxidative PPP. Its application to cultured neurons utilizing glucose as the sole exogenous substrate has demonstrated substantial oxygen-independent glucose

  13. Cycling in Sydney, Australia

    Directory of Open Access Journals (Sweden)

    Alexis Zander

    2013-01-01

    Full Text Available Introduction. Cycling can be an enjoyable way to meet physical activity recommendations and is suitable for older people; however cycling participation by older Australians is low. This qualitative study explored motivators, enablers, and barriers to cycling among older people through an age-targeted cycling promotion program. Methods. Seventeen adults who aged 50–75 years participated in a 12-week cycling promotion program which included a cycling skills course, mentor, and resource pack. Semistructured interviews at the beginning and end of the program explored motivators, enablers, and barriers to cycling. Results. Fitness and recreation were the primary motivators for cycling. The biggest barrier was fear of cars and traffic, and the cycling skills course was the most important enabler for improving participants’ confidence. Reported outcomes from cycling included improved quality of life (better mental health, social benefit, and empowerment and improved physical health. Conclusions. A simple cycling program increased cycling participation among older people. This work confirms the importance of improving confidence in this age group through a skills course, mentors, and maps and highlights additional strategies for promoting cycling, such as ongoing improvement to infrastructure and advertising.

  14. The action of piracetam on 14C-glucose metabolism in normal and posthypoxic rat cerebral cortex slices

    International Nuclear Information System (INIS)

    Domanska-Janik, K.; Zaleska, M.

    1977-01-01

    The stimulating effect of piracetam on the respiration and glycolysis was observed in rat brain cortex slices incubated under oxygen atmosphere. After preincubation of the slices under pure nitrogen atmosphere, piracetam influenced also decarboxylation of the C 1 -glucose carbon, indicating stimulation of the pentose cycle. Any significant effect of piracetam on the lowered by anoxia incorporation of 14 C from U- 14 C-glucose into macromolecular fractions was not observed. The results have supported a protective effect of piracetam against oxygen deficiency, caused mainly by stimulation of metabolic glucose pathways, connected with energy production in CNS. (author)

  15. Life cycle assessment (LCA)

    DEFF Research Database (Denmark)

    Thrane, Mikkel; Schmidt, Jannick Andresen

    2004-01-01

    The chapter introduces Life Cycle Assessment (LCA) and its application according to the ISO 1404043 standards.......The chapter introduces Life Cycle Assessment (LCA) and its application according to the ISO 1404043 standards....

  16. Thorium fuel cycle management

    International Nuclear Information System (INIS)

    Zajac, R.; Darilek, P.; Breza, J.; Necas, V.

    2010-01-01

    In this presentation author deals with the thorium fuel cycle management. Description of the thorium fuels and thorium fuel cycle benefits and challenges as well as thorium fuel calculations performed by the computer code HELIOS are presented.

  17. Chords in longest cycles

    DEFF Research Database (Denmark)

    Thomassen, Carsten

    2017-01-01

    If a graph G is 3-connected and has minimum degree at least 4, then some longest cycle in G has a chord. If G is 2-connected and cubic, then every longest cycle in G has a chord.......If a graph G is 3-connected and has minimum degree at least 4, then some longest cycle in G has a chord. If G is 2-connected and cubic, then every longest cycle in G has a chord....

  18. Denatured fuel cycles

    International Nuclear Information System (INIS)

    Till, C.E.

    1979-01-01

    This paper traces the history of the denatured fuel concept and discusses the characteristics of fuel cycles based on the concept. The proliferation resistance of denatured fuel cycles, the reactor types they involve, and the limitations they place on energy generation potential are discussed. The paper concludes with some remarks on the outlook for such cycles

  19. Life Cycle Management

    DEFF Research Database (Denmark)

    Bey, Niki

    2018-01-01

    This chapter gives an overview of Life Cycle Management (LCM)—a discipline that deals with the managerial tasks related to practicing sustainable development in an organisation . Just as Life Cycle Assessment, LCM advocates the life cycle perspective , and it applies this perspective in decision...

  20. Termination of cycle rewriting

    NARCIS (Netherlands)

    Zantema, H.; König, B.; Bruggink, H.J.S.; Dowek, G.

    2014-01-01

    String rewriting can not only be applied on strings, but also on cycles and even on general graphs. In this paper we investigate termination of string rewriting applied on cycles, shortly denoted as cycle rewriting, which is a strictly stronger requirement than termination on strings. Most

  1. Gaseous environment of plants and activity of enzymes of carbohydrate catabolism

    International Nuclear Information System (INIS)

    Ivanov, B.F.; Zemlyanukhin, A.A.; Igamberdiev, A.U.; Salam, A.M.M.

    1989-01-01

    The authors investigated the action of hypoxia and high CO 2 concentration in the atmosphere on activity of phosphofructokinase, aldolase, glucose phosphate isomerase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, alcohol dehydrogenase, and isocitrate lyase in pea seedlings (Pisum sativum L.), corn scutella (Zea mays L.), and hemp cotyledons (Cannabis sativa L.). The first 4-12h of hypoxia witnessed suppression of enzymes of the initial stages of glycolysis (glucose-6-phosphate isomerase, phosphofructokinase)and activation of enzymes of its final stages (alcohol dehydrogenase and lactate dehydrogenase) and enzymes linking glycolysis and the pentose phosphate pathway (aldolase and glucose-6-phosphate dehydrogenase). An excess of CO 2 in the environment accelerated and amplified this effect. At the end of a 24-h period of anaerobic incubation, deviations of enzyme activity from the control were leveled in both gaseous environments. An exception was observed in the case of phosphofructokinase, whose activity increased markedly at this time in plants exposed to CO 2 . Changes in activity of the enzymes were coupled with changes in their kinetic parameters (apparent K m and V max values). The activity of isocitrate lyase was suppressed in both variants of hypoxic gaseous environments, a finding that does not agree with the hypothesis as to participation of the glyoxylate cycle in the metabolic response of plants to oxygen stress. Thus, temporary inhibition of the system of glycolysis and activation of the pentose phosphate pathway constituted the initial response of the plants to O 2 stress, and CO 2 intensified this metabolic response

  2. Inhibition of intestinal disaccharidase activity by pentoses

    DEFF Research Database (Denmark)

    Halschou-Jensen, Kia

    on carbohydrate- ingesting enzymes activity in vitro and possible effects on human postprandial blood response. In paper 1 the effects of sugar beet polyphenols from molasses and the potential inhibition of sucrase activity in vitro, was investigated. Two different polyphenol-rich fractions from chromatographic...... separation of molasses from sugar beets and pure ferulic acid were tested. We found no effects of the two fractions of molasses. The pure ferulic acid indicated an inhibition of sucrase in vitr. Both in vitro and in vivo studies have investigated the effects of L-arabinose and D-xylose on carbohydrate...

  3. Biobutanol Production from Hexose and Pentose Sugars

    NARCIS (Netherlands)

    Raganati, F.; Procentese, A.; Olivieri, G.; Salatino, P.; Marzocchella, A.

    2014-01-01

    The Acetone-Butanol-Ethanol (ABE) fermentation is receiving renewed interest as a way to upgrade renewable resources for the production of products with high added value as chemicals and fuels. Main pre-requisites of fermentation feedstocks are abundance and un-competitiveness with food sources and

  4. Marine nitrogen cycle

    Digital Repository Service at National Institute of Oceanography (India)

    Naqvi, S.W.A.

    ) such as the Marine nitrogen cycle The marine nitrogen cycle. ‘X’ and ‘Y’ are intra-cellular intermediates that do not accumulate in water column. (Source: Codispoti et al., 2001) Page 1 of 3Marine nitrogen cycle - Encyclopedia of Earth 11/20/2006http://www... and nitrous oxide budgets: Moving targets as we enter the anthropocene?, Sci. Mar., 65, 85-105, 2001. Page 2 of 3Marine nitrogen cycle - Encyclopedia of Earth 11/20/2006http://www.eoearth.org/article/Marine_nitrogen_cycle square6 Gruber, N.: The dynamics...

  5. Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle.

    Science.gov (United States)

    Sato, Masakazu; Kawana, Kei; Adachi, Katsuyuki; Fujimoto, Asaha; Yoshida, Mitsuyo; Nakamura, Hiroe; Nishida, Haruka; Inoue, Tomoko; Taguchi, Ayumi; Takahashi, Juri; Eguchi, Satoko; Yamashita, Aki; Tomio, Kensuke; Wada-Hiraike, Osamu; Oda, Katsutoshi; Nagamatsu, Takeshi; Osuga, Yutaka; Fujii, Tomoyuki

    2016-05-31

    The Warburg effect is a metabolic hallmark of cancer cells; cancer cells, unlike normal cells, exclusively activate glycolysis, even in the presence of enough oxygen. On the other hand, intratumoral heterogeneity is currently of interest in cancer research, including that involving cancer stem cells (CSCs). In the present study, we attempted to gain an understanding of metabolism in CSCs that is distinct from that in non-CSCs. After forming spheroids from the OVTOKO (ovarian clear cell adenocarcinoma) and SiHa (cervical squamous cell carcinoma) cell lines, the metabolites of these cells were compared with the metabolites of cancer cells that were cultured in adherent plates. A principle components analysis clearly divided their metabolic features. Amino acids that participate in tricarboxylic acid (TCA) cycle reactions, such as serine and glutamine, were significantly increased in the spheroids. Indeed, spheroids from each cell line contained more total adenylates than did their corresponding cells in adherent cultures. This study demonstrated that cancer metabolism is not limited to aerobic glycolysis (i.e. the Warburg effect), but is flexible and context-dependent. In addition, activation of TCA cycles was suggested to be a metabolic feature of CSCs that was distinct from non-CSCs. The amino acid metabolic pathways discussed here are already considered as targets for cancer therapy, and they are additionally proposed as potential targets for CSC treatment.

  6. The Krebs Uric Acid Cycle: A Forgotten Krebs Cycle.

    Science.gov (United States)

    Salway, Jack G

    2018-05-25

    Hans Kornberg wrote a paper entitled 'Krebs and his trinity of cycles' commenting that every school biology student knows of the Krebs cycle, but few know that Krebs discovered two other cycles. These are (i) the ornithine cycle (urea cycle), (ii) the citric acid cycle (tricarboxylic acid or TCA cycle), and (iii) the glyoxylate cycle that was described by Krebs and Kornberg. Ironically, Kornberg, codiscoverer of the 'glyoxylate cycle', overlooked a fourth Krebs cycle - (iv) the uric acid cycle. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Prognostic value of total lesion glycolysis on preoperative {sup 18}F-FDG PET/CT in patients with uterine carcinosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jeong-Won [Sungkyunkwan University School of Medicine, Department of Obstetrics and Gynecology, Seoul (Korea, Republic of); Sungkyunkwan University School of Medicine, Samsung Advanced Institute for Health Sciences and Technology, Seoul (Korea, Republic of); Heo, Eun Jin [Sungkyunkwan University School of Medicine, Department of Obstetrics and Gynecology, Seoul (Korea, Republic of); Moon, Seung Hwan [Sungkyunkwan University School of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Lee, Hyunjong; Cheon, Gi Jeong [Seoul National University College of Medicine, Department of Nuclear Medicine, Seoul (Korea, Republic of); Lee, Maria; Kim, Hee Seung; Chung, Hyun Hoon [Seoul National University College of Medicine, Department of Obstetrics and Gynecology, Cancer Research Institute, Seoul (Korea, Republic of)

    2016-11-15

    To investigate the relationship between functional tumour parameters measured during preoperative {sup 18}F-FDG PET/CT and clinical outcomes in patients with uterine carcinosarcoma. For patients with pathologically proven uterine carcinosarcoma, we determined the maximal and average standardized uptake values, cumulative total lesion glycolysis (TLG) and sum of all metabolic tumour volumes (MTVs). Their predictive value for recurrence and the effects of pretreatment functional tumour activity on patient survival were compared. Clinicopathological data from 28 eligible patients were reviewed. The median duration of progression-free survival was 18.6 months (range 6.1-84.5 months), and 10 (35.7 %) patients experienced recurrences. Univariate analyses showed significant associations between recurrence and tumour size, lymph node metastasis, high TLG and MTV values, and ovarian invasion. Multivariate analysis identified high TLG value as an independent risk factor for recurrence (p = 0.048, hazard ratio 115.261, 95 % confidence interval 1.041-12,765.483). Kaplan-Meier survival curves showed that progression-free survival significantly differed in groups categorized according to TLG (p = 0.007, log-rank test). Preoperative TLG measured with {sup 18}F-FDG PET/CT was statistically significantly associated with uterine carcinosarcoma recurrence. Metabolic parameters can provide useful quantitative criteria for disease prognostication in patients with uterine carcinosarcoma before treatment. (orig.)

  8. Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis.

    Directory of Open Access Journals (Sweden)

    Xiwen Xiong

    Full Text Available Forkhead transcription factors FoxO1/3/4 have pleiotrophic functions including anti-oxidative stress and metabolism. With regard to glucose metabolism, most studies have been focused on FoxO1. To further investigate their hepatic functions, we generated liver-specific FoxO1/3/4 knockout mice (LTKO and examined their collective impacts on glucose homeostasis under physiological and pathological conditions. As compared to wild-type mice, LTKO mice had lower blood glucose levels under both fasting and non-fasting conditions and they manifested better glucose and pyruvate tolerance on regular chow diet. After challenged by a high-fat diet, wild-type mice developed type 2 diabetes, but LTKO mice remained euglycemic and insulin-sensitive. To understand the underlying mechanisms, we examined the roles of SIRT6 (Sirtuin 6 and Gck (glucokinase in the FoxO-mediated glucose metabolism. Interestingly, ectopic expression of SIRT6 in the liver only reduced gluconeogenesis in wild-type but not LTKO mice whereas knockdown of Gck caused glucose intolerance in both wild-type and LTKO mice. The data suggest that both decreased gluconeogenesis and increased glycolysis may contribute to the overall glucose phenotype in the LTKO mice. Collectively, FoxO1/3/4 transcription factors play important roles in hepatic glucose homeostasis.

  9. MicroRNA-129-5p Regulates Glycolysis and Cell Proliferation by Targeting the Glucose Transporter SLC2A3 in Gastric Cancer Cells

    Directory of Open Access Journals (Sweden)

    Di Chen

    2018-05-01

    Full Text Available Tumor cells increase their glucose consumption through aerobic glycolysis to manufacture the necessary biomass required for proliferation, commonly known as the Warburg effect. Accumulating evidences suggest that microRNAs (miRNAs interact with their target genes and contribute to metabolic reprogramming in cancer cells. By integrating high-throughput screening data and the existing miRNA expression datasets, we explored the roles of candidate glycometabolism-regulating miRNAs in gastric cancer (GC. Subsequent investigation of the characterized miRNAs indicated that miR-129-5p inhibits glucose metabolism in GC cells. miRNA-129-5p directly targets the 3′-UTR of SLC2A3, thereby suppressing glucose consumption, lactate production, cellular ATP levels, and glucose uptake of GC cells. In addition, the PI3K-Akt and MAPK signaling pathways are involved in the effects of the miR-129-5p/SLC2A3 axis, regulating GC glucose metabolism and growth. These results reveal a novel role of the miR-129-5p/SLC2A3 axis in reprogramming the glycometabolism process in GC cells and indicate a potential therapeutic target for the treatment of this disease.

  10. Osteoblast-like MC3T3-E1 Cells Prefer Glycolysis for ATP Production but Adipocyte-like 3T3-L1 Cells Prefer Oxidative Phosphorylation.

    Science.gov (United States)

    Guntur, Anyonya R; Gerencser, Akos A; Le, Phuong T; DeMambro, Victoria E; Bornstein, Sheila A; Mookerjee, Shona A; Maridas, David E; Clemmons, David E; Brand, Martin D; Rosen, Clifford J

    2018-06-01

    Mesenchymal stromal cells (MSCs) are early progenitors that can differentiate into osteoblasts, chondrocytes, and adipocytes. We hypothesized that osteoblasts and adipocytes utilize distinct bioenergetic pathways during MSC differentiation. To test this hypothesis, we compared the bioenergetic profiles of preosteoblast MC3T3-E1 cells and calvarial osteoblasts with preadipocyte 3T3L1 cells, before and after differentiation. Differentiated MC3T3-E1 osteoblasts met adenosine triphosphate (ATP) demand mainly by glycolysis with minimal reserve glycolytic capacity, whereas nondifferentiated cells generated ATP through oxidative phosphorylation. A marked Crabtree effect (acute suppression of respiration by addition of glucose, observed in both MC3T3-E1 and calvarial osteoblasts) and smaller mitochondrial membrane potential in the differentiated osteoblasts, particularly those incubated at high glucose concentrations, indicated a suppression of oxidative phosphorylation compared with nondifferentiated osteoblasts. In contrast, both nondifferentiated and differentiated 3T3-L1 adipocytes met ATP demand primarily by oxidative phosphorylation despite a large unused reserve glycolytic capacity. In sum, we show that nondifferentiated precursor cells prefer to use oxidative phosphorylation to generate ATP; when they differentiate to osteoblasts, they gain a strong preference for glycolytic ATP generation, but when they differentiate to adipocytes, they retain the strong preference for oxidative phosphorylation. Unique metabolic programming in mesenchymal progenitor cells may influence cell fate and ultimately determine the degree of bone formation and/or the development of marrow adiposity. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research.

  11. Driving and engine cycles

    CERN Document Server

    Giakoumis, Evangelos G

    2017-01-01

    This book presents in detail the most important driving and engine cycles used for the certification and testing of new vehicles and engines around the world. It covers chassis and engine-dynamometer cycles for passenger cars, light-duty vans, heavy-duty engines, non-road engines and motorcycles, offering detailed historical information and critical review. The book also provides detailed examples from SI and diesel engines and vehicles operating during various cycles, with a focus on how the engine behaves during transients and how this is reflected in emitted pollutants, CO2 and after-treatment systems operation. It describes the measurement methods for the testing of new vehicles and essential information on the procedure for creating a driving cycle. Lastly, it presents detailed technical specifications on the most important chassis-dynamometer cycles around the world, together with a direct comparison of those cycles.

  12. International Business Cycle

    OpenAIRE

    Marek Lubiński

    2007-01-01

    Prime stylized facts of international business cycle theory refer to positive correlation in the cyclical components of important macroeconomic variables across countries. However a number of indicators of business cycle synchronization do not point to clear trends. It can be ascribed to the fact that different forces influence level of business cycle correlation. When investigating into the forces behind the commonness in aggregate fluctuations economic research seems to have pointed in two ...

  13. Fast breeder fuel cycle

    International Nuclear Information System (INIS)

    1978-09-01

    Basic elements of the ex-reactor part of the fuel cycle (reprocessing, fabrication, waste handling and transportation) are described. Possible technical and proliferation measures are evaluated, including current methods of accountability, surveillance and protection. The reference oxide based cycle and advanced cycles based on carbide and metallic fuels are considered utilizing conventional processes; advanced nonaqueous reprocessing is also considered. This contribution provides a comprehensive data base for evaluation of proliferation risks

  14. [Cycling in Zagreb].

    Science.gov (United States)

    Matos, Stipan; Krapac, Ladislav; Krapac, Josip

    2007-01-01

    Cycling in Zagreb, as means of urban transport inside and outside the city, has a bright past, hazy presence but a promising future. Every day, aggressive citizens who lack urban traffic culture mistreat many cyclists but also many pedestrians. Sedentary way of living, unhealthy eating habits and inadequate recreation would surely be reduced if Zagreb had a network of cycling tracks (190 cm) or lanes (80 cm). Main city roads were constructed at the beginning of the 20th century. Today, the lack of cycling tracks is particularly evident in terms of missing connections between northern and southern parts of the city. Transportation of bikes in public vehicles, parking of bikes as well as cycling along the foot of the mountains Medvednica and Zumberacko gorje is not adequately organized. Better organization is necessary not only because of the present young generation but also because of the young who will shortly become citizens of the EU, where cycling is enormously popular. Cycling tourism is not known in Zagreb, partly due to inadequate roads. The surroundings of Zagreb are more suitable for cycling tourism and attractive brochures and tourist guides offer information to tourists on bikes. Professional, acrobatic and sports cycling do not have a tradition in Zagreb and in Croatia. The same holds true for recreational cycling and indoor exercise cycling. The authors discuss the impact of popularization of cycling using print and electronic media. The role of district and local self-government in the construction and improvement of traffic roads in Zagreb is very important. It is also significant for the implementation of legal regulations that must be obeyed by all traffic participants in order to protect cyclists, the most vulnerable group of traffic participants besides passengers. Multidisciplinary action of all benevolent experts would surely increase safety and pleasure of cycling in the city and its surroundings. This would also help reduce daily stress and

  15. Measuring Business Cycle Time.

    OpenAIRE

    Stock, James H

    1987-01-01

    The business cycle analysis of Arthur F. Burns and Wesley C. Mitchell and the National Bureau of Economic Research presumed that aggregate economic variables evolve on a time scale defined by business cycle turning points rather than by months or quarters. Do macroeconomic variables appear to evolve on an economic rather than a calendar time scale? Evidence presented here suggests that they do. However, the estimated economic time scales are only weakly related to business cycle time scales, ...

  16. Thorium cycles and proliferation

    International Nuclear Information System (INIS)

    Lovins, A.B.

    1979-01-01

    This paper analyzes several prevalent misconceptions about nuclear fuel cycles that breed fissile uranium-233 from thorium. Its main conclusions are: U-233, despite the gamma radioactivity of associated isotopes, is a rather attractive material for making fission bombs, and is a credible material for subnational as well as national groups to use for this purpose; (2) pure thorium cycles, which in effect merely substitute U-233 for Pu, would take many decades and much U to establish, and offer no significant safeguards advantage over Pu, cycles; (3) denatured Th-U cycles, which dilute the U-233 with inert U-238 to a level not directly usable in bombs, are not an effective safeguard even against subnational bomb-making; (4) several other features of mixed Th-U cycles are rather unattractive from a safeguards point of view; (5) thus, Th cycles of any kind are not a technical fix for proliferation (national or subnational) and, though probably more safeguardable than Pu cycles, are less so than once-through U cycles that entail no reprocessing; (6) while thorium cycles have some potential technical advantages, including flexibility, they cannot provide major savings in nuclear fuel resources compared to simpler ways of saving neutrons and U; and (7) while advocates of nuclear power may find Th cycles worth exploring, such cycles do not differ fundamentally from U cycles in any of the respects--including safeguards and fuel resources--that are relevant to the broader nuclear debate, and should not be euphorically embraced as if they did

  17. Alternative fuel cycles

    International Nuclear Information System (INIS)

    Penn, W.J.

    1979-05-01

    Uranium resource utilization and economic considerations provide incentives to study alternative fuel cycles as future options to the PHWR natural uranium cycle. Preliminary studies to define the most favourable alternatives and their possible introduction dates are discussed. The important and uncertain components which influence option selection are reviewed, including nuclear capacity growth, uranium availability and demand, economic potential, and required technological developments. Finally, a summary of Ontario Hydro's program to further assess cycle selection and define development needs is given. (auth)

  18. Edgeworth cycles revisited

    International Nuclear Information System (INIS)

    Doyle, Joseph; Muehlegger, Erich; Samphantharak, Krislert

    2010-01-01

    Some gasoline markets exhibit remarkable price cycles, where price spikes are followed by a series of small price declines: a pattern consistent with a model of Edgeworth cycles described by Maskin and Tirole. We extend the model and empirically test its predictions with a new dataset of daily station-level prices in 115 US cities. Consistent with the theory, and often in contrast with previous empirical work, we find the least and most concentrated markets are much less likely to exhibit cycling behavior both within and across cities; areas with more independent convenience-store gas stations are also more likely to cycle. (author)

  19. Metabolic Cooperation of Glucose and Glutamine Is Essential for the Lytic Cycle of Obligate Intracellular Parasite Toxoplasma gondii.

    Science.gov (United States)

    Nitzsche, Richard; Zagoriy, Vyacheslav; Lucius, Richard; Gupta, Nishith

    2016-01-01

    Toxoplasma gondii is a widespread protozoan parasite infecting nearly all warm-blooded organisms. Asexual reproduction of the parasite within its host cells is achieved by consecutive lytic cycles, which necessitates biogenesis of significant energy and biomass. Here we show that glucose and glutamine are the two major physiologically important nutrients used for the synthesis of macromolecules (ATP, nucleic acid, proteins, and lipids) in T. gondii, and either of them is sufficient to ensure the parasite survival. The parasite can counteract genetic ablation of its glucose transporter by increasing the flux of glutamine-derived carbon through the tricarboxylic acid cycle and by concurrently activating gluconeogenesis, which guarantee a continued biogenesis of ATP and biomass for host-cell invasion and parasite replication, respectively. In accord, a pharmacological inhibition of glutaminolysis or oxidative phosphorylation arrests the lytic cycle of the glycolysis-deficient mutant, which is primarily a consequence of impaired invasion due to depletion of ATP. Unexpectedly, however, intracellular parasites continue to proliferate, albeit slower, notwithstanding a simultaneous deprivation of glucose and glutamine. A growth defect in the glycolysis-impaired mutant is caused by a compromised synthesis of lipids, which cannot be counterbalanced by glutamine but can be restored by acetate. Consistently, supplementation of parasite cultures with exogenous acetate can amend the lytic cycle of the glucose transport mutant. Such plasticity in the parasite's carbon flux enables a growth-and-survival trade-off in assorted nutrient milieus, which may underlie the promiscuous survival of T. gondii tachyzoites in diverse host cells. Our results also indicate a convergence of parasite metabolism with cancer cells. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Metabolic Cooperation of Glucose and Glutamine Is Essential for the Lytic Cycle of Obligate Intracellular Parasite Toxoplasma gondii*

    Science.gov (United States)

    Nitzsche, Richard; Zagoriy, Vyacheslav; Lucius, Richard; Gupta, Nishith

    2016-01-01

    Toxoplasma gondii is a widespread protozoan parasite infecting nearly all warm-blooded organisms. Asexual reproduction of the parasite within its host cells is achieved by consecutive lytic cycles, which necessitates biogenesis of significant energy and biomass. Here we show that glucose and glutamine are the two major physiologically important nutrients used for the synthesis of macromolecules (ATP, nucleic acid, proteins, and lipids) in T. gondii, and either of them is sufficient to ensure the parasite survival. The parasite can counteract genetic ablation of its glucose transporter by increasing the flux of glutamine-derived carbon through the tricarboxylic acid cycle and by concurrently activating gluconeogenesis, which guarantee a continued biogenesis of ATP and biomass for host-cell invasion and parasite replication, respectively. In accord, a pharmacological inhibition of glutaminolysis or oxidative phosphorylation arrests the lytic cycle of the glycolysis-deficient mutant, which is primarily a consequence of impaired invasion due to depletion of ATP. Unexpectedly, however, intracellular parasites continue to proliferate, albeit slower, notwithstanding a simultaneous deprivation of glucose and glutamine. A growth defect in the glycolysis-impaired mutant is caused by a compromised synthesis of lipids, which cannot be counterbalanced by glutamine but can be restored by acetate. Consistently, supplementation of parasite cultures with exogenous acetate can amend the lytic cycle of the glucose transport mutant. Such plasticity in the parasite's carbon flux enables a growth-and-survival trade-off in assorted nutrient milieus, which may underlie the promiscuous survival of T. gondii tachyzoites in diverse host cells. Our results also indicate a convergence of parasite metabolism with cancer cells. PMID:26518878

  1. Life cycle management (LCM)

    DEFF Research Database (Denmark)

    Remmen, Arne; Thrane, Mikkel

    2004-01-01

    The chapter gives an introduction to Life Cycle Management (LCM) and shows how LCM can be practiced in different contexts and at different ambition levels.......The chapter gives an introduction to Life Cycle Management (LCM) and shows how LCM can be practiced in different contexts and at different ambition levels....

  2. Nutrient cycling strategies.

    NARCIS (Netherlands)

    Breemen, van N.

    1995-01-01

    This paper briefly reviews pathways by which plants can influence the nutrient cycle, and thereby the nutrient supply of themselves and of their competitors. Higher or lower internal nutrient use efficiency positively feeds back into the nutrient cycle, and helps to increase or decrease soil

  3. Life Cycle Impact Assessment

    DEFF Research Database (Denmark)

    Rosenbaum, Ralph K.; Hauschild, Michael Zwicky; Boulay, Anne-Marie

    2018-01-01

    This chapter is dedicated to the third phase of an LCA study, the Life Cycle Impact Assessment (LCIA) where the life cycle inventory’s information on elementary flows is translated into environmental impact scores. In contrast to the three other LCA phases, LCIA is in practice largely automated...

  4. Rock Cycle Roulette.

    Science.gov (United States)

    Schmidt, Stan M.; Palmer, Courtney

    2000-01-01

    Introduces an activity on the rock cycle. Sets 11 stages representing the transitions of an earth material in the rock cycle. Builds six-sided die for each station, and students move to the stations depending on the rolling side of the die. Evaluates students by discussing several questions in the classroom. Provides instructional information for…

  5. Universal cycle periods

    NARCIS (Netherlands)

    Groot, de E.A. (Bert); Franses, P.H.P.H.

    2009-01-01

    We present a meta-analysis of cycles in historical economic data. The literature on stochastic and deterministic cycles in variables such as the consumer price index, employment, interest rates, commodity prices, and GDP is huge and scattered, but our meta-analysis reveals various communalities. Our

  6. Stability through cycles

    NARCIS (Netherlands)

    E.A. de Groot (Bert); Ph.H.B.F. Franses (Philip Hans)

    2006-01-01

    textabstractEconomic variables like GDP growth, employment, interest rates and consumption show signs of cyclical behavior. Many variables display multiple cycles, with lengths ranging in between 5 to even up to 100 years. We argue that multiple cycles can be associated with long-run stability of

  7. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-09-08

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

  8. Regulation of the yeast metabolic cycle by transcription factors with periodic activities

    Directory of Open Access Journals (Sweden)

    Pellegrini Matteo

    2011-10-01

    Full Text Available Abstract Background When growing budding yeast under continuous, nutrient-limited conditions, over half of yeast genes exhibit periodic expression patterns. Periodicity can also be observed in respiration, in the timing of cell division, as well as in various metabolite levels. Knowing the transcription factors involved in the yeast metabolic cycle is helpful for determining the cascade of regulatory events that cause these patterns. Results Transcription factor activities were estimated by linear regression using time series and genome-wide transcription factor binding data. Time-translation matrices were estimated using least squares and were used to model the interactions between the most significant transcription factors. The top transcription factors have functions involving respiration, cell cycle events, amino acid metabolism and glycolysis. Key regulators of transitions between phases of the yeast metabolic cycle appear to be Hap1, Hap4, Gcn4, Msn4, Swi6 and Adr1. Conclusions Analysis of the phases at which transcription factor activities peak supports previous findings suggesting that the various cellular functions occur during specific phases of the yeast metabolic cycle.

  9. Identification of MicroRNA-124 as a Major Regulator of Enhanced Endothelial Cell Glycolysis in Pulmonary Arterial Hypertension via PTBP1 (Polypyrimidine Tract Binding Protein) and Pyruvate Kinase M2.

    Science.gov (United States)

    Caruso, Paola; Dunmore, Benjamin J; Schlosser, Kenny; Schoors, Sandra; Dos Santos, Claudia; Perez-Iratxeta, Carol; Lavoie, Jessie R; Zhang, Hui; Long, Lu; Flockton, Amanda R; Frid, Maria G; Upton, Paul D; D'Alessandro, Angelo; Hadinnapola, Charaka; Kiskin, Fedir N; Taha, Mohamad; Hurst, Liam A; Ormiston, Mark L; Hata, Akiko; Stenmark, Kurt R; Carmeliet, Peter; Stewart, Duncan J; Morrell, Nicholas W

    2017-12-19

    Pulmonary arterial hypertension (PAH) is characterized by abnormal growth and enhanced glycolysis of pulmonary artery endothelial cells. However, the mechanisms underlying alterations in energy production have not been identified. Here, we examined the miRNA and proteomic profiles of blood outgrowth endothelial cells (BOECs) from patients with heritable PAH caused by mutations in the bone morphogenetic protein receptor type 2 ( BMPR2 ) gene and patients with idiopathic PAH to determine mechanisms underlying abnormal endothelial glycolysis. We hypothesized that in BOECs from patients with PAH, the downregulation of microRNA-124 (miR-124), determined with a tiered systems biology approach, is responsible for increased expression of the splicing factor PTBP1 (polypyrimidine tract binding protein), resulting in alternative splicing of pyruvate kinase muscle isoforms 1 and 2 (PKM1 and 2) and consequently increased PKM2 expression. We questioned whether this alternative regulation plays a critical role in the hyperglycolytic phenotype of PAH endothelial cells. Heritable PAH and idiopathic PAH BOECs recapitulated the metabolic abnormalities observed in pulmonary artery endothelial cells from patients with idiopathic PAH, confirming a switch from oxidative phosphorylation to aerobic glycolysis. Overexpression of miR-124 or siRNA silencing of PTPB1 restored normal proliferation and glycolysis in heritable PAH BOECs, corrected the dysregulation of glycolytic genes and lactate production, and partially restored mitochondrial respiration. BMPR2 knockdown in control BOECs reduced the expression of miR-124, increased PTPB1 , and enhanced glycolysis. Moreover, we observed reduced miR-124, increased PTPB1 and PKM2 expression, and significant dysregulation of glycolytic genes in the rat SUGEN-hypoxia model of severe PAH, characterized by reduced BMPR2 expression and endothelial hyperproliferation, supporting the relevance of this mechanism in vivo. Pulmonary vascular and

  10. Prognostic value of metabolic tumour volume and total lesion glycolysis in 18F-FDG PET/CT scans in locally advanced breast cancer staging.

    Science.gov (United States)

    Jiménez-Ballvé, A; García García-Esquinas, M; Salsidua-Arroyo, O; Serrano-Palacio, A; García-Sáenz, J A; Ortega Candil, A; Fuentes Ferrer, M E; Rodríguez Rey, C; Román-Santamaría, J M; Moreno, F; Carreras-Delgado, J L

    To determine whether metabolic tumour volume (MTV) and total lesion glycolysis (TLG) are able to predict recurrence risk in locally advanced breast cancer (LABC) patients. Retrospective study of LABC patients who undertook neoadjuvant, local and adjuvant treatment and follow up. A 18 F-FDG PET/CT study for initial staging was performed analysing in this study different metabolic parameters (MTV, TLG, SUVmax and SUVmed) both in the primary tumour (T) as well as in axillary nodes (N) and whole-body (WB). Forty females were included between January 2010-2011; follow up until January 2015 was completed. The average follow-up was 46 months. Twenty percent presented recurrence: local disease (n=2) and distant metastasis (n=6); 3 patients died (38% of the patients which recurred and 7.5% from the total). SUVmax, MTV and TLG, in T, N and WB, were higher in those patients with recurrence. The MTV and TLG parameters in the tumour (T) were related to the recurrence rate (P=.020 and P=.028, respectively); whereas SUVmax in the lymph nodes (N) was significantly related (P=.008) to the recurrence rate. The best cut-off points to predict recurrence where: MTV T ≥19.3cm 3 , TLG T≥74.4g and SUVmax N≥13.8, being 10-12 times more likely to recidivate when these thresholds where exceeded. Tumour grade was the only clinical-pathological variable which was related to recurrence probability (p=.035). In this study of LABC patients the metabolic parameters which have a better relationship with recurrence rate are: MTV and TLG in the primary tumour, SUVmax in the regional lymph node disease and whole-body PET data. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  11. A "footprint" of plant carbon fixation cycle functions during the development of a heterotrophic fungus.

    Science.gov (United States)

    Lyu, Xueliang; Shen, Cuicui; Xie, Jiatao; Fu, Yanping; Jiang, Daohong; Hu, Zijin; Tang, Lihua; Tang, Liguang; Ding, Feng; Li, Kunfei; Wu, Song; Hu, Yanping; Luo, Lilian; Li, Yuanhao; Wang, Qihua; Li, Guoqing; Cheng, Jiasen

    2015-08-11

    Carbon fixation pathway of plants (CFPP) in photosynthesis converts solar energy to biomass, bio-products and biofuel. Intriguingly, a large number of heterotrophic fungi also possess enzymes functionally associated with CFPP, raising the questions about their roles in fungal development and in evolution. Here, we report on the presence of 17 CFPP associated enzymes (ten in Calvin-Benson-Basham reductive pentose phosphate pathway and seven in C4-dicarboxylic acid cycle) in the genome of Sclerotinia sclerotiorum, a heterotrophic phytopathogenic fungus, and only two unique enzymes: ribulose-1, 5-bisphosphate carboxylase-oxygenase (Rubisco) and phosphoribulokinase (PRK) were absent. This data suggested an incomplete CFPP-like pathway (CLP) in fungi. Functional profile analysis demonstrated that the activity of the incomplete CLP was dramatically regulated during different developmental stages of S. sclerotiorum. Subsequent experiments confirmed that many of them were essential to the virulence and/or sclerotial formation. Most of the CLP associated genes are conserved in fungi. Phylogenetic analysis showed that many of them have undergone gene duplication, gene acquisition or loss and functional diversification in evolutionary history. These findings showed an evolutionary links in the carbon fixation processes of autotrophs and heterotrophs and implicated the functions of related genes were in course of continuous change in different organisms in evolution.

  12. Two Quantum Polytropic Cycles

    Science.gov (United States)

    Arias-Hernández, L. A.; Morales-Serrano, A. F.

    2002-11-01

    In this work we follow the Bender et al paper [1] to study the quantum analogues of the Stirling and Ericsson polytropic cycles. In the context of the classical thermodynamics, the Stirling and Ericsson cycles correspond to reversible heat engines with two isothermal processes joined by two polytropic branches which occur in a device called regenerator. If this device is an ideal one, the efficiency of these cycles is the Carnot efficiency. Here, we introduce the quantum analogues of the Stirling and Ericsson cycles, the first one based on a double square potential well with a finite potential barrier, since in this system the tunnel effect could be the analogue to the regeneration classical process, therefore the isochoric quantum branches would really correspond to an internal energy storage, and the last one with an unknown system where the isobaric quantum processes don't induce changes in its quantum state. With these systems the quantum engines have cycles consisting of polytropic and isothermal quantum processes analogues to the corresponding classical processes. We show that in both cases the quantum cycles have an efficiency given by ηCQM = 1 - EC/EH, which is the same expression for the quantum analogue of the Carnot cycle studied by Bender.

  13. Fuel cycle management

    International Nuclear Information System (INIS)

    Herbin, H.C.

    1977-01-01

    The fuel cycle management is more and more dependent on the management of the generation means among the power plants tied to the grid. This is due mainly because of the importance taken by the nuclear power plants within the power system. The main task of the fuel cycle management is to define the refuelling pattern of the new and irradiated fuel assemblies to load in the core as a function of: 1) the differences which exist between the actual conditions of the core and what was expected for the present cycle, 2) the operating constraints and the reactor availability, 3) the technical requirements in safety and the technological limits of the fuel, 4) the economics. Three levels of fuel cycle management can be considered: 1) a long term management: determination of enrichments and expected cycle lengths, 2) a mid term management whose aim corresponds to the evaluation of the batch to load within the core as a function of both: the next cycle length to achieve and the integrated power history of all the cycles up to the present one, 3) a short term management which deals with the updating of the loaded fuel utilisations to take into account the operation perturbations, or with the alteration of the loading pattern of the next batch to respect unexpected conditions. (orig.) [de

  14. On approximating restricted cycle covers

    NARCIS (Netherlands)

    Manthey, Bodo

    2008-01-01

    A cycle cover of a graph is a set of cycles such that every vertex is part of exactly one cycle. An $L$-cycle cover is a cycle cover in which the length of every cycle is in the set $L$. The weight of a cycle cover of an edge-weighted graph is the sum of the weights of its edges. We come close to

  15. Future fuel cycles

    International Nuclear Information System (INIS)

    Archinoff, G.H.

    1980-01-01

    A fuel cycle must offer both financial and resource savings if it is to be considered for introduction into Ontario's nuclear system. The most promising alternative CANDU fuel cycles are examined in the context of both of these factors over a wide range of installed capacity growth rates and economic assumptions, in order to determine which fuel cycle, or cycles, should be introduced, and when. It is concluded that the optimum path for the long term begins with the prompt introduction of the low-enriched-uranium fuel cycle. For a wide range of conditions, this cycle remains the optimum throughout the very long term. Conditions of rapid nuclear growth and very high uranium price escalation rates warrant the supersedure of the low-enriched-uranium cycle by either a plutonium-topped thorium cycle or plutonium recycle, beginning between 2010 and 2025. It is also found that the uranium resource position is sound in terms of both known resources and production capability. Moreover, introduction of the low-enriched-uranium fuel cycle and 1250 MWe reactor units will assure the economic viability of nuclear power until at least 2020, even if uranium prices increase at a rate of 3.5% above inflation. The interrelationship between these two conclusions lies in the tremendous incentive for exploration which will occur if the real uranium price escalation rate is high. From a competitive viewpoint, nuclear power can withstand increases in the price of uranium. However, such increases will likely further expand the resource base, making nuclear an even more reliable energy source. (auth)

  16. International Business Cycle Accounting

    OpenAIRE

    Keisuke Otsu

    2009-01-01

    In this paper, I extend the business cycle accounting method a la Chari, Kehoe and McGrattan (2007) to a two-country international business cycle model and quantify the effect of the disturbances in relevant markets on the business cycle correlation between Japan and the US over the 1980-2008 period. This paper finds that disturbances in the labor market and production efficiency are important in accounting for the recent increase in the cross-country output correlation. If international fina...

  17. Life Cycle Sustainability Dashboard

    DEFF Research Database (Denmark)

    Traverso, Marzia; Finkbeiner, Matthias; Jørgensen, Andreas

    2012-01-01

    One method to assess the sustainability performance of products is life cycle sustainability assessment (LCSA), which assesses product performance considering the environmental,economic, and social dimensions of the life cycle. The results of LCSA can be used to compare different products...... of sustainability is the communicability of the results by means of a graphical representation (a cartogram), characterized by a suitable chromatic scale and ranking score. The integration of LCSA and the dashboard of sustainability into a so-called Life Cycle Sustainability Dashboard (LCSD) is described here...

  18. STUDYING BUSINESS CYCLES SYNCHRONIZATION

    Directory of Open Access Journals (Sweden)

    N. Servetnyk

    2014-06-01

    Full Text Available The paper researches business cycles synchronization. The fluctuations in post-Soviet countries are considered. The study examines different measures of synchronization in groups of countries according to some criteria.

  19. The thorium fuel cycle

    International Nuclear Information System (INIS)

    Merz, E.R.

    1977-01-01

    The utilization of the thorium fuel cycle has long since been considered attractive owing to the excellent neutronic characteristics of 233 U, and the widespread and cheap thorium resources. Rapidly increasing uranium prices, public reluctance for widespread Pu recycling and expected delays for the market penetration of fast breeders have led to a reconsideration of the thorium fuel cycle merits. In addition, problems associated with reprocessing and waste handling, particularly with re-fabrication by remote handling of 233 U, are certainly not appreciably more difficult than for Pu recycling. To divert from uranium as a nuclear energy source it seems worth while intensifying future efforts for closing the Th/ 233 U fuel cycle. HTGRs are particularly promising for economic application. However, further research and development activities should not concentrate on this reactor type alone. Light- and heavy-water-moderated reactors, and even future fast breeders, may just as well take advantage of a demonstrated thorium fuel cycle. (author)

  20. Educational Business Cycles

    DEFF Research Database (Denmark)

    Tepe, Markus; Vanhuysse, Pieter

    Strong institutional constraints and better-informed voters may lead re-election seeking incumbents to shift the use of political business cycle mechanisms away from monetary and fiscal policy towards other policy domains that are more easily manipulable, targetable, and timeable. We investigate...... teacher employment patterns at the state level in Germany and find strong evidence of cycling mechanisms, in the form of electioneering and honeymooning. Against a backdrop of a continuously shrinking total teachers' pool, German state-level incumbents accelerate the hiring of new teachers during election...... periods and partly reverse this during politically safer points in the electoral cycle. Cycles are mediated by issue salience: heightened attention to German public schooling after the notorious PISA-2000 tests further strengthens the manipulation of new teacher hiring for electoral purposes....

  1. Educational Business Cycles

    DEFF Research Database (Denmark)

    Tepe, Markus; Vanhuysse, Pieter

    2009-01-01

    Strong institutional constraints and better-informed voters may lead re-election seeking incumbents to shift the use of political business cycle mechanisms away from monetary and fiscal policy towards other policy domains that are more easily manipulable, targetable, and timeable. We investigate...... teacher employment patterns at the state level in Germany and find strong evidence of cycling mechanisms, in the form of electioneering and honeymooning. Against a backdrop of a continuously shrinking total teachers' pool, German state-level incumbents accelerate the hiring of new teachers during election...... periods and partly reverse this during politically safer points in the electoral cycle. Cycles are mediated by issue salience: heightened attention to German public schooling after the notorious PISA-2000 tests further strengthens the manipulation of new teacher hiring for electoral purposes....

  2. Cycles in graphs

    CERN Document Server

    Alspach, BR

    1985-01-01

    This volume deals with a variety of problems involving cycles in graphs and circuits in digraphs. Leading researchers in this area present here 3 survey papers and 42 papers containing new results. There is also a collection of unsolved problems.

  3. The Rock Cycle

    Science.gov (United States)

    Singh, Raman J.; Bushee, Jonathan

    1977-01-01

    Presents a rock cycle diagram suitable for use at the secondary or introductory college levels which separates rocks formed on and below the surface, includes organic materials, and separates products from processes. (SL)

  4. Extended fuel cycle length

    International Nuclear Information System (INIS)

    Bruyere, M.; Vallee, A.; Collette, C.

    1986-09-01

    Extended fuel cycle length and burnup are currently offered by Framatome and Fragema in order to satisfy the needs of the utilities in terms of fuel cycle cost and of overall systems cost optimization. We intend to point out the consequences of an increased fuel cycle length and burnup on reactor safety, in order to determine whether the bounding safety analyses presented in the Safety Analysis Report are applicable and to evaluate the effect on plant licensing. This paper presents the results of this examination. The first part indicates the consequences of increased fuel cycle length and burnup on the nuclear data used in the bounding accident analyses. In the second part of this paper, the required safety reanalyses are presented and the impact on the safety margins of different fuel management strategies is examined. In addition, systems modifications which can be required are indicated

  5. Fuel cycle studies

    International Nuclear Information System (INIS)

    Anon.

    1978-01-01

    Programs are being conducted in the following areas: advanced solvent extraction techniques, accident consequences, fuel cycles for nonproliferation, pyrochemical and dry processes, waste encapsulation, radionuclide transport in geologic media, hull treatment, and analytical support for LWBR

  6. Traffic Signal Cycle Lengths

    Data.gov (United States)

    Town of Chapel Hill, North Carolina — Traffic signal location list for the town of Chapel Hill. This data set includes light cycle information as well as as intersection information.The Town of Chapel...

  7. International Real Business Cycles

    OpenAIRE

    Mario J. Crucini

    2006-01-01

    This paper is a non-technical review of research developments in the international real business cycle literature. International business cycle facts are summarize with particular attention to the sources of output variance from the expenditure side of the NIPA and the production side, using a familiar neoclassical production function. Theoretical developments focus on the how consumption smoothing and investment dynamics shape the current account; the search for sources and propagation mecha...

  8. The global carbon cycle

    International Nuclear Information System (INIS)

    Maier-Reimer, E.

    1991-01-01

    Basic concepts of the global carbon cycle on earth are described; by careful analyses of isotopic ratios, emission history and oceanic ventilation rates are derived, which provide crucial tests for constraining and calibrating models. Effects of deforestation, fertilizing, fossil fuel burning, soil erosion, etc. are quantified and compared, and the oceanic carbon process is evaluated. Oceanic and terrestrial biosphere modifications are discussed and a carbon cycle model is proposed

  9. IFR fuel cycle

    International Nuclear Information System (INIS)

    Battles, J.E.; Miller, W.E.; Lineberry, M.J.; Phipps, R.D.

    1992-01-01

    The next major milestone of the IFR program is engineering-scale demonstration of the pyroprocess fuel cycle. The EBR-II Fuel Cycle Facility has just entered a startup phase, which includes completion of facility modifications and installation and cold checkout of process equipment. This paper reviews the development of the electrorefining pyroprocess, the design and construction of the facility for the hot demonstration, the design and fabrication of the equipment, and the schedule and initial plan for its operation

  10. Hat cycle dynamic simulation

    International Nuclear Information System (INIS)

    Trucco, A.; Corallo, C.; Pini Prato, A.; Porro, S.

    1999-01-01

    Among the innovative cycle recently proposed in literature, the Humid Air Turbine Cycle - Hat better seems to fulfil the main energy market requirements of today: High efficiency in a large power ranger, low pollution, low specific capital cost. The previous results of an analysis at partial load and transient conditions are here presented, where the Hat plant has been simulated using the original model implemented in LEGO environment [it

  11. Quantifying the Adaptive Cycle.

    Directory of Open Access Journals (Sweden)

    David G Angeler

    Full Text Available The adaptive cycle was proposed as a conceptual model to portray patterns of change in complex systems. Despite the model having potential for elucidating change across systems, it has been used mainly as a metaphor, describing system dynamics qualitatively. We use a quantitative approach for testing premises (reorganisation, conservatism, adaptation in the adaptive cycle, using Baltic Sea phytoplankton communities as an example of such complex system dynamics. Phytoplankton organizes in recurring spring and summer blooms, a well-established paradigm in planktology and succession theory, with characteristic temporal trajectories during blooms that may be consistent with adaptive cycle phases. We used long-term (1994-2011 data and multivariate analysis of community structure to assess key components of the adaptive cycle. Specifically, we tested predictions about: reorganisation: spring and summer blooms comprise distinct community states; conservatism: community trajectories during individual adaptive cycles are conservative; and adaptation: phytoplankton species during blooms change in the long term. All predictions were supported by our analyses. Results suggest that traditional ecological paradigms such as phytoplankton successional models have potential for moving the adaptive cycle from a metaphor to a framework that can improve our understanding how complex systems organize and reorganize following collapse. Quantifying reorganization, conservatism and adaptation provides opportunities to cope with the intricacies and uncertainties associated with fast ecological change, driven by shifting system controls. Ultimately, combining traditional ecological paradigms with heuristics of complex system dynamics using quantitative approaches may help refine ecological theory and improve our understanding of the resilience of ecosystems.

  12. The Nuclear Fuel Cycle

    International Nuclear Information System (INIS)

    2011-08-01

    This brochure describes the nuclear fuel cycle, which is an industrial process involving various activities to produce electricity from uranium in nuclear power reactors. The cycle starts with the mining of uranium and ends with the disposal of nuclear waste. The raw material for today's nuclear fuel is uranium. It must be processed through a series of steps to produce an efficient fuel for generating electricity. Used fuel also needs to be taken care of for reuse and disposal. The nuclear fuel cycle includes the 'front end', i.e. preparation of the fuel, the 'service period' in which fuel is used during reactor operation to generate electricity, and the 'back end', i.e. the safe management of spent nuclear fuel including reprocessing and reuse and disposal. If spent fuel is not reprocessed, the fuel cycle is referred to as an 'open' or 'once-through' fuel cycle; if spent fuel is reprocessed, and partly reused, it is referred to as a 'closed' nuclear fuel cycle.

  13. Thorium fuel cycle analysis

    Energy Technology Data Exchange (ETDEWEB)

    Yamaji, K [Central Research Inst. of Electric Power Industry, Tokyo (Japan)

    1980-07-01

    Systems analysis of the thorium cycle, a nuclear fuel cycle accomplished by using thorium, is reported in this paper. Following a brief review on the history of the thorium cycle development, analysis is made on the three functions of the thorium cycle; (1) auxiliary system of U-Pu cycle to save uranium consumption, (2) thermal breeder system to exert full capacity of the thorium resource, (3) symbiotic system to utilize special features of /sup 233/U and neutron sources. The effects of the thorium loading in LWR (Light Water Reactor), HWR (Heavy Water Reactor) and HTGR (High Temperature Gas-cooled Reactor) are considered for the function of auxiliary system of U-Pu cycle. Analysis is made to find how much uranium is saved by /sup 233/U recycling and how the decrease in Pu production influences the introduction of FBR (Fast Breeder Reactor). Study on thermal breeder system is carried out in the case of MSBR (Molten Salt Breeder Reactor). Under a certain amount of fissile material supply, the potential system expansion rate of MSBR, which is determined by fissile material balance, is superior to that of FBR because of the smaller specific fissile inventory of MSBR. For symbiotic system, three cases are treated; i) nuclear heat supply system using HTGR, ii) denatured fuel supply system for nonproliferation purpose, and iii) hybrid system utilizing neutron sources other than fission reactor.

  14. Cycles and Common Cycles in Property and Related Sectors

    OpenAIRE

    Peijie Wang

    2003-01-01

    This paper examines cycles and common cycles in the property market and the economy. While focusing on common cycles, the study also incorporates common trends in the meantime, so it covers the whole spectrum of dynamic analysis. It has been found that property shares common cycles, particularly with those sectors that are the user markets of property. The mechanisms of common cycles and the relative magnitudes of cycles of the sectors related to property are discussed to shed light on proper...

  15. Multiparameter Cell Cycle Analysis.

    Science.gov (United States)

    Jacobberger, James W; Sramkoski, R Michael; Stefan, Tammy; Woost, Philip G

    2018-01-01

    Cell cycle cytometry and analysis are essential tools for studying cells of model organisms and natural populations (e.g., bone marrow). Methods have not changed much for many years. The simplest and most common protocol is DNA content analysis, which is extensively published and reviewed. The next most common protocol, 5-bromo-2-deoxyuridine S phase labeling detected by specific antibodies, is also well published and reviewed. More recently, S phase labeling using 5'-ethynyl-2'-deoxyuridine incorporation and a chemical reaction to label substituted DNA has been established as a basic, reliable protocol. Multiple antibody labeling to detect epitopes on cell cycle regulated proteins, which is what this chapter is about, is the most complex of these cytometric cell cycle assays, requiring knowledge of the chemistry of fixation, the biochemistry of antibody-antigen reactions, and spectral compensation. However, because this knowledge is relatively well presented methodologically in many papers and reviews, this chapter will present a minimal Methods section for one mammalian cell type and an extended Notes section, focusing on aspects that are problematic or not well described in the literature. Most of the presented work involves how to segment the data to produce a complete, progressive, and compartmentalized cell cycle analysis from early G1 to late mitosis (telophase). A more recent development, using fluorescent proteins fused with proteins or peptides that are degraded by ubiquitination during specific periods of the cell cycle, termed "Fucci" (fluorescent, ubiquitination-based cell cycle indicators) provide an analysis similar in concept to multiple antibody labeling, except in this case cells can be analyzed while living and transgenic organisms can be created to perform cell cycle analysis ex or in vivo (Sakaue-Sawano et al., Cell 132:487-498, 2007). This technology will not be discussed.

  16. Diagnostic importance of 18F-FDG PET/CT parameters and total lesion glycolysis in differentiating between benign and malignant adrenal lesions.

    Science.gov (United States)

    Ciftci, Esra; Turgut, Bulent; Cakmakcilar, Ali; Erturk, Seyit A

    2017-09-01

    Benign adrenal lesions are prevalent in oncologic imaging and make metastatic disease diagnoses difficult. This study evaluates the diagnostic importance of metabolic, volumetric, and metabolovolumetric parameters measured by fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT in differentiating between benign and malignant adrenal lesions in cancer patients. In this retrospective study, we evaluated F-FDG PET/CT parameters of adrenal lesions of follow-up cancer patients referred to our clinic between January 2012 and November 2016. The diagnosis of adrenal malignant lesions was made on the basis of interval growth or reduction after chemotherapy. Patient demographics, analysis of metabolic parameters such as maximum standard uptake value (SUVmax), tumor SUVmax/liver SUVmean ratio (T/LR), morphologic parameters such as size, Hounsfield Units, and computed tomography (CT) volume, and metabolovolumetric parameters such as metabolic tumor volume and total lesion glycolysis (TLG) of adrenal lesions were calculated. PET/CT parameters were assessed using the Mann-Whitney U-test and receiving operating characteristic analysis. In total, 186 adrenal lesions in 163 cancer patients (108 men/54 women; mean±SD age: 64±10.9 years) were subjected to F-FDG PET/CT for tumor evaluation. SUVmax values (mean±SD) were 2.8±0.8 and 10.6±6; TLG were 10.8±9.2 and 124.4±347.9; and T/LR were 1±0.3 and 4.1±2.6 in benign and malignant adrenal lesions, respectively. On the basis of the area under the curve, adrenal lesion SUVmax and T/LR had similar highest diagnostic performance for predicting malignant lesions (area under the curve: 0.993 and 0.991, respectively, P<0.001). Multivariate logistic regression analysis showed that T/LR, adrenal lesion SUVmax, and Hounsfield Units were independent predictive factors for malignancy rather than TLG. Irrespective of whether TLG was statistically highly significant for differentiating benign from malignant adrenal lesions, it did not reach the

  17. Baseline Metabolic Tumor Volume and Total Lesion Glycolysis Are Associated With Survival Outcomes in Patients With Locally Advanced Pancreatic Cancer Receiving Stereotactic Body Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Dholakia, Avani S. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Chaudhry, Muhammad; Leal, Jeffrey P. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Chang, Daniel T. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Raman, Siva P. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hacker-Prietz, Amy [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Su, Zheng; Pai, Jonathan [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Oteiza, Katharine E.; Griffith, Mary E. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Wahl, Richard L. [Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tryggestad, Erik [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Pawlik, Timothy [Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Laheru, Daniel A. [Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Wolfgang, Christopher L. [Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Koong, Albert C. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); and others

    2014-07-01

    Purpose: Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT). Materials and Methods: Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUV{sub max} and SUV{sub peak}) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Liver{sub mean} + [2 × Liver{sub sd}]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses. Results: Of the 32 patients, the majority were male (n=19, 59%), 65 years or older (n=21, 66%), and had tumors located in the pancreatic head (n=27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8 months (95% confidence interval [CI], 15.7-22.0). An MTV of 26.8 cm{sup 3} or greater (hazard ratio [HR] 4.46, 95% CI 1.64-5.88, P<.003) and TLG of 70.9 or greater (HR 3.08, 95% CI 1.18-8.02, P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19-22.21, P=.029) and TLG (HR 3.34, 95% CI 1.07-10.48, P=.038) remained independently associated with overall survival in separate multivariate analyses. Conclusions: Pre-SBRT MTV and TLG are potential predictive factors for overall survival in patients with LAPC and may assist in

  18. Baseline Metabolic Tumor Volume and Total Lesion Glycolysis Are Associated With Survival Outcomes in Patients With Locally Advanced Pancreatic Cancer Receiving Stereotactic Body Radiation Therapy

    International Nuclear Information System (INIS)

    Dholakia, Avani S.; Chaudhry, Muhammad; Leal, Jeffrey P.; Chang, Daniel T.; Raman, Siva P.; Hacker-Prietz, Amy; Su, Zheng; Pai, Jonathan; Oteiza, Katharine E.; Griffith, Mary E.; Wahl, Richard L.; Tryggestad, Erik; Pawlik, Timothy; Laheru, Daniel A.; Wolfgang, Christopher L.; Koong, Albert C.

    2014-01-01

    Purpose: Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT). Materials and Methods: Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUV max and SUV peak ) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Liver mean + [2 × Liver sd ]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses. Results: Of the 32 patients, the majority were male (n=19, 59%), 65 years or older (n=21, 66%), and had tumors located in the pancreatic head (n=27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8 months (95% confidence interval [CI], 15.7-22.0). An MTV of 26.8 cm 3 or greater (hazard ratio [HR] 4.46, 95% CI 1.64-5.88, P<.003) and TLG of 70.9 or greater (HR 3.08, 95% CI 1.18-8.02, P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19-22.21, P=.029) and TLG (HR 3.34, 95% CI 1.07-10.48, P=.038) remained independently associated with overall survival in separate multivariate analyses. Conclusions: Pre-SBRT MTV and TLG are potential predictive factors for overall survival in patients with LAPC and may assist in tailoring therapy

  19. Historicising the Hydrosocial Cycle

    Directory of Open Access Journals (Sweden)

    Jeremy J. Schmidt

    2014-02-01

    Full Text Available This paper examines the historical claims made in support of the hydrosocial cycle. In particular, it considers how arguments advancing the hydrosocial cycle make historical claims regarding modernist conceptions of what water is (i.e. H2O and its fit with society. The paper gives special emphasis to the society/nature dualism and to the notion of agency as key sites of contest in arguments regarding the hydrosocial cycle. It finds that, while several versions of the hydrosocial cycle seek to advance a political ecology more sensitive to non-human actions, these same accounts often do not address the robust account of non-human agency in the historical record. Evidence is presented regarding water’s agency amongst late 19th and early 20th century architects of key water management norms in the United States. This evidence troubles accounts of the hydrosocial cycle that critique the US experience and suggests new directions for rethinking the role of historical and institutional norms in water policy.

  20. Differential Editosome Protein Function between Life Cycle Stages of Trypanosoma brucei.

    Science.gov (United States)

    McDermott, Suzanne M; Guo, Xuemin; Carnes, Jason; Stuart, Kenneth

    2015-10-09

    Uridine insertion and deletion RNA editing generates functional mitochondrial mRNAs in Trypanosoma brucei. The mRNAs are differentially edited in bloodstream form (BF) and procyclic form (PF) life cycle stages, and this correlates with the differential utilization of glycolysis and oxidative phosphorylation between the stages. The mechanism that controls this differential editing is unknown. Editing is catalyzed by multiprotein ∼20S editosomes that contain endonuclease, 3'-terminal uridylyltransferase, exonuclease, and ligase activities. These editosomes also contain KREPB5 and KREPA3 proteins, which have no functional catalytic motifs, but they are essential for parasite viability, editing, and editosome integrity in BF cells. We show here that repression of KREPB5 or KREPA3 is also lethal in PF, but the effects on editosome structure differ from those in BF. In addition, we found that point mutations in KREPB5 or KREPA3 differentially affect cell growth, editosome integrity, and RNA editing between BF and PF stages. These results indicate that the functions of KREPB5 and KREPA3 editosome proteins are adjusted between the life cycle stages. This implies that these proteins are involved in the processes that control differential editing and that the 20S editosomes differ between the life cycle stages. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Superfluid thermodynamic cycle refrigerator

    Science.gov (United States)

    Swift, Gregory W.; Kotsubo, Vincent Y.

    1992-01-01

    A cryogenic refrigerator cools a heat source by cyclically concentrating and diluting the amount of .sup.3 He in a single phase .sup.3 He-.sup.4 He solution. The .sup.3 He in superfluid .sup.4 He acts in a manner of an ideal gas in a vacuum. Thus, refrigeration is obtained using any conventional thermal cycle, but preferably a Stirling or Carnot cycle. A single phase solution of liquid .sup.3 He at an initial concentration in superfluid .sup.4 He is contained in a first variable volume connected to a second variable volume through a superleak device that enables free passage of .sup.4 He while restricting passage of .sup.3 He. The .sup.3 He is compressed (concentrated) and expanded (diluted) in a phased manner to carry out the selected thermal cycle to remove heat from the heat load for cooling below 1 K.

  2. The nuclear fuel cycle

    International Nuclear Information System (INIS)

    Patarin, L.

    2002-01-01

    This book treats of the different aspects of the industrial operations linked with the nuclear fuel, before and after its use in nuclear reactors. The basis science of this nuclear fuel cycle is chemistry. Thus a recall of the elementary notions of chemistry is given in order to understand the phenomena involved in the ore processing, in the isotope enrichment, in the fabrication of fuel pellets and rods (front-end of the cycle), in the extraction of recyclable materials (residual uranium and plutonium), and in the processing and conditioning of wastes (back-end of the fuel cycle). Nuclear reactors produce about 80% of the French electric power and the Cogema group makes 40% of its turnover at the export. Thus this book contains also some economic and geopolitical data in order to clearly position the stakes. The last part, devoted to the management of wastes, presents the solutions already operational and also the research studies in progress. (J.S.)

  3. Fuel cycle based safeguards

    International Nuclear Information System (INIS)

    De Montmollin, J.M.; Higinbotham, W.A.; Gupta, D.

    1985-07-01

    In NPT safeguards the same model approach and absolute-quantity inspection goals are applied at present to all similar facilities, irrespective of the State's fuel cycle. There is a continuing interest and activity on the part of the IAEA in new NPT safeguards approaches that more directly address a State's nuclear activities as a whole. This fuel cycle based safeguards system is expected to a) provide a statement of findings for the entire State rather than only for individual facilities; b) allocate inspection efforts so as to reflect more realistically the different categories of nuclear materials in the different parts of the fuel cycle and c) provide more timely and better coordinated information on the inputs, outputs and inventories of nuclear materials in a State. (orig./RF) [de

  4. The nuclear fuel cycle

    International Nuclear Information System (INIS)

    Jones, P.M.S.

    1987-01-01

    This chapter explains the distinction between fissile and fertile materials, examines briefly the processes involved in fuel manufacture and management, describes the alternative nuclear fuel cycles and considers their advantages and disadvantages. Fuel management is usually divided into three stages; the front end stage of production and fabrication, the back end stage which deals with the fuel after it is removed from the reactor (including reprocessing and waste treatment) and the stage in between when the fuel is actually in the reactor. These stages are illustrated and explained in detail. The plutonium fuel cycle and thorium-uranium-233 fuel cycle are explained. The differences between fuels for thermal reactors and fast reactors are explained. (U.K.)

  5. CO2 cycle

    Science.gov (United States)

    Titus, Timothy N.; Byrne, Shane; Colaprete, Anthony; Forget, Francois; Michaels, Timothy I.; Prettyman, Thomas H.

    2017-01-01

    This chapter discusses the use of models, observations, and laboratory experiments to understand the cycling of CO2 between the atmosphere and seasonal Martian polar caps. This cycle is primarily controlled by the polar heat budget, and thus the emphasis here is on its components, including solar and infrared radiation, the effect of clouds (water- and CO2-ice), atmospheric transport, and subsurface heat conduction. There is a discussion about cap properties including growth and regression rates, albedos and emissivities, grain sizes and dust and/or water-ice contamination, and curious features like cold gas jets and araneiform (spider-shaped) terrain. The nature of the residual south polar cap is discussed as well as its long-term stability and ability to buffer atmospheric pressures. There is also a discussion of the consequences of the CO2 cycle as revealed by the non-condensable gas enrichment observed by Odyssey and modeled by various groups.

  6. Political Budget Cycles

    DEFF Research Database (Denmark)

    Aaskoven, Lasse; Lassen, David Dreyer

    2017-01-01

    The political budget cycle—how elections affect government fiscal policy—is one of the most studied subjects in political economy and political science. The key theoretical question is whether incumbent governments can time or structure public finances in ways that improve their chances of reelec......The political budget cycle—how elections affect government fiscal policy—is one of the most studied subjects in political economy and political science. The key theoretical question is whether incumbent governments can time or structure public finances in ways that improve their chances...... on political budget cycles have recently focused on conditions under which such cycles are likely to obtain. Much recent research focuses on subnational settings, allowing comparisons of governments in similar institutional environments, and a consensus on the presences of cycles in public finances...

  7. Theory of limit cycles

    CERN Document Server

    Ye, Yan-Qian; Lo, Chi Y

    1986-01-01

    Over the past two decades the theory of limit cycles, especially for quadratic differential systems, has progressed dramatically in China as well as in other countries. This monograph, updating the 1964 first edition, includes these recent developments, as revised by eight of the author's colleagues in their own areas of expertise. The first part of the book deals with limit cycles of general plane stationary systems, including their existence, nonexistence, stability, and uniqueness. The second section discusses the global topological structure of limit cycles and phase-portraits of quadratic systems. Finally, the last section collects important results that could not be included under the subject matter of the previous two sections or that have appeared in the literature very recently. The book as a whole serves as a reference for college seniors, graduate students, and researchers in mathematics and physics.

  8. The thorium fuel cycle

    International Nuclear Information System (INIS)

    Merz, E.R.

    1977-01-01

    The utilization of the thorium fuel cycle has long since been considered attractive due to the excellent neutronic characteristics of 233 U, and the widespread and cheap thorium resources. Although the uranium ore as well as the separative work requirements are usually lower for any thorium-based fuel cycle in comparison to present uranium-plutonium fuel cycles of thermal water reactors, interest by nuclear industry has hitherto been marginal. Fast increasing uranium prices, public reluctance against widespread Pu-recycling and expected retardations for the market penetration of fast breeders have led to a reconsideration of the thorium fuel cycle merits. In addition, it could be learned in the meantime that problems associated with reprocessing and waste handling, but particularly with a remote refabrication of 233 U are certainly not appreciably more difficult than for Pu-recycling. This may not only be due to psychological constraints but be based upon technological as well as economical facts, which have been mostly neglected up till now. In order to diversify from uranium as a nuclear energy source it seems to be worthwhile to greatly intensify efforts in the future for closing the Th/ 233 U fuel cycle. HTGR's are particularly promising for economic application. However, further R and D activites should not be solely focussed on this reactor type alone. Light and heavy-water moderated reactors, as well as even fast breeders later on, may just as well take advantage of a demonstrated thorium fuel cycle. A summary is presented of the state-of-the-art of Th/ 233 U-recycling technology and the efforts still necessary to demonstrate this technology all the way through to its industrial application

  9. Steam turbine cycle

    International Nuclear Information System (INIS)

    Okuzumi, Naoaki.

    1994-01-01

    In a steam turbine cycle, steams exhausted from the turbine are extracted, and they are connected to a steam sucking pipe of a steam injector, and a discharge pipe of the steam injector is connected to an inlet of a water turbine. High pressure discharge water is obtained from low pressure steams by utilizing a pressurizing performance of the steam injector and the water turbine is rotated by the high pressure water to generate electric power. This recover and reutilize discharged heat of the steam turbine effectively, thereby enabling to improve heat efficiency of the steam turbine cycle. (T.M.)

  10. Life Cycle Environmental Management

    DEFF Research Database (Denmark)

    Pedersen, Claus Stig; Jørgensen, Jørgen; Pedersen, Morten Als

    1996-01-01

    A precondition for environmentally conscious management is the awareness of the environmental impact potentials created by an industrial company. There is an obvious need for management tools to support the implementation of relevant environmental criteria into the industrial decision making...... processes. The discipline of life cycle environmental management (LCEM) focuses on the incorporation of environmental criteria from the life cycles of products and other company activities into the company management processes. This paper introduces the concept of LCEM as an important element...... of the complete set of environmental objects in an industrial manufacturing company....

  11. Carbon cycle makeover

    DEFF Research Database (Denmark)

    Canfield, Donald Eugene; Kump, Lee R.

    2013-01-01

    remaining in sediments after respiration leave a residual of oxygen in the atmosphere. The source of oxygen to the atmosphere represented by organic matter burial is balanced by oxygen sinks associated with rock weathering and chemical reaction with volcanic gases. This is the long-term carbon and oxygen...... geochemical cycle. But Earth is an old planet, and oxygen levels have changed through time (2). On page 540 of this issue, Schrag et al. (3) challenge the most commonly used geochemical approach to assess long-term changes in the coupled oxygen and carbon cycles....

  12. Resurrecting Equilibria Through Cycles

    DEFF Research Database (Denmark)

    Barnett, Richard C.; Bhattacharya, Joydeep; Bunzel, Helle

    equilibria because they asymptotically violate some economic restriction of the model. The literature has always ruled out such paths. This paper studies a pure-exchange monetary overlapping generations economy in which real balances cycle forever between momentary equilibrium points. The novelty is to show...... that segments of the offer curve that have been previously ignored, can in fact be used to produce asymptotically valid cyclical paths. Indeed, a cycle can bestow dynamic validity on momentary equilibrium points that had erstwhile been classified as dynamically invalid....

  13. 24-month fuel cycles

    International Nuclear Information System (INIS)

    Rosenstein, R.G.; Sipes, D.E.; Beall, R.H.; Donovan, E.J.

    1986-01-01

    Twenty-four month reload cycles can potentially lessen total power generation costs. While 24-month cores increase purchased fuel costs, the longer cycles reduce the number of refueling outages and thus enhance plant availability; men-rem exposure to site personnel and other costs associated with reload core design and licensing are also reduced. At dual unit sites an operational advantage can be realized by refueling each plant alternately on a 1-year offset basis. This results in a single outage per site per year which can be scheduled for off-peak periods or when replacement power costs are low

  14. Global water cycle

    Science.gov (United States)

    Robertson, Franklin; Goodman, Steven J.; Christy, John R.; Fitzjarrald, Daniel E.; Chou, Shi-Hung; Crosson, William; Wang, Shouping; Ramirez, Jorge

    1993-01-01

    This research is the MSFC component of a joint MSFC/Pennsylvania State University Eos Interdisciplinary Investigation on the global water cycle extension across the earth sciences. The primary long-term objective of this investigation is to determine the scope and interactions of the global water cycle with all components of the Earth system and to understand how it stimulates and regulates change on both global and regional scales. Significant accomplishments in the past year are presented and include the following: (1) water vapor variability; (2) multi-phase water analysis; (3) global modeling; and (4) optimal precipitation and stream flow analysis and hydrologic processes.

  15. A plant pathogenic bacterium exploits the tricarboxylic acid cycle metabolic pathway of its insect vector

    Science.gov (United States)

    Nehela, Yasser; Hijaz, Faraj; Vincent, Christopher I.

    2018-01-01

    ABSTRACT Huanglongbing in citrus is caused by a phloem-limited, uncultivable, gram-negative α-proteobacterium, Candidatus Liberibacter asiaticus (CLas). CLas is transmitted by the phloem-sucking insect, Diaphorina citri (Hemiptera: Liviidae), in a persistent, circulative, and propagative manner. In this study, we investigated the metabolomic and respiration rates changes in D. citri upon infection with CLas using gas chromatography-mass spectrometry (GC-MS) and gas exchange analysis. The level of glycine, L-serine, L-threonine, and gamma-amino butyric acid were higher in CLas-infected D. citri, while L-proline, L-aspartic acid, and L-pyroglutamic acid were lower in CLas-infected D. citri compared with the control. Citric acid was increased in CLas-infected D. citri, whereas malic and succinic acids were reduced. Interestingly, most of the reduced metabolites such as malate, succinate, aspartate, and L-proline are required for the growth of CLas. The increase in citric acid, serine, and glycine indicated that CLas induced glycolysis and the tricarboxylic acid cycle (TCA) in its vector. In agreement with the GC-MS results, the gene expression results also indicated that glycolysis and TCA were induced in CLas-infected D. citri and this was accompanied with an increases in respiration rate. Phosphoric acid and most of the sugar alcohols were higher in CLas-infected D. citri, indicating a response to the biotic stress or cell damage. Only slight increases in the levels of few sugars were observed in CLas-infected D. citri, which indicated that sugars are tightly regulated by D. citri. Our results indicated that CLas induces nutrient and energetic stress in its host insect. This study may provide some insights into the mechanism of colonization of CLas in its vector. PMID:28594267

  16. Menstrual cycle pattern and fertility

    DEFF Research Database (Denmark)

    Kolstad, Henrik A.; Bonde, Jens Peter; Hjøllund, Niels Henrik

    1999-01-01

    To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss.......To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss....

  17. Entrepreneurship and the business cycle

    NARCIS (Netherlands)

    Koellinger, Philipp D.; Thurik, A. Roy

    2012-01-01

    We find new empirical regularities in the business cycle in a cross-country panel of 22 OECD countries for the period 1972 to 2007; entrepreneurship Granger-causes the cycles of the world economy. Furthermore, the entrepreneurial cycle is positively affected by the national unemployment cycle. We

  18. World nuclear fuel cycle

    International Nuclear Information System (INIS)

    Anon.

    1979-01-01

    A coloured pull-out wall chart is presented showing the fuel cycle interests of the world. Place names are marked and symbols are used to indicate regions associated with uranium or thorium deposits, mining, milling, enrichment, reprocessing and fabrication. (UK)

  19. Deuterium in atmospheric cycle

    International Nuclear Information System (INIS)

    Pontikis, M.C.

    Interest of the study concerning the deuterium content variation (HDO) in the atmospheric water. Standards and measurement methods. Molecule HDO cycle in the atmospheric water. Application to the study of hail-generating cumulus-nimbus and of the mantle of snow [fr

  20. Nuclear fuel cycle

    International Nuclear Information System (INIS)

    1993-01-01

    Status of different nuclear fuel cycle phases in 1992 is discussed including the following issues: uranium exploration, resources, supply and demand, production, market prices, conversion, enrichment; reactor fuel technology; spent fuel management, as well as trends of these phases development up to the year 2010. 10 refs, 11 figs, 15 tabs

  1. Life Cycle Inventory Analysis

    DEFF Research Database (Denmark)

    Bjørn, Anders; Moltesen, Andreas; Laurent, Alexis

    2018-01-01

    of different sources. The output is a compiled inventory of elementary flows that is used as basis of the subsequent life cycle impact assessment phase. This chapter teaches how to carry out this task through six steps: (1) identifying processes for the LCI model of the product system; (2) planning...

  2. Fuel cycle centres

    International Nuclear Information System (INIS)

    Hagen, M.

    1977-01-01

    The concept of co-locating and integrating fuel cycle facilities at one site is discussed. This concept offers considerable advantages, especially in minimizing the amount of radioactive material to be transported on public roads. Safeguards and physical protection as relating to such an integrated system of facilities are analysed in detail, also industrial and commercial questions. An overall risk-benefit evaluation turns out to be in favour of fuel cycle centres. These centres seem to be specifically attractive with regard to the back end of the fuel cycle, including on-site disposal of radioactive wastes. The respective German approach is presented as an example. Special emphasis is given to the site selection procedures in this case. Time scale and cost for the implementation of this concept are important factors to be looked at. Since participation of governmental institutions in these centres seems to be indispensable their respective roles as compared to industry must be clearly defined. The idea of adjusting fuel cycle centres to regional rather than national use might be an attractive option, depending on the specific parameters in the region, though results of existing multinational ventures are inconclusive in this respect. Major difficulties might be expected e.g. because of different national safety regulations and standards as well as commercial conditions among partner countries. Public acceptance in the host country seems to be another stumbling block for the realization of this type of multinational facilities

  3. Life Cycle Collection Management

    Directory of Open Access Journals (Sweden)

    Helen Shenton

    2003-09-01

    Full Text Available Life cycle collection management is a way of taking a long-term approach to the responsible stewardship of the British Library's collections and is one of the Library's strategic strands. It defines the different stages in a collection item's existence over time. These stages range from selection and acquisitions processing, cataloguing and press marking, through to preventive conservation, storage and retrieval. Life cycle collection management seeks to identify the costs of each stage in order to show the economic interdependencies between the phases over time. It thereby aims to demonstrate the long-term consequences of what the library takes into its collections, by making explicit the financial and other implications of decisions made at the beginning of the life cycle for the next 100 plus years. This paper describes the work over the past year at the British Library on this complex and complicated subject. It presents the emerging findings and suggests how it can be used for practical reasons (by individual curators and selectors and for economic, governance and political purposes. The paper describes the next steps in the project, for example, on a predictive data model. The British Library is seeking to benchmark itself against comparable organisations in this area. It intends to work with others on specific comparison for example, of life cycle costing of electronic and paper journals, as a prelude to eliding digital and 'traditional' formats.

  4. Boundedly rational credit cycles

    OpenAIRE

    Sáez, María

    1996-01-01

    We propose an evolutionary model of a credit market. We show that the economy exhibits credit cycles. The model predicts dynamics which are consistent with some evidence about the Great Depression. Real shocks trigger episodes of credit--crunch which are observed in the process of adjustment towards the post shock equilibrium.

  5. 90-Day Cycle Handbook

    Science.gov (United States)

    Park, Sandra; Takahashi, Sola

    2013-01-01

    90-Day Cycles are a disciplined and structured form of inquiry designed to produce and test knowledge syntheses, prototyped processes, or products in support of improvement work. With any type of activity, organizations inevitably encounter roadblocks to improving performance and outcomes. These barriers might include intractable problems at…

  6. Mosquito Life Cycle

    Science.gov (United States)

    Knowing the stages of the mosquito's life will help you prevent mosquitoes around your home and help you choose the right pesticides for your needs, if you decide to use them. All mosquito species go through four distinct stages during their live cycle.

  7. Reasoning with Causal Cycles

    Science.gov (United States)

    Rehder, Bob

    2017-01-01

    This article assesses how people reason with categories whose features are related in causal cycles. Whereas models based on causal graphical models (CGMs) have enjoyed success modeling category-based judgments as well as a number of other cognitive phenomena, CGMs are only able to represent causal structures that are acyclic. A number of new…

  8. Skills, sunspots and cycles

    DEFF Research Database (Denmark)

    Busato, Francesco; Marchetti, Enrico

    This paper explores the ability of a class of one-sector,multi-input models to generate indeterminate equilibrium paths, andendogenous cycles, without relying on factors' hoarding. The modelpresents a novel theoretical economic mechanism that supportssunspot-driven expansions without requiring...

  9. WLTP Random Cycle Generator

    NARCIS (Netherlands)

    Kooijman, D.G.; Balau, A.E.; Wilkins, S.; Ligterink, N.; Cuelenaere, R.

    2015-01-01

    European light duty vehicle emission legislation is gradually shifting the focus from test procedures with merely static test cycles, towards procedures including Real Driving Emissions (RDE), as they are a mean to achieve the European (NOx) emission reduction target. Hence a RDE trip must represent

  10. WLTP random cycle generator

    NARCIS (Netherlands)

    Kooijman, D.G.; Balau, A.E.; Wilkins, S.; Ligterink, N.; Cuelenaere, R.

    2015-01-01

    European light duty vehicle emission legislation is gradually shifting the focus from test procedures with merely static test cycles, towards procedures including Real Driving Emissions (RDE), as they are a mean to achieve the European (NOx) emission reduction target. Hence a RDE trip must represent

  11. Combined-cycle plants

    International Nuclear Information System (INIS)

    Valenti, M.

    1991-01-01

    This paper reports that as tougher emissions standards take hold throughout the industrialized world, manufacturers such as GE, Siemens, Foster Wheeler, and Asea Brown Boveri are designing advanced combined-cycle equipment that offers improved environmental performance without sacrificing power efficiency

  12. ITER fuel cycle

    International Nuclear Information System (INIS)

    Leger, D.; Dinner, P.; Yoshida, H.

    1991-01-01

    Resulting from the Conceptual Design Activities (1988-1990) by the parties involved in the International Thermonuclear Experimental Reactor (ITER) project, this document summarizes the design requirements and the Conceptual Design Descriptions for each of the principal subsystems and design options of the ITER Fuel Cycle conceptual design. The ITER Fuel Cycle system provides for the handling of all tritiated water and gas mixtures on ITER. The system is subdivided into subsystems for fuelling, primary (torus) vacuum pumping, fuel processing, blanket tritium recovery, and common processes (including isotopic separation, fuel management and storage, and processes for detritiation of solid, liquid, and gaseous wastes). After an introduction describing system function and conceptual design procedure, a summary of the design is presented including a discussion of scope and main parameters, and the fuel design options for fuelling, plasma chamber vacuum pumping, fuel cleanup, blanket tritium recovery, and auxiliary and common processes. Design requirements are defined and design descriptions are given for the various subsystems (fuelling, plasma vacuum pumping, fuel cleanup, blanket tritium recovery, and auxiliary/common processes). The document ends with sections on fuel cycle design integration, fuel cycle building layout, safety considerations, a summary of the research and development programme, costing, and conclusions. Refs, figs and tabs

  13. Understanding Solar Cycle Variability

    Energy Technology Data Exchange (ETDEWEB)

    Cameron, R. H.; Schüssler, M., E-mail: cameron@mps.mpg.de [Max-Planck-Institut für Sonnensystemforschung, Justus-von-Liebig-Weg 3, D-37077 Göttingen (Germany)

    2017-07-10

    The level of solar magnetic activity, as exemplified by the number of sunspots and by energetic events in the corona, varies on a wide range of timescales. Most prominent is the 11-year solar cycle, which is significantly modulated on longer timescales. Drawing from dynamo theory, together with the empirical results of past solar activity and similar phenomena for solar-like stars, we show that the variability of the solar cycle can be essentially understood in terms of a weakly nonlinear limit cycle affected by random noise. In contrast to ad hoc “toy models” for the solar cycle, this leads to a generic normal-form model, whose parameters are all constrained by observations. The model reproduces the characteristics of the variable solar activity on timescales between decades and millennia, including the occurrence and statistics of extended periods of very low activity (grand minima). Comparison with results obtained with a Babcock–Leighton-type dynamo model confirm the validity of the normal-mode approach.

  14. The plutonium fuel cycles

    International Nuclear Information System (INIS)

    Pigford, T.H.; Ang, K.P.

    1975-01-01

    The quantities of plutonium and other fuel actinides have been calculated for equilibrium fuel cycles for 1000-MW water reactors fueled with slightly enriched uranium, water reactors fueled with plutonium and natural uranium, fast-breder reactors, gas-cooled reactors fueled with thorium and highly enriched uranium, and gas-cooled reactors fueled with thorium, plutonium and recycled uranium. The radioactivity quantities of plutonium, americium and curium processed yearly in these fuel cycles are greatest for the water reactors fueled with natural uranium and recycled plutonium. The total amount of actinides processed is calculated for the predicted future growth of the U.S. nuclear power industry. For the same total installed nuclear power capacity, the introduction of the plutonium breeder has little effect upon the total amount of plutonium in this century. The estimated amount of plutonium in the low-level process wastes in the plutonium fuel cycles is comparable to the amount of plutonium in the high-level fission product wastes. The amount of plutonium processed in the nuclear fuel cycles can be considerably reduced by using gas-cooled reactors to consume plutonium produced in uranium-fueled water reactors. These, and other reactors dedicated for plutonium utilization, could be co-located with facilities for fuel reprocessing ad fuel fabrication to eliminate the off-site transport of separated plutonium. (author)

  15. Fuel cycle oriented approach

    International Nuclear Information System (INIS)

    Petit, A.

    1987-01-01

    The term fuel cycle oriented approach is currently used to designate two quite different things: the attempt to consider all or part of a national fuel cycle as one material balance area (MBA) or to consider individual MBAs existing in a state while designing a unique safeguards approach for each and applying the principle of nondiscrimination to fuel cycles as a whole, rather than to individual facilities. The merits of such an approach are acceptability by the industry and comparison with the contemplated establishment of long-term criteria. The following points concern the acceptability by the industry: (1) The main interest of the industry is to keep an open international market and therefore, to have effective and efficient safeguards. (2) The main concerns of the industry regarding international safeguards are economic burden, intrusiveness, and discrimination. Answers to these legitimate concerns, which retain the benefits of a fuel cycle oriented approach, are needed. More specifically, the problem of reimbursing the operator the costs that he has incurred for the safeguards must be considered

  16. The Geologic Nitrogen Cycle

    Science.gov (United States)

    Johnson, B. W.; Goldblatt, C.

    2013-12-01

    N2 is the dominant gas in Earth's atmosphere, and has been so through the majority of the planet's history. Originally thought to only be cycled in significant amounts through the biosphere, it is becoming increasingly clear that a large degree of geologic cycling can occur as well. N is present in crustal rocks at 10s to 100s of ppm and in the mantle at 1s to perhaps 10s of ppm. In light of new data, we present an Earth-system perspective of the modern N cycle, an updated N budget for the silicate Earth, and venture to explain the evolution of the N cycle over time. In an fashion similar to C, N has a fast, biologically mediated cycle and a slower cycle driven by plate tectonics. Bacteria fix N2 from the atmosphere into bioavailable forms. N is then cycled through the food chain, either by direct consumption of N-fixing bacteria, as NH4+ (the primary waste form), or NO3- (the most common inorganic species in the modern ocean). Some organic material settles as sediment on the ocean floor. In anoxic sediments, NH4+ dominates; due to similar ionic radii, it can readily substitute for K+ in mineral lattices, both in sedimentary rocks and in oceanic lithosphere. Once it enters a subduction zone, N may either be volatilized and returned to the atmosphere at arc volcanoes as N2 or N2O, sequestered into intrusive igneous rocks (as NH4+?), or subducted deep into the mantle, likely as NH4+. Mounting evidence indicates that a significant amount of N may be sequestered into the solid Earth, where it may remain for long periods (100s m.y.) before being returned to the atmosphere/biosphere by volcanism or weathering. The magnitude fluxes into the solid Earth and size of geologic N reservoirs are poorly constrained. The size of the N reservoirs contained in the solid Earth directly affects the evolution of Earth's atmosphere. It is possible that N now sequestered in the solid Earth was once in the atmosphere, which would have resulted in a higher atmospheric pressure, and

  17. Riding the cycle

    Energy Technology Data Exchange (ETDEWEB)

    Webster, G. [Canadian Association of Petroleum Producers, Calgary, AB (Canada)

    2001-07-01

    The current state of the Canadian oil and natural gas industry is reviewed as part of a discussion of economic cycles focusing in particular on the most recent cycle and the impact it has had on the industry. The review of the state of the industry includes discussion of production, exports, commodity prices, the stimulating effect of price increases on the number of oil and natural gas wells drilled, drilling rig operating days. Also discussed are the effect of foreign exchange rates, capital spending, industry financial performance in terms of return on capital employed, the impact of oil and gas prices on Alberta provincial revenues, estimates of Canada's ultimate crude oil and natural gas resources potential, pipelines and pipeline proposals for northern gas, and projection of crude oil and natural gas production in Canada to 2010.

  18. Fuel cycle services

    International Nuclear Information System (INIS)

    Gruber, Gerhard J.

    1990-01-01

    TRIGA reactor operators are increasingly concerned about the back end of their Fuel Cycle due to a new environmental policy in the USA. The question how to close the Fuel Cycle will have to be answered by all operators sooner or later. Reprocessing of the TRIGA fuel elements is not available. Only long term storage and final disposal can be considered. But for such a storage or disposal a special treatment of the fuel elements and of course a final depository is necessary. NUKEM plans to undertake efforts to assist the TRIGA operators in this area. For that reason we need to know your special needs for today and tomorrow - so that potential processors can consider whether to offer these services on the market. (orig.)

  19. Riding the cycle

    International Nuclear Information System (INIS)

    Webster, G.

    2001-01-01

    The current state of the Canadian oil and natural gas industry is reviewed as part of a discussion of economic cycles focusing in particular on the most recent cycle and the impact it has had on the industry. The review of the state of the industry includes discussion of production, exports, commodity prices, the stimulating effect of price increases on the number of oil and natural gas wells drilled, drilling rig operating days. Also discussed are the effect of foreign exchange rates, capital spending, industry financial performance in terms of return on capital employed, the impact of oil and gas prices on Alberta provincial revenues, estimates of Canada's ultimate crude oil and natural gas resources potential, pipelines and pipeline proposals for northern gas, and projection of crude oil and natural gas production in Canada to 2010

  20. Assessing Cycling Participation in Australia

    Directory of Open Access Journals (Sweden)

    Chris Rissel

    2013-01-01

    Full Text Available Planning and evaluating cycling programs at a national or state level requires accurate measures of cycling participation. However, recent reports of cycling participation have produced very different estimates. This paper examines the reported rates of cycling in five recent population surveys of cycling. Three surveys (one national and two from Sydney asking respondents when they last rode a bicycle generated cycling participation (cycled in the past year estimates of 29.7%, 34.1% and 28.9%. Two other national surveys which asked participants to recall (unprompted any physical activity done for exercise, recreation or sport in the previous 12 months, estimated cycling in the past year as 11.1% and 6.5%. While unprompted recall of cycling as a type of physical activity generates lower estimates of cycling participation than specific recall questions, both assessment approaches produced similar patterns of cycling by age and sex with both approaches indicating fewer women and older adults cycling. The different question styles most likely explain the substantial discrepancies between the estimates of cycling participation. Some differences are to be expected due to sampling variability, question differences, and regional variation in cycling.

  1. Forests and water cycle

    Directory of Open Access Journals (Sweden)

    Iovino F

    2009-06-01

    Full Text Available Based on a comprehensive literature analysis, a review on factors that control water cycle and water use in Mediterranean forest ecosystems is presented, including environmental variables and silvicultural treatments. This important issue is considered in the perspective of sustainable forest management of Mediterranean forests, with special regard to crucial environmental hazards such as forest fires and desertification risks related to climate change.

  2. Stirling cycle engine

    Science.gov (United States)

    Lundholm, Gunnar

    1983-01-01

    In a Stirling cycle engine having a plurality of working gas charges separated by pistons reciprocating in cylinders, the total gas content is minimized and the mean pressure equalization among the serial cylinders is improved by using two piston rings axially spaced at least as much as the piston stroke and by providing a duct in the cylinder wall opening in the space between the two piston rings and leading to a source of minimum or maximum working gas pressure.

  3. The nuclear fuel cycle

    International Nuclear Information System (INIS)

    Anon.

    1975-01-01

    The papers presented at the International Conference on The Nuclear Fuel Cycle, held at Stockholm, 28 to 31 October 1975, are reviewed. The meeting, organised by the U.S. Atomic Industrial Forum, and the Swedish Nuclear Forum, was concerned more particularly with economic, political, social and commercial aspects than with tecnology. The papers discussed were considered under the subject heading of current status, uranium resources, enrichment, and reprocessing. (U.K.)

  4. Nuclear fuel cycle

    Energy Technology Data Exchange (ETDEWEB)

    1975-12-01

    The papers presented at the International Conference on The Nuclear Fuel Cycle, held at Stockholm, 28 to 31 October 1975, are reviewed. The meeting, organised by the U.S. Atomic Industrial Forum, and the Swedish Nuclear Forum, was concerned more particularly with economic, political, social and commercial aspects than with tecnology. The papers discussed were considered under the subject heading of current status, uranium resources, enrichment, and reprocessing.

  5. Alternative nuclear fuel cycles

    International Nuclear Information System (INIS)

    Till, C.E.

    1979-01-01

    This diffuse subject involves value judgments that are political as well as technical, and is best understood in that context. The four questions raised here, however, are mostly from the technical viewpoints: (1) what are alternative nuclear fuel cycles; (2) what generalizations are possible about their characteristics; (3) what are the major practical considerations; and (4) what is the present situation and what can be said about the outlook for the future

  6. HCl removal using cycled carbide slag from calcium looping cycles

    International Nuclear Information System (INIS)

    Xie, Xin; Li, Yingjie; Wang, Wenjing; Shi, Lei

    2014-01-01

    Highlights: • Cycled carbide slag from calcium looping cycles is used to remove HCl. • The optimum temperature for HCl removal of cycled carbide slag is 700 °C. • The presence of CO 2 restrains HCl removal of cycled carbide slag. • CO 2 capture conditions have important effects on HCl removal of cycled carbide slag. • HCl removal capacity of carbide slag drops with cycle number rising from 1 to 50. - Abstract: The carbide slag is an industrial waste from chlor-alkali plants, which can be used to capture CO 2 in the calcium looping cycles, i.e. carbonation/calcination cycles. In this work, the cycled carbide slag from the calcium looping cycles for CO 2 capture was proposed to remove HCl in the flue gas from the biomass-fired and RDFs-fired boilers. The effects of chlorination temperature, HCl concentration, particle size, presence of CO 2 , presence of O 2 , cycle number and CO 2 capture conditions in calcium looping cycles on the HCl removal behavior of the carbide slag experienced carbonation/calcination cycles were investigated in a triple fixed-bed reactor. The chlorination product of the cycled carbide slag from the calcium looping after absorbing HCl is not CaCl 2 but CaClOH. The optimum temperature for HCl removal of the cycled carbide slag from the carbonation/calcination cycles is 700 °C. The chlorination conversion of the cycled carbide slag increases with increasing the HCl concentration. The cycled carbide slag with larger particle size exhibits a lower chlorination conversion. The presence of CO 2 decreases the chlorination conversions of the cycled carbide slag and the presence of O 2 has a trifling impact. The chlorination conversion of the carbide slag experienced 1 carbonation/calcination cycle is higher than that of the uncycled calcined sorbent. As the number of carbonation/calcination cycles increases from 1 to 50, the chlorination conversion of carbide slag drops gradually. The high calcination temperature and high CO 2

  7. Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells.

    Science.gov (United States)

    Filipp, Fabian V; Scott, David A; Ronai, Ze'ev A; Osterman, Andrei L; Smith, Jeffrey W

    2012-05-01

    The tricarboxylic acid (TCA) cycle is the central hub of oxidative metabolism, running in the classic forward direction to provide carbon for biosynthesis and reducing agents for generation of ATP. Our metabolic tracer studies in melanoma cells showed that in hypoxic conditions the TCA cycle is largely disconnected from glycolysis. By studying the TCA branch point metabolites, acetyl CoA and citrate, as well as the metabolic endpoint glutamine and fatty acids, we developed a comprehensive picture of the rewiring of the TCA cycle that occurs in hypoxia. Hypoxic tumor cells maintain proliferation by running the TCA cycle in reverse. The source of carbon for acetyl CoA, citrate, and fatty acids switches from glucose in normoxia to glutamine in hypoxia. This hypoxic flux from glutamine into fatty acids is mediated by reductive carboxylation. This reductive carboxylation is catalyzed by two isocitrate dehydrogenases, IDH1 and IDH2. Their combined action is necessary and sufficient to effect the reverse TCA flux and maintain cellular viability. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

  8. The urea cycle disorders.

    Science.gov (United States)

    Helman, Guy; Pacheco-Colón, Ileana; Gropman, Andrea L

    2014-07-01

    The urea cycle is the primary nitrogen-disposal pathway in humans. It requires the coordinated function of six enzymes and two mitochondrial transporters to catalyze the conversion of a molecule of ammonia, the α-nitrogen of aspartate, and bicarbonate into urea. Whereas ammonia is toxic, urea is relatively inert, soluble in water, and readily excreted by the kidney in the urine. Accumulation of ammonia and other toxic intermediates of the cycle lead to predominantly neurologic sequelae. The disorders may present at any age from the neonatal period to adulthood, with the more severely affected patients presenting earlier in life. Patients are at risk for metabolic decompensation throughout life, often triggered by illness, fasting, surgery and postoperative states, peripartum, stress, and increased exogenous protein load. Here the authors address neurologic presentations of ornithine transcarbamylase deficiency in detail, the most common of the urea cycle disorders, neuropathology, neurophysiology, and our studies in neuroimaging. Special attention to late-onset presentations is given. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  9. International Business Cycle

    Directory of Open Access Journals (Sweden)

    Marek Lubiński

    2007-04-01

    Full Text Available Prime stylized facts of international business cycle theory refer to positive correlation in the cyclical components of important macroeconomic variables across countries. However a number of indicators of business cycle synchronization do not point to clear trends. It can be ascribed to the fact that different forces influence level of business cycle correlation. When investigating into the forces behind the commonness in aggregate fluctuations economic research seems to have pointed in two directions. One strand of the literature examines the idea of common exogenous shocks that affect economies simultaneously. In addition to that economic interdependencies such as trade in goods and services or capital account transactions may serve as the channels through which disturbances spill over across countries.The observed degree of output co movement reflects both the nature of the shocks that have occurred and the degree of economic interdependence. In the periods when common shocks prevail level of synchronization is usually higher than in times of transmission dominance.

  10. Closing the fuel cycle

    International Nuclear Information System (INIS)

    Aycoberry, C.; Rougeau, J.P.

    1987-01-01

    The progressive implementation of some key nuclear fuel cycle capecities in a country corresponds to a strategy for the acquisition of an independant energy source, France, Japan, and some European countries are engaged in such strategic programs. In France, COGEMA, the nuclear fuel company, has now completed the industrial demonstration of the closed fuel cycle. Its experience covers every step of the front-end and of the back-end: transportation of spent fuels, storage, reprocessing, wastes conditioning. The La Hague reprocessing plant smooth operation, as well as the large investment program under active progress can testify of full mastering of this industry. Together with other French and European companies, COGEMA is engaged in the recycling industry, both for uranium through conversion of uranyl nitrate for its further reeichment, and for plutonium through MOX fuel fabrication. Reprocessing and recycling offer the optimum solution for a complete, economic, safe and future-oriented fuel cycle, hence contributing to the necessary development of nuclear energy. (author)

  11. The Contemporary Carbon Cycle

    Science.gov (United States)

    Houghton, R. A.

    2003-12-01

    The global carbon cycle refers to the exchanges of carbon within and between four major reservoirs: the atmosphere, the oceans, land, and fossil fuels. Carbon may be transferred from one reservoir to another in seconds (e.g., the fixation of atmospheric CO2 into sugar through photosynthesis) or over millennia (e.g., the accumulation of fossil carbon (coal, oil, gas) through deposition and diagenesis of organic matter). This chapter emphasizes the exchanges that are important over years to decades and includes those occurring over the scale of months to a few centuries. The focus will be on the years 1980-2000 but our considerations will broadly include the years ˜1850-2100. Chapter 8.09, deals with longer-term processes that involve rates of carbon exchange that are small on an annual timescale (weathering, vulcanism, sedimentation, and diagenesis).The carbon cycle is important for at least three reasons. First, carbon forms the structure of all life on the planet, making up ˜50% of the dry weight of living things. Second, the cycling of carbon approximates the flows of energy around the Earth, the metabolism of natural, human, and industrial systems. Plants transform radiant energy into chemical energy in the form of sugars, starches, and other forms of organic matter; this energy, whether in living organisms or dead organic matter, supports food chains in natural ecosystems as well as human ecosystems, not the least of which are industrial societies habituated (addicted?) to fossil forms of energy for heating, transportation, and generation of electricity. The increased use of fossil fuels has led to a third reason for interest in the carbon cycle. Carbon, in the form of carbon dioxide (CO2) and methane (CH4), forms two of the most important greenhouse gases. These gases contribute to a natural greenhouse effect that has kept the planet warm enough to evolve and support life (without the greenhouse effect the Earth's average temperature would be -33

  12. How well can business cycle accounting account for business cycles?

    OpenAIRE

    Keisuke Otsu

    2012-01-01

    The business cycle accounting method introduced by Chari, Kehoe and McGrattan (2007) is a useful tool to decompose business cycle fluctuations into their contributing factors. However, the model estimated by the maximum likelihood method cannot replicate business cycle moments computed from data. Moment-based estimation might be an attractive alternative if the purpose of the research is to study business cycle properties such as volatility, persistence and cross-correlation of variables inst...

  13. Nuclear fuel cycle system analysis

    International Nuclear Information System (INIS)

    Ko, W. I.; Kwon, E. H.; Kim, S. G.; Park, B. H.; Song, K. C.; Song, D. Y.; Lee, H. H.; Chang, H. L.; Jeong, C. J.

    2012-04-01

    The nuclear fuel cycle system analysis method has been designed and established for an integrated nuclear fuel cycle system assessment by analyzing various methodologies. The economics, PR(Proliferation Resistance) and environmental impact evaluation of the fuel cycle system were performed using improved DB, and finally the best fuel cycle option which is applicable in Korea was derived. In addition, this research is helped to increase the national credibility and transparency for PR with developing and fulfilling PR enhancement program. The detailed contents of the work are as follows: 1)Establish and improve the DB for nuclear fuel cycle system analysis 2)Development of the analysis model for nuclear fuel cycle 3)Preliminary study for nuclear fuel cycle analysis 4)Development of overall evaluation model of nuclear fuel cycle system 5)Overall evaluation of nuclear fuel cycle system 6)Evaluate the PR for nuclear fuel cycle system and derive the enhancement method 7)Derive and fulfill of nuclear transparency enhancement method The optimum fuel cycle option which is economical and applicable to domestic situation was derived in this research. It would be a basis for establishment of the long-term strategy for nuclear fuel cycle. This work contributes for guaranteeing the technical, economical validity of the optimal fuel cycle option. Deriving and fulfillment of the method for enhancing nuclear transparency will also contribute to renewing the ROK-U.S Atomic Energy Agreement in 2014

  14. Alternative ORC bottoming cycles FOR combined cycle power plants

    International Nuclear Information System (INIS)

    Chacartegui, R.; Sanchez, D.; Munoz, J.M.; Sanchez, T.

    2009-01-01

    In this work, low temperature Organic Rankine Cycles are studied as bottoming cycle in medium and large scale combined cycle power plants. The analysis aims to show the interest of using these alternative cycles with high efficiency heavy duty gas turbines, for example recuperative gas turbines with lower gas turbine exhaust temperatures than in conventional combined cycle gas turbines. The following organic fluids have been considered: R113, R245, isobutene, toluene, cyclohexane and isopentane. Competitive results have been obtained for toluene and cyclohexane ORC combined cycles, with reasonably high global efficiencies. The paper is structured in four main parts. A review of combined cycle and ORC cycle technologies is presented, followed by a thermodynamic analysis of combined cycles with commercial gas turbines and ORC low temperature bottoming cycles. Then, a parametric optimization of an ORC combined cycle plant is performed in order to achieve a better integration between these two technologies. Finally, some economic considerations related to the use of ORC in combined cycles are discussed.

  15. Building carbon-carbon bonds using a biocatalytic methanol condensation cycle.

    Science.gov (United States)

    Bogorad, Igor W; Chen, Chang-Ting; Theisen, Matthew K; Wu, Tung-Yun; Schlenz, Alicia R; Lam, Albert T; Liao, James C

    2014-11-11

    Methanol is an important intermediate in the utilization of natural gas for synthesizing other feedstock chemicals. Typically, chemical approaches for building C-C bonds from methanol require high temperature and pressure. Biological conversion of methanol to longer carbon chain compounds is feasible; however, the natural biological pathways for methanol utilization involve carbon dioxide loss or ATP expenditure. Here we demonstrated a biocatalytic pathway, termed the methanol condensation cycle (MCC), by combining the nonoxidative glycolysis with the ribulose monophosphate pathway to convert methanol to higher-chain alcohols or other acetyl-CoA derivatives using enzymatic reactions in a carbon-conserved and ATP-independent system. We investigated the robustness of MCC and identified operational regions. We confirmed that the pathway forms a catalytic cycle through (13)C-carbon labeling. With a cell-free system, we demonstrated the conversion of methanol to ethanol or n-butanol. The high carbon efficiency and low operating temperature are attractive for transforming natural gas-derived methanol to longer-chain liquid fuels and other chemical derivatives.

  16. Cancer cell metabolism and mitochondria: Nutrient plasticity for TCA cycle fueling.

    Science.gov (United States)

    Corbet, Cyril; Feron, Olivier

    2017-08-01

    Warburg's hypothesis that cancer cells take up a lot of glucose in the presence of ambient oxygen but convert pyruvate into lactate due to impaired mitochondrial function led to the misconception that cancer cells rely on glycolysis as their major source of energy. Most recent 13 C-based metabolomic studies, including in cancer patients, indicate that cancer cells may also fully oxidize glucose. In addition to glucose-derived pyruvate, lactate, fatty acids and amino acids supply substrates to the TCA cycle to sustain mitochondrial metabolism. Here, we discuss how the metabolic flexibility afforded by these multiple mitochondrial inputs allows cancer cells to adapt according to the availability of the different fuels and the microenvironmental conditions such as hypoxia and acidosis. In particular, we focused on the role of the TCA cycle in interconnecting numerous metabolic routes in order to highlight metabolic vulnerabilities that represent attractive targets for a new generation of anticancer drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Breaking the ritual metabolic cycle in order to save acetyl CoA: A potential role for mitochondrial humanin in T2 bladder cancer aggressiveness

    Directory of Open Access Journals (Sweden)

    Nesreen Nabil Omar

    2017-06-01

    Full Text Available Introduction: Cancer cells may exhibit outsourcing of their high energy need in order to avoid the intrinsic mitochondrial apoptosis. Reduced mitochondrial respiration and accumulation of mitochondrial genome mutations are among metabolic transformations in this regard. Mitochondrial humanin (MT-RNR2 is a small peptide with anti-apoptotic activities attributed to binding some pro-apoptotic proteins. Aim of the work: The current study aims at investigating the expression of mitochondrial humanin in bladder tumor cells and the possible casting of humanin anti-apoptotic action through orchestrating some of the mitochondrial metabolic enzymes. Material and methods: Here messenger RNA of humanin, succinate dehydrogenase, glutaminase, isocitrate dehydrogenase were compared in tissues from patients with T2 bladder carcinoma in comparison to tumor associated normal tissues from the same patients. Levels of lactate and mitochondrial pyruvate carrier (MPC1 mRNA were determined to scrutinize the prevalence of aerobic glycolysis. Results: The present study found that tumor cells had suppressed aerobic glycolysis, augmented mitochondrial respiration and interrupted tricarboxylic acid cycle, all of which were suggested to serve tumor aggressiveness. MT-RNR2 was found closely related to the alterations in mitochondrial activity. Conclusion: MT-RNR2 plays its anti-apoptotic role partly by avoiding deploying energy from complete oxidation of organic compounds to inorganic wastes. Thus MT-RNR2 can potentially serve as a new biomarker in the diagnosis of bladder carcinoma especially that it is present in blood circulation.

  18. GEOSS Water Cycle Integrator

    Science.gov (United States)

    Koike, Toshio; Lawford, Richard; Cripe, Douglas

    2013-04-01

    It is critically important to recognize and co-manage the fundamental linkages across the water-dependent domains; land use, including deforestation; ecosystem services; and food-, energy- and health-securities. Sharing coordinated, comprehensive and sustained observations and information for sound decision-making is a first step; however, to take full advantage of these opportunities, we need to develop an effective collaboration mechanism for working together across different disciplines, sectors and agencies, and thereby gain a holistic view of the continuity between environmentally sustainable development, climate change adaptation and enhanced resilience. To promote effective multi-sectoral, interdisciplinary collaboration based on coordinated and integrated efforts, the intergovernmental Group on Earth Observations (GEO) is implementing the Global Earth Observation System of Systems (GEOSS). A component of GEOSS now under development is the "GEOSS Water Cycle Integrator (WCI)", which integrates Earth observations, modeling, data and information, management systems and education systems. GEOSS/WCI sets up "work benches" by which partners can share data, information and applications in an interoperable way, exchange knowledge and experiences, deepen mutual understanding and work together effectively to ultimately respond to issues of both mitigation and adaptation. (A work bench is a virtual geographical or phenomenological space where experts and managers collaborate to use information to address a problem within that space). GEOSS/WCI enhances the coordination of efforts to strengthen individual, institutional and infrastructure capacities, especially for effective interdisciplinary coordination and integration. GEO has established the GEOSS Asian Water Cycle Initiative (AWCI) and GEOSS African Water Cycle Coordination Initiative (AfWCCI). Through regional, inter-disciplinary, multi-sectoral integration and inter-agency coordination in Asia and Africa, GEOSS

  19. Mole sieve cycle optimization

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, P. [Petro-Canada Oil and Gas, Inc., Calgary, AB (Canada)

    2004-07-01

    Maturing gas basins and declining reservoirs have prompted the search for energy and cost reduction initiatives to maintain operation sustainability. This paper discusses the development of an algorithm to improve the efficiency of the Brazeau mole sieve dehydration system. Details of the operating unit and an outline of the system were provided, as well as an operator interface. The main objectives of the research were to reduce the number of corresponding regeneration cycles; reduce annual energy requirements; and extend the life of the dessicant. Reductions were anticipated at 35 per cent, leading towards fuel savings of $45,000 a year, and carbon dioxide reductions of 670 tonnes a year. However, significant barriers were also noted, including operations, maintenance and equipment replacement issues. Equations of state were used to estimate vapor pressure or water content in gases. Approximate water content was measured with gas flow rate. The resulting algorithm was implemented using a basic best fit curve generated for one variable with a correction factor applied as a second variable. Data books were provided to present water content of hydrocarbon gas, with implementation procedures. Benefits of the new system included longer service life and reduced chemical and outside service costs, and reduced lost production during sieve changes. Additional benefits included enhanced distributed computing system (DCS) interfaces within plant operations; extension of the adsorption cycle via the functionality of the algorithm; and the fact that during a plant upset, the algorithm froze cycle sequencing and eliminated the possibility of switching the beds and repeating regeneration. The improved system resulted in savings of $87,000. tabs, figs.

  20. The Life Cycle of Centrioles

    OpenAIRE

    Hatch, E.; Stearns, T.

    2010-01-01

    Centrioles organize the centrosome and nucleate the ciliary axoneme, and the centriole life cycle has many parallels to the chromosome cycle. The centriole cycle in animals begins at fertilization with the contribution of two centrioles by the male gamete. In the ensuing cell cycles, the duplication of centrioles is controlled temporally, spatially, and numerically. As a consequence of the duplication mechanism, the two centrioles in a typical interphase cell are of different ages and have di...

  1. DETECTING ALIEN LIMIT CYCLES NEAR A HAMILTONIAN 2-SADDLE CYCLE

    OpenAIRE

    LUCA, Stijn; DUMORTIER, Freddy; Caubergh, M.; Roussarie, R.

    2009-01-01

    This paper aims at providing and example of a cubic Hamiltonian 2-saddle cycle that after bifurcation can give rise to an alien limit cycle; this is a limit cycle that is not controlled by a zero of the related Abelian integral. To guarantee the existence of an alien limit cycle one can verify generic conditions on the Abelian integral and on the transition map associated to the connections of the 2-saddle cycle. In this paper, a general method is developed to compute the first and second der...

  2. Optimum gas turbine cycle for combined cycle power plant

    International Nuclear Information System (INIS)

    Polyzakis, A.L.; Koroneos, C.; Xydis, G.

    2008-01-01

    The gas turbine based power plant is characterized by its relatively low capital cost compared with the steam power plant. It has environmental advantages and short construction lead time. However, conventional industrial engines have lower efficiencies, especially at part load. One of the technologies adopted nowadays for efficiency improvement is the 'combined cycle'. The combined cycle technology is now well established and offers superior efficiency to any of the competing gas turbine based systems that are likely to be available in the medium term for large scale power generation applications. This paper has as objective the optimization of a combined cycle power plant describing and comparing four different gas turbine cycles: simple cycle, intercooled cycle, reheated cycle and intercooled and reheated cycle. The proposed combined cycle plant would produce 300 MW of power (200 MW from the gas turbine and 100 MW from the steam turbine). The results showed that the reheated gas turbine is the most desirable overall, mainly because of its high turbine exhaust gas temperature and resulting high thermal efficiency of the bottoming steam cycle. The optimal gas turbine (GT) cycle will lead to a more efficient combined cycle power plant (CCPP), and this will result in great savings. The initial approach adopted is to investigate independently the four theoretically possible configurations of the gas plant. On the basis of combining these with a single pressure Rankine cycle, the optimum gas scheme is found. Once the gas turbine is selected, the next step is to investigate the impact of the steam cycle design and parameters on the overall performance of the plant, in order to choose the combined cycle offering the best fit with the objectives of the work as depicted above. Each alterative cycle was studied, aiming to find the best option from the standpoint of overall efficiency, installation and operational costs, maintainability and reliability for a combined power

  3. The nuclear fuel cycle

    International Nuclear Information System (INIS)

    1998-05-01

    After a short introduction about nuclear power in the world, fission physics and the French nuclear power plants, this brochure describes in a digest way the different steps of the nuclear fuel cycle: uranium prospecting, mining activity, processing of uranium ores and production of uranium concentrates (yellow cake), uranium chemistry (conversion of the yellow cake into uranium hexafluoride), fabrication of nuclear fuels, use of fuels, reprocessing of spent fuels (uranium, plutonium and fission products), recycling of energetic materials, and storage of radioactive wastes. (J.S.)

  4. Liquid air cycle engines

    Science.gov (United States)

    Rosevear, Jerry

    1992-01-01

    Given here is a definition of Liquid Air Cycle Engines (LACE) and existing relevant technologies. Heat exchanger design and fabrication techniques, the handling of liquid hydrogen to achieve the greatest heat sink capabilities, and air decontamination to prevent heat exchanger fouling are discussed. It was concluded that technology needs to be extended in the areas of design and fabrication of heat exchangers to improve reliability along with weight and volume reductions. Catalysts need to be improved so that conversion can be achieved with lower quantities and lower volumes. Packaging studies need to be investigated both analytically and experimentally. Recycling with slush hydrogen needs further evaluation with experimental testing.

  5. Cycle 7 outage experience

    International Nuclear Information System (INIS)

    Gadeken, A.D.

    1986-03-01

    The scheduled 58-day refueling outage in preparation for the seventh operating cycle of the Fast Flux Test Facility (FFTF) was successfully completed three days ahead of schedule. The planning and execution of the outage was greatly aided by Project/2 automated scheduling capabilities. For example, the use of ''maintenance windows'' and resource loading capabilities was particularly effective. The value of the planning process was demonstrated by the smooth transition into the outage phase after an early shutdown and set the stage for our best outage to date

  6. Nuclear Fuel Cycle Objectives

    International Nuclear Information System (INIS)

    2013-01-01

    . The four Objectives publications include Nuclear General Objectives, Nuclear Power Objectives, Nuclear Fuel Cycle Objectives, and Radioactive Waste management and Decommissioning Objectives. This publication sets out the objectives that need to be achieved in the area of the nuclear fuel cycle to ensure that the Nuclear Energy Basic Principles are satisfied. Within each of these four Objectives publications, the individual topics that make up each area are addressed. The five topics included in this publication are: resources; fuel engineering and performance; spent fuel management and reprocessing; fuel cycles; and the research reactor nuclear fuel cycle

  7. The software life cycle

    CERN Document Server

    Ince, Darrel

    1990-01-01

    The Software Life Cycle deals with the software lifecycle, that is, what exactly happens when software is developed. Topics covered include aspects of software engineering, structured techniques of software development, and software project management. The use of mathematics to design and develop computer systems is also discussed. This book is comprised of 20 chapters divided into four sections and begins with an overview of software engineering and software development, paying particular attention to the birth of software engineering and the introduction of formal methods of software develop

  8. Closing the fuel cycle

    International Nuclear Information System (INIS)

    Wolfe, B.; Judson, B.F.

    1984-01-01

    The possibilities for closing the fuel cycle in today's nuclear climate in the US are compared with those envisioned in 1977. Reprocessing, the fast breeder reactor program, and the uranium supply are discussed. The conclusion drawn is that the nuclear world is less healthy and less stable than the one previously envisioned and that the major task before the international nuclear community is to develop technologies, institutions, and accepted procedures that will allow to economically provide the huge store of energy from reprocessing and the breeder that it appears the world will desperately need

  9. Entrepreneurship and the Business Cycle

    NARCIS (Netherlands)

    Ph.D. Koellinger (Philipp); A.R. Thurik (Roy)

    2011-01-01

    textabstractWe find new empirical regularities in the business cycle in a cross-country panel of 22 OECD countries for the period 1972-2007; entrepreneurship Granger-causes the cycles of the world economy. Furthermore, the entrepreneurial cycle is positively affected by the national unemployment

  10. Sometimes "Newton's Method" Always "Cycles"

    Science.gov (United States)

    Latulippe, Joe; Switkes, Jennifer

    2012-01-01

    Are there functions for which Newton's method cycles for all non-trivial initial guesses? We construct and solve a differential equation whose solution is a real-valued function that two-cycles under Newton iteration. Higher-order cycles of Newton's method iterates are explored in the complex plane using complex powers of "x." We find a class of…

  11. Culture in cycles: considering H.T. Odum's 'information cycle'

    Science.gov (United States)

    Abel, Thomas

    2014-01-01

    'Culture' remains a conundrum in anthropology. When recast in the mold of 'information cycles,' culture is transformed. New fault lines appear. Information is splintered into parallel or nested forms. Dynamics becomes cycling. Energy is essential. And culture has function in a directional universe. The 'information cycle' is the crowning component of H.T. Odum's theory of general systems. What follows is an application of the information cycle to the cultural domains of discourse, social media, ritual, education, journalism, technology, academia, and law, which were never attempted by Odum. In information cycles, cultural information is perpetuated - maintained against Second Law depreciation. Conclusions are that culture is in fact a nested hierarchy of cultural forms. Each scale of information production is semi-autonomous, with its own evolutionary dynamics of production and selection in an information cycle. Simultaneously, each information cycle is channeled or entrained by its larger scale of information and ultimately human-ecosystem structuring.

  12. The centriole duplication cycle

    Science.gov (United States)

    Fırat-Karalar, Elif Nur; Stearns, Tim

    2014-01-01

    Centrosomes are the main microtubule-organizing centre of animal cells and are important for many critical cellular and developmental processes from cell polarization to cell division. At the core of the centrosome are centrioles, which recruit pericentriolar material to form the centrosome and act as basal bodies to nucleate formation of cilia and flagella. Defects in centriole structure, function and number are associated with a variety of human diseases, including cancer, brain diseases and ciliopathies. In this review, we discuss recent advances in our understanding of how new centrioles are assembled and how centriole number is controlled. We propose a general model for centriole duplication control in which cooperative binding of duplication factors defines a centriole ‘origin of duplication’ that initiates duplication, and passage through mitosis effects changes that license the centriole for a new round of duplication in the next cell cycle. We also focus on variations on the general theme in which many centrioles are created in a single cell cycle, including the specialized structures associated with these variations, the deuterosome in animal cells and the blepharoplast in lower plant cells. PMID:25047614

  13. The sunspot cycle revisited

    International Nuclear Information System (INIS)

    Lomb, Nick

    2013-01-01

    The set of sunspot numbers observed since the invention of the telescope is one of the most studied time series in astronomy and yet it is also one of the most complex. Fourteen frequencies are found in the yearly mean sunspot numbers from 1700 to 2011using the Lomb-Scargle periodogram and prewhitening. All of the frequencies corresponding to shorter term periods can be matched with simple algebraic combinations of the frequency of the main 11-year period and the frequencies of the longer term periods in the periodogram. This is exactly what can be expected from amplitude and phase modulation of an 11.12-year periodicity by longer term variations. Similar, though not identical, results are obtained after correcting the sunspot number series as proposed by Svalgaard. On looking separately at the amplitude and phase modulation a clear relationship is found between the two modulations although this relationship has broken down for the last four solar cycles. The phase modulation implies that there is a definite underlying period for the solar cycle. Such a clock mechanism does seem to be a possibility in models of the solar dynamo incorporating a conveyor-belt-like meridional circulation between high polar latitudes and the equator.

  14. Reference thorium fuel cycle

    International Nuclear Information System (INIS)

    Driggers, F.E.

    1978-08-01

    In the reference fuel cycle for the TFCT program, fissile U will be denatured by mixing with 238 U; the plants will be located in secure areas, with Pu being recycled within these secure areas; Th will be recycled with recovered U and Pu; the head end will handle a variety of core and blanket fuel assembly designs for LWRs and HWRs; the fuel may be a homogeneous mixture either of U and Th oxide pellets or sol-gel microspheres; the cladding will be Zircaloy; and MgO may be added to the fuel to improve Th dissolution. Th is being considered as the fertile component of fuel in order to increase proliferation resistance. Spent U recovered from Th-based fuels must be re-enriched before recycle to prevent very rapid buildup of 238 U. Stainless steel will be considered as a backup to Zircaloy cladding in case Zr is incompatible with commercial aqueous dissolution. Storage of recovered irradiated Th will be considered as a backup to its use in the recycle of recovered Pu and U. Estimates are made of the time for introducing the Th fuel cycle into the LWR power industry. Since U fuel exposures in LWRs are likely to increase from 30,000 to 50,000 MWD/MT, the Th reprocessing plant should also be designed for Th fuel with 50,000 MWD/MT exposure

  15. Fast breeder fuel cycle

    International Nuclear Information System (INIS)

    1978-07-01

    This contribution is prepared for the answer to the questionnaire of working group 5, subgroup B. B.1. is the short review of the fast breeder fuel cycles based on the reference large commercial Japanese LMFBR. The LMFBRs are devided into two types. FBR-A is the reactor to be used before 2000, and its burnup and breeding ratio are relatively low. The reference fuel cycle requirement is calculated based on the FBR-A. FBR-B is the one to be used after 2000, and its burnup and breeding ratio are relatively high. B.2. is basic FBR fuel reprocessing scheme emphasizing the differences with LWR reprocessing. This scheme is based on the conceptual design and research and development work on the small scale LMFBR reprocessing facility of Japan. The facility adopts a conventional PUREX process except head end portions. The report also describes the effects of technical modifications of conventional reprocessing flow sheets, and the problems to be solved before the adoption of these alternatives

  16. Changing global carbon cycle

    International Nuclear Information System (INIS)

    Canadell, Pep

    2007-01-01

    Full text: The increase in atmospheric carbon dioxide (C02) is the single largest human perturbation on the earth's radiative balance contributing to climate change. Its rate of change reflects the balance between anthropogenic carbon emissions and the dynamics of a number of terrestrial and ocean processes that remove or emit C02. It is the long term evolution of this balance that will determine to large extent the speed and magnitude of the human induced climate change and the mitigation requirements to stabilise atmospheric C02 concentrations at any given level. In this talk, we show new trends in global carbon sources and sinks, with particularly focus on major shifts occurring since 2000 when the growth rate of atmospheric C02 has reached its highest level on record. The acceleration in the C02 growth results from the combination of several changes in properties of the carbon cycle, including: acceleration of anthropogenic carbon emissions; increased carbon intensity of the global economy, and decreased efficiency of natural carbon sinks. We discuss in more detail some of the possible causes of the reduced efficiency of natural carbon sinks on land and oceans, such as the decreased net sink in the Southern Ocean and on terrestrial mid-latitudes due to world-wide occurrence of drought. All these changes reported here characterise a carbon cycle that is generating stronger than expected climate forcing, and sooner than expected

  17. Part 5. Fuel cycle options

    International Nuclear Information System (INIS)

    Lineberry, M.J.; McFarlane, H.F.; Amundson, P.I.; Goin, R.W.; Webster, D.S.

    1980-01-01

    The results of the FBR fuel cycle study that supported US contributions to the INFCE are presented. Fuel cycle technology is reviewed from both generic and historical standpoints. Technology requirements are developed within the framework of three deployment scenarios: the reference international, the secured area, and the integral cycle. Reprocessing, fabrication, waste handling, transportation, and safeguards are discussed for each deployment scenario. Fuel cycle modifications designed to increase proliferation defenses are described and assessed for effectiveness and technology feasibility. The present status of fuel cycle technology is reviewed and key issues that require resolution are identified

  18. Ammonia-water Rankine cycle

    International Nuclear Information System (INIS)

    Bo Hanliang; Ma Changwen; Wu Shaorong

    1997-01-01

    On characteristics of heating source and cooling source in nuclear heating reactor cooperation, the authors advance a new kind of power cycle in which a multicomponent mixture as the work fluid, ammonia-water Rankine cycle, describe its running principle, and compare it with steam Rankine cycle in the same situation. The result is that: the new kind of power cycle, ammonia-water Rankine cycle has higher electricity efficiency; it suits for the situation of heating source and cooling source which offered by nuclear heating reactor cooperation. For low temperature heating source, it maybe has a widely application

  19. Cycling infrastructure for reducing cycling injuries in cyclists.

    Science.gov (United States)

    Mulvaney, Caroline A; Smith, Sherie; Watson, Michael C; Parkin, John; Coupland, Carol; Miller, Philip; Kendrick, Denise; McClintock, Hugh

    2015-12-10

    Cycling is an attractive form of transport. It is beneficial to the individual as a form of physical activity that may fit more readily into an individual's daily routine, such as for cycling to work and to the shops, than other physical activities such as visiting a gym. Cycling is also beneficial to the wider community and the environment as a result of fewer motorised journeys. Cyclists are seen as vulnerable road users who are frequently in close proximity to larger and faster motorised vehicles. Cycling infrastructure aims to make cycling both more convenient and safer for cyclists. This review is needed to guide transport planning. To:1. evaluate the effects of different types of cycling infrastructure on reducing cycling injuries in cyclists, by type of infrastructure;2. evaluate the effects of cycling infrastructure on reducing the severity of cycling injuries in cyclists;3. evaluate the effects of cycling infrastructure on reducing cycling injuries in cyclists with respect to age, sex and social group. We ran the most recent search on 2nd March 2015. We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (OvidSP), Embase Classic + Embase(OvidSP), PubMed and 10 other databases. We searched websites, handsearched conference proceedings, screened reference lists of included studies and previously published reviews and contacted relevant organisations. We included randomised controlled trials, cluster randomised controlled trials, controlled before-after studies, and interrupted time series studies which evaluated the effect of cycling infrastructure (such as cycle lanes, tracks or paths, speed management, roundabout design) on cyclist injury or collision rates. Studies had to include a comparator, that is, either no infrastructure or a different type of infrastructure. We excluded studies that assessed collisions that occurred as a result of competitive cycling. Two review authors examined the titles and

  20. LIFE CYCLE OF INFORMATION SYSTEMS

    Directory of Open Access Journals (Sweden)

    Y. S. Sennik

    2015-01-01

    Full Text Available This work is a generalization of the theoretical propositions related to the life cycle of information systems. There was given the definition of the life cycle, specify which items you should include every step of the cycle. Describes the methodology division of the life cycle on the main stage, including methodology Rational Unified Process. The description of the fundamental standards in this area. Special attention was paid to the work of the basic life cycle models. It was carried out their comparative characteristics. On the basis of the theoretical propositions, it was concluded that the preferred model of the life cycle for the corporate network is a spiral model and the use of international standards in the life cycle saves a lot of effort, time and material resources.

  1. The supercontinent cycle

    Energy Technology Data Exchange (ETDEWEB)

    Nance, R.D.; Worsley, T.R.; Moody, J.B.

    1988-07-01

    This paper discusses a new theory of plate tectonics which proposes that Pangaea was only the most recent in a series of supercontinents that have been breaking up and reassembling every 500 million years or so. The cycle, driven by heat percolating up from the mantle, splits continents and drives interrelated processes that shape the earth's geology and climate and play a role in biological evolution. The framework of the supercontinent theory makes it possible to understand the timing of changes in sea level that have taken place in the past 570 million years, and also helps to explain periods of intense mountain building, episodes of glaciation, and changes in the nature of life on the earth.

  2. The nuclear power cycle

    International Nuclear Information System (INIS)

    2004-01-01

    Fifty years after the first nuclear reactor come on-line, nuclear power is fourth among the world's primary energy sources, after oil, coal and gas. In 2002, there were 441 reactors in operation worldwide. The United States led the world with 104 reactors and an installed capacity of 100,000 MWe, or more than one fourth of global capacity. Electricity from nuclear energy represents 78% of the production in France, 57% in Belgium, 46% in Sweden, 40% in Switzerland, 39% in South Korea, 34% in Japan, 30% in Germany, 30% in Finland, 26% in Spain, 22% in Great Britain, 20% in the United States and 16% in Russia. Worldwide, 32 reactors are under construction, including 21 in Asia. This information document presents the Areva activities in the nuclear power cycle: the nuclear fuel, the nuclear reactors, the spent fuel reprocessing and recycling and nuclear cleanup and dismantling. (A.L.B.)

  3. CANDU advanced fuel cycles

    International Nuclear Information System (INIS)

    Slater, J.B.

    1986-03-01

    This report is based on informal lectures and presentations made on CANDU Advanced Fuel Cycles over the past year or so, and discusses the future role of CANDU in the changing environment for the Canadian and international nuclear power industry. The changing perspectives of the past decade lead to the conclusion that a significant future market for a CANDU advanced thermal reactor will exist for many decades. Such a reactor could operate in a stand-alone strategy or integrate with a mixed CANDU-LWR or CANDU-FBR strategy. The consistent design focus of CANDU on enhanced efficiency of resource utilization combined with a simple technology to achieve economic targets, will provide sufficient flexibility to maintain CANDU as a viable power producer for both the medium- and long-term future

  4. Open cycle thermoacoustics

    Energy Technology Data Exchange (ETDEWEB)

    Reid, Robert Stowers [Georgia Inst. of Technology, Atlanta, GA (United States)

    2000-01-01

    A new type of thermodynamic device combining a thermodynamic cycle with the externally applied steady flow of an open thermodynamic process is discussed and experimentally demonstrated. The gas flowing through this device can be heated or cooled in a series of semi-open cyclic steps. The combination of open and cyclic flows makes possible the elimination of some or all of the heat exchangers (with their associated irreversibility). Heat is directly exchanged with the process fluid as it flows through the device when operating as a refrigerator, producing a staging effect that tends to increase First Law thermodynamic efficiency. An open-flow thermoacoustic refrigerator was built to demonstrate this concept. Several approaches are presented that describe the physical characteristics of this device. Tests have been conducted on this refrigerator with good agreement with a proposed theory.

  5. The planning cycle.

    Science.gov (United States)

    Johnson, William

    2005-01-01

    Information technology planning can be described as a continuous cyclical process composed of three phases whose primary purpose is optimum allocation of scarce resources. In the assessment phase, planners assess user needs, environmental factors, business objectives, and IT infrastructure needs to develop IT projects that address needs in each of these areas. A major goal of this phase is to develop a broad IT inventory. The prioritization phase seeks to ensure optimum allocation of scarce resources by prioritizing ITprojects based on: Costs--total life cycle costs. Benefits--both quantitative and non-quantitative, including support for the organization's strategic business objectives. Risks--subjective assessments of technological and non-technological risks. Implementation requirements--time and personnel requirements to implement the system. The scheduling phase incorporates sequencing considerations, personnel availability, and budgetary constraints to produce an IT plan in which project priorities are adjusted to meet organizational realities.

  6. Variable cycle engine

    Energy Technology Data Exchange (ETDEWEB)

    Adamson, A.P.; Sprunger, E.V.

    1980-09-16

    A variable cycle turboshaft engine includes a remote fan system and respective high and low pressure systems for selectively driving the fan system in such a manner as to provide VTOL takeoff capability and minimum specific fuel consumption (SFC) at cruise and loiter conditions. For takeoff the fan system is primarily driven by the relatively large low pressure system whose combustor receives the motive fluid from a core bypass duct and, for cruise and loiter conditions, the fan system is driven by both a relatively small high pressure core and the low pressure system with its combustor inoperative. A mixer is disposed downstream of the high pressure system for mixing the relatively cold air from the bypass duct and the relatively hot air from the core prior to its flow to the low pressure turbine.

  7. HTGR fuel cycle

    International Nuclear Information System (INIS)

    1987-08-01

    In the spring of 1987, the HTGR fuel cycle project has been existing for ten years, and for this reason a status seminar has been held on May 12, 1987 in the Juelich Nuclear Research Center, that gathered the participants in this project for a discussion on the state of the art in HTGR fuel element development, graphite development, and waste management. The papers present an overview of work performed so far and an outlook on future tasks and goals, and on taking stock one can say that the project has been very successful so far: The HTGR fuel element now available meets highest requirements and forms the basis of today's HTGR safety philosophy; research work on graphite behaviour in a high-temperature reactor has led to complete knowledge of the temperature or neutron-induced effects, and with the concept of direct ultimate waste disposal, the waste management problem has found a feasible solution. (orig./GL) [de

  8. The uranium cycle

    International Nuclear Information System (INIS)

    Ferguson, J.

    1988-01-01

    In identifying uranium provinces, and, more importantly, mineralized zones within these provinces, it is of paramount importance to attempt to trace the geochemical behaviour of an element through all stages of Earth's evolution. Aspects that need to be addressed in this regard include solar abundance levels and fractionation processes during accretion, changing patterns of crustal evolution, effects of an evolving atmosphere, and the weathering cycle. Abundance patterns and partition coefficients of some of the siderophile elements in mantle rocks lend support to a multistage accretionary process. Lack of a terrestrial record in the first 500 Ma necessitates that lunar models be invoked, which suggests that early fractionation of a mafic/ultramafic magma resulted in an anorthositic crust. Fractionation of the mantle and transfer of materials to the upper levels must be central to any model invoked for development of the crust. Given high heat flow conditions in the early Archaean it would seem inescapable that the process of sea floor spreading and plate tectonics was an ongoing process. If the plate tectonic model is taken back to 3500 Ma, and assuming current speading rates, then about half of the mantle has passed through the irreversible differentiation cycle. Arguments in support of recycled material must be balanced against mantle metasomatism effects. With the associated advent of partial melting of the mantle material a partitioning of minor and trace elements into the melt fraction would take place. The early primitive mafic and ultramafic komatiites exemplify this feature by concentrating U and Th by a factor of 5 compared to chondritic abundances. It is of tantamount importance to understand the generation of the magmas in order to predict which are the 'fertile' bodies in terms of radioelement concentrations. In that the granitoid magmas image their source compositions, the association of high radioelements will primarily be source-dependent. Uranium

  9. The Hamburg oceanic carbon cycle circulation model. Cycle 1

    International Nuclear Information System (INIS)

    Maier-Reimer, E.; Heinze, C.

    1992-02-01

    The carbon cycle model calculates the prognostic fields of oceanic geochemical carbon cycle tracers making use of a 'frozen' velocity field provided by a run of the LSG oceanic circulation model (see the corresponding manual, LSG=Large Scale Geostrophic). The carbon cycle model includes a crude approximation of interactions between sediment and bottom layer water. A simple (meridionally diffusive) one layer atmosphere model allows to calculate the CO 2 airborne fraction resulting from the oceanic biogeochemical interactions. (orig.)

  10. Creeping of hysteresis cycles; Reptation des cycles d'hysteresis

    Energy Technology Data Exchange (ETDEWEB)

    Neel, L [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires; Faculte des Sciences de Grenoble, 38 (France)

    1959-07-01

    Creeping consists of a kind of progressive translation of dissymmetric ferromagnetic hysteresis cycles as a function of the order number of the cycle. It is interpreted here by means of a probable coupling field, the existence of which is connected to a statistical conception of the distribution of the elementary regions. (author) [French] La reptation consiste en une sorte de translation progressive des cycles d'hysteresis ferromagnetiques dissymetriques en fonction du numero d'ordre du cycle. L'auteur l'interprete au moyen d'un champ aleatoire de couplage dont l'existence est liee a une conception statistique de la distribution des domaines elementaires. (auteur)

  11. Flux response of glycolysis and storage metabolism during rapid feast/famine conditions in Penicillium chrysogenum using dynamic (13)C labeling.

    Science.gov (United States)

    de Jonge, Lodewijk; Buijs, Nicolaas A A; Heijnen, Joseph J; van Gulik, Walter M; Abate, Alessandro; Wahl, S Aljoscha

    2014-03-01

    The scale-up of fermentation processes frequently leads to a reduced productivity compared to small-scale screening experiments. Large-scale mixing limitations that lead to gradients in substrate and oxygen availability could influence the microorganism performance. Here, the impact of substrate gradients on a penicillin G producing Penicillium chrysogenum cultivation was analyzed using an intermittent glucose feeding regime. The intermittent feeding led to fluctuations in the extracellular glucose concentration between 400 μM down to 6.5 μM at the end of the cycle. The intracellular metabolite concentrations responded strongly and showed up to 100-fold changes. The intracellular flux changes were estimated on the basis of dynamic (13) C mass isotopomer measurements during three cycles of feast and famine using a novel hybrid modeling approach. The flux estimations indicated a high turnover of internal and external storage metabolites in P. chrysogenum under feast/famine conditions. The synthesis and degradation of storage requires cellular energy (ATP and UTP) in competition with other cellular functions including product formation. Especially, 38% of the incoming glucose was recycled once in storage metabolism. This result indicated that storage turnover is increased under dynamic cultivation conditions and contributes to the observed decrease in productivity compared to reference steady-state conditions. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. In anticipation of cycle 24

    Science.gov (United States)

    Kunches, Joseph; van der Linden, Ronald; Lundstedt, Henrik

    Anxious eyes are watching for the beginnings of new solar cycle 24. The watchers are many; scientists, engineers, academics, forecasters, end users. Their needs however vary, from the attraction of a better understanding of our nearest star, to how its increase in luminosity will affect particular aspects such as satellite orbits or the strength of the episodic storms that are most likely to occur during the height of the cycle. The first sign, however fleeting, occurred in January, 2008, when an ephemeral new cycle spot was numbered by NOAA as 10981. It was gone quickly but did mark the possible beginning of the new cycle. There has been great debate among solar physicists on how strong cycle 24 will be; and when it will start, reach maximum, and decline. This talk will give the status of the efforts to predict cycle 24, and the most recent projections.

  13. Menstrual cycle pattern and fertility

    DEFF Research Database (Denmark)

    Kolstad, Henrik A.; Bonde, Jens Peter; Hjøllund, Niels Henrik

    1999-01-01

    OBJECTIVE: To characterize how the menstrual cycle pattern relates to fertility regardless of potential biases caused by inappropriate coital timing during the menstrual cycle or early embryonal loss. DESIGN: Prospective follow-up study. SETTING: Healthy couples recruited throughout Denmark....... PATIENT(S): Two hundred ninety-five couples who were planning their first pregnancy were followed up from the discontinuation of birth control until a pregnancy was recognized within six menstrual cycles. Early embryonal losses were detected by changes in urinary hCG levels. INTERVENTION(S): None. MAIN...... OUTCOME MEASURE(S): The probability of pregnancy occurring within one menstrual cycle (fecundity). RESULT(S): In women who had a cycle length that differed by >10 days from the usual cycle length, fecundity was approximately 25% that of women who had no variation (odds ratio 0.25, 95% confidence interval...

  14. The Global Nitrogen Cycle

    Science.gov (United States)

    Galloway, J. N.

    2003-12-01

    Once upon a time nitrogen did not exist. Today it does. In the intervening time the universe was formed, nitrogen was created, the Earth came into existence, and its atmosphere and oceans were formed! In this analysis of the Earth's nitrogen cycle, I start with an overview of these important events relative to nitrogen and then move on to the more traditional analysis of the nitrogen cycle itself and the role of humans in its alteration.The universe is ˜15 Gyr old. Even after its formation, there was still a period when nitrogen did not exist. It took ˜300 thousand years after the big bang for the Universe to cool enough to create atoms; hydrogen and helium formed first. Nitrogen was formed in the stars through the process of nucleosynthesis. When a star's helium mass becomes great enough to reach the necessary pressure and temperature, helium begins to fuse into still heavier elements, including nitrogen.Approximately 10 Gyr elapsed before Earth was formed (˜4.5 Ga (billion years ago)) by the accumulation of pre-assembled materials in a multistage process. Assuming that N2 was the predominate nitrogen species in these materials and given that the temperature of space is -270 °C, N2 was probably a solid when the Earth was formed since its boiling point (b.p.) and melting point (m.p.) are -196 °C and -210 °C, respectively. Towards the end of the accumulation period, temperatures were probably high enough for significant melting of some of the accumulated material. The volcanic gases emitted by the resulting volcanism strongly influenced the surface environment. Nitrogen was converted from a solid to a gas and emitted as N2. Carbon and sulfur were probably emitted as CO and H2S (Holland, 1984). N2 is still the most common nitrogen volcanic gas emitted today at a rate of ˜2 TgN yr-1 (Jaffee, 1992).Once emitted, the gases either remained in the atmosphere or were deposited to the Earth's surface, thus continuing the process of biogeochemical cycling. The rate of

  15. The life cycle of centrioles.

    Science.gov (United States)

    Hatch, E; Stearns, T

    2010-01-01

    Centrioles organize the centrosome and nucleate the ciliary axoneme, and the centriole life cycle has many parallels to the chromosome cycle. The centriole cycle in animals begins at fertilization with the contribution of two centrioles by the male gamete. In the ensuing cell cycles, the duplication of centrioles is controlled temporally, spatially, and numerically. As a consequence of the duplication mechanism, the two centrioles in a typical interphase cell are of different ages and have different functions. Here, we discuss how new centrioles are assembled, what mechanisms limit centriole number, and the consequences of the inherent asymmetry of centriole duplication and segregation.

  16. Reproductive cycles of deer.

    Science.gov (United States)

    Asher, G W

    2011-04-01

    The cervids are a complex assemblage of taxa showing extreme diversity in morphology, physiology, ecology and geographical distribution. Reproductive strategies adopted by various species are also diverse, and include a range from highly seasonal to completely aseasonal birth patterns. The recent growth in knowledge on cervid reproduction is strongly biased towards the larger-bodied, gregarious mixed grazer-browser species that have adapted well to human management and commercialisation. These species tend to represent 'K-selected' climax species characterised by very productive annual breeding success, singleton births and long breeding life (10+ years). Conversely, we know relatively little about the reproductive patterns of the 'r-selected' smaller-bodied, solitary (and often highly territorial), forest-dwelling browser species, often characterised by great fecundity (twinning) and shorter breeding life (<10 years). This group includes many of the endangered cervid taxa. This review extends earlier reviews to include more recent work on cervid reproductive cycles, particularly in relation to environmental factors influencing gestation length. Copyright © 2010 Elsevier B.V. All rights reserved.

  17. The nitrogen cycle.

    Science.gov (United States)

    Stein, Lisa Y; Klotz, Martin G

    2016-02-08

    Nitrogen is the fourth most abundant element in cellular biomass, and it comprises the majority of Earth's atmosphere. The interchange between inert dinitrogen gas (N2) in the extant atmosphere and 'reactive nitrogen' (those nitrogen compounds that support, or are products of, cellular metabolism and growth) is entirely controlled by microbial activities. This was not the case, however, in the primordial atmosphere, when abiotic reactions likely played a significant role in the inter-transformation of nitrogen oxides. Although such abiotic reactions are still important, the extant nitrogen cycle is driven by reductive fixation of dinitrogen and an enzyme inventory that facilitates dinitrogen-producing reactions. Prior to the advent of the Haber-Bosch process (the industrial fixation of N2 into ammonia, NH3) in 1909, nearly all of the reactive nitrogen in the biosphere was generated and recycled by microorganisms. Although the Haber-Bosch process more than quadrupled the productivity of agricultural crops, chemical fertilizers and other anthropogenic sources of fixed nitrogen now far exceed natural contributions, leading to unprecedented environmental degradation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Biomass Gasification Combined Cycle

    Energy Technology Data Exchange (ETDEWEB)

    Judith A. Kieffer

    2000-07-01

    Gasification combined cycle continues to represent an important defining technology area for the forest products industry. The ''Forest Products Gasification Initiative'', organized under the Industry's Agenda 2020 technology vision and supported by the DOE ''Industries of the Future'' program, is well positioned to guide these technologies to commercial success within a five-to ten-year timeframe given supportive federal budgets and public policy. Commercial success will result in significant environmental and renewable energy goals that are shared by the Industry and the Nation. The Battelle/FERCO LIVG technology, which is the technology of choice for the application reported here, remains of high interest due to characteristics that make it well suited for integration with the infrastructure of a pulp production facility. The capital cost, operating economics and long-term demonstration of this technology area key input to future economically sustainable projects and must be verified by the 200 BDT/day demonstration facility currently operating in Burlington, Vermont. The New Bern application that was the initial objective of this project is not currently economically viable and will not be implemented at this time due to several changes at and around the mill which have occurred since the inception of the project in 1995. The analysis shows that for this technology, and likely other gasification technologies as well, the first few installations will require unique circumstances, or supportive public policies, or both to attract host sites and investors.

  19. The earth's hydrological cycle

    CERN Document Server

    Bonnet, R-M; Calisto, M; Destouni, G; Gurney, R; Johannessen, J; Kerr, Y; Lahoz, WA; Rast, M

    2014-01-01

    This book gives a comprehensive presentation of our present understanding of the Earth's Hydrological cycle and the problems, consequences and impacts that go with this topic. Water is a central component in the Earth's system. It is indispensable for life on Earth in its present form and influences virtually every aspect of our planet's life support system. On relatively short time scales, atmospheric water vapor interacts with the atmospheric circulation and is crucial in forming the Earth's climate zones. Water vapor is the most powerful of the greenhouse gases and serves to enhance the tropospheric temperature. The dominant part of available water on Earth resides in the oceans. Parts are locked up in the land ice on Greenland and Antarctica and a smaller part is estimated to exist as groundwater. If all the ice over the land and all the glaciers were to melt, the sea level would rise by some 80 m. In comparison, the total amount of water vapor in the atmosphere is small; it amounts to ~ 25 kg/m2, or the ...

  20. The closed fuel cycle

    International Nuclear Information System (INIS)

    Froment, Antoine; Gillet, Philippe

    2007-01-01

    Available in abstract form only. Full text of publication follows: The fast growth of the world's economy coupled with the need for optimizing use of natural resources, for energy security and for climate change mitigation make energy supply one of the 21. century most daring challenges. The high reliability and efficiency of nuclear energy, its competitiveness in an energy market undergoing a new oil shock are as many factors in favor of the 'renaissance' of this greenhouse gas free energy. Over 160,000 tHM of LWR1 and AGR2 Used Nuclear Fuel (UNF) have already been unloaded from the reactor cores corresponding to 7,000 tons discharged per year worldwide. By 2030, this amount could exceed 400,000 tHM and annual unloading 14,000 tHM/year. AREVA believes that closing the nuclear fuel cycle through the treatment and recycling of Used Nuclear Fuel sustains the worldwide nuclear power expansion. It is an economically sound and environmentally responsible choice, based on the preservation of natural resources through the recycling of used fuel. It furthermore provides a safe and secure management of wastes while significantly minimizing the burden left to future generations. (authors)