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Hexose kinase 2 inhibitors

Adrian Westhaus, Eva Maria Blumrich, Ralf Dringen
Metformin is the most frequently used drug for the treatment of type 2 diabetes in humans. However, only little is known about effects of metformin on brain metabolism. To investigate potential metabolic consequences of an exposure of brain cells to metformin, we incubated rat astrocyte-rich primary cultures with this compound. Metformin in concentrations of up to 30 mM did not acutely compromise the viability of astrocytes, but caused a time- and concentration-dependent increase in cellular glucose consumption and lactate production...
October 3, 2015: Neurochemical Research
Annika Pfeiffer, Martin Jaeckel, Jan Lewerenz, Rebecca Noack, Alireza Pouya, Teresa Schacht, Christina Hoffmann, Jennifer Winter, Susann Schweiger, Michael K E Schäfer, Axel Methner
BACKGROUND AND PURPOSE: The hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Extracellular glutamate depletes cellular glutathione by blocking the glutamate/cystine antiporter system xc-. Glutathione depletion induces a well-defined programme of cell death characterized by an increase in reactive oxygen species and mitochondrial dysfunction. EXPERIMENTAL APPROACH: We compared the mitochondrial shape, the abundance of mitochondrial complexes and the mitochondrial respiration of HT22 cells, selected based on their resistance to glutamate, with those of the glutamate-sensitive parental cell line...
April 2014: British Journal of Pharmacology
Shiraj Sen, Bijoy K Kundu, Henry Cheng-Ju Wu, S Shahrukh Hashmi, Patrick Guthrie, Landon W Locke, R Jack Roy, G Paul Matherne, Stuart S Berr, Matthew Terwelp, Brian Scott, Sylvia Carranza, O Howard Frazier, David K Glover, Wolfgang H Dillmann, Michael J Gambello, Mark L Entman, Heinrich Taegtmeyer
BACKGROUND: Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose-6-phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6-phosphate (G6P) accumulation. METHODS AND RESULTS: We subjected the working rat heart ex vivo to a high workload in the presence of different energy-providing substrates including glucose, glucose analogues, and noncarbohydrate substrates...
June 2013: Journal of the American Heart Association
Santiago Diaz-Moralli, Antonio Ramos-Montoya, Silvia Marin, Ana Fernandez-Alvarez, Marta Casado, Marta Cascante
Carbohydrate response element-binding protein (ChREBP) is a transcription factor that mediates glucose signaling in mammalian liver, leading to the expression of different glycolytic and lipogenic genes, such as pyruvate kinase (L-PK) and fatty acid synthase (FAS). The current model for ChREBP activation in response to sugar phosphates holds that glucose metabolization to xylulose 5-phosphate (X-5-P) triggers the activation of protein phosphatase 2A, which dephosphorylates ChREBP and leads to its nuclear translocation and activation...
July 15, 2012: American Journal of Physiology. Endocrinology and Metabolism
Yin Wang, Yan Liu, Cindy Wu, Beth McNally, Yang Liu, Pan Zheng
A long-standing but poorly understood observation in experimental cancer therapy is the heterogeneity in cancer susceptibility to energy deprivation. Here, we show that the hexose kinase inhibitor 2-deoxyglucose (2-dG) preferentially kills cancer cells with defective laforin expression and significantly increases the survival of mice with aggressive lymphoma due to a genetic defect of the laforin-encoding Epm2a gene. Normal cells from Epm2a(-/-) mice also had greatly increased susceptibility to 2-dG. Thus, laforin is a novel regulator for cellular response to energy deprivation and its defects in cancer cells may be targeted for cancer therapy...
June 1, 2008: Cancer Research
Maude Le Gall, Vanessa Tobin, Emilie Stolarczyk, Véronique Dalet, Armelle Leturque, Edith Brot-Laroche
Sugar consumption and subsequent sugar metabolism are known to regulate the expression of genes involved in intestinal sugar absorption and delivery. Here we investigate the hypothesis that sugar-sensing detectors in membranes facing the intestinal lumen or the bloodstream can also modulate intestinal sugar absorption. We used wild-type and GLUT2-null mice, to show that dietary sugars stimulate the expression of sucrase-isomaltase (SI) and L-pyruvate kinase (L-PK) by GLUT2-dependent mechanisms, whereas the expression of GLUT5 and SGLT1, did not rely on the presence of GLUT2...
December 2007: Journal of Cellular Physiology
Evgenia Alpert, Arie Gruzman, Tamar Tennenbaum, Shlomo Sasson
Selective inhibitors of cyclooxygenase-2 (prostaglandin-endoperoxide synthase-2; COX-2) augment the rate of hexose uptake in myotubes by recruiting glucose transporter-4 (GLUT-4) to the plasma membrane in an insulin- and AMPKalpha-independent manner [Alpert E, Gruzman A, Lardi-Studler B, Cohen G, Reich R, Sasson S. Cyclooxygenase-2 (PTGS2) inhibitors augment the rate of hexose transport in L6 myotubes in an insulin- and AMPKalpha-independent manner. Diabetologia 2006;49:562-70]. We aimed at elucidating the molecular interactions that mediate this effect of COX-2 inhibitors in L6 myotubes...
February 1, 2007: Biochemical Pharmacology
G J Tanner, L Copeland, J F Turner
The subcellular localization of hexose phosphorylating activity in extracts of pea stems has been studied by differential centrifugation and sucrose density gradient centrifugation. The hexokinase (EC was associated with the mitochondria, whereas fructokinase (EC was in the cytosolic fraction. Some properties of the mitochondrial hexokinase were studied. The enzyme had a high affinity for glucose (K(m) 76 micromolar) and mannose (K(m) 71 micromolar) and a relatively low affinity for fructose (K(m) 15...
July 1983: Plant Physiology
J F Turner, L Copeland
A second hexokinase (EC was obtained from pea seed (Pisum sativum L. var. Progress No. 9) extracts. The enzyme, termed hexokinase II, had a high affinity (K(m), 48 micromolar) for glucose and a relatively low affinity (K(m), 10 millimolar) for fructose. The K(m) for MgATP was 86 micromolar. Mg(2+) was required for activity, but excess Mg(2+) was inhibitory. MgADP inhibited hexokinase II. The addition of salts of monovalent cations increased hexokinase II activity. Al(3+) was a strong inhibitor of the enzyme at pH 6...
November 1981: Plant Physiology
E Alpert, A Gruzman, B Lardi-Studler, G Cohen, R Reich, S Sasson
AIMS/HYPOTHESIS: Some cyclooxygenase-2 (COX2, also known as prostaglandin-endoperoxide synthase 2 [PTGS2]) inhibitors have been shown to increase insulin sensitivity in man or induce hypoglycaemic episodes when overconsumed or taken in combination with oral hypoglycaemic drugs. These side-effects and their impact on patients are not always recognised in routine clinical practice. We investigated whether these side-effects of COX2 (PTGS2) inhibitors result from stimulation of the glucose transport system in skeletal muscle cells...
March 2006: Diabetologia
Nadeeja Wijesekara, Amanda Tung, Farah Thong, Amira Klip
Contracting skeletal muscle increases glucose uptake to sustain energy demand. This is achieved through a gain in GLUT4 at the membrane, but the traffic mechanisms and regulatory signals involved are unknown. Muscle contraction is elicited by membrane depolarization followed by a rise in cytosolic Ca2+ and actomyosin activation, drawing on ATP stores. It is unknown whether one or more of these events triggers the rise in surface GLUT4. Here, we investigate the effect of membrane depolarization on GLUT4 cycling using GLUT4myc-expressing L6 myotubes devoid of sarcomeres and thus unable to contract...
June 2006: American Journal of Physiology. Endocrinology and Metabolism
Giulio Agnetti, Tullia Maraldi, Diana Fiorentini, Emanuele Giordano, Cecilia Prata, Gabriele Hakim, Claudio Muscari, Carlo Guarnieri, Claudio Marcello Caldarera
Glucose transport into cells may be regulated by a variety of conditions, including ischemia. We investigated whether some enzymes frequently involved in the metabolic adaptation to ischemia are also required for glucose transport activation. Ischemia was simulated by incubating during 3 h H9c2 cardiomyoblasts in a serum- and glucose-free medium in hypoxia. Under these conditions 2-deoxy-d-[2,6-(3)H]-glucose uptake was increased (57% above control levels, p<0.0001) consistently with GLUT1 and GLUT4 translocation to sarcolemma...
December 5, 2005: Life Sciences
Volodymyr Gerzanich, Svetlana Ivanova, J Marc Simard
We studied the early pathophysiological response of lenticulostriate arterioles in rats in three models of human conditions associated with stroke: (a) chronic angiotensin II-hypertension; (b) chronic nicotine administration; (c) oxidative endothelial injury. In all three models, quantitative patch clamp analysis of freshly isolated vascular smooth muscle cells from lenticulostriate arterioles and posterior cerebral arteries showed significant increases in activity of functional L-type calcium channels that were due to an increase in open channel probability, with no change in other biophysical properties or in channel expression...
2003: Clinical Hemorheology and Microcirculation
Johanne Bentley, Dalina Itchayanan, Kay Barnes, Elizabeth McIntosh, Xiuwen Tang, C Peter Downes, Geoffrey D Holman, Anthony D Whetton, P Jane Owen-Lynch, Stephen A Baldwin
Maintenance of glucose uptake is a key component in the response of hematopoietic cells to survival factors. To investigate the mechanism of this response we employed the interleukin-3 (IL-3)-dependent murine mast cell line IC2.9. In these cells, hexose uptake decreased markedly upon withdrawal of IL-3, whereas its readdition led to rapid (t(1/2) approximately 10 min) stimulation of transport, associated with an approximately 4-fold increase in Vmax but no change in Km. Immunocytochemistry and photoaffinity labeling revealed that IL-3 caused translocation of intracellular GLUT1 transporters to the cell surface, whereas a second transporter isoform, GLUT3, remained predominantly intracellular...
October 10, 2003: Journal of Biological Chemistry
Jonathan E Markham, Nicholas J Kruger
A cDNA encoding 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase was isolated from a Spinacia oleracea leaf library and used to express a recombinant enzyme in Escherichia coli and Spodoptera frugiperda cells. The insoluble protein expressed in E. coli was purified and used to raise antibodies. Western blot analysis of a protein extract from spinach leaf showed a single band of 90.8 kDa. Soluble protein was purified to homogeneity from S. frugiperda cells infected with recombinant baculovirus harboring the isolated cDNA...
February 2002: European Journal of Biochemistry
R Somwar, D Y Kim, G Sweeney, C Huang, W Niu, C Lador, T Ramlal, A Klip
We previously reported that SB203580, an inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), attenuates insulin-stimulated glucose uptake without altering GLUT4 translocation. These results suggested that insulin might activate GLUT4 via a p38 MAPK-dependent pathway. Here we explore this hypothesis by temporal and kinetic analyses of the stimulation of GLUT4 translocation, glucose uptake and activation of p38 MAPK isoforms by insulin. In L6 myotubes stably expressing GLUT4 with an exofacial Myc epitope, we found that GLUT4 translocation (t(1/2)=2...
November 1, 2001: Biochemical Journal
D Fiorentini, G Hakim, L Bonsi, G P Bagnara, T Maraldi, L Landi
The present study was undertaken to: (i) compare the effect of some hematopoietic growth factors, like interleukine-3, thrombopoietin, granulocyte-megakaryocyte colony-stimulating factor, stem cell factor, and reactive oxygen species such as H(2)O(2) on glucose uptake in a human leukemic megakaryocytic cell line, M07; (ii) investigate the changes in kinetic parameters of the transport activity induced by these stimuli; and (iii) evaluate the effect of genistein, a tyrosine kinase inhibitor, on the glucose uptake activation by the cited agents...
October 1, 2001: Free Radical Biology & Medicine
V L Knowles, C S Smith, C R Smith, W C Plaxton
Pyruvate kinase (PK) from the cyanobacterium Synechococcus PCC 6301 was purified 1,300-fold to electrophoretic homogeneity and a final specific activity of 222 micromol of pyruvate produced/min/mg of protein. The enzyme was shown to have a pI of 5.7 and to exist as a 280-kDa homotetramer composed of 66-kDa subunits. This PK appears to be immunologically related to Bacillus PK and a green algal chloroplast PK, but not to rabbit muscle PK, or vascular plant cytosolic and plastidic PKs. The N-terminal amino acid sequence of the Synechococcus PK exhibited maximal (67%) identity with the corresponding region of a putative PK-A sequence deduced from the genome of the cyanobacterium, Synechocystis PCC 6803...
June 15, 2001: Journal of Biological Chemistry
C G Lechuga, J J Carrillo, J C Sánchez-Gutiérrez, J E Felíu
The influence of the hypoglycemic agent glipizide (0-100 microM) on the rate of gluconeogenesis from lactate, as well as on the levels of fructose 2,6-bisphosphate, has been investigated in hepatocytes isolated from genetically obese (fa/fa) Zucker rats and from their corresponding lean (Fa/-) littermates. As compared to lean rat hepatocytes, liver cells isolated from obese animals showed a lower rate of basal gluconeogenesis (0.9 +/- 0.2 vs 5.4 +/- 0.5 micromol of lactate converted to glucose/g cell x 30 min, n=4) and higher levels of fructose 2,6-bisphosphate (11...
February 23, 2001: Life Sciences
K Teramachi, M Izawa
Most solid tumors, including gastric cancers, respond poorly to non-surgical treatments which are expected to induce an apoptosis-dependent involution. We hypothesize that the apoptotic machinery in solid tumors is either defective or in a suppressed condition. Overcoming the ineffective induction of apoptosis may improve the responsiveness of solid tumors to non-surgical treatments. Recently, sorbitol, a kind of hexose, has been found to be an effective inducer of apoptosis in HEp-2 cells. Therefore, it is of particular interest to examine the effect of sorbitol-treatment on gastric cancer cells...
April 2000: Apoptosis: An International Journal on Programmed Cell Death
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