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Lactate AND Oxamate

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https://www.readbyqxmd.com/read/28728159/oxamate-enhances-the-anti-inflammatory-and-insulin-sensitizing-effects-of-metformin-in-diabetic-mice
#1
Mu-Chao Wu, Wei-Ran Ye, Yi-Jia Zheng, Shan-Shan Zhang
Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice...
July 21, 2017: Pharmacology
https://www.readbyqxmd.com/read/28680051/lactate-dehydrogenase-a-promotes-the-invasion-and-proliferation-of-pituitary-adenoma
#2
Jiayin An, Yin Zhang, Jiaojiang He, Zhenle Zang, Zheng Zhou, Xiangdong Pei, Xin Zheng, Weihua Zhang, Hui Yang, Song Li
Lactate dehydrogenase A (LDHA) has been reported to be involved in the initiation and progression of tumors. However, the potential role of LDHA in pituitary adenoma (PA) remains unknown. In this study, we showed that the expression levels of LDHA mRNA and protein were significantly elevated in invasive PA samples, and positively correlated with higher Ki-67 index. Overexpression of LDHA in a PA cell line (GH3) promoted glucose uptake through the upregulation of glucose transporter-1 (Glut1), lactate secretion and induced cellular invasion by upregulation of matrix metalloproteinase2 (MMP2)...
July 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28591943/-heregulin-%C3%AE-1-induced-glycolysis-promotes-migration-of-breast-cancer-cell-line-mcf7
#3
Su-Fang Jiang, Kai-Ling Tu, Lan Zhou, Qiang Fu, Yu-Hua Zhao
OBJECTIVES: To explore whether heregulin-β1 (HRG-β1) can induce glycolysis and the role of HRG-β1-induced glycolysis in the migration of human breast cancer cell line MCF7. METHODS: MCF7 cells were treated with PBS (PBS group) or HRG-β1 for 12, 24 and 48 h. Culture media were harvested for glucose uptake and lactate production assays, and cells were collected and lactate dehydrogenase A (LDHA) protein levels were detected by using Western blot. MCF7 cells were treated with PBS (PBS group), HRG-β1 or HRG-β1 plus oxamate (OX) for 24 h...
July 2016: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28571757/hmgb1-promotes-hlf-1-proliferation-and-ecm-production-through-activating-hif1-%C3%AE-regulated-aerobic-glycolysis
#4
JianNing Xu, JingYing Li, ZhiHong Yu, HaiWei Rao, Shu Wang, HaiBing Lan
Aerobic glycolysis is a crucial event in fibroblast differentiation, and extracellular matrix (ECM) production in the progression of pulmonary fibrosis (PF). Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of PF. However, whether aerobic glycolysis contributes to HMGB1-induced fibroblast proliferation and ECM production in PF has not yet been determined. In this study, we investigated the effects of HMGB1 on human embryonic lung fibroblast (HLF-1) proliferation, ECM production, and aerobic glycolysis...
May 29, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28564593/the-occurrence-of-l-lactate-dehydrogenase-in-the-inner-mitochondrial-compartment-of-pig-liver
#5
Gianluca Paventi, Roberto Pizzuto, Salvatore Passarella
Although pig represents a model species in biomedical research including studies dealing with liver patho-physiology, some aspects of liver metabolism need to be addressed. In particular, whether and how pig mitochondria can metabolize l-lactate remains to be established. We show here that pig liver mitochondria (PLM) possess their own l-lactate dehydrogenase (mL-LDH). This was shown both via immunological analysis and by assaying photometrically the L-LDH reaction in solubilised PLM. The mL-LDH reaction shows hyperbolic dependence on the substrate concentration, it is inhibited by oxamate and proves to differ from the cytosolic activity (cL-LDH), as revealed by the difference found in both pH profiles and temperature dependence of m- and cL-LDH...
May 28, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28413646/role-of-malate-dehydrogenase-in-facilitating-lactate-dehydrogenase-to-support-the-glycolysis-pathway-in-tumors
#6
Siavash Mansouri, Ali Shahriari, Hadi Kalantar, Taraneh Moini Zanjani, Mojtaba Haghi Karamallah
High aerobic glycolysis, as one of the hallmarks of cancer cells, requires nicotinamide adenine dinucleotide (NAD(+)) as a vital co-factor, to guarantee the flow of glycolysis. Malate dehydrogenase (MDH), as an important enzyme in cancer metabolism, is a source of NAD(+) additional to lactate dehydrogenase (LDH). The current study aimed to elucidate the kinetic parameters of MDH in human breast cancer and evaluate its supportive role in the glycolysis pathway. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of MDH were determined in the crude extracts of human breast tumors and healthy tissue samples, which were obtained directly from the operating theatre...
April 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28391608/mechanistic-analysis-of-fluorescence-quenching-of-reduced-nicotinamide-adenine-dinucleotide-by-oxamate-in-lactate-dehydrogenase-ternary-complexes
#7
Huo-Lei Peng, Robert Callender
Fluorescence of Reduced Nicotinamide Adenine Dinucleotide (NADH) is extensively employed in studies of oxidoreductases. A substantial amount of static and kinetic work has focused on the binding of pyruvate or substrate mimic oxamate to LDH•NADH where substantial fluorescence quenching is typically observed. However, the quenching mechanism is not well understood limiting structural interpretation. Based on time-dependent density functional theory (TDDFT) computations with cam-B3LYP functional in conjunction with the analysis of previous experimental results, we propose that bound oxamate acts as an electron acceptor in the quenching of fluorescence of NADH in the ternary complex, where a charge transfer (CT) state characterized by excitation from the highest occupied molecular orbital (HOMO) of the nicotinamide moiety of NADH to the lowest unoccupied molecular orbital (LUMO) of oxamate exists close to the locally excited (LE) state involving only the nicotinamide moiety...
April 9, 2017: Photochemistry and Photobiology
https://www.readbyqxmd.com/read/27721794/inhibition-of-non-flux-controlling-enzymes-deters-cancer-glycolysis-by-accumulation-of-regulatory-metabolites-of-controlling-steps
#8
Álvaro Marín-Hernández, José S Rodríguez-Zavala, Isis Del Mazo-Monsalvo, Sara Rodríguez-Enríquez, Rafael Moreno-Sánchez, Emma Saavedra
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...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27698900/anti-inflammatory-and-antitumor-activity-of-a-triple-therapy-for-a-colitis-related-colorectal-cancer
#9
Gabriela Figueroa-González, Verónica García-Castillo, Jossimar Coronel-Hernández, Eduardo López-Urrutia, Sonia León-Cabrera, Luis E Arias-Romero, L I Terrazas, Miriam Rodríguez-Sosa, Alma Delia Campos-Parra, Eduardo Zúñiga-Calzada, Cesar Lopez-Camarillo, Fermín Morales-González, Nadia J Jacobo-Herrera, Carlos Pérez-Plasencia
Colorectal cancer (CRC) is an important health issue worldwide, accounting for the third place of cancer incidence. Chronic inflammation, as seen in Crohn's disease and ulcerative colitis, is the most important risk factor for developing CRC, as it favours neoplastic transformation by enhancing epithelial cell turnover in the colonic mucosa. Treatments for CRC need to be improved; currently they are not specific and have several secondary effects in patients. The main objective of this work was to evaluate a new therapeutic strategy against a colitis-related colorectal cancer in vivo and in vitro by targeting mTOR-signaling and lactate dehydrogenase A...
2016: Journal of Cancer
https://www.readbyqxmd.com/read/27622920/lactate-dehydrogenase-inhibitors-can-reverse-inflammation-induced-changes-in-colon-cancer-cells
#10
Marcella Manerba, Lorenza Di Ianni, Marzia Govoni, Marinella Roberti, Maurizio Recanatini, Giuseppina Di Stefano
The inflammatory microenvironment is an essential component of neoplastic lesions and can significantly impact on tumor progression. Besides facilitating invasive growth, inflammatory cytokines were also found to reprogram cancer cell metabolism and to induce aerobic glycolysis. Previous studies did not consider the possible contribution played in these changes by lactate dehydrogenase (LDH). The A isoform of LDH (LDH-A) is the master regulator of aerobic glycolysis; it actively reduces pyruvate and causes enhanced lactate levels in tumor tissues...
January 1, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27618187/lactate-metabolism-is-associated-with-mammalian-mitochondria
#11
Ying-Jr Chen, Nathaniel G Mahieu, Xiaojing Huang, Manmilan Singh, Peter A Crawford, Stephen L Johnson, Richard W Gross, Jacob Schaefer, Gary J Patti
It is well established that lactate secreted by fermenting cells can be oxidized or used as a gluconeogenic substrate by other cells and tissues. It is generally assumed, however, that within the fermenting cell itself, lactate is produced to replenish NAD(+) and then is secreted. Here we explore the possibility that cytosolic lactate is metabolized by the mitochondria of fermenting mammalian cells. We found that fermenting HeLa and H460 cells utilize exogenous lactate carbon to synthesize a large percentage of their lipids...
November 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27319381/active-loop-dynamics-within-the-michaelis-complex-of-lactate-dehydrogenase-from-bacillus-stearothermophilus
#12
COMPARATIVE STUDY
Beining Nie, Kara Lodewyks, Hua Deng, Ruel Z B Desamero, Robert Callender
Laser-induced temperature-jump relaxation spectroscopy was used to study the active site mobile-loop dynamics found in the binding of the NADH nucleotide cofactor and oxamate substrate mimic to lactate dehydrogenase in Bacillus stearothermophilus thermophilic bacteria (bsLDH). The kinetic data can be best described by a model in which NADH can bind only to the open-loop apoenzyme, oxamate can bind only to the bsLDH·NADH binary complex in the open-loop conformation, and oxamate binding is followed by closing of the active site loop preventing oxamate unbinding...
July 12, 2016: Biochemistry
https://www.readbyqxmd.com/read/27222229/overcoming-cetuximab-resistance-in-ewing-s%C3%A2-sarcoma-by-inhibiting-lactate-dehydrogenase-a
#13
Jiaxin Fu, Han Jiang, Chenxuan Wu, Yi Jiang, Lianping Xiao, Yonggang Tian
Ewing's sarcoma, the second most common type of malignant bone tumor, generally occurs in children and young adults. The current treatment of Ewing's sarcoma comprises systemic anti‑cancer chemotherapy with complete surgical resection. However, the majority of patients with Ewing's sarcoma develop resistance to chemotherapy. The present study revealed an oncogenic role of lactate dehydrogenase‑A (LDHA) in the resistance of Ewing's sarcoma to cetuximab. LDHA was shown to be upregulated at the protein and mRNA level in cetuximab‑resistant Ewing's sarcoma tissues and a cell line...
July 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27069123/inhibition-of-growth-by-combined-treatment-with-inhibitors-of-lactate-dehydrogenase-and-either-phenformin-or-inhibitors-of-6-phosphofructo-2-kinase-fructose-2-6-bisphosphatase-3
#14
Michael A Lea, Yolanda Guzman, Charles Desbordes
Enhanced glycolysis in cancer cells presents a target for chemotherapy. Previous studies have indicated that proliferation of cancer cells can be inhibited by treatment with phenformin and with an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB) namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). In the present work, the action of two inhibitors that are effective at lower concentrations than 3PO, namely 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP) and 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) were investigated...
April 2016: Anticancer Research
https://www.readbyqxmd.com/read/27010533/hypoxia-inducible-proteins-hif1%C3%AE-and-lactate-dehydrogenase-ldh5-key-markers-of-anaerobic-metabolism-relate-with-stem-cell-markers-and-poor-post-radiotherapy-outcome-in-bladder-cancer
#15
Michael I Koukourakis, Christos Kakouratos, Dimitra Kalamida, Zoi Bampali, Sophia Mavropoulou, Efthimios Sivridis, Alexandra Giatromanolaki
PURPOSE: To assess whether anaerobic metabolism, proliferation activity and stem cell content are linked with radioresistance in bladder cancer. MATERIALS AND METHODS: Tissue sections from 66 patients with invasive transitional cell bladder cancer treated with hypofractionated accelerated radiotherapy, was immunohistochemically analyzed for the Hypoxia-Inducible Factor 1α (HIF1α) and the anaerobic glycolysis enzyme lactate dehydrogenase 5 (LDH5). Proliferation index (Ki-67) and stem-cell marker (cluster of differentiation CD44, aldehyde dehydrogenase ALDH1) expression was also examined...
July 2016: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/26961189/characterization-and-inhibitor-screening-of-plateau-zokor-lactate-dehydrogenase-c4
#16
Qinghua He, Qinglian Zhang, Lin Huang, Jinhu Ma
Lactate dehydrogenase C4 (LDH-C4) is considered to be a target protein for the development of contraceptives. In this work, the characterization of plateau zokor LDH-C4 and the screening of a series of N-substituted oxamic acids as inhibitors against zokor LDH-C4 were reported. The cDNA of zokor LDH-C gene was cloned and expressed in Escherichia coli, from which the protein was purified and further characterized. The protein was a tetramer (LDH-C4) and thermally stable up to 62 °C with a K m of 63.9 μM for pyruvate and with optimal pH values of 7...
July 2016: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/26938239/oxamate-improves-glycemic-control-and-insulin-sensitivity-via-inhibition-of-tissue-lactate-production-in-db-db-mice
#17
Weiran Ye, Yijia Zheng, Shanshan Zhang, Li Yan, Hua Cheng, Muchao Wu
Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin-resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350-750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice...
2016: PloS One
https://www.readbyqxmd.com/read/26936618/fasn-erbb2-mediated-glycolysis-is-required-for-breast-cancer-cell-migration
#18
Lan Zhou, Sufang Jiang, Qiang Fu, Kelly Smith, Kailing Tu, Hua Li, Yuhua Zhao
Both fatty acid synthase (FASN) and ErbB2 have been shown to promote breast cancer cell migration. However, the underlying molecular mechanism remains poorly understood and there is no reported evidence that directly links glycolysis to breast cancer cell migration. In this study, we investigated the role of FASN, ErbB2-mediated glycolysis in breast cancer cell migration. First, we compared lactate dehydrogenase A (LDHA) protein levels, glycolysis and cell migration between FASN, ErbB2-overexpressing SK-BR-3 cells and FASN, ErbB2-low-expressing MCF7 cells...
May 2016: Oncology Reports
https://www.readbyqxmd.com/read/26827545/-establishment-of-rp-hplc-detection-method-of-n-isopropyl-oxamate-in-the-serum-of-plateau-pikas
#19
Yang Wang, Lian Wei, Lin-na Wei, Xiao Li, Li-na Xu, Deng-bang Wei
OBJECTIVE: To explore the intergrating of N-isopropyl oxamate and serum protein and establish a high performance liquid chromatography (HPLC) detection method of N-isopropyl oxamate (specific inhibitor of testis-specific lactate dehydrogenase (LDH-C4)) in the blood of plateau pikas. METHODS: Twenty highland pika 150-200 g, were randomly divided into two groups (n = 10): control group and inhibitor group. Different concentrations of N-isopropyl oxamate were added to examine the intergrating of N-isopropyl oxamate and serum protein...
September 2015: Chinese Journal of Applied Physiology
https://www.readbyqxmd.com/read/26661210/hemichannel-mediated-release-of-lactate
#20
Anastassios Karagiannis, Sergiy Sylantyev, Anna Hadjihambi, Patrick S Hosford, Sergey Kasparov, Alexander V Gourine
In the central nervous system lactate contributes to the extracellular pool of readily available energy substrates and may also function as a signaling molecule which mediates communication between glial cells and neurons. Monocarboxylate transporters are believed to provide the main pathway for lactate transport across the membranes. Here we tested the hypothesis that lactate could also be released via opening of pannexin and/or functional connexin hemichannels. In acute slices prepared from the brainstem, hippocampus, hypothalamus and cortex of adult rats, enzymatic amperometric biosensors detected significant tonic lactate release inhibited by compounds, which block pannexin/connexin hemichannels and facilitated by lowering extracellular [Ca(2+)] or increased PCO2 Enhanced lactate release triggered by hypoxia was reduced by ∼50% by either connexin or monocarboxylate transporter blockers...
July 2016: Journal of Cerebral Blood Flow and Metabolism
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