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Pyruvate dehydrogenase

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https://www.readbyqxmd.com/read/29150396/identification-of-pyruvate-dehydrogenase-kinase-1-inhibitors-with-anti-osteosarcoma-activity
#1
Aiping Fang, Huiqiang Luo, Liping Liu, Haibo Fan, Yaying Zhou, Yuqin Yao, Yue Zhang
Overexpression of pyruvate dehydrogenase kinases (PDKs), especially PDK1 has been observed in a variety of cancers. Thus, targeting PDK1 offers an attractive opportunity for the development of cancer therapies. In this letter, we reported the identification of two novel PDK1 inhibitors as anti-osteosarcoma agents. We found that TM-1 and TM-2 inhibited PDK1 with the IC50 values of 2.97 and 3.41 μM, respectively. Furthermore, TM-1 and TM-2 dose-dependently reduced phosphorylation of pyruvate dehydrogenase complex in MG-63 osteosarcoma cells...
October 31, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#2
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
November 16, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29143921/dichloroacetate-induced-intracellular-acidification-in-glioblastoma-in-vivo-detection-using-aacid-cest-mri-at-9-4%C3%A2-tesla
#3
Mohammed Albatany, Alex Li, Susan Meakin, Robert Bartha
Intracellular pH (pHi) plays an important role in the maintenance of normal cell function, and is maintained within a narrow range by the activity of transporters located at the plasma membrane. Modulation of tumor pHi may influence proliferation, apoptosis, chemotherapy resistance, and thermosensitivity. Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is dependent on cellular pH. Amine and amide concentration-independent detection (AACID) is a recently developed CEST contrast method that is intracellular pH (pHi) weighted...
November 16, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29143082/spatial-separation-of-photosynthesis-and-ethanol-production-by-cell-type-specific-metabolic-engineering-of-filamentous-cyanobacteria
#4
Shigeki Ehira, Takuto Takeuchi, Akiyoshi Higo
Cyanobacteria, which perform oxygenic photosynthesis, have drawn attention as hosts for the direct production of biofuels and commodity chemicals from CO2 and H2O using light energy. Although cyanobacteria capable of producing diverse chemicals have been generated by metabolic engineering, anaerobic non-photosynthetic culture conditions are often necessary for their production. In this study, we conducted cell type-specific metabolic engineering of the filamentous cyanobacterium Anabaena sp. PCC 7120, which forms a terminally differentiated cell called a heterocyst with a semi-regular spacing of 10-15 cells...
November 15, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/29142828/metabolic-engineering-of-ustilago-trichophora-tz1-for-improved-malic-acid-production
#5
Thiemo Zambanini, Hamed Hosseinpour Tehrani, Elena Geiser, Christiane K Sonntag, Joerg M Buescher, Guido Meurer, Nick Wierckx, Lars M Blank
Ustilago trichophora RK089 has been found recently as a good natural malic acid producer from glycerol. This strain has previously undergone adaptive laboratory evolution for enhanced substrate uptake rate resulting in the strain U. trichophora TZ1. Medium optimization and investigation of process parameters enabled titers and rates that are able to compete with those of organisms overexpressing major parts of the underlying metabolic pathways. Metabolic engineering can likely further increase the efficiency of malate production by this organism, provided that basic genetic tools and methods can be established for this rarely used and relatively obscure species...
June 2017: Metabolic Engineering Communications
https://www.readbyqxmd.com/read/29137417/inhibition-of-retinoic-acid-receptor-%C3%AE-signaling-confers-glycolytic-dependence-and-sensitization-to-dichloroacetate-in-melanoma-cells
#6
Cecilie Abildgaard, Christina Dahl, Ahmad Abdul-Al, Annette Christensen, Per Guldberg
Dysregulation of metabolism during melanoma progression is tightly associated with the acquisition of genetic and epigenetic alterations in regulators of metabolic pathways. Retinoic acid receptor beta (RARβ) is epigenetically silenced in a large proportion of melanomas, but a link between RARβ and metabolic rewiring of melanoma has not been established. Here, we show that in primary human melanocytes, all-trans retinoic acid (a RARβ agonist) induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RARβ led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29134060/modelling-pyruvate-dehydrogenase-under-hypoxia-and-its-role-in-cancer-metabolism
#7
Filmon Eyassu, Claudio Angione
Metabolism is the only biological system that can be fully modelled at genome scale. As a result, metabolic models have been increasingly used to study the molecular mechanisms of various diseases. Hypoxia, a low-oxygen tension, is a well-known characteristic of many cancer cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle and is a key enzyme in metabolic reprogramming in cancer metabolism. Here, we develop and manually curate a constraint-based metabolic model to investigate the mechanism of pyruvate dehydrogenase under hypoxia...
October 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/29131158/ucp1-independent-signaling-involving-serca2b-mediated-calcium-cycling-regulates-beige-fat-thermogenesis-and-systemic-glucose-homeostasis
#8
Kenji Ikeda, Qianqian Kang, Takeshi Yoneshiro, Joao Paulo Camporez, Hiroko Maki, Mayu Homma, Kosaku Shinoda, Yong Chen, Xiaodan Lu, Pema Maretich, Kazuki Tajima, Kolapo M Ajuwon, Tomoyoshi Soga, Shingo Kajimura
Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca(2+) cycling by sarco/endoplasmic reticulum Ca(2+)-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein...
November 13, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29129554/development-of-a-novel-observer-reported-outcome-tool-as-the-primary-efficacy-outcome-measure-for-a-rare-disease-randomized-controlled-trial
#9
Peter W Stacpoole, Jonathan Shuster, John L P Seamus Thompson, Sara Jo Nixon, Robert A Prather, Lee Ann Lawson, Baiming Zou, Richard Buchsbaum
We developed an Observer-Reported Outcome (ObsRO) survey instrument to be applied in a multicenter, placebo-controlled, crossover randomized controlled trial of dichloroacetate in children with pyruvate dehydrogenase complex deficiency. The instrument quantifies a subject's at-home level of functionality, as reported by a parent/caregiver, who were instrumental in providing the clinical descriptors and domains that formed the instrument's content. Feasibility testing of the ObsRO tool showed it to be easy to use and comprehensive in capturing the major clinical functional limitations of affected children and requires less than 5min for a parent/caregiver to complete daily...
November 9, 2017: Mitochondrion
https://www.readbyqxmd.com/read/29128903/impairment-of-thiamine-transport-at-the-gut-bbb-axis-contributes-to-wernicke-s-encephalopathy
#10
P M Abdul-Muneer, Saleena Alikunju, Heather Schuetz, Adam M Szlachetka, Xiaotang Ma, James Haorah
Wernicke's encephalopathy, a common neurological disease, is caused by thiamine (vitamin B1) deficiency. Neuropathy resulting from thiamine deficiency is a hallmark of Wernicke-Korsakoff syndrome in chronic alcohol users. The underlying mechanisms of this deficiency and progression of neuropathy remain to be understood. To uncover the unknown mechanisms of thiamine deficiency in alcohol abuse, we used chronic alcohol consumption or thiamine deficiency diet ingestion in animal models. Observations from animal models were validated in primary human neuronal culture for neurodegenerative process...
November 11, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/29128353/pyruvate-dehydrogenase-kinase-4-mediates-lipogenesis-and-contributes-to-the-pathogenesis-of-nonalcoholic-steatohepatitis
#11
Ming Zhang, Yujie Zhao, Zhen Li, Congying Wang
Nonalcoholic steatohepatitis (NASH) is a progressive disease and poses a high risk of severe liver damage. However, the pathogenesis of NASH is still unclear. Accumulation of lipid droplets and insulin resistance is the hallmark of NASH. Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) plays key role in glucose metabolism via regulating the activity of pyruvate dehydrogenase complex (PDC). Here, we demonstrated a novel of PDK4 in NASH by regulating hepatic steatosis and insulin signaling pathway in methionine and choline deficient (MCD) diet induced NASH model...
November 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29127360/a-mouse-model-of-autoimmune-cholangitis-via-syngeneic-bile-duct-protein-immunization
#12
Wen-Tao Ma, Qing-Zhi Liu, Jing-Bo Yang, Yan-Qing Yang, Zhi-Bin Zhao, Hong-Di Ma, M Eric Gershwin, Zhe-Xiong Lian
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of interlobular biliary ductules, which progressively leads to cholestasis, hepatic fibrosis, cirrhosis, and eventually liver failure. Several mouse models have been used to clarify the pathogenesis of PBC and are generally considered reflective of an autoimmune cholangitis. Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29120739/lipoyl-e2-pdh-gets-a-second-job
#13
Seth W Dickey, Michael Otto
Pyruvate dehydrogenase (PDH) plays a well-known metabolic role inside cells. In this issue of Cell Host & Microbe, Grayczyk et al. (2017) show that the bacterial pathogen Staphylococcus aureus unexpectedly secretes and repurposes the lipoylated E2 subunit of PDH to suppress TLR-mediated activation of host macrophages by bacterial lipoproteins.
November 8, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/29120091/running-wheel-activity-delays-mitochondrial-respiratory-flux-decline-in-aging-mouse-muscle-via-a-post-transcriptional-mechanism
#14
Sarah Stolle, Jolita Ciapaite, Aaffien C Reijne, Alzbeta Talarovicova, Justina C Wolters, Raúl Aguirre-Gamboa, Pieter van der Vlies, Kim de Lange, Pieter B Neerincx, Gerben van der Vries, Patrick Deelen, Morris A Swertz, Yang Li, Rainer Bischoff, Hjalmar P Permentier, Peter L Horvatovitch, Albert K Groen, Gertjan van Dijk, Dirk-Jan Reijngoud, Barbara M Bakker
Loss of mitochondrial respiratory flux is a hallmark of skeletal muscle aging, contributing to a progressive decline of muscle strength. Endurance exercise alleviates the decrease in respiratory flux, both in humans and in rodents. Here, we dissect the underlying mechanism of mitochondrial flux decline by integrated analysis of the molecular network. Mice were given a lifelong ad libitum low-fat or high-fat sucrose diet and were further divided into sedentary and running-wheel groups. At 6, 12, 18 and 24 months, muscle weight, triglyceride content and mitochondrial respiratory flux were analysed...
November 9, 2017: Aging Cell
https://www.readbyqxmd.com/read/29118438/substrate-specificity-and-allosteric-regulation-of-a-d-lactate-dehydrogenase-from-a-unicellular-cyanobacterium-are-altered-by-an-amino-acid-substitution
#15
Shoki Ito, Masahiro Takeya, Takashi Osanai
Lactate/lactic acid is an important chemical compound for the manufacturing of bioplastics. The unicellular cyanobacterium Synechocystis sp. PCC 6803 can produce lactate from carbon dioxide and possesses D-lactate dehydrogenase (Ddh). Here, we performed a biochemical analysis of the Ddh from this cyanobacterium (SyDdh) using recombinant proteins. SyDdh was classified into a cyanobacterial clade similar to those from Gram-negative bacteria, although it was distinct from them. SyDdh can use both pyruvate and oxaloacetate as a substrate and is activated by fructose-1,6-bisphosphate and repressed by divalent cations...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29117193/immunohistochemical-analysis-of-pdk1-phd3-and-hif-1%C3%AE-expression-defines-the-hypoxic-status-of-neuroblastoma-tumors
#16
Marzia Ognibene, Davide Cangelosi, Martina Morini, Daniela Segalerba, Maria Carla Bosco, Angela Rita Sementa, Alessandra Eva, Luigi Varesio
Neuroblastoma (NB) is the most common solid tumor during infancy and the first cause of death among the preschool age diseases. The availability of several NB genomic profiles improves the prognostic ability, but the outcome prediction for this pathology remains imperfect. We previously produced a novel prognostic gene signature based on the response of NB cells to hypoxia, a condition of tumor microenvironment strictly connected with cancer aggressiveness. Here we attempted to further define the expression of hypoxia-modulated specific genes, looking at their protein level in NB specimens, considering in particular the hypoxia inducible factor-1α (HIF-1α), the mitochondrial pyruvate dehydrogenase kinase 1 (PDK1), and the HIF-prolyl hydroxylase domain 3 (PHD3)...
2017: PloS One
https://www.readbyqxmd.com/read/29116682/flavin-n5-covalent-intermediate-in-the-non-redox-dehalogenation-reaction-catalyzed-by-an-atypical-flavoenzyme
#17
Yumin Dai, Karina Kizjakina, Ashley C Campbell, David A Korasick, John J Tanner, Pablo Sobrado
The flavin-dependent enzyme 2-haloacrylate hydratase (2-HAH) catalyzes the conversion of 2-chloroacrylate, a major component in the manufacture of acrylic polymers, to pyruvate. The enzyme from has been expressed in Escherichia coli, purified, and characterized. 2-HAH is monomeric in solution and contains a non-covalent, yet tightly bound, FAD. Although the reaction catalyzed is redox neutral, 2-HAH is active only in the reduced state. A covalent flavin-substrate intermediate, consistent with the flavin-acrylate iminium ion, was trapped with cyanoborohydride and characterized by mass spectrometry...
November 8, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29110475/preslaughter-transport-effect-on-broiler-meat-quality-and-post-mortem-glycolysis-metabolism-of-muscles-with-different-fiber-types
#18
Xiaofei Wang, Jiaolong Li, Jiahui Cong, Xiangxing Chen, Xudong Zhu, Lin Zhang, Feng Gao, Guanghong Zhou
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...
November 14, 2017: Journal of Agricultural and Food Chemistry
https://www.readbyqxmd.com/read/29109438/vsig4-inhibits-proinflammatory-macrophage-activation-by-reprogramming-mitochondrial-pyruvate-metabolism
#19
Jialin Li, Bo Diao, Sheng Guo, Xiaoyong Huang, Chengying Yang, Zeqing Feng, Weiming Yan, Qin Ning, Lixin Zheng, Yongwen Chen, Yuzhang Wu
Exacerbation of macrophage-mediated inflammation contributes to pathogenesis of various inflammatory diseases, but the immunometabolic programs underlying regulation of macrophage activation are unclear. Here we show that V-set immunoglobulin-domain-containing 4 (VSIG4), a B7 family-related protein that is expressed by resting macrophages, inhibits macrophage activation in response to lipopolysaccharide. Vsig4 (-/-) mice are susceptible to high-fat diet-caused obesity and murine hepatitis virus strain-3 (MHV-3)-induced fulminant hepatitis due to excessive macrophage-dependent inflammation...
November 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29109080/central-leptin-regulates-heart-lipid-content-by-selectively-increasing-ppar-%C3%AE-%C3%AE-expression
#20
Cristina Mora, Cristina Pintado, Blanca Rubio, Lorena Mazuecos, Virginia Lopez, Alejandro Fernandez, Aurora Salamanca, Brenda Barcena, Teresa Fernandez-Agullo, Carmen Arribas, Nilda Gallardo, Antonio Andres
The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective up-regulation of gene and protein expression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and their target genes, adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), pyruvate dehydrogenase kinase 4 (PDK4), and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization...
November 6, 2017: Journal of Endocrinology
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