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  1 / 1501 MEDLINE  
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[PMID]:28601082
[Au] Autor:Tsepkova PM; Artiukhov AV; Boyko AI; Aleshin VA; Mkrtchyan GV; Zvyagintseva MA; Ryabov SI; Ksenofontov AL; Baratova LA; Graf AV; Bunik VI
[Ad] Endereço:Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, 119234, Russia. bunik@belozersky.msu.ru.
[Ti] Título:Thiamine Induces Long-Term Changes in Amino Acid Profiles and Activities of 2-Oxoglutarate and 2-Oxoadipate Dehydrogenases in Rat Brain.
[So] Source:Biochemistry (Mosc);82(6):723-736, 2017 Jun.
[Is] ISSN:1608-3040
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Molecular mechanisms of long-term changes in brain metabolism after thiamine administration (single i.p. injection, 400 mg/kg) were investigated. Protocols for discrimination of the activities of the thiamine diphosphate (ThDP)-dependent 2-oxoglutarate and 2-oxoadipate dehydrogenases were developed to characterize specific regulation of the multienzyme complexes of the 2-oxoglutarate (OGDHC) and 2-oxoadipate (OADHC) dehydrogenases by thiamine. The thiamine-induced changes depended on the brain-region-specific expression of the ThDP-dependent dehydrogenases. In the cerebral cortex, the original levels of OGDHC and OADHC were relatively high and not increased by thiamine, whereas in the cerebellum thiamine upregulated the OGDHC and OADHC activities, whose original levels were relatively low. The effects of thiamine on each of the complexes were different and associated with metabolic rearrangements, which included (i) the brain-region-specific alterations of glutamine synthase and/or glutamate dehydrogenase and NADP+-dependent malic enzyme, (ii) the brain-region-specific changes of the amino acid profiles, and (iii) decreased levels of a number of amino acids in blood plasma. Along with the assays of enzymatic activities and average levels of amino acids in the blood and brain, the thiamine-induced metabolic rearrangements were assessed by analysis of correlations between the levels of amino acids. The set and parameters of the correlations were tissue-specific, and their responses to the thiamine treatment provided additional information on metabolic changes, compared to that gained from the average levels of amino acids. Taken together, the data suggest that thiamine decreases catabolism of amino acids by means of a complex and long-term regulation of metabolic flux through the tricarboxylic acid cycle, which includes coupled changes in activities of the ThDP-dependent dehydrogenases of 2-oxoglutarate and 2-oxoadipate and adjacent enzymes.
[Mh] Termos MeSH primário: Aminoácidos/metabolismo
Córtex Cerebral/enzimologia
Complexo Cetoglutarato Desidrogenase/metabolismo
Cetona Oxirredutases/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Tiamina/farmacologia
[Mh] Termos MeSH secundário: Animais
Feminino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Nerve Tissue Proteins); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex); X66NSO3N35 (Thiamine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170612
[St] Status:MEDLINE
[do] DOI:10.1134/S0006297917060098


  2 / 1501 MEDLINE  
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[PMID]:28540498
[Au] Autor:Karigane D; Takubo K
[Ad] Endereço:Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.
[Ti] Título:Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions.
[So] Source:Int J Hematol;106(1):18-26, 2017 Jul.
[Is] ISSN:1865-3774
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.
[Mh] Termos MeSH primário: Metabolismo Energético
Células-Tronco Hematopoéticas/metabolismo
Homeostase
Leucemia/metabolismo
Células-Tronco Neoplásicas/metabolismo
Estresse Fisiológico
[Mh] Termos MeSH secundário: Adipócitos/metabolismo
Animais
Diferenciação Celular
Ciclo do Ácido Cítrico
Epigênese Genética
Ácidos Graxos/metabolismo
Regulação Leucêmica da Expressão Gênica
Glicólise
Hematopoese
Células-Tronco Hematopoéticas/citologia
Seres Humanos
Hipóxia/metabolismo
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Cetona Oxirredutases/metabolismo
Leucemia/genética
Ácidos Nucleicos/metabolismo
Fosforilação Oxidativa
Fase de Repouso do Ciclo Celular
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Fatty Acids); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Nucleic Acids); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.1.51 (pyruvate dehydrogenase (NADP+))
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1007/s12185-017-2261-x


  3 / 1501 MEDLINE  
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[PMID]:28148899
[Au] Autor:Zhang Y; Zhang Y; Ding GL; Liu XM; Ye J; Sheng JZ; Fan J; Huang HF
[Ad] Endereço:International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
[Ti] Título:Regulation of hepatic pyruvate dehydrogenase phosphorylation in offspring glucose intolerance induced by intrauterine hyperglycemia.
[So] Source:Oncotarget;8(9):15205-15212, 2017 Feb 28.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIM: Gestational diabetes mellitus (GDM) has been shown to be associated with a high risk of diabetes in offspring. In mitochondria, the inhibition of pyruvate dehydrogenase (PDH) activity by PDH phosphorylation is involved in the development of diabetes. We aimed to determine the role of PDH phosphorylation in the liver in GDM-induced offspring glucose intolerance. RESULTS: PDH phosphorylation was increased in lymphocytes from the umbilical cord blood of the GDM patients and in high glucose-treated hepatic cells. Both the male and female offspring from GDM mice had elevated liver weights and glucose intolerance. Further, PDH phosphorylation was increased in the livers of both the male and female offspring from GDM mice, and elevated acetylation may have contributed to this increased phosphorylation. MATERIALS AND METHODS: We obtained lymphocytes from umbilical cord blood collected from both normal and GDM pregnant women. In addition, we obtained the offspring of streptozotocin-induced GDM female pregnant mice. The glucose tolerance test was performed to assess glucose tolerance in the offspring. Further, Western blotting was conducted to detect changes in protein levels. CONCLUSIONS: Intrauterine hyperglycemia induced offspring glucose intolerance by inhibiting PDH activity, along with increased PDH phosphorylation in the liver, and this effect might be mediated by enhanced mitochondrial protein acetylation.
[Mh] Termos MeSH primário: Diabetes Gestacional/fisiopatologia
Regulação Enzimológica da Expressão Gênica
Intolerância à Glucose/etiologia
Hiperglicemia/complicações
Cetona Oxirredutases/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Glicemia/metabolismo
Feminino
Intolerância à Glucose/enzimologia
Intolerância à Glucose/patologia
Teste de Tolerância a Glucose
Seres Humanos
Masculino
Camundongos
Fosforilação
Gravidez
Piruvatos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Pyruvates); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.1.51 (pyruvate dehydrogenase (NADP+))
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170203
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14837


  4 / 1501 MEDLINE  
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[PMID]:28086092
[Au] Autor:Nagaraj R; Sharpley MS; Chi F; Braas D; Zhou Y; Kim R; Clark AT; Banerjee U
[Ad] Endereço:Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
[Ti] Título:Nuclear Localization of Mitochondrial TCA Cycle Enzymes as a Critical Step in Mammalian Zygotic Genome Activation.
[So] Source:Cell;168(1-2):210-223.e11, 2017 Jan 12.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during zygotic genome activation (ZGA) at the 2-cell stage. Pyruvate is essential for development beyond this stage, which is at odds with the low activity of mitochondria in this period. We now show that a number of enzymatically active mitochondrial enzymes associated with the TCA cycle are essential for epigenetic remodeling and are transiently and partially localized to the nucleus. Pyruvate is essential for this nuclear localization, and a failure of TCA cycle enzymes to enter the nucleus correlates with loss of specific histone modifications and a block in ZGA. At later stages, however, these enzymes are exclusively mitochondrial. In humans, the enzyme pyruvate dehydrogenase is transiently nuclear at the 4/8-cell stage coincident with timing of human embryonic genome activation, suggesting a conserved metabolic control mechanism underlying early pre-implantation development.
[Mh] Termos MeSH primário: Ciclo do Ácido Cítrico
Genoma
Zigoto/metabolismo
[Mh] Termos MeSH secundário: Animais
Blastocisto/metabolismo
Núcleo Celular/metabolismo
Epigênese Genética
Glicosilação
Histonas/metabolismo
Cetona Oxirredutases/metabolismo
Camundongos
Mitocôndrias/enzimologia
Mitocôndrias/metabolismo
Ácido Pirúvico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histones); 8558G7RUTR (Pyruvic Acid); EC 1.2.- (Ketone Oxidoreductases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE


  5 / 1501 MEDLINE  
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[PMID]:28073046
[Au] Autor:Stapel B; Kotsiari A; Scherr M; Hilfiker-Kleiner D; Bleich S; Frieling H; Kahl KG
[Ad] Endereço:Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Department of Cardiology and Angiology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
[Ti] Título:Olanzapine and aripiprazole differentially affect glucose uptake and energy metabolism in human mononuclear blood cells.
[So] Source:J Psychiatr Res;88:18-27, 2017 May.
[Is] ISSN:1879-1379
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only. Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients.
[Mh] Termos MeSH primário: Antipsicóticos/farmacologia
Aripiprazol/farmacologia
Benzodiazepinas/farmacologia
Glucose/metabolismo
Leucócitos Mononucleares/efeitos dos fármacos
Leucócitos Mononucleares/metabolismo
[Mh] Termos MeSH secundário: Antígenos CD/metabolismo
Metilação de DNA/efeitos dos fármacos
Relação Dose-Resposta a Droga
Citometria de Fluxo
Fluordesoxiglucose F18
Regulação da Expressão Gênica/efeitos dos fármacos
Transportador de Glucose Tipo 3/genética
Transportador de Glucose Tipo 3/metabolismo
Proteínas de Transporte de Glutamato da Membrana Plasmática/genética
Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo
Seres Humanos
Cetona Oxirredutases/metabolismo
Proteínas Quinases/metabolismo
RNA Mensageiro/metabolismo
RNA Ribossômico 18S/genética
RNA Ribossômico 18S/metabolismo
Estatísticas não Paramétricas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Antipsychotic Agents); 0 (Glucose Transporter Type 3); 0 (Glutamate Plasma Membrane Transport Proteins); 0 (RNA, Messenger); 0 (RNA, Ribosomal, 18S); 0 (SLC1A2 protein, human); 0 (SLC2A3 protein, human); 0Z5B2CJX4D (Fluorodeoxyglucose F18); 12794-10-4 (Benzodiazepines); 82VFR53I78 (Aripiprazole); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.1.51 (pyruvate dehydrogenase (NADP+)); EC 2.7.- (Protein Kinases); EC 2.7.1.- (AMP-activated protein kinase kinase); IY9XDZ35W2 (Glucose); N7U69T4SZR (olanzapine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE


  6 / 1501 MEDLINE  
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[PMID]:27871875
[Au] Autor:Sharkia I; Hadad Erlich T; Landolina N; Assayag M; Motzik A; Rachmin I; Kay G; Porat Z; Tshori S; Berkman N; Levi-Schaffer F; Razin E
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
[Ti] Título:Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor.
[So] Source:J Allergy Clin Immunol;140(1):204-214.e8, 2017 Jul.
[Is] ISSN:1097-6825
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We have recently observed that oxidative phosphorylation-mediated ATP production is essential for mast cell function. Pyruvate dehydrogenase (PDH) is the main regulator of the Krebs cycle and is located upstream of the electron transport chain. However, the role of PDH in mast cell function has not been described. Microphthalmia transcription factor (MITF) regulates the development, number, and function of mast cells. Localization of MITF to the mitochondria and its interaction with mitochondrial proteins has not been explored. OBJECTIVE: We sought to explore the role played by PDH in mast cell exocytosis and to determine whether MITF is localized in the mitochondria and involved in regulation of PDH activity. METHODS: Experiments were performed in vitro by using human and mouse mast cells, as well as rat basophil leukemia cells, and in vivo in mice. The effect of PDH inhibition on mast cell function was examined. PDH interaction with MITF was measured before and after immunologic activation. Furthermore, mitochondrial localization of MITF and its effect on PDH activity were determined. RESULTS: PDH is essential for immunologically mediated degranulation of mast cells. After activation, PDH is serine dephosphorylated. In addition, for the first time, we show that MITF is partially located in the mitochondria and interacts with PDH. This interaction is dependent on the phosphorylation state of PDH. Furthermore, mitochondrial MITF regulates PDH activity. CONCLUSION: The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.
[Mh] Termos MeSH primário: Cetona Oxirredutases/imunologia
Mastócitos/imunologia
Fator de Transcrição Associado à Microftalmia/imunologia
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Alérgenos/imunologia
Animais
Asma/imunologia
Líquido da Lavagem Broncoalveolar/citologia
Contagem de Células
Degranulação Celular
Linhagem Celular Tumoral
Células Cultivadas
Exocitose
Feminino
Células HEK293
Seres Humanos
Masculino
Mastócitos/metabolismo
Mastócitos/fisiologia
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C3H
Fator de Transcrição Associado à Microftalmia/genética
Mitocôndrias/imunologia
Mitocôndrias/metabolismo
Ovalbumina/imunologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Allergens); 0 (Microphthalmia-Associated Transcription Factor); 8L70Q75FXE (Adenosine Triphosphate); 9006-59-1 (Ovalbumin); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.1.51 (pyruvate dehydrogenase (NADP+))
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161123
[St] Status:MEDLINE


  7 / 1501 MEDLINE  
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[PMID]:27744476
[Au] Autor:Lu XM; Chen C; Zheng TL
[Ad] Endereço:Institute for Eco-Environmental Sciences, Wenzhou Vocational College of Science & Technology, Wenzhou, 325006, People's Republic of China. 13736961468@163.com.
[Ti] Título:Metagenomic Insights into Effects of Chemical Pollutants on Microbial Community Composition and Function in Estuarine Sediments Receiving Polluted River Water.
[So] Source:Microb Ecol;73(4):791-800, 2017 May.
[Is] ISSN:1432-184X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrosequencing and metagenomic profiling were used to assess the phylogenetic and functional characteristics of microbial communities residing in sediments collected from the estuaries of Rivers Oujiang (OS) and Jiaojiang (JS) in the western region of the East China Sea. Another sediment sample was obtained from near the shore far from estuaries, used for contrast (CS). Characterization of estuary sediment bacterial communities showed that toxic chemicals potentially reduced the natural variability in microbial communities, while they increased the microbial metabolic enzymes and pathways. Polycyclic aromatic hydrocarbons (PAHs) and nitrobenzene were negatively correlated with the bacterial community variation. The dominant class in the sediments was Gammaproteobacteria. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) enzyme profiles, dominant enzymes were found in estuarine sediments, which increased greatly, such as 2-oxoglutarate synthase, acetolactate synthase, inorganic diphosphatase, and aconitate hydratase. In KEGG pathway profiles, most of the pathways were also dominated by specific metabolism in these sediments and showed a marked increase, for instance alanine, aspartate, and glutamate metabolism, carbon fixation pathways in prokaryotes, and aminoacyl-tRNA biosynthesis. The estuarine sediment bacterial diversity varied with the polluted river water inputs. In the estuary receiving river water from the more seriously polluted River Oujiang, the sediment bacterial community function was more severely affected.
[Mh] Termos MeSH primário: Bactérias/classificação
Bactérias/genética
Estuários
Sedimentos Geológicos/microbiologia
Metagenômica/métodos
Consórcios Microbianos/genética
Rios/microbiologia
Poluentes Químicos da Água/análise
[Mh] Termos MeSH secundário: Acetolactato Sintase/metabolismo
Aconitato Hidratase/metabolismo
Aminoácidos/metabolismo
Bactérias/enzimologia
Bactérias/metabolismo
Sequência de Bases
Ciclo do Carbono
China
Água Doce
Sedimentos Geológicos/química
Cetona Oxirredutases/metabolismo
Redes e Vias Metabólicas
Consórcios Microbianos/efeitos dos fármacos
Nitrobenzenos/efeitos adversos
Filogenia
Hidrocarbonetos Aromáticos Policíclicos/efeitos adversos
RNA Ribossômico 16S/genética
Salinidade
Análise de Sequência
Poluentes Químicos da Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Nitrobenzenes); 0 (Polycyclic Aromatic Hydrocarbons); 0 (RNA, Ribosomal, 16S); 0 (Water Pollutants, Chemical); E57JCN6SSY (nitrobenzene); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.7.3 (2-oxoglutarate synthase); EC 2.2.1.6 (Acetolactate Synthase); EC 4.2.1.3 (Aconitate Hydratase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161017
[St] Status:MEDLINE
[do] DOI:10.1007/s00248-016-0868-8


  8 / 1501 MEDLINE  
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[PMID]:27666939
[Au] Autor:Louie S; Haley B; Marshall B; Heidersbach A; Yim M; Brozynski M; Tang D; Lam C; Petryniak B; Shaw D; Shim J; Miller A; Lowe JB; Snedecor B; Misaghi S
[Ad] Endereço:Early Stage Cell Culture, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080.
[Ti] Título:FX knockout CHO hosts can express desired ratios of fucosylated or afucosylated antibodies with high titers and comparable product quality.
[So] Source:Biotechnol Bioeng;114(3):632-644, 2017 Mar.
[Is] ISSN:1097-0290
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During antibody dependent cell cytotoxicity (ADCC) the target cells are killed by monocytes and natural killer cells. ADCC is enhanced when the antibody heavy chain's core N-linked glycan lacks the fucose molecule(s). Several strategies have been utilized to generate fully afucosylated antibodies. A commonly used and efficient approach has been knocking out the FUT8 gene of the Chinese hamster ovary (CHO) host cells, which results in expression of antibody molecules with fully afucosylated glycans. However, a major drawback of the FUT8-KO host is the requirement for undertaking two separate cell line development (CLD) efforts in order to obtain both primarily fucosylated and fully afucosylated antibody species for comparative studies in vitro and in vivo. Even more challenging is obtaining primarily fucosylated and FUT8-KO clones with similar enough product quality attributes to ensure that any observed ADCC advantage(s) can be strictly attributed to afucosylation. Here, we report generation and use of a FX knockout (FXKO) CHO host cell line that is capable of expressing antibody molecules with either primarily fucosylated or fully afucosylated glycan profiles with otherwise similar product quality attributes, depending on addition of fucose to the cell culture media. Hence, the FXKO host not only obviates the requirement for undertaking two separate CLD efforts, but it also averts the need for screening many colonies to identify clones with comparable product qualities. Finally, FXKO clones can express antibodies with the desired ratio of primarily fucosylated to afucosylated glycans when fucose is titrated into the production media, to allow achieving intended levels of FcγRIII-binding and ADCC for an antibody. Biotechnol. Bioeng. 2017;114: 632-644. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Anticorpos/química
Fucose/metabolismo
Cetona Oxirredutases/genética
Engenharia de Proteínas/métodos
Proteínas Recombinantes/química
[Mh] Termos MeSH secundário: Animais
Anticorpos/genética
Anticorpos/metabolismo
Células CHO
Sistemas CRISPR-Cas
Cricetinae
Cricetulus
Fucose/química
Edição de Genes
Técnicas de Inativação de Genes
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Recombinant Proteins); 28RYY2IV3F (Fucose); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.1.- (GDP-4-keto-6-deoxy-D-mannose reductase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160927
[St] Status:MEDLINE
[do] DOI:10.1002/bit.26188


  9 / 1501 MEDLINE  
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[PMID]:27639802
[Au] Autor:Wang Y; Huang D; Chen KY; Cui M; Wang W; Huang X; Awadellah A; Li Q; Friedman A; Xin WW; Di Martino L; Cominelli F; Miron A; Chan R; Fox JG; Xu Y; Shen X; Kalady MF; Markowitz S; Maillard I; Lowe JB; Xin W; Zhou L
[Ad] Endereço:Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
[Ti] Título:Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma.
[So] Source:Gastroenterology;152(1):193-205.e10, 2017 Jan.
[Is] ISSN:1528-0012
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIMS: De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. METHODS: FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). RESULTS: Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. CONCLUSIONS: In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.
[Mh] Termos MeSH primário: Adenocarcinoma/etiologia
Carboidratos Epimerases/deficiência
Colite/etiologia
Colite/metabolismo
Colo/metabolismo
Neoplasias do Colo/etiologia
Mucosa Intestinal/metabolismo
Cetona Oxirredutases/deficiência
[Mh] Termos MeSH secundário: Adenocarcinoma/química
Adenocarcinoma/patologia
Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Transplante de Medula Óssea
Carboidratos Epimerases/genética
Carcinogênese
Ceco/patologia
Proliferação Celular
Colite/patologia
Colite/prevenção & controle
Colo/patologia
Neoplasias do Colo/química
Neoplasias do Colo/patologia
Citocinas/genética
Citocinas/metabolismo
Fezes/microbiologia
Feminino
Fucose/administração & dosagem
Microbioma Gastrointestinal
Guanosina Difosfato Fucose/biossíntese
Guanosina Difosfato Fucose/deficiência
Seres Humanos
Cetona Oxirredutases/genética
Masculino
Camundongos
Camundongos Knockout
Meia-Idade
Permeabilidade
RNA Mensageiro/metabolismo
Receptor Notch1/metabolismo
Receptor Notch2/metabolismo
Transdução de Sinais
Fatores de Transcrição HES-1/análise
Fatores de Transcrição HES-1/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytokines); 0 (Hes1 protein, mouse); 0 (Notch1 protein, mouse); 0 (Notch2 protein, mouse); 0 (RNA, Messenger); 0 (Receptor, Notch1); 0 (Receptor, Notch2); 0 (TSTA3 protein, mouse); 0 (Transcription Factor HES-1); 15839-70-0 (Guanosine Diphosphate Fucose); 28RYY2IV3F (Fucose); EC 1.2.- (Ketone Oxidoreductases); EC 5.1.3.- (Carbohydrate Epimerases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160919
[St] Status:MEDLINE


  10 / 1501 MEDLINE  
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[PMID]:27748833
[Au] Autor:Harting T; Stubbendorff M; Willenbrock S; Wagner S; Schadzek P; Ngezahayo A; Murua Escobar HM; Nolte I
[Ad] Endereço:Small Animal Clinic, University of Veterinary Medicine Hannover, Foundation, D-30559 Hannover, Germany.
[Ti] Título:The effect of dichloroacetate in canine prostate adenocarcinomas and transitional cell carcinomas in vitro.
[So] Source:Int J Oncol;49(6):2341-2350, 2016 12.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:The Warburg effect describes the ability of cancer cells to produce energy via aerobic glycolysis instead of oxidative phosphorylation of pyruvate. This deviation in mitochondrial metabolism inhibits apoptosis, allowing increased proliferation under conditions of reduced oxygen levels. Dichloroacetate (DCA) was successfully used in several human cancer cell lines to reactivate oxidative phosphorylation in mitochondria. The aim of this study was the characterization and response of canine cancer cell lines after DCA exposure. The effect of 10 mM DCA was characterized in vitro on a set of six canine prostate adenocarcinoma and transitional cell carcinoma (TCC) derived cell lines. Cell counts, lactate levels, apoptosis, expression of apoptotic proteins, survival factors and different miRNAs were analyzed. Additionally, metabolic activity, mitochondrial activity and proliferation were investigated. DCA significantly decreased cell number of all but one utilized cell lines and leads to a significant reduction of lactate release. Decreased survivin levels were found in all cell lines, two of which presented a significant reduction in metabolic activity. Increased miR-375 levels were measured in all TCC cell lines. Reactivation of pyruvate dehydrogenase and an elevated mitochondrial activity appear to induce the transition from aerobic glycolysis back to oxidative phosphorylation. Further, these results display that DCA treatment has a suppressant effect on proliferation of canine cancer cells.
[Mh] Termos MeSH primário: Adenocarcinoma/patologia
Carcinoma de Células de Transição/patologia
Ácido Dicloroacético/farmacologia
Glicólise/efeitos dos fármacos
Cetona Oxirredutases/metabolismo
Fosforilação Oxidativa/efeitos dos fármacos
Neoplasias da Próstata/patologia
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cães
Masculino
MicroRNAs/genética
Mitocôndrias/metabolismo
Próstata/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MicroRNAs); 9LSH52S3LQ (Dichloroacetic Acid); EC 1.2.- (Ketone Oxidoreductases); EC 1.2.1.51 (pyruvate dehydrogenase (NADP+)); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170712
[Lr] Data última revisão:
170712
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161018
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2016.3720



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