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Pesquisa : D08.811.913.696.620.010 [Categoria DeCS]
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[PMID]:28468960
[Au] Autor:Navarro G; Abdolazimi Y; Zhao Z; Xu H; Lee S; Armstrong NA; Annes JP
[Ad] Endereço:Department of Medicine and Division of Endocrinology, Stanford University, Stanford, CA.
[Ti] Título:Genetic Disruption of Adenosine Kinase in Mouse Pancreatic ß-Cells Protects Against High-Fat Diet-Induced Glucose Intolerance.
[So] Source:Diabetes;66(7):1928-1938, 2017 07.
[Is] ISSN:1939-327X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Islet ß-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of ß-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate ß-cell replication. Here, we evaluated whether ADK disruption in mouse ß-cells affects ß-cell mass and/or protects against high-fat diet (HFD)-induced glucose dysregulation. Mice targeted at the locus were bred to Rip-Cre and Ins1-Cre/ERT mice to enable constitutive (ßADKO) and conditional (ißADKO) disruption of ADK expression in ß-cells, respectively. Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion (GSIS) were longitudinally monitored in normal chow (NC)-fed and HFD-fed mice. In addition, ß-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult ßADKO and ißADKO mice displayed glucose tolerance, insulin tolerance and ß-cell mass comparable to control animals. By contrast, HFD-fed ßADKO and ißADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased ß-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive ß-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive ß-cell response.
[Mh] Termos MeSH primário: Adenosina Quinase/genética
Glicemia/metabolismo
Dieta Hiperlipídica
Intolerância à Glucose/genética
Células Secretoras de Insulina/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Imunofluorescência
Intolerância à Glucose/metabolismo
Técnicas In Vitro
Resistência à Insulina
Células Secretoras de Insulina/patologia
Ilhotas Pancreáticas/metabolismo
Ilhotas Pancreáticas/patologia
Camundongos
Camundongos Knockout
Tamanho do Órgão
Ganho de Peso
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Blood Glucose); EC 2.7.1.20 (Adenosine Kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.2337/db16-0816


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[PMID]:28789481
[Au] Autor:Luan G; Wang X; Gao Q; Guan Y; Wang J; Deng J; Zhai F; Chen Y; Li T
[Ad] Endereço:Department of Neurosurgery, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Epilepsy Research, Sanbo Brain Hospital, Capital Medical University, Beijing, China (GL, XW, YG, FZ); Department of Brain Institute, Center of Epilepsy, Beijing Institute for Brain Disord
[Ti] Título:Upregulation of Neuronal Adenosine A1 Receptor in Human Rasmussen Encephalitis.
[So] Source:J Neuropathol Exp Neurol;76(8):720-731, 2017 Aug 01.
[Is] ISSN:1554-6578
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Rasmussen encephalitis (RE) is a rare neurological disorder characterized by unilateral inflammation of cerebral cortex and other structures, most notably the hippocampus, progressive cognitive deterioration, and pharmacoresistant focal epilepsy. The pathogenesis of RE with unilateral cortical atrophy and focal seizures is still enigmatic. Activation of adenosine A1 receptors (A1R) has been proven to prevent the spatial spread of seizures. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in neuronal A1R expression. Immunnohistochemistry was used to examine the expression of A1R and adenosine kinase (ADK) in cortical specimens from RE (n = 12), and compared with control cortical tissue. The quantification of A1R and ADK expression was evaluated by Western blot. A1R was predominantly localized in perinuclear of neurons and not in astrocytes or microglia. Upregulation of neuronal A1R was observed in the lesions of RE. Reactive astrocytes and subpopulation of remaining neurons demonstrated over-expression of the ADK within the lesions of RE. Significant increase of A1R and ADK expression in RE compared with controls was confirmed by Western blot. These results suggest that over-expression of ADK is a common pathologic hallmark of RE, and that upregulation of neuronal A1R in RE is crucial in preventing the spread of seizures.
[Mh] Termos MeSH primário: Córtex Cerebral/patologia
Encefalite/patologia
Neurônios/metabolismo
Receptor A1 de Adenosina/metabolismo
Regulação para Cima/fisiologia
[Mh] Termos MeSH secundário: Adenosina Quinase/metabolismo
Adolescente
Córtex Cerebral/diagnóstico por imagem
Criança
Pré-Escolar
Citocinas/metabolismo
Proteínas de Ligação a DNA/metabolismo
Eletroencefalografia
Encefalite/diagnóstico por imagem
Seguimentos
Seres Humanos
Imagem por Ressonância Magnética
Proteínas do Tecido Nervoso/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AIF1 protein, human); 0 (Cytokines); 0 (DNA-Binding Proteins); 0 (Nerve Tissue Proteins); 0 (Receptor, Adenosine A1); EC 2.7.1.20 (Adenosine Kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.1093/jnen/nlx053


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[PMID]:28689095
[Au] Autor:Brogi S; Ramunno A; Savi L; Chemi G; Alfano G; Pecorelli A; Pambianchi E; Galatello P; Compagnoni G; Focher F; Biamonti G; Valacchi G; Butini S; Gemma S; Campiani G; Brindisi M
[Ad] Endereço:European Research Centre for Drug Discovery and Development (NatSynDrugs), Department of Biotechnology, Chemistry, and Pharmacy, Università degli Studi di Siena via Aldo Moro 2, 53100 Siena, Italy.
[Ti] Título:First dual AK/GSK-3ß inhibitors endowed with antioxidant properties as multifunctional, potential neuroprotective agents.
[So] Source:Eur J Med Chem;138:438-457, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The manuscript deals with the design, synthesis and biological evaluation of novel benzoxazinone-based and indole-based compounds as multifunctional neuroprotective agents. These compounds inhibit human adenosine kinase (hAK) and human glycogen synthase kinase 3 beta (hGSK-3ß) enzymes. Computational analysis based on a molecular docking approach underlined the potential structural requirements for simultaneously targeting both proteins' allosteric sites. In silico hints drove the synthesis of appropriately decorated benzoxazinones and indoles (5a-s, and 6a-c) and biochemical analysis revealed their behavior as allosteric inhibitors of hGSK-3ß. For both our hit 4 and the best compounds of the series (5c,l and 6b) the potential antioxidant profile was assessed in human neuroblastoma cell lines (IMR 32, undifferentiated and neuronal differentiated), by evaluating the protective effect of selected compounds against H O cytotoxicity and reactive oxygen species (ROS) production. Results showed a strong efficacy of the tested compounds, even at the lower doses, in counteracting the induced oxidative stress (50 µM of H O ) and in preventing ROS formation. In addition, the tested compounds did not show any cytotoxic effect determined by the LDH release, at the concentration range analyzed (from 0.1 to 50 µM). This study allowed the identification of compound 5l, as the first dual hAK/hGSK-3ß inhibitor reported to date. Compound 5l, which behaves as an effective antioxidant, holds promise for the development of new series of potential therapeutic agents for the treatment of neurodegenerative diseases characterized by an innovative pharmacological profile.
[Mh] Termos MeSH primário: Adenosina Quinase/antagonistas & inibidores
Antioxidantes/farmacologia
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores
Neuroblastoma/metabolismo
Fármacos Neuroprotetores/farmacologia
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Adenosina Quinase/metabolismo
Antioxidantes/síntese química
Antioxidantes/química
Linhagem Celular Tumoral
Relação Dose-Resposta a Droga
Glicogênio Sintase Quinase 3 beta/metabolismo
Seres Humanos
Peróxido de Hidrogênio/antagonistas & inibidores
Peróxido de Hidrogênio/farmacologia
Estrutura Molecular
Neuroblastoma/patologia
Fármacos Neuroprotetores/síntese química
Fármacos Neuroprotetores/química
Estresse Oxidativo/efeitos dos fármacos
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Espécies Reativas de Oxigênio/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antioxidants); 0 (Neuroprotective Agents); 0 (Protein Kinase Inhibitors); 0 (Reactive Oxygen Species); BBX060AN9V (Hydrogen Peroxide); EC 2.7.1.20 (Adenosine Kinase); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170710
[St] Status:MEDLINE


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[PMID]:28504647
[Au] Autor:Nayar U; Sadek J; Reichel J; Hernandez-Hopkins D; Akar G; Barelli PJ; Sahai MA; Zhou H; Totonchy J; Jayabalan D; Niesvizky R; Guasparri I; Hassane D; Liu Y; Sei S; Shoemaker RH; Warren JD; Elemento O; Kaye KM; Cesarman E
[Ad] Endereço:Department of Pathology and Laboratory Medicine.
[Ti] Título:Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies.
[So] Source:J Clin Invest;127(6):2066-2080, 2017 Jun 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in treating leukemias and T cell lymphomas, and 6-ETI may fill this niche for the treatment of PEL, plasmablastic lymphoma, MM, and other ADK-expressing cancers.
[Mh] Termos MeSH primário: Adenosina Quinase/metabolismo
Antineoplásicos/farmacologia
Linfoma de Efusão Primária/tratamento farmacológico
Nucleosídeos de Purina/farmacologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos
Seres Humanos
Concentração Inibidora 50
Linfoma de Efusão Primária/enzimologia
Masculino
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (NSC39368); 0 (Purine Nucleosides); EC 2.7.1.20 (Adenosine Kinase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE


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[PMID]:27975140
[Au] Autor:Eisner C; Kim S; Grill A; Qin Y; Hoerl M; Briggs J; Castrop H; Thiel M; Schnermann J
[Ad] Endereço:National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA. christoph.eisner@med.uni-heidelberg.de.
[Ti] Título:Profound hypothermia after adenosine kinase inhibition in A1AR-deficient mice suggests a receptor-independent effect of intracellular adenosine.
[So] Source:Pflugers Arch;469(2):339-347, 2017 Feb.
[Is] ISSN:1432-2013
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Administration of the nucleoside adenosine has been shown to induce hypothermia in a number of species, an effect mediated predominantly by the adenosine 1 receptor (A1AR) subtype. The present experiments were performed to explore the possibility that the rise of intracellular adenosine levels expected to accompany adenosine administration may contribute to the hypothermic effect of adenosine independent of A1AR activation. Since phosphorylation of adenosine by adenosine kinase (ADK) is causal in the maintenance of low intracellular adenosine, we have examined the effect of ADK inhibition on core body temperature (CBT). Our data show that inhibition of ADK by A-134974 causes a long-lasting deep hypothermia in wild-type mice. Since there was an about 4-fold increase of adenosine plasma levels, experiments were repeated in A1AR-/- mice. ADK inhibition caused deep hypothermia despite the absence of A1AR, although the effect was significantly reduced compared to WT. Furthermore, the dose-dependent hypothermia caused by adenosine administration in WT mice was found to be reduced, but not abolished in A1AR-/- mice. To assess the possible role of A2AR and A3AR activation in our experimental setting, we compared the effects of the agonists CPA (A1AR), CGS21680 (A2AR), and IB-MECA (A3AR) on CBT. Hypothermia induced by CPA was much greater than that caused by CGS21680 or IB-MECA indicating that A1AR activation is the major receptor-dependent pathway for adenosine-induced hypothermia under our experimental conditions. Induction of deep hypothermia by inhibition of ADK, maintenance of this effect in A1AR-/- mice, and maintenance of adenosine-induced hypothermia in A1AR-deficient mice suggest that a receptor-independent action of adenosine requiring intact function of adenosine kinase contributes importantly to the hypothermia induced by adenosine.
[Mh] Termos MeSH primário: Adenosina Quinase/antagonistas & inibidores
Adenosina/metabolismo
Hipotermia/metabolismo
Receptor A1 de Adenosina/metabolismo
[Mh] Termos MeSH secundário: Adenosina/análogos & derivados
Adenosina/farmacologia
Animais
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Nucleosídeos/farmacologia
Fenetilaminas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (A 134974); 0 (Nucleosides); 0 (Phenethylamines); 0 (Receptor, Adenosine A1); 120225-54-9 (2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine); 152918-18-8 (N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine); EC 2.7.1.20 (Adenosine Kinase); K72T3FS567 (Adenosine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161216
[St] Status:MEDLINE
[do] DOI:10.1007/s00424-016-1925-3


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[PMID]:27915186
[Au] Autor:Cieslak M; Wojtczak A; Komoszynski M
[Ad] Endereço:Neurology Clinic, Marek Cieslak, Torun, Poland.
[Ti] Título:Role of the purinergic signaling in epilepsy.
[So] Source:Pharmacol Rep;69(1):130-138, 2017 Feb.
[Is] ISSN:1734-1140
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:Adenine nucleotides and adenosine are signaling molecules that activate purinergic receptors P1 and P2. Activation of A1 adenosine receptors has an anticonvulsant action, whereas activation of A2A receptors might initiate seizures. Therefore, a significant limitation to the use of A1 receptor agonists as drugs in the CNS might be their peripheral side effects. The anti-epileptic activity of adenosine is related to its increased concentration outside the cell. This increase might result from the inhibition of the equilibrative nucleoside transporters (ENTs). Moreover, the implantation of implants or stem cells into the brain might cause slow and persistent increases in adenosine concentrations in the extracellular spaces of the brain. The role of adenosine in seizure inhibition has been confirmed by results demonstrating that in patients with epilepsy, the adenosine kinase (ADK) present in astrocytes is the only purine-metabolizing enzyme that exhibits increased expression. Increased ADK activity causes intensified phosphorylation of adenosine to 5'-AMP, which therefore lowers the adenosine level in the extracellular spaces. These changes might initiate astrogliosis and epileptogenesis, which are the manifestations of epilepsy. Seizures might induce inflammatory processes and vice versa. Activation of P2X7 receptors causes intensified release of pro-inflammatory cytokines (IL-1ß and TNF-α) and activates metabolic pathways that induce inflammatory processes in the CNS. Therefore, antagonists of P2X7 and the interleukin 1ß receptor might be efficient drugs for recurring seizures and prolonged status epilepticus. Inhibitors of ADK would simultaneously inhibit the seizures, prevent the astrogliosis and epileptogenesis processes and prevent the formation of new epileptogenic foci. Therefore, these drugs might become beneficial seizure-suppressing drugs.
[Mh] Termos MeSH primário: Epilepsia/metabolismo
Receptor A2A de Adenosina/metabolismo
Receptores Purinérgicos P2X7/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Adenosina/metabolismo
Adenosina/farmacologia
Adenosina Quinase/antagonistas & inibidores
Adenosina Quinase/metabolismo
Animais
Epilepsia/tratamento farmacológico
Seres Humanos
Antagonistas do Receptor Purinérgico P2X/metabolismo
Antagonistas do Receptor Purinérgico P2X/farmacologia
Antagonistas do Receptor Purinérgico P2X/uso terapêutico
Receptores Purinérgicos/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Purinergic P2X Receptor Antagonists); 0 (Receptor, Adenosine A2A); 0 (Receptors, Purinergic); 0 (Receptors, Purinergic P2X7); EC 2.7.1.20 (Adenosine Kinase); K72T3FS567 (Adenosine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170323
[Lr] Data última revisão:
170323
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161205
[St] Status:MEDLINE


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[PMID]:27903722
[Au] Autor:Sandau US; Colino-Oliveira M; Jones A; Saleumvong B; Coffman SQ; Liu L; Miranda-Lourenço C; Palminha C; Batalha VL; Xu Y; Huo Y; Diógenes MJ; Sebastião AM; Boison D
[Ad] Endereço:R.S. Dow Neurobiology Laboratories and.
[Ti] Título:Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity.
[So] Source:J Neurosci;36(48):12117-12128, 2016 Nov 30.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adk mice. These Adk mice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A receptor (A R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A receptor (A R) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A receptor activity in Adk mice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A R activity therapeutically can attenuate neurological symptoms in ADK deficiency. SIGNIFICANCE STATEMENT: A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures, and severe cognitive impairment. To model and understand the neurological phenotype of the human mutation, we generated a new conditional knock-out mouse with a brain-specific deletion of Adk (Adk ). Similar to ADK-deficient patients, Adk mice develop seizures and cognitive deficits. We identified increased basal synaptic transmission and enhanced adenosine A receptor (A R)-dependent synaptic plasticity as the underlying mechanisms that govern these phenotypes. Our data show that neurological phenotypes in ADK-deficient patients are intrinsic to ADK deficiency in the brain and that blocking A R activity therapeutically can attenuate neurological symptoms in ADK deficiency.
[Mh] Termos MeSH primário: Adenosina Quinase/deficiência
Adenosina/metabolismo
Encéfalo/fisiopatologia
Plasticidade Neuronal
Receptor A2A de Adenosina/metabolismo
Transmissão Sináptica
[Mh] Termos MeSH secundário: Adenosina Quinase/genética
Animais
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Transgênicos
Neurotransmissores/metabolismo
Sinapses/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurotransmitter Agents); 0 (Receptor, Adenosine A2A); EC 2.7.1.20 (Adenosine Kinase); K72T3FS567 (Adenosine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161202
[St] Status:MEDLINE


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[PMID]:27595538
[Au] Autor:Köse M; Schiedel AC; Bauer AA; Poschenrieder H; Burbiel JC; Akkinepally RR; Stachel HD; Müller CE
[Ad] Endereço:PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: mkoese@uni-bonn.de.
[Ti] Título:Focused screening to identify new adenosine kinase inhibitors.
[So] Source:Bioorg Med Chem;24(21):5127-5133, 2016 Nov 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Adenosine kinase (AdK) is a key player in controlling intra- and extracellular concentrations of the signaling molecule adenosine. Extensive evidence points to an important role of AdK in several diseases, and suggests that AdK inhibition might be a promising therapeutic strategy. The development of a new AdK assay and subsequent screening of part of our focused compound library led to the identification of 12 hit compounds (hit rate of 6%) representing six new classes of non-nucleoside human AdK inhibitors. The most potent inhibitor 1 displayed a K value of 184nM. Compound screening with a newly developed assay was useful and efficient for discovering novel AdK inhibitors which may serve as lead structures for developing drugs for adenosine augmentation therapy.
[Mh] Termos MeSH primário: Adenosina Quinase/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Adenosina Quinase/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); EC 2.7.1.20 (Adenosine Kinase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160906
[St] Status:MEDLINE


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[PMID]:27410258
[Au] Autor:Toti KS; Osborne D; Ciancetta A; Boison D; Jacobson KA
[Ad] Endereço:Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bldg. 8A, Rm. B1A-19, Bethesda, Maryland 20892-0810, United States.
[Ti] Título:South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase.
[So] Source:J Med Chem;59(14):6860-77, 2016 Jul 28.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5'-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5'-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N(6)-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ∼ 100 nM), while the 5'-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5'-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy.
[Mh] Termos MeSH primário: Adenosina Quinase/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
Tubercidina/farmacologia
[Mh] Termos MeSH secundário: Adenosina Quinase/metabolismo
Cristalografia por Raios X
Relação Dose-Resposta a Droga
Seres Humanos
Modelos Moleculares
Conformação Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Relação Estrutura-Atividade
Tubercidina/síntese química
Tubercidina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); EC 2.7.1.20 (Adenosine Kinase); M351LCX45Y (Tubercidin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160714
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b00689


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[PMID]:27288879
[Au] Autor:Zhu CZ; Gopalakrishnan S; Doyle K; Nikkel AL; Olson L; Abraham VC; Leys L; Widomski D; Salte K; Putman B; Pratt S; Ma J; Su Z; Gopalakrishnan M; Lee CH; McGaraughty SP
[Ad] Endereço:Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA. Electronic address: chang.z.zhu@abbvie.com.
[Ti] Título:A-306989, an inhibitor of adenosine kinase, is renoprotective in rodent models of podocyte, basement membrane, and obstructive injury.
[So] Source:Eur J Pharmacol;788:1-11, 2016 Oct 05.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Adenosine (ADO) is an important regulatory purine nucleoside that accumulates at sites of inflammation and tissue injury including in diseases associated with renal pathology. Endogenous levels of ADO may be increased by inhibiting the ADO-metabolizing enzyme, ADO kinase (AK). AK inhibitors have demonstrated protection in rodent models of diabetic nephropathy. To further investigate AK inhibition as a potential mechanism for renal protection, A-306989, a potent non-nucleoside AK inhibitor, was examined in both in vitro and in vivo assays of renal injury. A-306989 prevented podocyte damage (disruption of actin cytoskeleton) and increased podocyte survival following puromycin aminonucleoside (PAN) application in both mouse and human conditionally immortalized podocytes. Prophylactic oral administration of A-306989 (1.5, 5 and 15mg/kg) reduced proteinuria in a dose-dependent manner and repressed pro-inflammatory/fibrotic gene up-regulation; A-306989 was also efficacious when administered two days following the PAN-insult. A-306989 (10 and 30mg/kg) also significantly reduced proteinuria and macrophage infiltration in a rat model of glomerulonephritis. Finally, A-306989 (15 and 50mg/kg) reduced the expression levels of pro-inflammatory/fibrotic genes, and reduced macrophage infiltration (50mg/kg), but did not affect the deposition of interstitial collagen in fibrotic kidneys from mice with unilateral ureter obstruction. A-306989 also had beneficial actions on "quality of life" measures including improving body weight loss. Thus, these data indicate that enhancement of endogenous ADO levels by A-306989 can positively modulate renal pathology and mimic some of the previously reported beneficial actions of ADO A2A receptor agonists.
[Mh] Termos MeSH primário: Adenosina Quinase/antagonistas & inibidores
Membrana Basal/diagnóstico por imagem
Citoproteção/efeitos dos fármacos
Rim/citologia
Rim/lesões
Podócitos/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Animais
Fibrose
Rim/efeitos dos fármacos
Rim/patologia
Masculino
Camundongos
Podócitos/citologia
Podócitos/metabolismo
Puromicina Aminonucleosídeo/toxicidade
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protein Kinase Inhibitors); 58-60-6 (Puromycin Aminonucleoside); EC 2.7.1.20 (Adenosine Kinase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170806
[Lr] Data última revisão:
170806
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160612
[St] Status:MEDLINE



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