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[PMID]:28679626
[Au] Autor:Frigolet ME; Thomas G; Beard K; Lu H; Liu L; Fantus IG
[Ad] Endereço:Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
[Ti] Título:The bradykinin-cGMP-PKG pathway augments insulin sensitivity via upregulation of MAPK phosphatase-5 and inhibition of JNK.
[So] Source:Am J Physiol Endocrinol Metab;313(3):E321-E334, 2017 Sep 01.
[Is] ISSN:1522-1555
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bradykinin (BK) promotes insulin sensitivity and glucose uptake in adipocytes and other cell types. We demonstrated that in rat adipocytes BK enhances insulin-stimulated glucose transport via endothelial nitric oxide synthase, nitric oxide (NO) generation, and decreased activity of the mitogen-activated protein kinase (MAPK) JNK (c-Jun NH -terminal kinase). In endothelial cells, NO increases soluble guanylate cyclase (sGC) activity, which, in turn, activates protein kinase G (PKG) by increasing cGMP levels. In this study, we investigated whether BK acts via the sGC-cGMP-PKG pathway to inhibit the negative effects of JNK on insulin signaling and glucose uptake in rat adipocytes. BK augmented cGMP concentrations. The BK-induced enhancement of insulin-stimulated glucose uptake was mimicked by the sGC activator YC-1 and a cell-permeable cGMP analog, CPT-cGMP, and inhibited by the sGC inhibitor ODQ and the PKG inhibitor KT 5823. Transfection of dominant-negative PKG reduced the BK augmentation of insulin-induced Akt phosphorylation. The activation of JNK and ERK1/2 by insulin was attenuated by BK, which was mediated by the sGC-cGMP-PKG pathway. Whereas insulin-stimulated phosphorylation of upstream activators of JNK and ERK, i.e., MKK4 and MEK1/2, was unaffected, BK augmented insulin-mediated induction of MKP-5 mRNA and protein levels. Furthermore, zaprinast, a phosphodiesterase inhibitor, enhanced cGMP and MKP-5 and prolonged the action of BK. These data indicate that BK enhances insulin action by inhibition of negative feedback by JNK and ERK via upregulation of MKP-5, mediated by the sGC-cGMP-PKG signaling pathway.
[Mh] Termos MeSH primário: Adipócitos/efeitos dos fármacos
Bradicinina/farmacologia
Proteínas Quinases Dependentes de GMP Cíclico/efeitos dos fármacos
Fosfatases de Especificidade Dupla/efeitos dos fármacos
Resistência à Insulina
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores
Fosfatases da Proteína Quinase Ativada por Mitógeno/efeitos dos fármacos
RNA Mensageiro/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adipócitos/metabolismo
Animais
Western Blotting
GMP Cíclico/metabolismo
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo
Fosfatases de Especificidade Dupla/genética
Fosfatases de Especificidade Dupla/metabolismo
Glucose/metabolismo
Guanilato Ciclase/efeitos dos fármacos
Guanilato Ciclase/metabolismo
Imunoprecipitação
Proteínas Quinases JNK Ativadas por Mitógeno/efeitos dos fármacos
Masculino
Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo III/efeitos dos fármacos
Óxido Nítrico Sintase Tipo III/metabolismo
Inibidores de Fosfodiesterase/farmacologia
Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos
Purinonas/farmacologia
RNA Mensageiro/metabolismo
Ratos
Ratos Sprague-Dawley
Reação em Cadeia da Polimerase em Tempo Real
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphodiesterase Inhibitors); 0 (Purinones); 0 (RNA, Messenger); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.14.13.39 (Nos3 protein, rat); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases); EC 3.1.3.16 (Mitogen-Activated Protein Kinase Phosphatases); EC 3.1.3.48 (DUSP10 protein, rat); EC 3.1.3.48 (Dual-Specificity Phosphatases); EC 4.6.1.2 (Guanylate Cyclase); GXT25D5DS0 (zaprinast); H2D2X058MU (Cyclic GMP); IY9XDZ35W2 (Glucose); S8TIM42R2W (Bradykinin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1152/ajpendo.00298.2016


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[PMID]:27353547
[Au] Autor:Zagórska A; Bucki A; Kolaczkowski M; Siwek A; Gluch-Lutwin M; Starowicz G; Kazek G; Partyka A; Wesolowska A; Sloczynska K; Pekala E; Pawlowski M
[Ad] Endereço:a Department of Medicinal Chemistry.
[Ti] Título:Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents.
[So] Source:J Enzyme Inhib Med Chem;31(sup3):10-24, 2016.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4-21) were synthesized and evaluated for their serotonin (5-HT /5-HT ) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT , 5-HT and mixed 5-HT /5-HT receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.
[Mh] Termos MeSH primário: Ansiolíticos/farmacologia
Antidepressivos/farmacologia
Comportamento Animal/efeitos dos fármacos
Imidazóis/farmacologia
Atividade Motora/efeitos dos fármacos
Purinonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Ansiolíticos/síntese química
Ansiolíticos/química
Antidepressivos/síntese química
Antidepressivos/química
Cromatografia Capilar Eletrocinética Micelar
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Imidazóis/síntese química
Imidazóis/química
Camundongos
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
Modelos Moleculares
Estrutura Molecular
Diester Fosfórico Hidrolases/metabolismo
Purinonas/síntese química
Purinonas/química
Receptor 5-HT1A de Serotonina/metabolismo
Receptores de Serotonina/metabolismo
Relação Estrutura-Atividade
Natação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1H-imidazo(2,1-f)purine-2,4(3H,8H)-dione); 0 (Anti-Anxiety Agents); 0 (Antidepressive Agents); 0 (Imidazoles); 0 (Purinones); 0 (Receptors, Serotonin); 0 (serotonin 7 receptor); 112692-38-3 (Receptor, Serotonin, 5-HT1A); EC 3.1.4.- (PDE10A protein, human); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4); EC 3.1.4.17 (PDE4B protein, human)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170223
[Lr] Data última revisão:
170223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160630
[St] Status:MEDLINE


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[PMID]:27292096
[Au] Autor:Cheng Q; Sun GJ; Liu SB; Yang Q; Li XM; Li XB; Liu G; Zhao JN; Zhao MG
[Ad] Endereço:Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing, China.
[Ti] Título:A novel translocator protein 18 kDa ligand, ZBD-2, exerts neuroprotective effects against acute spinal cord injury.
[So] Source:Clin Exp Pharmacol Physiol;43(10):930-8, 2016 Oct.
[Is] ISSN:1440-1681
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Traumatic spinal cord injury (SCI) happens accidently and often leads to motor dysfunction due to a series of biochemical and pathological events and damage, either temporarily or permanently. Translocator protein 18 (TSPO) has been found to be involved in the synthesis of endogenous neurosteroids which have multiple effects on neurons, but the internal mechanisms are not clear. N-benzyl-N-ethyl-2-(7,8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2), a newly reported ligand of TSPO, shows some neuroprotective effect against focal cerebral ischemia in vivo and NMDA-induced neurotoxicity in vitro. The present study aims to examine the role of ZBD-2 in SCI mice and elucidate the underlying molecular mechanisms. The SCI model was established by crushing spinal cord. ZBD-2 (10 mg/kg) significantly enhanced the hindlimb locomotor functions after SCI and decreased the tissue damage and conserved the white matter of the spinal cord. High-dose ZBD-2 alleviated the oxidative stress induced by SCI and regulated the imbalance between NR2B-containing NMDA and GABA receptors by increasing the levels of GAD67 in the spinal cord of SCI mice. Additionally, ZBD-2 (10 mg/kg) increased phosphorylated Akt (p-Akt) and decreased the ratio of Bax/Bcl-2. These results demonstrate that ZBD-2 performs neuroprotection against SCI through regulating the synaptic transmission and the PI3K/AKT signaling pathway.
[Mh] Termos MeSH primário: Acetamidas/uso terapêutico
Fármacos Neuroprotetores/uso terapêutico
Purinonas/uso terapêutico
Traumatismos da Medula Espinal/tratamento farmacológico
Traumatismos da Medula Espinal/metabolismo
[Mh] Termos MeSH secundário: Acetamidas/farmacologia
Animais
Ligantes
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Fármacos Neuroprotetores/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Estresse Oxidativo/fisiologia
Purinonas/farmacologia
Traumatismos da Medula Espinal/patologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Ligands); 0 (N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide); 0 (Neuroprotective Agents); 0 (Purinones)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160614
[St] Status:MEDLINE
[do] DOI:10.1111/1440-1681.12606


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[PMID]:27131920
[Au] Autor:Resta F; Masi A; Sili M; Laurino A; Moroni F; Mannaioni G
[Ad] Endereço:Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Electronic address: francesco.resta@unifi.it.
[Ti] Título:Kynurenic acid and zaprinast induce analgesia by modulating HCN channels through GPR35 activation.
[So] Source:Neuropharmacology;108:136-43, 2016 Sep.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have a key role in the control of cellular excitability. HCN2, a subgroup of the HCN family channels, are heavily expressed in small dorsal root ganglia (DRG) neurons and their activation seems to be important in the determination of pain intensity. Intracellular elevation of cAMP levels activates HCN-mediated current (Ih) and small DRG neurons excitability. GPR35, a Gi/o coupled receptor, is highly expressed in small DRG neurons, and we hypothesized that its activation, mediated by endogenous or exogenous ligands, could lead to pain control trough a reduction of Ih current. Patch clamp recordings were carried out in primary cultures of rat DRG neurons and the effects of GPR35 activation on Ih current and neuronal excitability were studied in control conditions and after adenylate cyclase activation with either forskolin or prostaglandin E2 (PGE2). We found that both kynurenic acid (KYNA) and zaprinast, the endogenous and synthetic GPR35 agonist respectively, were able to antagonize the forskolin-induced depolarization of resting membrane potential by reducing Ih-mediated depolarization. Similar results were obtained when PGE2 was used to activate adenylate cyclase and to increase Ih current and the overall neuronal excitability. Finally, we tested the analgesic effect of both GPR35 agonists in an in vivo model of PGE2-induced thermal hyperalgesia. In accord with the hypothesis, both KYNA and zaprinast showed a dose dependent analgesic effect. In conclusion, GPR35 activation leads to a reduced excitability of small DRG neurons in vitro and causes a dose-dependent analgesia in vivo. GPR35 agonists, by reducing adenylate cyclase activity and inhibiting Ih in DRG neurons may represent a promising new group of analgesic drugs.
[Mh] Termos MeSH primário: Analgesia/métodos
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia
Ácido Cinurênico/uso terapêutico
Purinonas/uso terapêutico
Receptores Acoplados a Proteínas-G/agonistas
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Células Cultivadas
Relação Dose-Resposta a Droga
Gânglios Espinais/efeitos dos fármacos
Gânglios Espinais/metabolismo
Hiperalgesia/tratamento farmacológico
Hiperalgesia/metabolismo
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/agonistas
Ácido Cinurênico/farmacologia
Purinonas/farmacologia
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GPR35 protein, rat); 0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels); 0 (Purinones); 0 (Receptors, G-Protein-Coupled); GXT25D5DS0 (zaprinast); H030S2S85J (Kynurenic Acid)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170707
[Lr] Data última revisão:
170707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160502
[St] Status:MEDLINE


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[PMID]:26933036
[Au] Autor:Sidik SM; Hortua Triana MA; Paul AS; El Bakkouri M; Hackett CG; Tran F; Westwood NJ; Hui R; Zuercher WJ; Duraisingh MT; Moreno SN; Lourido S
[Ad] Endereço:From the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
[Ti] Título:Using a Genetically Encoded Sensor to Identify Inhibitors of Toxoplasma gondii Ca2+ Signaling.
[So] Source:J Biol Chem;291(18):9566-80, 2016 Apr 29.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The life cycles of apicomplexan parasites progress in accordance with fluxes in cytosolic Ca(2+) Such fluxes are necessary for events like motility and egress from host cells. We used genetically encoded Ca(2+) indicators (GCaMPs) to develop a cell-based phenotypic screen for compounds that modulate Ca(2+) signaling in the model apicomplexan Toxoplasma gondii In doing so, we took advantage of the phosphodiesterase inhibitor zaprinast, which we show acts in part through cGMP-dependent protein kinase (protein kinase G; PKG) to raise levels of cytosolic Ca(2+) We define the pool of Ca(2+) regulated by PKG to be a neutral store distinct from the endoplasmic reticulum. Screening a library of 823 ATP mimetics, we identify both inhibitors and enhancers of Ca(2+) signaling. Two such compounds constitute novel PKG inhibitors and prevent zaprinast from increasing cytosolic Ca(2+) The enhancers identified are capable of releasing intracellular Ca(2+) stores independently of zaprinast or PKG. One of these enhancers blocks parasite egress and invasion and shows strong antiparasitic activity against T. gondii The same compound inhibits invasion of the most lethal malaria parasite, Plasmodium falciparum Inhibition of Ca(2+)-related phenotypes in these two apicomplexan parasites suggests that depletion of intracellular Ca(2+) stores by the enhancer may be an effective antiparasitic strategy. These results establish a powerful new strategy for identifying compounds that modulate the essential parasite signaling pathways regulated by Ca(2+), underscoring the importance of these pathways and the therapeutic potential of their inhibition.
[Mh] Termos MeSH primário: Sinalização do Cálcio/efeitos dos fármacos
Proteínas Quinases Dependentes de GMP Cíclico
Retículo Endoplasmático
Proteínas de Protozoários
Purinonas/farmacologia
Toxoplasma
[Mh] Termos MeSH secundário: Proteínas Quinases Dependentes de GMP Cíclico/genética
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo
Retículo Endoplasmático/genética
Retículo Endoplasmático/metabolismo
Plasmodium falciparum/genética
Plasmodium falciparum/metabolismo
Proteínas de Protozoários/genética
Proteínas de Protozoários/metabolismo
Toxoplasma/genética
Toxoplasma/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Protozoan Proteins); 0 (Purinones); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases); GXT25D5DS0 (zaprinast)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160303
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.703546


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[PMID]:26933037
[Au] Autor:Brown KM; Lourido S; Sibley LD
[Ad] Endereço:From the Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110.
[Ti] Título:Serum Albumin Stimulates Protein Kinase G-dependent Microneme Secretion in Toxoplasma gondii.
[So] Source:J Biol Chem;291(18):9554-65, 2016 Apr 29.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Microneme secretion is essential for motility, invasion, and egress in apicomplexan parasites. Although previous studies indicate that Ca(2+) and cGMP control microneme secretion, little is known about how these pathways are naturally activated. Here we have developed genetically encoded indicators for Ca(2+) and microneme secretion to better define the signaling pathways that regulate these processes in Toxoplasma gondii We found that microneme secretion was triggered in vitro by exposure to a single host protein, serum albumin. The natural agonist serum albumin induced microneme secretion in a protein kinase G-dependent manner that correlated with increased cGMP levels. Surprisingly, serum albumin acted independently of elevated Ca(2+) and yet it was augmented by artificial agonists that raise Ca(2+), such as ethanol. Furthermore, although ethanol elevated intracellular Ca(2+), it alone was unable to trigger secretion without the presence of serum or serum albumin. This dichotomy was recapitulated by zaprinast, a phosphodiesterase inhibitor that elevated cGMP and separately increased Ca(2+) in a protein kinase G-independent manner leading to microneme secretion. Taken together, these findings reveal that microneme secretion is centrally controlled by protein kinase G and that this pathway is further augmented by elevation of intracellular Ca(2.)
[Mh] Termos MeSH primário: Sinalização do Cálcio/efeitos dos fármacos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo
GMP Cíclico/metabolismo
Proteínas de Protozoários/metabolismo
Albumina Sérica/farmacologia
Toxoplasma/metabolismo
[Mh] Termos MeSH secundário: Sinalização do Cálcio/genética
GMP Cíclico/genética
Proteínas Quinases Dependentes de GMP Cíclico/genética
Seres Humanos
Proteínas de Protozoários/genética
Purinonas/farmacologia
Toxoplasma/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protozoan Proteins); 0 (Purinones); 0 (Serum Albumin); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases); GXT25D5DS0 (zaprinast); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:170429
[Lr] Data última revisão:
170429
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160303
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.700518


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[PMID]:27064272
[Au] Autor:McCallum JE; Mackenzie AE; Divorty N; Clarke C; Delles C; Milligan G; Nicklin SA
[Ad] Endereço:Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
[Ti] Título:G-Protein-Coupled Receptor 35 Mediates Human Saphenous Vein Vascular Smooth Muscle Cell Migration and Endothelial Cell Proliferation.
[So] Source:J Vasc Res;52(6):383-95, 2015.
[Is] ISSN:1423-0135
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Vascular smooth muscle cell (VSMC) migration and proliferation is central to neointima formation in vein graft failure following coronary artery bypass. However, there are currently no pharmacological interventions that prevent vein graft failure through intimal occlusion. It is hence a therapeutic target. Here, we investigated the contribution of GPR35 to human VSMC and endothelial cell (EC) migration, using a scratch-wound assay, and also the contribution to proliferation, using MTS and BrdU assays, in in vitro models using recently characterized human GPR35 ortholog-selective small-molecule agonists and antagonists. Real-time PCR studies showed GPR35 to be robustly expressed in human VSMCs and ECs. Stimulation of GPR35, with either the human-selective agonist pamoic acid or the reference agonist zaprinast, promoted VSMC migration in the scratch-wound assay. These effects were blocked by coincubation with either of the human GPR35-specific antagonists, CID-2745687 or ML-145. These GPR35-mediated effects were produced by inducing alterations in the actin cytoskeleton via the Rho A/Rho kinase signaling axis. Additionally, the agonist ligands stimulated a proliferative response in ECs. These studies highlight the potential that small molecules that stimulate or block GPR35 activity can modulate vascular proliferation and migration. These data propose GPR35 as a translational therapeutic target in vascular remodeling.
[Mh] Termos MeSH primário: Movimento Celular
Proliferação Celular
Células Endoteliais/metabolismo
Músculo Liso Vascular/metabolismo
Miócitos de Músculo Liso/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Citoesqueleto de Actina/metabolismo
Ácidos Aminossalicílicos/farmacologia
Relação Dose-Resposta a Droga
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/patologia
Células HEK293
Seres Humanos
Hidrazonas/farmacologia
Músculo Liso Vascular/efeitos dos fármacos
Músculo Liso Vascular/patologia
Miócitos de Músculo Liso/efeitos dos fármacos
Miócitos de Músculo Liso/patologia
Naftóis/farmacologia
Purinonas/farmacologia
Receptores Acoplados a Proteínas-G/agonistas
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
Receptores Acoplados a Proteínas-G/genética
Veia Safena/metabolismo
Veia Safena/patologia
Transdução de Sinais
Tiazolidinas/farmacologia
Tioureia/análogos & derivados
Tioureia/farmacologia
Fatores de Tempo
Quinases Associadas a rho/metabolismo
Proteína rhoA de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-hydroxy-4-(4-(5-(2-methyl-3-phenylprop-2-enylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)butanoylamino)benzoic acid); 0 (Aminosalicylic Acids); 0 (GPR35 protein, human); 0 (Hydrazones); 0 (Naphthols); 0 (Purinones); 0 (Receptors, G-Protein-Coupled); 0 (Thiazolidines); 0 (methyl 5-((tert-butylcarbamothioylhydrazinylidene)methyl)-1-(2,4-difluorophenyl)pyrazole-4-carboxylate); 124671-05-2 (RHOA protein, human); 7RRQ8QZ38N (pamoic acid); EC 2.7.11.1 (rho-Associated Kinases); EC 3.6.5.2 (rhoA GTP-Binding Protein); GXT25D5DS0 (zaprinast); GYV9AM2QAG (Thiourea)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160412
[St] Status:MEDLINE
[do] DOI:10.1159/000444754


  8 / 635 MEDLINE  
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[PMID]:26299350
[Au] Autor:Jadhav GP; Kaur I; Maryati M; Airhihen B; Fischer PM; Winkler GS
[Ad] Endereço:School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
[Ti] Título:Discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as inhibitors of the human poly(A)-selective ribonuclease Caf1.
[So] Source:Bioorg Med Chem Lett;25(19):4219-24, 2015 Oct 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Eukaryotic mRNA contains a 3' poly(A) tail, which plays important roles in the regulation of mRNA stability and translation. Well-characterized enzymes involved in the shortening of the poly(A) tail include the multi-subunit Ccr4-Not deadenylase, which contains the Caf1 (Pop2) and Ccr4 catalytic components, and poly(A)-specific ribonuclease (PARN). Two Mg(2+) ions present in the active sites of these ribonucleases are required for RNA cleavage. Here, we report the discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as (sub)micromolar inhibitors of Caf1.
[Mh] Termos MeSH primário: Descoberta de Drogas
Purinonas/farmacologia
Fatores de Transcrição/antagonistas & inibidores
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Purinonas/síntese química
Purinonas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CNOT8 protein, human); 0 (Purinones); 0 (Transcription Factors)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150825
[St] Status:MEDLINE


  9 / 635 MEDLINE  
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[PMID]:26174423
[Au] Autor:Li XB; Guo HL; Shi TY; Yang L; Wang M; Zhang K; Guo YY; Wu YM; Liu SB; Zhao MG
[Ad] Endereço:Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
[Ti] Título:Neuroprotective effects of a novel translocator protein (18 kDa) ligand, ZBD-2, against focal cerebral ischemia and NMDA-induced neurotoxicity.
[So] Source:Clin Exp Pharmacol Physiol;42(10):1068-74, 2015 Oct.
[Is] ISSN:1440-1681
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Ligands of the translocator protein (18 kDa) (TSPO) have demonstrated rapid anxiolytic efficacy in stress responses and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids including pregnenolone, dehydroepiandrosterone, and progesterone. These neurosteroids promote γ-aminobutyric acid-mediated neurotransmission in the central neural system (CNS). A TSPO ligand, N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was recently synthesized. The purpose of the present study was to investigate the neuroprotective effects of ZBD-2 and. In cultured cortical neurons, treatment with ZBD-2 attenuated excitotoxicity induced by N-methyl-d-aspartate (NMDA) exposure. It significantly decreased the number of apoptotic cells by downregulating GluN2B-containing NMDA receptors (NMDARs), the ratio of Bax/Bcl-2, and levels of pro-caspase-3. Systemic treatment of ZBD-2 provided significant neuroprotection in mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that neuroprotection by ZBD-2 is partially mediated by inhibiting GluN2B-containing NMDA receptor-mediated excitotoxicity.
[Mh] Termos MeSH primário: Acetamidas/farmacologia
Isquemia Encefálica/prevenção & controle
N-Metilaspartato/toxicidade
Neurônios/efeitos dos fármacos
Fármacos Neuroprotetores/farmacologia
Purinonas/farmacologia
Receptores de GABA/metabolismo
[Mh] Termos MeSH secundário: Acetamidas/metabolismo
Animais
Apoptose/efeitos dos fármacos
Encéfalo/citologia
Isquemia Encefálica/patologia
Caspase 3/metabolismo
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Ligantes
Masculino
Camundongos
Neurônios/citologia
Neurônios/metabolismo
Fármacos Neuroprotetores/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Purinonas/metabolismo
Receptores de N-Metil-D-Aspartato/metabolismo
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Acetamides); 0 (Bzrp protein, mouse); 0 (Ligands); 0 (N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide); 0 (N-methyl D-aspartate receptor subtype 2A); 0 (NR2B NMDA receptor); 0 (Neuroprotective Agents); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Purinones); 0 (Receptors, GABA); 0 (Receptors, N-Methyl-D-Aspartate); 0 (bcl-2-Associated X Protein); 6384-92-5 (N-Methylaspartate); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:150916
[Lr] Data última revisão:
150916
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150716
[St] Status:MEDLINE
[do] DOI:10.1111/1440-1681.12460


  10 / 635 MEDLINE  
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[PMID]:25889665
[Au] Autor:Wang DS; Tian Z; Guo YY; Guo HL; Kang WB; Li S; Den YT; Li XB; Feng B; Feng D; Zhao JN; Liu G; Zhao MG
[Ad] Endereço:Department of Orthopedics, Jinling Hospital, Clinical School of Nanjing, Second Military Medical University, Nanjing, 210002, China. 573631248@qq.com.
[Ti] Título:Anxiolytic-like effects of translocator protein (TSPO) ligand ZBD-2 in an animal model of chronic pain.
[So] Source:Mol Pain;11:16, 2015 Mar 26.
[Is] ISSN:1744-8069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The activation of Translocator protein (18 kDa) (TSPO) has been demonstrated to mediate rapid anxiolytic efficacy in stress response and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids that promote γ-aminobutyric acid (GABA)-mediated neurotransmission in the central neural system. However, little is known about the functions and the underlying mechanisms of TSPO in chronic pain-induced anxiety-like behaviors. The novel TSPO ligand N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was used in the present study. We found that ZBD-2 (0.15 or 1.5 mg/kg) significantly attenuated anxiety-like behaviors in mice with chronic inflammatory pain induced by hindpaw injection of complete Freund's adjuvant (CFA). However, the treatment did not alter the nociceptive threshold or inflammation in the hindpaw. Hindpaw injection of CFA induced the upregulation of TSPO, GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and NR2B-containing N-methyl-D-aspartate (NMDA) receptors in the basolateral amygdala (BLA). ZBD-2 administration reversed the alterations of the abovementioned proteins in the BLA of the CFA-injected mice. Electrophysiological recording revealed that ZBD-2 could prevent an imbalance between excitatory and inhibitory transmissions in the BLA synapses of CFA-injected mice. Therefore, as the novel ligand of TSPO, ZBD-2 induced anxiolytic effects, but did not affect the nociceptive threshold of mice under chronic pain. The anxiolytic effects of ZBD-2 were related to the regulation of the balance between excitatory and inhibitory transmissions in the BLA.
[Mh] Termos MeSH primário: Acetamidas/metabolismo
Ansiolíticos/farmacologia
Dor Crônica/tratamento farmacológico
Purinonas/metabolismo
Receptores de GABA/metabolismo
Sinapses/metabolismo
[Mh] Termos MeSH secundário: Animais
Ansiedade/tratamento farmacológico
Modelos Animais de Doenças
Adjuvante de Freund/uso terapêutico
Masculino
Camundongos Endogâmicos C57BL
Transmissão Sináptica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Acetamides); 0 (Anti-Anxiety Agents); 0 (Bzrp protein, mouse); 0 (N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide); 0 (Purinones); 0 (Receptors, GABA); 9007-81-2 (Freund's Adjuvant)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:150420
[Lr] Data última revisão:
150420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150419
[St] Status:MEDLINE
[do] DOI:10.1186/s12990-015-0013-6



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