Base de dados : MEDLINE
Pesquisa : D12.776.157.530.450.625.155 [Categoria DeCS]
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[PMID]:29338548
[Au] Autor:Cioffi CL
[Ad] Endereço:a Departments of Basic and Clinical Sciences and Pharmaceutical Sciences , Albany College of Pharmacy and Health Sciences , Albany , NY , USA.
[Ti] Título:Glycine transporter-1 inhibitors: a patent review (2011-2016).
[So] Source:Expert Opin Ther Pat;28(3):197-210, 2018 Mar.
[Is] ISSN:1744-7674
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Numerous research groups have developed GlyT-1 inhibitors in the pursuit of providing a novel antipsychotic treatment for schizophrenia. Despite multiple compounds advancing into clinical trials, a GlyT-1 inhibitor has yet to emerge to treat patients. However, the approach remains heavily investigated as it presents potential therapeutic utility for several other CNS and non-CNS-related indications. Areas covered: This review discusses various GlyT-1 inhibitor chemotypes identified and provides an overview of patent applications filed and published during the period of 2011-2016. The review largely focuses on composition of matter patent applications, although two recently disclosed method of use patents are discussed. Clinical reports are also disseminated. Expert opinion: Mounting clinical failures with schizophrenic patients have blunted enthusiasm for GlyT-1 inhibition as an approach to treat the disease. However, research in the area remains quite active, as therapeutic potential for several additional indications has emerged. There are numerous and diverse GlyT-1 chemotypes now available that exhibit differentiating modes of binding and ligand-target binding kinetics, and this rich diversity of chemical matter may help further elucidate the target's pharmacological role in various indications and lead to the identification of a compound with optimal properties that may someday become a drug.
[Mh] Termos MeSH primário: Antipsicóticos/farmacologia
Desenho de Drogas
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Patentes como Assunto
Esquizofrenia/tratamento farmacológico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (Glycine Plasma Membrane Transport Proteins); 0 (SLC6A9 protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.1080/13543776.2018.1429408


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[PMID]:28874448
[Au] Autor:Bardóczi Z; Pál B; Koszeghy Á; Wilheim T; Watanabe M; Záborszky L; Liposits Z; Kalló I
[Ad] Endereço:Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, HAS, 1083, Budapest, Hungary.
[Ti] Título:Glycinergic Input to the Mouse Basal Forebrain Cholinergic Neurons.
[So] Source:J Neurosci;37(39):9534-9549, 2017 Sep 27.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The basal forebrain (BF) receives afferents from brainstem ascending pathways, which has been implicated first by Moruzzi and Magoun (1949) to induce forebrain activation and cortical arousal/waking behavior; however, it is very little known about how brainstem inhibitory inputs affect cholinergic functions. In the current study, glycine, a major inhibitory neurotransmitter of brainstem neurons, and gliotransmitter of local glial cells, was tested for potential interaction with BF cholinergic (BFC) neurons in male mice. In the BF, glycine receptor α subunit-immunoreactive (IR) sites were localized in choline acetyltransferase (ChAT)-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs (sIPSCs; 0.81 ± 0.25 × 10 Hz) recorded in whole-cell conditions. Potential neuronal as well as glial sources of glycine were indicated in the extracellular space of cholinergic neurons by glycine transporter type 1 (GLYT1)- and GLYT2-IR processes found in apposition to ChAT-IR cells. Ultrastructural analyses identified synapses of GLYT2-positive axon terminals on ChAT-IR neurons, as well as GLYT1-positive astroglial processes, which were localized in the vicinity of synapses of ChAT-IR neurons. The brainstem raphe magnus was determined to be a major source of glycinergic axons traced retrogradely from the BF. Our results indicate a direct effect of glycine on BFC neurons. Furthermore, the presence of high levels of plasma membrane glycine transporters in the vicinity of cholinergic neurons suggests a tight control of extracellular glycine in the BF. Basal forebrain cholinergic (BFC) neurons receive various activating inputs from specific brainstem areas and channel this information to the cortex via multiple projections. So far, very little is known about inhibitory brainstem afferents to the BF. The current study established glycine as a major regulator of BFC neurons by (1) identifying glycinergic neurons in the brainstem projecting to the BF, (2) showing glycine receptor α subunit-immunoreactive (IR) sites in choline acetyltransferase (ChAT)-IR neurons, (3) demonstrating glycine transporter type 2 (GLYT2)-positive axon terminals synapsing on ChAT-IR neurons, and (4) localizing GLYT1-positive astroglial processes in the vicinity of synapses of ChAT-IR neurons. The effect of glycine on BFC neurons was demonstrated by bicuculline-resistant, strychnine-sensitive spontaneous IPSCs recorded in whole-cell conditions.
[Mh] Termos MeSH primário: Neurônios Colinérgicos/metabolismo
Glicina/metabolismo
Prosencéfalo/metabolismo
[Mh] Termos MeSH secundário: Animais
Bicuculina/farmacologia
Colina O-Acetiltransferase/genética
Colina O-Acetiltransferase/metabolismo
Neurônios Colinérgicos/efeitos dos fármacos
Neurônios Colinérgicos/fisiologia
Feminino
Glicina/farmacologia
Glicinérgicos/farmacologia
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo
Potenciais Pós-Sinápticos Inibidores
Masculino
Camundongos
Neuroglia/metabolismo
Prosencéfalo/citologia
Estricnina/farmacologia
Sinapses/efeitos dos fármacos
Sinapses/metabolismo
Sinapses/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycine Agents); 0 (Glycine Plasma Membrane Transport Proteins); EC 2.3.1.6 (Choline O-Acetyltransferase); H9Y79VD43J (Strychnine); TE7660XO1C (Glycine); Y37615DVKC (Bicuculline)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171015
[Lr] Data última revisão:
171015
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3348-16.2017


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[PMID]:28847813
[Au] Autor:Moore LA; Trussell LO
[Ad] Endereço:Neuroscience Graduate Program and moorlu@ohsu.edu.
[Ti] Título:Corelease of Inhibitory Neurotransmitters in the Mouse Auditory Midbrain.
[So] Source:J Neurosci;37(39):9453-9464, 2017 Sep 27.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The central nucleus of the inferior colliculus (ICC) of the auditory midbrain, which integrates most ascending auditory information from lower brainstem regions, receives prominent long-range inhibitory input from the ventral nucleus of the lateral lemniscus (VNLL), a region thought to be important for temporal pattern discrimination. Histological evidence suggests that neurons in the VNLL release both glycine and GABA in the ICC, but functional evidence for their corelease is lacking. We took advantage of the mouse line (both male and female) to target expression of ChR2 to glycinergic afferents in the ICC and made whole-cell recordings while exciting glycinergic fibers with light. Using this approach, it was clear that a significant fraction of glycinergic boutons corelease GABA in the ICC. Viral injections were used to target ChR2 expression specifically to glycinergic fibers ascending from the VNLL, allowing for activation of fibers from a single source of ascending input in a way that has not been previously possible in the ICC. We then investigated aspects of the glycinergic versus GABAergic current components to probe functional consequences of corelease. Surprisingly, the time course and short-term plasticity of synaptic signaling were nearly identical for the two transmitters. We therefore conclude that the two neurotransmitters may be functionally interchangeable and that multiple receptor subtypes subserving inhibition may offer diverse mechanisms for maintaining inhibitory homeostasis. Corelease of neurotransmitters is a common feature of the brain. GABA and glycine corelease is particularly common in the spinal cord and brainstem, but its presence in the midbrain is unknown. We show corelease of GABA and glycine for the first time in the central nucleus of the inferior colliculus of the auditory midbrain. Glycine and GABA are both inhibitory neurotransmitters involved in fast synaptic transmission, so we explored differences between the currents to establish a physiological foundation for functional differences In contrast to the auditory brainstem, coreleased GABAergic and glycinergic currents in the midbrain are strikingly similar. This apparent redundancy may ensure homeostasis if one neurotransmitter system is compromised.
[Mh] Termos MeSH primário: Potenciais Pós-Sinápticos Excitadores
Glicina/metabolismo
Colículos Inferiores/metabolismo
Ácido gama-Aminobutírico/metabolismo
[Mh] Termos MeSH secundário: Animais
Channelrhodopsins
Exocitose
Feminino
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo
Homeostase
Colículos Inferiores/citologia
Colículos Inferiores/fisiologia
Masculino
Camundongos
Neurônios Aferentes/metabolismo
Neurônios Aferentes/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Channelrhodopsins); 0 (Glycine Plasma Membrane Transport Proteins); 0 (Slc6a5 protein, mouse); 56-12-2 (gamma-Aminobutyric Acid); TE7660XO1C (Glycine)
[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:170830
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1125-17.2017


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[PMID]:28410963
[Au] Autor:Yoganandarajah V; Li B; Umapathy A; Donaldson PJ; Lim JC
[Ad] Endereço:Department of Physiology, School of Medical Sciences, New Zealand National Eye Centre, University of Auckland, New Zealand.
[Ti] Título:Regional differences in glutathione accumulation pathways in the rat cornea: Mapping of amino acid transporters involved in glutathione synthesis.
[So] Source:Exp Eye Res;161:89-100, 2017 Aug.
[Is] ISSN:1096-0007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In this study we have sought to complete the identification and localisation of uptake pathways involved in accumulating precursor amino acids involved in GSH synthesis in the rat cornea. To do this, we performed reverse transcription PCR (RT-PCR) to identify the Excitatory Amino Acid Transporters (EAAT 1-5) responsible for glutamate uptake, and glycine transporters (GLYT 1-2) at the transcript level. Western blotting was used to verify protein expression, while immunolabelling of sagittal sections was used to localise transporters to the different layers of the cornea. Immunolabelling of en face sections was used to examine the subcellular distribution of proteins in the corneal endothelium. Our findings revealed EAAT 1-5 and GLYT 1-2 to be expressed at the transcript and protein level in the rat cornea. Immunohistochemistry revealed all amino acid transporters to be localised to the epithelium. In the majority of cases, labelling was restricted to the epithelium, and labelling absent from the stroma or endothelium. However, EAAT 4 and GLYT 2 labelling was detected in the stroma with EAAT 4 labelling also present in the endothelium. Overall, the identification of amino acid transporters strongly supports the existence of an intracellular GSH synthesis pathway in the rat corneal epithelium. This suggests that regional differences in GSH accumulation pathways exist, with direct uptake of GSH and intracellular synthesis of GSH restricted to the endothelial and epithelial cell layers, respectively. This information is important in the design of targeted strategies to enhance GSH levels in specific layers of the cornea to prevent against oxidative damage, corneal swelling and loss of corneal transparency.
[Mh] Termos MeSH primário: Sistema X-AG de Transporte de Aminoácidos/metabolismo
Córnea/metabolismo
Glutationa/biossíntese
Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo
[Mh] Termos MeSH secundário: Sistema X-AG de Transporte de Aminoácidos/genética
Sistemas de Transporte de Aminoácidos/fisiologia
Animais
Transporte Biológico
Western Blotting
Substância Própria/metabolismo
Epitélio Posterior/metabolismo
Epitélio Anterior/metabolismo
Técnica Indireta de Fluorescência para Anticorpo
Regulação da Expressão Gênica/fisiologia
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Ratos
Ratos Wistar
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acid Transport System X-AG); 0 (Amino Acid Transport Systems); 0 (Glycine Plasma Membrane Transport Proteins); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170416
[St] Status:MEDLINE


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[PMID]:28302446
[Au] Autor:Oyama M; Kuraoka S; Watanabe S; Iwai T; Tanabe M
[Ad] Endereço:Laboratory of Pharmacology, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
[Ti] Título:Electrophysiological evidence of increased glycine receptor-mediated phasic and tonic inhibition by blockade of glycine transporters in spinal superficial dorsal horn neurons of adult mice.
[So] Source:J Pharmacol Sci;133(3):162-167, 2017 Mar.
[Is] ISSN:1347-8648
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:To understand the synaptic and/or extrasynaptic mechanisms underlying pain relief by blockade of glycine transporter subtypes GlyT1 and GlyT2, whole-cell recordings were made from dorsal horn neurons in spinal slices from adult mice, and the effects of NFPS and ALX-1393, selective GlyT1 and GlyT2 inhibitors, respectively, on phasic evoked or miniature glycinergic inhibitory postsynaptic currents (eIPSCs or mIPSCs) were examined. NFPS and ALX-1393 prolonged the decay phase of eIPSCs without affecting their amplitude. In the presence of tetrodotoxin to record mIPSCs, NFPS and ALX-1393 induced a tonic inward current that was reversed by strychnine. Although NFPS had no statistically significant influences on mIPSCs, ALX-1393 significantly increased their frequency. We then further explored the role of GlyTs in the maintenance of glycinergic IPSCs. To facilitate vesicular release of glycine, repetitive high-frequency stimulation (HFS) was applied at 10 Hz for 3 min during continuous recordings of eIPSCs at 0.1 Hz. Prominent suppression of eIPSCs was evident after HFS in the presence of ALX-1393, but not NFPS. Thus, it appears that phasic and tonic inhibition may contribute to the analgesic effects of GlyT inhibitors. However, reduced glycinergic inhibition due to impaired vesicular refilling could hamper the analgesic efficacy of GlyT2 inhibitors.
[Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Glicina/fisiologia
Células do Corno Posterior/fisiologia
[Mh] Termos MeSH secundário: Animais
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores
Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos
Masculino
Camundongos
Células do Corno Posterior/efeitos dos fármacos
Sarcosina/análogos & derivados
Sarcosina/farmacologia
Serina/análogos & derivados
Serina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ALX 1393); 0 (Glycine Plasma Membrane Transport Proteins); 0 (N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine); 0 (Slc6a5 protein, mouse); 0 (Slc6a9 protein, mouse); 452VLY9402 (Serine); Z711V88R5F (Sarcosine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE


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[PMID]:28295336
[Au] Autor:Parker LM; Le S; Wearne TA; Hardwick K; Kumar NN; Robinson KJ; McMullan S; Goodchild AK
[Ad] Endereço:Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, NSW, 2109, Australia.
[Ti] Título:Neurochemistry of neurons in the ventrolateral medulla activated by hypotension: Are the same neurons activated by glucoprivation?
[So] Source:J Comp Neurol;525(9):2249-2264, 2017 Jun 15.
[Is] ISSN:1096-9861
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies have demonstrated that a range of stimuli activate neurons, including catecholaminergic neurons, in the ventrolateral medulla. Not all catecholaminergic neurons are activated and other neurochemical content is largely unknown hence whether stimulus specific populations exist is unclear. Here we determine the neurochemistry (using in situ hybridization) of catecholaminergic and noncatecholaminergic neurons which express c-Fos immunoreactivity throughout the rostrocaudal extent of the ventrolateral medulla, in Sprague Dawley rats treated with hydralazine or saline. Distinct neuronal populations containing PPCART, PPPACAP, and PPNPY mRNAs, which were largely catecholaminergic, were activated by hydralazine but not saline. Both catecholaminergic and noncatecholaminergic neurons containing preprotachykinin and prepro-enkephalin (PPE) mRNAs were also activated, with the noncatecholaminergic population located in the rostral C1 region. Few GlyT2 neurons were activated. A subset of these data was then used to compare the neuronal populations activated by 2-deoxyglucose evoked glucoprivation (Brain Structure and Function (2015) 220:117). Hydralazine activated more neurons than 2-deoxyglucose but similar numbers of catecholaminergic neurons. Commonly activated populations expressing PPNPY and PPE mRNAs were defined. These likely include PPNPY expressing catecholaminergic neurons projecting to vasopressinergic and corticotrophin releasing factor neurons in the paraventricular nucleus, which when activated result in elevated plasma vasopressin and corticosterone. Stimulus specific neurons included noncatecholaminergic neurons and a few PPE positive catecholaminergic neuron but neurochemical codes were largely unidentified. Reasons for the lack of identification of stimulus specific neurons, readily detectable using electrophysiology in anaesthetized preparations and for which neural circuits can be defined, are discussed.
[Mh] Termos MeSH primário: Bulbo/citologia
Neuroquímica
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
[Mh] Termos MeSH secundário: Animais
Anti-Hipertensivos/farmacologia
Catecolaminas/metabolismo
Desoxiglucose/farmacologia
Encefalinas/genética
Encefalinas/metabolismo
Regulação da Expressão Gênica/efeitos dos fármacos
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo
Hidralazina/farmacologia
Hipotensão/metabolismo
Hipotensão/patologia
Masculino
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Neuropeptídeo Y/genética
Neuropeptídeo Y/metabolismo
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo
Precursores de Proteínas/genética
Precursores de Proteínas/metabolismo
Proteínas Proto-Oncogênicas c-fos/genética
Proteínas Proto-Oncogênicas c-fos/metabolismo
Ratos
Ratos Sprague-Dawley
Taquicininas/genética
Taquicininas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adcyap1 protein, rat); 0 (Antihypertensive Agents); 0 (Catecholamines); 0 (Enkephalins); 0 (Glycine Plasma Membrane Transport Proteins); 0 (Nerve Tissue Proteins); 0 (Neuropeptide Y); 0 (Pituitary Adenylate Cyclase-Activating Polypeptide); 0 (Protein Precursors); 0 (Proto-Oncogene Proteins c-fos); 0 (Slc6a5 protein, rat); 0 (Tachykinins); 0 (cocaine- and amphetamine-regulated transcript protein); 0 (preprotachykinin); 26NAK24LS8 (Hydralazine); 93443-35-7 (preproenkephalin); 9G2MP84A8W (Deoxyglucose)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1002/cne.24203


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[PMID]:28108584
[Au] Autor:Ugbode C; Hu Y; Whalley B; Peers C; Rattray M; Dallas ML
[Ad] Endereço:Department of Biology, University of York, Heslington, York YO10 5DD, U.K.
[Ti] Título:Astrocytic transporters in Alzheimer's disease.
[So] Source:Biochem J;474(3):333-355, 2017 Feb 01.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Astrócitos/metabolismo
Proteínas de Membrana Transportadoras/genética
[Mh] Termos MeSH secundário: Transportadores de Cassetes de Ligação de ATP/genética
Transportadores de Cassetes de Ligação de ATP/metabolismo
Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Animais
Astrócitos/patologia
Proteínas da Membrana Plasmática de Transporte de GABA/genética
Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo
Regulação da Expressão Gênica
Proteínas Facilitadoras de Transporte de Glucose/genética
Proteínas Facilitadoras de Transporte de Glucose/metabolismo
Proteínas de Transporte de Glutamato da Membrana Plasmática/genética
Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo
Seres Humanos
Proteínas de Membrana Transportadoras/metabolismo
Família Multigênica
Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
Transdução de Sinais
ATPase Trocadora de Sódio-Potássio/genética
ATPase Trocadora de Sódio-Potássio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GABA Plasma Membrane Transport Proteins); 0 (Glucose Transport Proteins, Facilitative); 0 (Glutamate Plasma Membrane Transport Proteins); 0 (Glycine Plasma Membrane Transport Proteins); 0 (Membrane Transport Proteins); 0 (Serotonin Plasma Membrane Transport Proteins); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170616
[Lr] Data última revisão:
170616
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170122
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20160505


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[PMID]:28086241
[Au] Autor:Xiang C; Zhang ML; Zhao QZ; Xie QP; Yan HC; Yu X; Wang P; Wang Y
[Ad] Endereço:Department of Thyroid Surgery, Second Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China.
[Ti] Título:LncRNA-SLC6A9-5:2: A potent sensitizer in 131I-resistant papillary thyroid carcinoma with PARP-1 induction.
[So] Source:Oncotarget;8(14):22954-22967, 2017 Apr 04.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent studies have indicated that long non-coding RNAs play crucial roles in numerous cancers, including thyroid cancer, while their function in the mechanism of thyroid cancer 131I resistance has not been elucidated to date. The present study identified a functional long non-coding RNA, SLC6A9-5:2, which was involved in the radioactive therapy resistance of thyroid cancer. We demonstrated that SLC6A9-5:2 was remarkably downregulated in 131I-resistant thyroid cancer cell lines and 131I-insensitive patients and was positively correlated with Poly (ADP-ribose) polymerase 1 (PARP-1) expression and its activation. After downregulating SLC6A9 or blocking PARP-1 artificially, the sensitive thyroid cancer cells mostly displayed a tolerant phenotype under 131I exposure. Furthermore, SLC6A9-5:2 overexpression was positively correlated with PARP-1 mRNA and protein levels, which restored the sensitivity of resistant thyroid cancer cells. The present study further revealed that cancer cell death was primarily caused by ATP exhaustion in excessive DNA repair with high PARP-1 activity. In patients with thyroid cancer, a positive correlation between SLC6A9-5:2 and PARP-1 was identified, and low SLC6A9-5:2 expression was associated with a worse prognosis of papillary thyroid carcinoma. Hence, our data provide a new lncRNA-mediated regulatory mechanism implying that SLC6A9-5:2 can be used as a novel therapeutic target for 131I-resistant thyroid cancer.
[Mh] Termos MeSH primário: Carcinoma/genética
Carcinoma/radioterapia
Poli(ADP-Ribose) Polimerase-1/biossíntese
RNA Longo não Codificante/genética
Neoplasias da Glândula Tireoide/genética
Neoplasias da Glândula Tireoide/radioterapia
[Mh] Termos MeSH secundário: Carcinoma Papilar
Linhagem Celular Tumoral
Proliferação Celular/genética
Proliferação Celular/efeitos da radiação
Regulação para Baixo
Feminino
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Seres Humanos
Radioisótopos do Iodo
Masculino
Poli(ADP-Ribose) Polimerase-1/genética
RNA Longo não Codificante/biossíntese
Tolerância a Radiação
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycine Plasma Membrane Transport Proteins); 0 (Iodine Radioisotopes); 0 (RNA, Long Noncoding); 0 (SLC6A9 protein, human); EC 2.4.2.30 (PARP1 protein, human); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170114
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14578


  9 / 619 MEDLINE  
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[PMID]:28007991
[Au] Autor:Valencia Garcia S; Libourel PA; Lazarus M; Grassi D; Luppi PH; Fort P
[Ad] Endereço:Neuroscience Research Center of Lyon (CRNL), CNRS UMR 5292, INSERM U1028, SLEEP Team, Lyon, France.
[Ti] Título:Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder.
[So] Source:Brain;140(2):414-428, 2017 02.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:SEE SCHENCK AND MAHOWALD DOI101093/AWW329 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Idiopathic REM sleep behaviour disorder is characterized by the enactment of violent dreams during paradoxical (REM) sleep in the absence of normal muscle atonia. Accumulating clinical and experimental data suggest that REM sleep behaviour disorder might be due to the neurodegeneration of glutamate neurons involved in paradoxical sleep and located within the pontine sublaterodorsal tegmental nucleus. The purpose of the present work was thus to functionally determine first, the role of glutamate sublaterodorsal tegmental nucleus neurons in paradoxical sleep and second, whether their genetic inactivation is sufficient for recapitulating REM sleep behaviour disorder in rats. For this goal, we first injected two retrograde tracers in the intralaminar thalamus and ventral medulla to disentangle neuronal circuits in which sublaterodorsal tegmental nucleus is involved; second we infused bilaterally in sublaterodorsal tegmental nucleus adeno-associated viruses carrying short hairpin RNAs targeting Slc17a6 mRNA [which encodes vesicular glutamate transporter 2 (vGluT2)] to chronically impair glutamate synaptic transmission in sublaterodorsal tegmental nucleus neurons. At the neuroanatomical level, sublaterodorsal tegmental nucleus neurons specifically activated during paradoxical sleep hypersomnia send descending efferents to glycine/GABA neurons within the ventral medulla, but not ascending projections to the intralaminar thalamus. These data suggest a crucial role of sublaterodorsal tegmental nucleus neurons rather in muscle atonia than in paradoxical sleep generation. In line with this hypothesis, 30 days after adeno-associated virus injections into sublaterodorsal tegmental nucleus rats display a decrease of 30% of paradoxical sleep daily quantities, and a significant increase of muscle tone during paradoxical sleep concomitant to a tremendous increase of abnormal motor dream-enacting behaviours. These animals display symptoms and behaviours during paradoxical sleep that closely mimic human REM sleep behaviour disorder. Altogether, our data demonstrate that glutamate sublaterodorsal tegmental nucleus neurons generate muscle atonia during paradoxical sleep likely through descending projections to glycine/GABA premotor neurons in the ventral medulla. Although playing a role in paradoxical sleep regulation, they are, however, not necessary for inducing the state itself. The present work further validates a potent new preclinical REM sleep behaviour disorder model that opens avenues for studying and treating this disabling sleep disorder, and advances potential regions implicated in prodromal stages of synucleinopathies such as Parkinson's disease.
[Mh] Termos MeSH primário: Ácido Glutâmico/metabolismo
Neurônios/fisiologia
Área Pré-Tetal/patologia
Transtorno do Comportamento do Sono REM/patologia
[Mh] Termos MeSH secundário: Animais
Contagem de Células
Toxina da Cólera/farmacocinética
Dependovirus/genética
Modelos Animais de Doenças
Transportador 5 de Aminoácido Excitatório/genética
Transportador 5 de Aminoácido Excitatório/metabolismo
Regulação da Expressão Gênica/genética
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo
Masculino
Área Pré-Tetal/metabolismo
Proteínas Proto-Oncogênicas c-fos/metabolismo
Transtorno do Comportamento do Sono REM/etiologia
RNA Mensageiro/metabolismo
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Ratos
Ratos Sprague-Dawley
Privação do Sono/complicações
Análise Espectral
Estilbamidinas/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt); 0 (Excitatory Amino Acid Transporter 5); 0 (Glycine Plasma Membrane Transport Proteins); 0 (Proto-Oncogene Proteins c-fos); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Slc6a5 protein, rat); 0 (Stilbamidines); 3KX376GY7L (Glutamic Acid); 9012-63-9 (Cholera Toxin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161224
[St] Status:MEDLINE
[do] DOI:10.1093/brain/aww310


  10 / 619 MEDLINE  
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[PMID]:27843043
[Au] Autor:Masri A; Chung SK; Rees MI
[Ad] Endereço:Faculty of Medicine, The University of Jordan, P.O. Box 1612 Code, 11941 Amman, Jordan. Electronic address: masriamira69@hotmail.com.
[Ti] Título:Hyperekplexia: Report on phenotype and genotype of 16 Jordanian patients.
[So] Source:Brain Dev;39(4):306-311, 2017 Apr.
[Is] ISSN:1872-7131
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hyperekplexia, is a rare disorder characterized by excessive startle response to acoustic, visual, or other stimuli. It is inherited in autosomal recessive and dominant pattern. OBJECTIVE: To describe the clinical and genetic features of hyperekplexia in Jordanian patients. METHODS: This retrospective study includes all patients with proved genetic diagnosis of hyperekplexia who presented to our clinic at the Jordan University Hospital from January 2001 through July 2015. RESULTS: A total of 16 children from 12 families were included. The total follow up period ranged from one to eleven years. The majority of the patients (13/16=81.3%) were initially misdiagnosed as epilepsy. All patients had excessive startle response since birth. Tonic-apneic spells occurred in 15/16=93.8% patients. Fourteen patients (45/16=87.5%) received clonazepam. Stopping clonazepam by three years of age failed in 11/14 (78.6%) due to reappearance of tonic-apneic spells (8/14=57.1%), recurrent falling (10/14=71.4%) or due to both reasons (5/14=35.7%). Delayed motor development occurred in 7/16 (43.8%), speech delay in 4/16 (25.0%), global developmental delay in 1/16 (6.3%), and autism spectrum disorder in 1/16 (6.3%) patient. The mode of inheritance is autosomal recessive in all 12/12 (100%) families. Mutations in GLRA1 gene was present in 9/16 (56.3%); the most common mutation was in p.G254D (4/9; 44.5%). Mutations in the GLRB gene was present in 4/16 (25.0%) patients and the SLC6A5 gene in 3/16 (18.8%) patients. CONCLUSION: The clinical presentation of hyperekplexia in Jordanian patients is manifested by tonic-apneic spells in all homozygous patients. The persistence of apneic spells and recurrent falls throughout childhood necessitate continuous treatment and surveillance.
[Mh] Termos MeSH primário: Hiperecplexia/genética
Hiperecplexia/fisiopatologia
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Consanguinidade
Erros de Diagnóstico
Epilepsia/diagnóstico
Feminino
Seguimentos
Genótipo
Proteínas da Membrana Plasmática de Transporte de Glicina/genética
Seres Humanos
Hiperecplexia/diagnóstico
Hiperecplexia/terapia
Lactente
Recém-Nascido
Jordânia
Masculino
Fenótipo
Receptores da Glicina/genética
Estudos Retrospectivos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GLRB protein, human); 0 (Glycine Plasma Membrane Transport Proteins); 0 (Receptors, Glycine); 0 (SLC6A5 protein, human); 0 (glycine receptor alpha1)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170330
[Lr] Data última revisão:
170330
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE



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