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Pesquisa : D12.776.157.530.400.150.720 [Categoria DeCS]
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[PMID]:28469732
[Au] Autor:Cohen SA; Yu M; Baker K; Redman M; Wu C; Heinzerling TJ; Wirtz RM; Charalambous E; Pentheroudakis G; Kotoula V; Kalogeras KT; Fountzilas G; Grady WM
[Ad] Endereço:Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.
[Ti] Título:The CpG island methylator phenotype is concordant between primary colorectal carcinoma and matched distant metastases.
[So] Source:Clin Epigenetics;9:46, 2017.
[Is] ISSN:1868-7083
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The CpG island methylator phenotype (CIMP) in stage III colon cancer (CRC) has been associated with improved survival after treatment with adjuvant irinotecan-based chemotherapy. In this analysis, we determine whether CIMP status in the primary CRC is concordant with the CIMP status of matched metastases in order to determine if assessment of CIMP status in the primary tumor can be used to predict CIMP status of metastatic disease, which is relevant for patient management as well as for understanding the biology of CIMP CRCs. METHODS: We assessed the CIMP status of 70 pairs of primary CRC and matched metastases using a CRC-specific panel of five markers ( , , , , and ) where CIMP positive was defined as 3/5 positive markers at a percent methylated reference threshold of ≥10%. Concordance was compared using the Fisher's exact test and < 0.05 was considered significant. RESULTS: Sixty-nine of the pairs (98.6%) showed concordant CIMP status in the primary tumor and matched metastasis; five (7.0%) of the pairs were concordantly CIMP positive. Only one pair (1.4%) had divergent CIMP status, demonstrating CIMP positivity (4/5 markers positive) in the primary tumor, while the matched metastasis was CIMP negative (0 markers positive). CONCLUSIONS: CIMP status is generally concordant between primary CRCs and matched metastases. Thus, CIMP status in the primary tumor is maintained in matched metastases and can be used to inform CIMP-based therapy options for the metastases.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Neoplasias Colorretais/genética
Metilação de DNA
[Mh] Termos MeSH secundário: Adulto
Idoso
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Canais de Cálcio Tipo T/genética
Neoplasias Colorretais/patologia
Subunidade alfa 3 de Fator de Ligação ao Core/genética
Ilhas de CpG
Epigênese Genética
Feminino
Seres Humanos
Fator de Crescimento Insulin-Like II/genética
Masculino
Meia-Idade
Metástase Neoplásica
Proteínas do Tecido Nervoso/genética
Fenótipo
Proteína 1 Supressora da Sinalização de Citocina/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Biomarkers, Tumor); 0 (CACNA1G protein, human); 0 (Calcium Channels, T-Type); 0 (Core Binding Factor Alpha 3 Subunit); 0 (IGF2 protein, human); 0 (NEUROG1 protein, human); 0 (Nerve Tissue Proteins); 0 (Runx3 protein, human); 0 (SOCS1 protein, human); 0 (Suppressor of Cytokine Signaling 1 Protein); 67763-97-7 (Insulin-Like Growth Factor II)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1186/s13148-017-0347-1


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[PMID]:29183797
[Au] Autor:Rodrigues AL; Brescia M; Koschinski A; Moreira TH; Cameron RT; Baillie G; Beirão PSL; Zaccolo M; Cruz JS
[Ad] Endereço:Laboratório CaCIA, Faculdade de Ciências Humanas Sociais e da Saúde, Universidade FUMEC, Brazil. Electronic address: alaura@fumec.br.
[Ti] Título:Increase in Ca current by sustained cAMP levels enhances proliferation rate in GH3 cells.
[So] Source:Life Sci;192:144-150, 2018 Jan 01.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:AIMS: Ca and cAMP are important intracellular modulators. In order to generate intracellular signals with various amplitudes, as well as different temporal and spatial properties, a tightly and precise control of these modulators in intracellular compartments is necessary. The aim of this study was to evaluate the effects of elevated and sustained cAMP levels on voltage-dependent Ca currents and proliferation in pituitary tumor GH3 cells. MAIN METHODS: Effect of long-term exposure to forskolin and dibutyryl-cyclic AMP (dbcAMP) on Ca current density and cell proliferation rate were determined by using the whole-cell patch-clamp technique and real time cell monitoring system. The cAMP levels were assayed, after exposing transfected GH3 cells with the EPAC-1 cAMP sensor to forskolin and dbcAMP, by FRET analysis. KEY FINDINGS: Sustained forskolin treatment (24 and 48h) induced a significant increase in total Ca current density in GH3 cells. Accordingly, dibutyryl-cAMP incubation (dbcAMP) also elicited increase in Ca current density. However, the maximum effect of dbcAMP occurred only after 72h incubation, whereas forskolin showed maximal effect at 48h. FRET-experiments confirmed that the time-course to elevate intracellular cAMP was distinct between forskolin and dbcAMP. Mibefradil inhibited the fast inactivating current component selectively, indicating the recruitment of T-type Ca channels. A significant increase on cell proliferation rate, which could be related to the elevated and sustained intracellular levels of cAMP was observed. SIGNIFICANCE: We conclude that maintaining high levels of intracellular cAMP will cause an increase in Ca current density and this phenomenon impacts proliferation rate in GH3 cells.
[Mh] Termos MeSH primário: Canais de Cálcio/metabolismo
AMP Cíclico/metabolismo
[Mh] Termos MeSH secundário: Animais
Bucladesina/farmacologia
Bloqueadores dos Canais de Cálcio/farmacologia
Canais de Cálcio Tipo L/efeitos dos fármacos
Canais de Cálcio Tipo T/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Colforsina/farmacologia
Mibefradil/farmacologia
Técnicas de Patch-Clamp
Neoplasias Hipofisárias/metabolismo
Ratos
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Calcium Channels); 0 (Calcium Channels, L-Type); 0 (Calcium Channels, T-Type); 0 (Vasodilator Agents); 1F7A44V6OU (Colforsin); 27B90X776A (Mibefradil); 63X7MBT2LQ (Bucladesine); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE


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[PMID]:28450109
[Au] Autor:Lin SF; Wang B; Zhang FM; Fei YH; Gu JH; Li J; Bi LB; Liu XJ
[Ad] Endereço:Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, 100029, China; Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
[Ti] Título:T-type calcium channels, but not Cav3.2, in the peripheral sensory afferents are involved in acute itch in mice.
[So] Source:Biochem Biophys Res Commun;487(4):801-806, 2017 06 10.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:T-type calcium channels are prominently expressed in primary nociceptive fibers and well characterized in pain processes. Although itch and pain share many similarities including primary sensory fibers, the function of T-type calcium channels on acute itch has not been explored. We investigated whether T-type calcium channels expressed within primary sensory fibers of mouse skin, especially Ca 3.2 subtype, involve in chloroquine-, endothelin-1- and histamine-evoked acute itch using pharmacological, neuronal imaging and behavioral analyses. We found that pre-locally blocking three subtypes of T-type calcium channels in the peripheral afferents of skins, yielded an inhibition in acute itch or pain behaviors, while selectively blocking the Ca 3.2 channel in the skin peripheral afferents only inhibited acute pain but not acute itch. These results suggest that T-type Ca 3.1 or Ca 3.3, but not Ca 3.2 channel, have an important role in acute itch processing, and their distinctive roles in modulating acute itch are worthy of further investigation.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo T/metabolismo
Neurônios Aferentes/metabolismo
Prurido/metabolismo
Pele/metabolismo
[Mh] Termos MeSH secundário: Animais
Masculino
Mibefradil/farmacologia
Camundongos
Camundongos Endogâmicos C57BL
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cacna1h protein, mouse); 0 (Calcium Channels, T-Type); 27B90X776A (Mibefradil)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


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[PMID]:29024660
[Au] Autor:Zhao Y; Sivaji S; Chiang MC; Ali H; Zukowski M; Ali S; Kennedy B; Sklyar A; Cheng A; Guo Z; Reed AK; Kodali R; Borowski J; Frost G; Beukema P; Wills ZP
[Ad] Endereço:Department of Neurobiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
[Ti] Título:Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.
[So] Source:Neuron;96(2):355-372.e6, 2017 Oct 11.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Compelling evidence links amyloid beta (Aß) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aß are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aß receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal Aß activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of Aß-NgR signaling, mediating Aß's inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/farmacologia
Bloqueadores dos Canais de Cálcio/farmacologia
Canais de Cálcio Tipo T/fisiologia
Sinalização do Cálcio/fisiologia
Receptores Nogo/fisiologia
Fragmentos de Peptídeos/farmacologia
Sinapses/fisiologia
[Mh] Termos MeSH secundário: Animais
Células CHO
Sinalização do Cálcio/efeitos dos fármacos
Células Cultivadas
Cricetinae
Cricetulus
Feminino
Células HEK293
Seres Humanos
Masculino
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Técnicas de Cultura de Órgãos
Ratos
Ratos Long-Evans
Sinapses/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Calcium Channel Blockers); 0 (Calcium Channels, T-Type); 0 (Nogo Receptors); 0 (Peptide Fragments); 0 (amyloid beta-protein (1-42))
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE


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[PMID]:28934223
[Au] Autor:Adeyemi O; Alvarez-Laviada A; Schultz F; Ibrahim E; Trauner M; Williamson C; Glukhov AV; Gorelik J
[Ad] Endereço:Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
[Ti] Título:Ursodeoxycholic acid prevents ventricular conduction slowing and arrhythmia by restoring T-type calcium current in fetuses during cholestasis.
[So] Source:PLoS One;12(9):e0183167, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Increased maternal serum bile acid concentrations in intrahepatic cholestasis of pregnancy (ICP) are associated with fetal cardiac arrhythmias. Ursodeoxycholic acid (UDCA) has been shown to demonstrate anti-arrhythmic properties via preventing ICP-associated cardiac conduction slowing and development of reentrant arrhythmias, although the cellular mechanism is still being elucidated. METHODS: High-resolution fluorescent optical mapping of electrical activity and electrocardiogram measurements were used to characterize effects of UDCA on one-day-old neonatal and adult female Langendorff-perfused rat hearts. ICP was modelled by perfusion of taurocholic acid (TC, 400µM). Whole-cell calcium currents were recorded from neonatal rat and human fetal cardiomyocytes. RESULTS: TC significantly prolonged the PR interval by 11.0±3.5% (P<0.05) and slowed ventricular conduction velocity (CV) by 38.9±5.1% (P<0.05) exclusively in neonatal and not in maternal hearts. A similar CV decline was observed with the selective T-type calcium current (ICa,T) blocker mibefradil 1µM (23.0±6.2%, P<0.05), but not with the L-type calcium current (ICa,L) blocker nifedipine 1µM (6.9±6.6%, NS). The sodium channel blocker lidocaine (30µM) reduced CV by 60.4±4.5% (P<0.05). UDCA co-treatment was protective against CV slowing induced by TC and mibefradil, but not against lidocaine. UDCA prevented the TC-induced reduction in the ICa,T density in both isolated human fetal (-10.2±1.5 versus -5.5±0.9 pA/pF, P<0.05) and neonatal rat ventricular myocytes (-22.3±1.1 versus -9.6±0.8 pA/pF, P<0.0001), whereas UDCA had limited efficacy on the ICa,L. CONCLUSION: Our findings demonstrate that ICa,T plays a significant role in ICP-associated fetal cardiac conduction slowing and arrhythmogenesis, and is an important component of the fetus-specific anti-arrhythmic activity of UDCA.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo T/metabolismo
Colestase/prevenção & controle
Fenômenos Eletrofisiológicos/efeitos dos fármacos
Coração Fetal/efeitos dos fármacos
Ventrículos do Coração/efeitos dos fármacos
Ventrículos do Coração/fisiopatologia
Ácido Ursodesoxicólico/farmacologia
[Mh] Termos MeSH secundário: Animais
Cálcio/farmacologia
Colestase/metabolismo
Colestase/fisiopatologia
Feminino
Coração Fetal/metabolismo
Coração Fetal/fisiopatologia
Seres Humanos
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/metabolismo
Gravidez
Ratos
Ácido Taurocólico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, T-Type); 5E090O0G3Z (Taurocholic Acid); 724L30Y2QR (Ursodeoxycholic Acid); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183167


  6 / 1491 MEDLINE  
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[PMID]:28858620
[Au] Autor:Kim J; Kim Y; Nakajima R; Shin A; Jeong M; Park AH; Jeong Y; Jo S; Yang S; Park H; Cho SH; Cho KH; Shim I; Chung JH; Paik SB; Augustine GJ; Kim D
[Ad] Endereço:Department of Biological Sciences, KAIST, Daejeon 34141, Republic of Korea; Center for Neuroscience, KIST, Seoul 02792, Republic of Korea.
[Ti] Título:Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus.
[So] Source:Neuron;95(5):1181-1196.e8, 2017 Aug 30.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.
[Mh] Termos MeSH primário: Globo Pálido/fisiologia
Neurônios Motores/fisiologia
Inibição Neural/fisiologia
Tálamo/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação/fisiologia
Oxirredutases do Álcool/genética
Animais
Canais de Cálcio Tipo T/genética
Canais de Cálcio Tipo T/fisiologia
Dopamina/metabolismo
Distonia/dietoterapia
Distonia/tratamento farmacológico
Distonia/fisiopatologia
Feminino
Globo Pálido/citologia
Globo Pálido/metabolismo
Levodopa/uso terapêutico
Masculino
Erros Inatos do Metabolismo/dietoterapia
Erros Inatos do Metabolismo/tratamento farmacológico
Erros Inatos do Metabolismo/fisiopatologia
Camundongos
Camundongos Knockout
Contração Muscular/fisiologia
Vias Neurais/fisiologia
Neurônios/fisiologia
Transtornos Psicomotores/dietoterapia
Transtornos Psicomotores/tratamento farmacológico
Transtornos Psicomotores/fisiopatologia
Tálamo/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Calcium Channels, T-Type); 46627O600J (Levodopa); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.1.153 (sepiapterin reductase); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE


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[PMID]:28846697
[Au] Autor:Fornaro L; Vivaldi C; Lin D; Xue H; Falcone A; Wang Y; Crea F; Bootman MD
[Ad] Endereço:Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
[Ti] Título:Prognostic relevance of a T-type calcium channels gene signature in solid tumours: A correlation ready for clinical validation.
[So] Source:PLoS One;12(8):e0182818, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: T-type calcium channels (TTCCs) mediate calcium influx across the cell membrane. TTCCs regulate numerous physiological processes including cardiac pacemaking and neuronal activity. In addition, they have been implicated in the proliferation, migration and differentiation of tumour tissues. Although the signalling events downstream of TTCC-mediated calcium influx are not fully elucidated, it is clear that variations in the expression of TTCCs promote tumour formation and hinder response to treatment. METHODS: We examined the expression of TTCC genes (all three subtypes; CACNA-1G, CACNA-1H and CACNA-1I) and their prognostic value in three major solid tumours (i.e. gastric, lung and ovarian cancers) via a publicly accessible database. RESULTS: In gastric cancer, expression of all the CACNA genes was associated with overall survival (OS) among stage I-IV patients (all p<0.05). By combining the three potential biomarkers, a TTCC signature was developed, which retained a significant association with OS both in stage IV and stage I-III patients. In lung and ovarian cancer, association with OS was also significant when all tumour stages were considered, but was partly lost or inconclusive after splitting cases into localized and metastatic subsets. CONCLUSIONS: Alterations in CACNA gene expression are linked to tumour prognosis. Gastric cancer represents the most promising setting for further evaluation.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo T/genética
Neoplasias Pulmonares/genética
Neoplasias Ovarianas/genética
Neoplasias Gástricas/genética
[Mh] Termos MeSH secundário: Biomarcadores Tumorais
Bases de Dados Genéticas
Feminino
Seres Humanos
Neoplasias Pulmonares/mortalidade
Neoplasias Pulmonares/patologia
Masculino
Neoplasias Ovarianas/mortalidade
Neoplasias Ovarianas/patologia
Prognóstico
Neoplasias Gástricas/mortalidade
Neoplasias Gástricas/patologia
Taxa de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Calcium Channels, T-Type)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182818


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[PMID]:28806761
[Au] Autor:Ha SE; Lee MY; Kurahashi M; Wei L; Jorgensen BG; Park C; Park PJ; Redelman D; Sasse KC; Becker LS; Sanders KM; Ro S
[Ad] Endereço:Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, United States of America.
[Ti] Título:Transcriptome analysis of PDGFRα+ cells identifies T-type Ca2+ channel CACNA1G as a new pathological marker for PDGFRα+ cell hyperplasia.
[So] Source:PLoS One;12(8):e0182265, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Platelet-derived growth factor receptor alpha (PDGFRα)+ cells are distributed into distinct morphological groups within the serosal, muscular, and submucosal layers as well as the myenteric and deep muscular plexi. PDGFRα+ cells directly interact with interstitial cells of Cajal (ICC) and smooth muscle cells (SMC) in gastrointestinal smooth muscle tissue. These three cell types, SMC, ICC, and PDGFRα+ cells (SIP cells), form an electrical syncytium, which dynamically regulates gastrointestinal motility. We have previously reported the transcriptomes of SMC and ICC. To complete the SIP cell transcriptome project, we obtained transcriptome data from jejunal and colonic PDGFRα+ cells. The PDGFRα+ cell transcriptome data were added to the Smooth Muscle Genome Browser that we previously built for the genome-scale gene expression data of ICC and SMC. This browser provides a comprehensive reference for all transcripts expressed in SIP cells. By analyzing the transcriptomes, we have identified a unique set of PDGFRα+ cell signature genes, growth factors, transcription factors, epigenetic enzymes/regulators, receptors, protein kinases/phosphatases, and ion channels/transporters. We demonstrated that the low voltage-dependent T-type Ca2+ channel Cacna1g gene was particularly expressed in PDGFRα+ cells in the intestinal serosal layer in mice. Expression of this gene was significantly induced in the hyperplasic PDGFRα+ cells of obstructed small intestine in mice. This gene was also over-expressed in colorectal cancer, Crohn's disease, and diverticulitis in human patients. Taken together, our data suggest that Cacna1g exclusively expressed in serosal PDGFRα+ cells is a new pathological marker for gastrointestinal diseases.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo T/metabolismo
Perfilação da Expressão Gênica
Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo
[Mh] Termos MeSH secundário: Animais
Canais de Cálcio Tipo T/genética
Desdiferenciação Celular
Proliferação Celular/genética
Separação Celular
Regulação da Expressão Gênica
Genoma
Seres Humanos
Hiperplasia
Hipertrofia
Canais Iônicos/genética
Canais Iônicos/metabolismo
Jejuno/metabolismo
Camundongos
Músculo Liso/metabolismo
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CACNA1G protein, human); 0 (Cacna1g protein, mouse); 0 (Calcium Channels, T-Type); 0 (Ion Channels); 0 (Protein Isoforms); 0 (RNA, Messenger); EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171123
[Lr] Data última revisão:
171123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182265


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[PMID]:28720332
[Au] Autor:Kim JH; Jeong HR; Jung DW; Yoon HB; Kim SY; Kim HJ; Lee KT; Gadotti VM; Huang J; Zhang FX; Zamponi GW; Lee JY
[Ad] Endereço:Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
[Ti] Título:Synthesis and biological evaluation of fluoro-substituted 3,4-dihydroquinazoline derivatives for cytotoxic and analgesic effects.
[So] Source:Bioorg Med Chem;25(17):4656-4664, 2017 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Ca 3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca 3.2 currents (>90% inhibition) at 10µM concentration and exhibited cytotoxic effect (IC =5.9µM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Ca 3.2 channels.
[Mh] Termos MeSH primário: Analgésicos/síntese química
Bloqueadores dos Canais de Cálcio/síntese química
Quinazolinas/química
Quinidina/análogos & derivados
[Mh] Termos MeSH secundário: Células A549
Analgésicos/química
Analgésicos/toxicidade
Animais
Bloqueadores dos Canais de Cálcio/química
Bloqueadores dos Canais de Cálcio/toxicidade
Canais de Cálcio Tipo T/química
Canais de Cálcio Tipo T/genética
Canais de Cálcio Tipo T/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Estabilidade de Medicamentos
Flúor/química
Células HEK293
Seres Humanos
Concentração Inibidora 50
Microssomos Hepáticos/metabolismo
Técnicas de Patch-Clamp
Quinazolinas/síntese química
Quinazolinas/toxicidade
Quinidina/síntese química
Quinidina/química
Quinidina/toxicidade
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Calcium Channel Blockers); 0 (Calcium Channels, T-Type); 0 (KCP10068F); 0 (KYS 05090); 0 (Quinazolines); 284SYP0193 (Fluorine); 8P68XPY4HG (hydroquinidine); ITX08688JL (Quinidine)
[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:170720
[St] Status:MEDLINE


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[PMID]:28720324
[Au] Autor:Hong JR; Choi YJ; Keum G; Nam G
[Ad] Endereço:Division of Bio-Medical Sciences & Technology, KIST School, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon 305-350, Republic of Korea.
[Ti] Título:Synthesis and diabetic neuropathic pain-alleviating effects of 2N-(pyrazol-3-yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives.
[So] Source:Bioorg Med Chem;25(17):4677-4685, 2017 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A novel series of fused-benzensulfonamide 2-N-(pyrazol-3-yl)methylbenzo[d]isothiazole-1,1-dioxide derivatives was designed and synthesized as metabolically stable T-type calcium channel inhibitors. Several compounds, 9, 10, and 17, displayed potent T-type channel inhibitory activity. Among them, compounds 10 and 17 showed good metabolic stability in human liver microsomes, and low hERG channel and CYP450 inhibition. Compound 10 exhibited diabetic neuropathic pain-alleviating effects in a streptozotocin-induced peripheral diabetic neuropathy (PDN) model. The maximum efficacy of compound 10, which was 3-fold more potent than gabapentin, was observed at 1h after administration, and co-administration of compound 10 with gabapentin showed a considerable synergic effect.
[Mh] Termos MeSH primário: Bloqueadores dos Canais de Cálcio/química
Tiazóis/química
[Mh] Termos MeSH secundário: Animais
Bloqueadores dos Canais de Cálcio/farmacocinética
Bloqueadores dos Canais de Cálcio/uso terapêutico
Canais de Cálcio Tipo T/química
Canais de Cálcio Tipo T/metabolismo
Neuropatias Diabéticas/induzido quimicamente
Neuropatias Diabéticas/complicações
Neuropatias Diabéticas/tratamento farmacológico
Modelos Animais de Doenças
Meia-Vida
Seres Humanos
Concentração Inibidora 50
Masculino
Microssomos Hepáticos/metabolismo
Neuralgia/etiologia
Neuralgia/prevenção & controle
Pirazóis/química
Ratos
Relação Estrutura-Atividade
Tiazóis/farmacocinética
Tiazóis/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channel Blockers); 0 (Calcium Channels, T-Type); 0 (Pyrazoles); 0 (Thiazoles); 3QD5KJZ7ZJ (pyrazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170720
[St] Status:MEDLINE



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